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In the Drosophila olfactory system most odorants are encoded in the antennal lobe in a combinatory way, activating several glomerular circuits. However, odorants of particular ecological role for the fly are encoded through activation of a single specialized olfactory pathway. Comparative analyses of densely reconstructed connectomes of one broadly tuned glomerulus (DL5) and one narrowly tuned glomerulus (DA2) gained detailed insight into the variations of synaptic circuitries of glomeruli with different computational tasks. Our approach combined laser-branding of glomeruli of interest with volume based focused ion beam-scanning electron microscopy (FIB-SEM) to enable precise targeting and analysis of the two glomeruli. We discovered differences in their neuronal innervation, synaptic composition and specific circuit diagrams of their major cell types: olfactory sensory neurons (OSNs), uniglomerular projection neurons (uPNs) and multiglomerular neurons (MGNs). By comparing our data with a previously mapped narrowly tuned glomerulus (VA1v), we identified putative generic features of narrowly tuned glomerular circuits, including higher density of neuronal fibers and synapses, lower degree of OSN lateralization, stronger axo-axonic connections between OSNs, dendro-dendritic connections between many uPNs, and lower degree of presynaptic input on OSN axons. In addition, this work revealed that the dendrites of the single uPN in DL5 contain a substantial amount of autapses interconnecting distant regions of the dendritic tree. The comparative analysis of glomeruli allows to formulate synaptic motifs implemented in olfactory circuits with different computational demands.
The detection and localization of signals rely on arrays of receptors, and their spatial organization plays a key role in determining the accuracy of the system. Weakly electric ghost knifefish rely on a distributed array of electroreceptors to detect spatially diffuse electric signals from conspecifics. While we know that spatial resolution for small objects, such as prey, is enhanced near the head due to a high receptor density, it is not clear how receptor organization influences the processing of global and diffuse signals from conspecifics. Using spatially realistic modeling, we quantified how receptor density influences detection and localization accuracy for conspecific signals across varying distances. Our main result demonstrates that receptor density markedly enhances detection accuracy in frontal regions at intermediate distances (35-50 cm) yet surprisingly contributes minimally to improving localization accuracy. This highlights a fundamental principle: receptor convergence primarily benefits signal detection when dealing with spatially diffuse stimuli, even though higher receptor density can enhance localization accuracy for spatially delineated signals. Our findings extend beyond the electrosensory modality, drawing parallels with other sensory systems, and offer broader insights into spatial processing principles.
The detection and localization of signals rely on arrays of receptors, and their spatial organization plays a key role in determining the accuracy of the system. Weakly electric ghost knifefish rely on a distributed array of electroreceptors to detect spatially diffuse electric signals from conspecifics. While we know that spatial resolution for small objects, such as prey, is enhanced near the head due to a high receptor density, it is not clear how receptor organization influences the processing of global and diffuse signals from conspecifics. Using spatially realistic modeling, we quantified how receptor density influences detection and localization accuracy for conspecific signals across varying distances. Our main result demonstrates that receptor density markedly enhances detection accuracy in frontal regions at intermediate distances (35-50 cm) yet surprisingly contributes minimally to improving localization accuracy. This highlights a fundamental principle: receptor convergence primarily benefits signal detection when dealing with spatially diffuse stimuli, even though higher receptor density can enhance localization accuracy for spatially delineated signals. Our findings extend beyond the electrosensory modality, drawing parallels with other sensory systems, and offer broader insights into spatial processing principles.
Dreams incorporate recent experiences, and memory-related brain activity is reactivated during sleep, suggesting that dreaming, memory consolidation and reactivation are tightly linked. We devised a paradigm to investigate whether memory reprocessing during sleep contributes to dreaming. Participants listened to different audiobooks before falling asleep, introducing dissimilar experiences to be processed at night. We show that audiobook content was reprocessed at the neural level using multivariate pattern analyses. Brain activity during rapid eye movement sleep, particularly in the beta range, carried information about the audiobook. While the amount of neural reinstatement did not correlate with memory retention, global beta power during REM sleep was associated with better memory performance. Moreover, blind raters could determine which audiobook participants had studied based on dream reports. Participants who dreamt of the audiobook also showed stronger neural reinstatement. Reprocessing of pre-sleep experiences during sleep may thus shape our brain activity, our dreams, and our memories.
Beta band rhythms often appear as brief bursts, but how variations in burst properties impact neural function is unclear. We probed beta burst heterogeneity by developing two complementary detection algorithms. One isolates brief high amplitude events (bursts of power, BoP) and another that identifies consistent oscillations that span multiple cycles (bursts of consistency, BoC). Examining frontal LFP and ECoG recordings from mice and macaques, these two burst types occupied the same 15 to 30 Hz frequency band yet showed minimal temporal overlap, indicating independent phenomena probably with distinct neural generators. Crucially, when task demands shifted between high and low cognitive control states, BoC bursts were enriched during demanding phases, whereas BoP bursts dominated routine phases. These results demonstrate that frontal beta activity comprises at least two rhythmically distinct regimes linked to different levels of cognitive control. Our dual mode framework refines mechanistic models of transient oscillations and underscores the significance of burst waveform diversity for flexible brain function.
Cognitive decline associated with healthy ageing is multifactorial: brain-based and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing models of neurocognitive ageing such as compensation, maintenance, or reserve, we explore how various known brain-based and cardiorespiratory fitness factors intersect to better understand cognitive decline. In a pre-registered study (https://osf.io/6fqg7), we tested 73 healthy older adults aged 60--81 (M = 65.51, SD = 4.94) and collected neuroimaging (functional, structural, and perfusion MRI), cardiorespiratory fitness, and cognitive data to investigate a prominent challenge for older adults: word-finding failures. fMRI signal was recorded while participants responded to a definition-based tip-of-the-tongue task, T1-weighted imaging estimated grey matter volume, and cerebral blood flow was indexed using multi-delay pseudo-continuous arterial spin labelling. Commonality analyses were used to analyse these multi-domain data (neuroimaging, cardiorespiratory fitness, language skills, demographic characteristics) and uncover associations between predictors in explaining age-related tip-of-the-tongue rates. Commonality analyses revealed that functional activation of language networks associated with tip-of-the-tongue states is in part linked with age and, interestingly, cardiorespiratory fitness: the combination of higher cardiorespiratory fitness and functional recruitment in some older adults offsets part of the age-related variance in tip-of-the-tongues. Moreover, age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongues. Our findings can be interpreted in the context of the classic models of neurocognitive ageing, suggesting compensation. Brain health indices in concordance with cardiorespiratory fitness can provide a more holistic explanation of individual differences in age-related cognitive decline. HighlightsO_LIWord-finding problems are linked to brain health and cardiorespiratory fitness (CRF) C_LIO_LIBrain activity linked to word-finding failures is modulated by CRF and age C_LIO_LIDistinct contribution of structure and perfusion also associated with word-finding C_LIO_LILinking brain and CRF factors provides better account of age-related cognitive decline C_LI
With advancing age, the distinctiveness of neural representations of information declines. While the finding of this so-called age-related neural dedifferentiation in category-selective neural regions is well-described, how neural dedifferentiation manifests at the level of large-scale functional networks is less understood. Furthermore, the relationship between age-related changes in network organization and dedifferentiation is unknown. Here, we investigated age-related neural dedifferentiation of category-selective regions as well as whole-brain functional networks. We additionally examined age differences in connectivity of category-selective regions to the rest of the brain. Younger and older adults viewed blocks of face and house stimuli while performing memory encoding and retrieval in the fMRI scanner. We found an age-related decline in neural distinctiveness for faces in the fusiform gyrus (FG) and for houses in the parahippocampal gyrus (PHG). Functional connectivity analyses revealed age-related dedifferentiation of global network structure as well as age differences in the connectivity profiles to category-selective regions. Together, our findings suggest that age-related neural dedifferentiation manifests both in regional categorical representations as well as in whole- brain functional networks. HighlightsO_LICategory representations are less distinctive, or dedifferentiated, in older adults C_LIO_LIFunctional networks are less segregated in older adults C_LIO_LIOlder adults reveal less connectivity between fusiform gyrus and visual cortices C_LI
Synchronous neuronal ensembles play a pivotal role in the consolidation of long-term memory in the hippocampus. However, their organization during the acquisition of spatial memory remains less clear. In this study, we used neuronal population voltage imaging to investigate the synchronization patterns of CA1 pyramidal neuronal ensembles during the exploration of a new environment, a critical phase for spatial memory acquisition. We found synchronous ensembles comprising approximately 40% of CA1 pyramidal neurons, firing simultaneously in brief windows ([~]25ms) during immobility and locomotion in novel exploration. Notably, these synchronous ensembles were not associated with contralateral ripple oscillations but were instead phase-locked to theta waves recorded in the contralateral CA1 region. Moreover, the subthreshold membrane potentials of neurons exhibited coherent intracellular theta oscillations with a depolarizing peak at the moment of synchrony. Among newly formed place cells, pairs with more robust synchronization during locomotion displayed more distinct place-specific activities. These findings underscore the role of synchronous ensembles in coordinating place cells of different place fields.
Cortical activity shows the ability to recover from distractions. We analyzed neural activity from the prefrontal cortex (PFC) of monkeys performing working memory tasks with mid-memory-delay distractions (a cued gaze shift or an irrelevant visual input). After distraction there were state-space rotational dynamics that returned spiking to population patterns similar to those pre-disruption. In fact, rotations were fuller when the task was performed correctly versus when errors were made. We found a correspondence between state-space rotations and traveling waves across the surface of the PFC. This suggests a role for emergent dynamics like state-space rotations and traveling waves in recovery from distractions.
Estimating dynamic network communication is attracting increased attention, spurred by rapid advancements in multi-site neural recording technologies and efforts to better understand cognitive processes. Yet, traditional methods, which infer communication from statistical dependencies among distributed neural recordings, face core limitations: they do not incorporate possible mechanisms of neural communication, neglect spatial information from the recording setup, and yield predominantly static estimates that cannot capture rapid changes in the brain. To address these issues, we introduce the graph diffusion autoregressive model. Designed for distributed field potential recordings, our model combines vector autoregression with a network communication process to produce a high-resolution communication signal. We successfully validated the model on simulated neural activity and recordings from subdural and intracortical micro-electrode arrays placed in macaque sensorimotor cortex demonstrating its ability to describe rapid communication dynamics induced by optogenetic stimulation, changes in resting state communication, and neural correlates of behavior during a reach task.
Although hippocampal place cells replay nonlocal trajectories, the computational function of these events remains controversial. One hypothesis, formalized in a prominent reinforcement learning account, holds that replay plans routes to current goals. However, recent puzzling data appear to contradict this perspective by showing that replayed destinations lag current goals. These results may support an alternative hypothesis that replay updates route information to build a "cognitive map." Yet no similar theory exists to formalize this view, it is unclear how such a map is represented or what role replay plays in computing it. We address these gaps by introducing a theory of replay that learns a map of routes to candidate goals, before reward is available or when its location may change. Replay is then focused on current goals (as with planning) and/or potential future goals (like a map), depending on the animal's expectations about future goal switching. Our work thus generalizes the planning account to capture a general map-building function for replay, reconciling it with data, and revealing an unexpected relationship between the seemingly distinct hypotheses. The theory offers a unifying explanation why data from tasks with different goal dynamics have seemingly supported different hypotheses for the function of replay, and suggests new predictions for experiments testing these effects.
The superior colliculus (SC) is traditionally considered a brain region that functions as an interface between processing visual inputs and generating eye movement outputs. Although its role as a primary reflex center is thought to be conserved across vertebrate species, evidence suggests that the SC has evolved to support higher-order cognitive functions including spatial attention. When it comes to oculomotor areas such as the SC, it is critical that high precision fixation and eye movements are maintained even in the presence of signals related to ongoing changes in cognition and brain state, both of which have the potential to interfere with eye position encoding and movement generation. In this study, we recorded spiking responses of neuronal populations in the SC while monkeys performed a memory-guided saccade task and found that the activity of some of the neurons fluctuated over tens of minutes. By leveraging the statistical power afforded by high-dimensional neuronal recordings, we were able to identify a low-dimensional pattern of activity that was correlated with the subjects' arousal levels. Importantly, we found that the spiking responses of deep-layer SC neurons were less correlated with this brain-wide arousal signal, and that neural activity associated with changes in pupil size and saccade tuning did not overlap in population activity space with movement initiation signals. Taken together, these findings provide a framework for understanding how signals related to cognition and arousal can be embedded in the population activity of oculomotor structures without compromising the fidelity of the motor output.
Humans routinely anticipate upcoming language, but whether such predictions come at a cognitive cost remains debated. In this study, we demonstrate the resource-dependent nature of predictive mechanisms in language comprehension across the lifespan: Experimentally limiting executive resources through a concurrent task reduces the effect of language predictability on reading time. Participants (N=175, replication N=96) read short articles presented word-by-word while completing a secondary font colour n-back task, thus varying cognitive demand. Language predictability was indexed by word surprisal as derived from a pre-trained large language model (GPT-2). Across two independent samples, our findings reveal that language predictions are not cost-free: They draw on executive control resources, and this dependency becomes more pronounced with age (18-85 years). These results help resolve the debate over cognitive demands in language comprehension and highlight prediction as a dynamic, resource-dependent process across the lifespan.
A greater understanding of the neurobiology of nicotine is needed to reduce or prevent chronic addiction, ameliorate detrimental nicotine withdrawal effects, and improve cessation rates. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), 4{beta}2 and 7. Protein kinase B-{beta} (Pkb-{beta} or Akt2) expression is restricted to astrocytes in mice and humans and is activated by nicotine. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specific Akt2 conditional knockout (cKO) and full Akt2 KO mice. For in/ex vivo studies, we examined mice exposed to chronic nicotine for two weeks in drinking water (200 g/mL) or following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 hrs. Our in vitro studies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereas Akt2 cKO mice showed enhanced acute responses and reduced area following chronic exposure. In culture, we found 100 M nicotine sufficient for morphological changes and blocking 7 or 4{beta}2 nAChRs prevented observed morphologic changes. We performed conditioned place preference (CPP) in Akt2 cKO mice, which revealed reduced nicotine preference in cKO mice compared to controls. Finally, we performed RNASeq comparing nicotine- and LPS-mediated gene expression, identifying robust differences between these two astrocytic stimuli. These findings show the importance of nAChRs and AKT2 signaling in the astrocytic response to nicotine. Main PointsO_LINicotine regulates astrocytes in vivo: acute exposure boosts complexity; chronic exposure diminishes it. C_LIO_LIAKT2, expressed in astroglia, modulates morphological changes in response to nicotine and nicotine-dependent conditioned place preference. C_LI
Time-resolved functional network connectivity (trFNC) assesses the time-resolved coupling between brain regions using functional magnetic resonance imaging (fMRI) data. This study aims to compare two techniques used to estimate trFNC, to investigate their similarities and differences when applied to fMRI data. These techniques are the sliding window Pearson correlation (SWPC), an amplitude-based approach, and phase synchronization (PS), a phase-based technique. To accomplish our objective, we used resting-state fMRI data from the Human Connectome Project (HCP) with 827 subjects (repetition time: 0.7s) and the Function Biomedical Informatics Research Network (fBIRN) with 311 subjects (repetition time: 2s), which included 151 schizophrenia patients and 160 controls. Our simulations reveal distinct strengths in two connectivity methods: SWPC captures high-magnitude, low-frequency connectivity, while PS detects low-magnitude, high-frequency connectivity. Stronger correlations between SWPC and PS align with pronounced fMRI oscillations. For fMRI data, higher correlations between SWPC and PS occur with matched frequencies and smaller SWPC window sizes ([~]30s), but larger windows ([~]88s) sacrifice clinically relevant information. Both methods identify a schizophrenia-associated brain network state but show different patterns: SWPC highlights low anti-correlations between visual, subcortical, auditory, and sensory-motor networks, while PS shows reduced positive synchronization among these networks. In sum, our findings underscore the complementary nature of SWPC and PS, elucidating their respective strengths and limitations without implying the superiority of one over the other. Impact StatementThis study demonstrates that SWPC and PS provide complementary insights into dynamic functional connectivity, revealing different aspects of brain dynamics based on signal focus. For tasks involving slow dynamics, SWPC amplitude is ideal, while the PS phase is more suitable for transient dynamics. In schizophrenia, typically associated with general dysconnectivity, we uncover a dual dysconnectivity profile depending on phase or amplitude dynamics. This novel approach offers researchers a platform to explore task-specific dysconnectivity profiles, enabling more targeted interventions. These findings will guide methodology choices, deepen understanding of brain dynamics, and support the development of precise neuropsychiatric biomarkers. HighlightsO_LITime-resolved functional network connectivity (trFNC) is widely used; here we study two approaches often pit against one another: 1) phase synchrony (PS), a phase-based method, and 2) sliding window Pearson correlation (SWPC), an amplitude-based method. C_LIO_LISWPC is sensitive to the choice of window size, while PS requires a narrow frequency band. Both can result in the loss of relevant information. C_LIO_LIWe find through simulation that SWPC better captures high-magnitude slow-varying amplitude-encoded connectivity while PS better captures low-magnitude fast-varying phase-encoded connectivity. C_LIO_LIWe find that while both SWPC and PS detect disconnected states mostly associated with schizophrenia they exhibit unique complementary patterns. C_LIO_LIWe conclude that SWPC and PS are complementary techniques, each with distinct assumptions and constraints, which should be selected based on the focus of the study. C_LI
Perceptual similarity is a cornerstone for human learning and generalization. However, in assessing the similarity between two stimuli differing in multiple dimensions, it is not well- defined which feature(s) one should focus on. The problem has accordingly been considered ill-posed. We hypothesize that similarity judgments may be, in a sense, metacognitive: The stimuli rated as subjectively similar are those that are in fact more challenging for oneself to discern in practice, in near-threshold settings (e.g., psychophysics experiments). This self- knowledge about ones own perceptual capacities provides a quasi-objective ground truth as to whether two stimuli should be judged as similar. To test this idea, we measured perceptual discrimination capacity between face pairs, and asked subjects to rank the similarity between them. We found a positive association between perceptual discrimination capacity and subjective perceptual dissimilarity, with this association being importantly specific to each individual. The results indicate that perceptual similarity judgment reflects and predicts ones own perceptual capacities, supporting our hypothesis that perceptual similarity judgment is metacognitive.
Pain is a prominent and debilitating symptom in myotonic disorders, including myotonia congenita and myotonic dystrophy type 1 (DM1). Although patients frequently report chronic pain, its underlying mechanisms remain poorly defined. In both disorders, impaired chloride conductance through voltage-gated CLC-1 chloride channels in skeletal muscle disrupts membrane repolarization, leading to delayed relaxation and persistent muscle hyperexcitability. Here, we investigated the pathophysiology of pain in mouse models of acute and chronic myotonia. In the acute model, a single intraperitoneal injection of anthracene 9 carboxylic acid (9-AC, 30 mg/kg), a selective ClC-1 antagonist, induced transient muscle stiffness, cramping, and gait abnormalities, followed by prolonged pain like behavior, including static and dynamic mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity for up to 48 hours. Whole-cell patch-clamp recordings from dorsal root ganglion neurons demonstrated increased action potential firing in small diameter sensory neurons, consistent with enhanced peripheral excitability of putative nociceptors. Compound action potentials from isolated sciatic nerves revealed that 9-AC impaired A-fiber recruitment and stimulus-response gain without affecting conduction velocity, suggesting a reduction in non-nociceptive fiber input that may disinhibit central nociceptive processing. To assess central mechanisms of sensitization, we performed in vivo fiber photometry of the parabrachial nucleus (PBN), a key supraspinal hub for pain signaling. Mice treated with 9-AC exhibited exaggerated PBN responses to normally innocuous mechanical and cold stimuli, indicative of enhanced central nociceptive transmission. Having established that acute myotonia can evoke both peripheral and central sensitization, we next examined whether chronic myotonic activity in a disease-relevant genetic model produces similar pathophysiological changes. To model chronic myotonia, we evaluated HSA LR20b mice, a transgenic model of DM1 carrying a skeletal muscle-specific CTG repeat expansion. These mice displayed persistent mechanical and thermal hypersensitivity, along with elevated dorsal root ganglia neuron excitability, supporting sustained peripheral sensitization in a genetic model of myotonic disease. Together, these findings establish robust preclinical models of myotonic pain and demonstrate that myotonia drives a prolonged nociplastic pain state through combined peripheral and central mechanisms. These results provide a foundation for future studies aimed at identifying and validating therapeutic targets for pain associated with myotonic disorders.
In the early olfactory system, adult-neurogenesis, a process of neuronal replacement results in the continuous reorganization of synaptic connections and network architecture throughout the animals life. This poses a critical challenge: How does the olfactory system maintain stable representations of odors and therefore allow for stable sensory perceptions amidst this ongoing circuit instability? Utilizing a detailed spiking network model of early olfactory circuits, we uncovered dual roles for adult-neurogenesis: one that both supports representational stability to faithfully encode odor information and also one that facilitates plasticity to allow for learning and adaptation. In the main olfactory bulb, adult-neurogenesis affects neural codes in individual mitral and tufted cells but preserves odor representations at the neuronal population level. By contrast, in the olfactory piriform cortex, both individual cell responses and overall population dynamics undergo progressive changes due to adult-neurogenesis. This leads to representational drift, a gradual alteration in sensory perception. Both processes are dynamic and depend on experience such that repeated exposure to specific odors reduces the drift due to adult-neurogenesis; thus, when the odor environment is stable over the course of adult-neurogenesis, it is neurogenesis that actually allows the representations to remain stable in piriform cortex; when those olfactory environments change, adult-neurogenesis allows the cortical representations to track environmental change. Whereas perceptual stability and plasticity due to learning are often thought of as two distinct, often contradictory processing in neuronal coding, we find that adult-neurogenesis serves as a shared mechanism for both. In this regard, adult-neurogenesis in the mammalian olfactory bulb that has been the focus of considerable study in chemosensory neuroscience may be the mechanistic underpinning behind an array of complex computations.
While we often assume that memory encoding occurs from an in-body (first-person) perspective, out-of-body experiences demonstrate that we can form memories from a third-person perspective. This phenomenon provides a distinctive opportunity to examine the interaction between embodiment and visual perspective during encoding, and how this interplay shapes the recall of past events. Participants formed memories for naturalistic events following a manipulation of their sense of embodiment from in-body and out-of-body perspectives and recalled them during functional scanning. Region of interest multivariate analyses examined how the angular gyrus, precuneus, and hippocampus reflected visual perspective, embodiment, and their interaction during remembering. Patterns of activity during retrieval in the left angular gyrus and bilateral precuneus predicted embodiment on its own separated from visual perspective. In contrast, we observed only inconclusive evidence that these posterior parietal regions predicted visual perspective independent of embodiment. While the left angular gyrus distinguished between in-body and out-of-body perspectives during the retrieval of events associated with both strong and weak embodiment, decoding accuracy predicting visual perspective was only above chance for events encoded with strong embodiment in the precuneus bilaterally. Our results suggest that the contribution of posterior parietal regions in establishing visual perspectives within memories is tightly interconnected with embodiment. Encoding events from an embodied in-body perspective compared to embodied out-of-body perspective led to higher memory accuracy following repeated retrieval. These results elucidate how fundamental feelings of being located in and experiencing the world from our own bodys perspective are integrated within memory.
Goal-directed learning arises from distributed neural circuits including the prefrontal, posterior parietal and temporal cortices. However, the role of cortico-cortical functional interactions remains unclear. To address this question, we integrated information dynamics analysis with magnetoencephalography to investigate the encoding of learning signals through neural interactions. Our findings revealed that information gain (the reduction in uncertainty about the causal relationship between actions and outcomes) is represented over the visual, parietal, lateral prefrontal and ventromedial/orbital prefrontal cortices. Cortico-cortical interactions encoded information gain synergistically at the level of pairwise and higher-order relations, such as triplets and quadruplets. Higher-order synergistic interactions were characterized by long-range relationships centered in the ventromedial and orbitofrontal cortices, which served as key receivers in the broadcast of information gain across cortical circuits. Overall, this study provides evidence that information gain is encoded through synergistic and higher-order functional interactions and is broadcast to prefrontal reward circuits.
A high degree of structural complexity arises in dynamic neuronal dendrites due to extensive branching patterns and diverse spine morphologies, which enable the nervous system to adjust function, construct complex input pathways and thereby enhance the computational power of the system. Owing to the determinant role of dendrite morphology in the functionality of the nervous system, recognition of pathological changes due to neurodegenerative disorders is of crucial importance. We show that the statistical analysis of a temporary signal generated by cargos that have diffusively passed through the complex dendritic structure yields vital information about dendrite morphology. As a feasible scenario, we propose engineering mRNA-carrying multilamellar liposomes to diffusively reach the soma and release mRNAs, which are translated into a specific protein upon encountering ribosomes. The concentration of this protein over a large population of neurons can be externally measured, as a detectable temporary signal. Using a stochastic coarse-grained approach for first-passage through dendrites, we connect the key morphological properties affected by neurodegenerative diseases--including the density and size of spines, the extent of the tree, and the segmental increase of dendrite diameter towards soma--to the characteristics of the evolving signal. Thus, we establish a direct link between the dendrite morphology and the statistical characteristics of the detectable signal. Our approach provides a fast noninvasive measurement technique to indirectly extract vital information about the morphological evolution of dendrites in the course of neurodegenerative disease progression.
Core body temperature (Tb) is defended within narrow limits through thermoregulatory behaviors like huddling, nesting, and physical activity as well as autonomic responses like brown fat thermogenesis and peripheral vasodilation. While Tb displays regulated fluctuations across different behavioral states and rest/arousal cycles, the neural control of these transitions is poorly understood. Here, we investigate the relationship between oxytocin neurons of the paraventricular hypothalamus (PVNOT) and behavioral and autonomic thermoeffector pathways across physiological states in mice. First, we show that PVNOT neurons are activated during social thermoregulation. We then demonstrate that--in both social and nonsocial contexts--in vivo PVNOT calcium dynamics align with transitions from rest to thermogenesis and behavioral arousal. Using a computer vision model to track thermoeffector pathways, we demonstrate that precisely timed stimulation of PVNOT during low-Tb resting states increases thermogenesis and behavioral arousal. We therefore suggest a model in which PVNOT neurons facilitate state-dependent transitions in thermo-behavioral states.
Unilateral spatial neglect (USN) is a common consequence of right-hemisphere stroke, traditionally attributed to structural lesions and dysfunctional attention networks. However, the brain is fundamentally a rhythmic and dynamical system, and how disrupted neural synchronization underlies USN remains unknown. We recorded steady-state visual evoked potentials (SSVEPs; 3 - 30 Hz flicker) in stroke patients with USN, without USN, and healthy controls. Only the USN group exhibited significant hemispheric asymmetry at 9 Hz, driven by exaggerated responses in the intact hemisphere rather than suppression in the lesioned hemisphere. This effect appeared only during stimulation, not at rest, indicating its specificity to sensory processing. The enhanced 9 Hz entrainment in the intact hemisphere was accompanied by increased phase-amplitude coupling (PAC) between alpha phase and gamma amplitude, reflecting systematic coordination of high-frequency activity. Transfer entropy analysis further revealed increased feedforward information flow from the right visual to the left frontal cortex, highlighting large-scale asymmetry. To explore the mechanism underlying this frequency-specific bias, we implemented a coupled-oscillator model. The model showed that the hemispheric asymmetry arises from resonance between intrinsic alpha rhythms and external input, amplified by asymmetric right-to-left interhemispheric coupling. These findings suggest that USN arises from a selective impairment of alpha-band synchrony capacity. This study offers a novel framework conceptualizing USN as a disorder of disrupted oscillatory dynamics underlying spatial attention, and points toward frequency-specific neuromodulatory intervention as a potential therapeutic approach.
Rapid and high local calcium (Ca2+) signals are essential for triggering neurotransmitter release from presynaptic terminals. In specialized bipolar ribbon synapses of the retina, these local Ca2+ signals control multiple processes, including the priming, docking, and translocation of vesicles on the ribbon before exocytosis, endocytosis, and the replenishment of release-ready vesicles to the fusion sites for sustained neurotransmission. However, our knowledge about Ca2+ signals along the axis of the ribbon active zone is limited. Here, we used fast confocal quantitative dual-color ratiometric line-scan imaging of a fluorescently labeled ribbon binding peptide and Ca2+ indicators to monitor the spatial and temporal aspects of Ca2+ transients of individual ribbon active zones in zebrafish retinal rod bipolar cells (RBCs). We observed that a Ca2+ transient elicited a much greater fluorescence amplitude when the Ca2+ indicator was conjugated to a ribeye-binding peptide than when using a soluble Ca2+ indicator, and the estimated Ca2+ levels at the ribbon active zone exceeded 26 M in response to a 10-millisecond stimulus, as measured by a ribbon-bound low-affinity Ca2+ indicator. Our quantitative modeling of Ca2+ diffusion and buffering is consistent with this estimate and provides a detailed view of the spatiotemporal [Ca2+] dynamics near the ribbon. Importantly, our data demonstrates that the local Ca2+ levels may vary between ribbons of different RBCs and within the same cells. The variation in local Ca2+ signals is found to correlate with ribbon size and active zone extent. Our serial electron microscopy results provide new information about the heterogeneity in ribbon size, shape, and area of the ribbon in contact with the plasma membrane.
Complex behavioral and cognitive functions emerge from coordinated dynamic communication between often disparate brain regions, implying a systems-level arrangement of underlying neural signals. This study introduces multivariate mixture and hidden Markov modeling approaches to analyze phase coherence networks in fMRI data, capturing macroscale dynamic functional synchronization in the human brain. We show that 1) phase coherence is inherently a complex-valued phenomenon and should beanalyzed as such, 2) statistical models for assessing complex-valued phase coherence, particularly the complex angular central gaussian (ACG) distribution, outperform amplitude and phase-amplitude methods on synthetic and task fMRI data as well as existing phase coherence modeling approaches (including LEiDA), 3) models of phase coherence should account for the inherent anisotropy of the brains interconnections by including a covariance matrix in each mixture component. We provide a Python-based toolbox ("Phase Coherence Mixture Modeling" (PCMM): github.com/anders-s-olsen/PCMM) to facilitate implementation of phase coherence models.
Connectomics is a field of neuroscience that maps the brains intricate wiring diagram. Accurate neuron segmentation from microscopy volumes is essential for automating connectome reconstruction. However, state-of-the-art algorithms use image-based convolutional neural networks limited to local neuron shape context. Thus, we introduce a new framework that reasons over global neuron shape with a novel point affinity transformer. Our framework embeds a (multi-)neuron point cloud into a fixed-length feature set from which we can decode any point pair affinities, enabling clustering neuron point clouds for automatic proofreading. We also show that the learned feature set can easily be mapped to a contrastive embedding space that enables neuron type classification using a simple classifier. Our approach excels in two demanding connectomics tasks: correcting segmentation errors and classifying neuron types. Evaluated on three benchmark datasets derived from state-of-the-art connectomes, our method outperforms point transformers, graph neural networks, and unsupervised clustering baselines.
Human walking involves tightly coordinated movements of the right and left legs. We recently developed and tested a "dynamic treadmill walking" paradigm that changes the treadmill speed within a single step to provide asymmetric training for persons with gait dysfunction. We previously demonstrated that this approach could induce changes in human gait symmetry; however, if this approach is to be used in rehabilitation, we also need to understand how movements of the legs are coordinated to produce these asymmetric gait changes. The goal of this study was to examine the temporal (phase shift) and spatial (center of oscillation difference) aspects of interlimb coordination during dynamic treadmill walking in ten young adults without gait impairment. We found that dynamic treadmill walking drove significant changes in phase shift and center of oscillation difference that were dependent on the timing of the treadmill speed change within the gait cycle. For example, slowing the treadmill during the stance phase extended the double limb support period, and these changes were strongly correlated with a phase shift between the two legs. Accelerating the treadmill late in stance led to extensions in the trailing limb angle that were strongly correlated with changes in the center of oscillation difference. Overall, dynamic treadmill walking can be configured to drive changes in many spatiotemporal, kinematic, and interlimb coordination parameters, creating a variety of options for restoring gait symmetry and targeting aspects of spatial and temporal interlimb coordination in clinical populations with heterogenous patterns of gait asymmetry.
Sexual differentiation of the nervous system drives profound neurobiological and behavioral differences between the sexes across various organisms, including Caenorhabditis elegans. Using single-nucleus RNA sequencing, we profiled and compared adult male and hermaphrodite C. elegans neurons, generating an atlas of adult male-specific and sex-shared neurons. We expanded the molecular map of male-specific neurons, and identified highly dimorphic expression of GPCRs, neuropeptides, and ion channels. Our data demonstrate sex-shared neurons exhibit substantial heterogeneity between the sexes, while sex-specific neurons repurpose conserved molecular pathways to regulate dimorphic behaviors. We show that the PHD neurons display remarkable similarity to sex-shared AWA neurons, suggesting partial repurposing of conserved pathways, and that they and the GPCR SRT-18 may play a role in pheromone sensing. We further demonstrate that the ubiquitously expressed MAPK phosphatase vhp-1 regulates both sex-specific and sex-shared behaviors. Our data provide a rich resource for discovering sex-specific transcriptomic differences and the molecular basis of sex-specific behaviors.
Neuromodulation therapies are often applied to peripheral nerves. These nerves can have physiological activity that interacts with the activity evoked by electrical stimulation, potentially influencing targeted neural output and clinical outcomes. Our goal was to quantify changes in sensory neural unit activity in response to variations in electrical stimulation frequency and amplitude. In a feline model, we applied cutaneous brushing to evoke pudendal nerve afferent activity with and without electrical stimulation via a pudendal nerve cuff electrode. We recorded neural output with microelectrode arrays implanted in ipsilateral sacral dorsal root ganglia (DRG). Combined inter-spike interval distributions for all DRG units showed ranges of flattening, increases, and shifts in response to electrical stimulation. These distributions and changes within them due to electrical stimulation were largely driven by a select few units. Mixed-effects models revealed that quicker firing units generally decreased in firing rate in response to electrical stimulation and, conversely, slower firing units increased in firing rate. A units underlying firing rate also drove the magnitude of change in mean output firing rate in response to stimulation. Further, the models reported a small, negative correlation between the output mean unit firing rate and the applied electrical stimulation frequency. These results demonstrate the potential impact of electrical stimulation on underlying neural firing activity and output. Peripheral neuromodulation may normalize abnormal firing patterns in nerves contributing to pathological disorders or alter unrelated physiological activity in off-target neurons. These factors should be considered when selecting neuromodulation settings in animal subjects and human patients.
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. The presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.
Sensory stimuli vary across a variety of dimensions, like contrast, orientation, or texture. The brain must rely on population representations to distinguish changes in one dimension from changes in another. To understand how the visual system might extract separable stimulus representations, we recorded multiunit neuronal responses to texture images varying along two dimensions: contrast, a property represented as early as the retina, and naturalistic statistical structure, a property that modulates neuronal responses in V2 and V4, but not in V1. We measured how sites in these 3 cortical areas responded to variation in both dimensions. Contrast modulated responses in all areas. In V2 and V4, the presence of naturalistic structure both modulated responses and increased contrast sensitivity. Tuning for naturalistic structure was strongest in V4; tuning in both dimensions was most heterogeneous in V4. We measured how well populations in each area could support the linear readout of both dimensions. Populations in V2 and V4 could support the linear readout of naturalistic structure, but in V4, this readout was more robust to variations in contrast. Significance StatementTo support flexible behavior, the brain must simultaneously represent different stimulus dimensions. Single neurons are typically modulated by multiple dimensions, and so cannot distinguish them - they must be extracted by decoding neural populations. We studied neuronal responses in three cortical visual areas - V1, V2, V4 - using texture images varying in both contrast and naturalistic image structure. We used population decoders to read out each dimension. In all areas, contrast was decoded independently of image structure. V1 could not decode image structure independent of contrast, and V2 could do so only poorly. Because the selectivity of individual sites for texture and contrast in V4 was more diverse than V1 or V2, only there could we extract separate representations of both dimensions.
Despite showing significant impact in cognitive preservation, the relationship between brain activity captured with functional Magnetic Resonance Imaging (fMRI) in gray matter and ventricular cerebrospinal fluid dynamics remains poorly understood. We analyzed 599 fMRI scans from 163 elderly participants at rest with varying degrees of cognitive impairment employing a unified phase coupling analysis that breaks from convention by incorporating both tissue and ventricular signal fluctuations. This whole-brain approach identified distinct brain-ventricle coupling modes that differentiate between cognitive status groups and correlate with specific cognitive abilities. Beyond the previously reported anti-phase coupling between global brain signals and ventricles--which we confirm occurs more frequently in cognitively normal controls--our analysis method uncovered additional coupling modes where signals in specific brain networks temporarily align with ventricle signals. At the cortical level, these modes reveal patterns corresponding to known resting-state networks: one overlapping with the Default Mode Network occurs significantly less frequently in Alzheimers Disease patients, while another revealing the Frontoparietal Network correlates positively with memory scores. Our findings demonstrate that different brain-ventricle coupling modes correlate with specific cognitive domains, with particular modes predicting memory, executive function, and visuospatial abilities. The coupling between signals in brain ventricles and established resting-state networks challenges our current understanding of functional network formation, suggesting an integral link with brain fluid motion. This reconceptualization of brain dynamics through the lens of fluid-tissue interactions establishes a fundamental physical basis for cognitive preservation, suggesting that therapeutic interventions targeting these interactions may prove more effective than approaches focused solely on cellular or molecular mechanisms.
Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.
A key challenge in todays fast-paced digital world is to integrate information from various sources, which differ in their reliability. Yet, little is known about how explicit probabilistic information about the likelihood that a source provides correct information is used in decision-making. Here, we investigated how such explicit reliability markers are integrated and the extent to which individuals have metacognitive insight into this process. We developed a novel paradigm where participants viewed opinions from sources of varying reliability to make a choice between two options. After each decision, they rated how much they felt a given source influenced their choice. Using computational modelling, we estimated the effective reliability participants assigned to each source and how leaky their decision process was. Overall, we found that participants acted as if sources were more informative than they actually were, inflating the reliability they were communicated. Interestingly, we show that even though sources were explicitly labelled as unreliable, these sources biased choices, as if these were treated as moderately reliable. Additionally, the presence of sources known to be lying, reliably voting for the incorrect answer, impaired performance by increasing decision leakiness. Despite these biases, participants showed some metacognitive awareness of what influenced their choices: they were generally accurate in reporting the degree to which a source influenced them and were aware of the impact unreliable sources had on their decisions. These results suggest that people make suboptimal use of explicit source reliability, but have some awareness of their suboptimal choices.
The Lateral Habenula (LHb) is a small brain structure specialized in encoding aversive signals. Bursting activity in the LHb has been consistently linked to mood regulation, with increased bursting activity proposed to promote depressive behaviors. Bursting is a complex dynamic process that has been extensively studied and modeled in other neuronal contexts. However, at the LHb this type of activity has typically been described only as transient periods of high frequency firing. Here, to provide a deeper understanding of LHb bursting, we analyzed this activity from the perspective of dynamical systems. Ex vivo, LHb neurons display a variety of bursting patterns, characterized at one extreme by a dominating square-wave type and in other by parabolic type, plus transitional forms referred to as triangular bursting. Notably, these bursting patterns, which reflect different LHb output modes, can occur within the same neuron, suggesting that they may correspond to distinct dynamic states of the same LHb neuron. To capture these complex behaviors, we propose an idealized multiple-timescale dynamical model. This model successfully reproduces the three main bursting patterns observed in experimental data. Furthermore, we identify a special point in the parameter space, termed the saddle-node homoclinic bifurcation, which acts as an organizing center demarcating the boundary between the two primary bursting patterns and around which the third pattern appear. Our model suggests that LHb bursting activity is structured around distinct dynamic states with potentially diverse and unexplored impacts on mood regulation. By providing new insights into the dynamic principles underlying LHb bursting, this framework may advance our understanding of its biological significance.
Cryopreserving the adult brain is challenging due to damage from ice formation, and traditional freezing methods fail to maintain neural architecture and function. Vitrification offers a promising alternative but has not been surveyed in the brain. Here, we demonstrate near-physiological recovery of the adult murine hippocampus after vitrification of brain slices and of the whole brain in situ. Key features of the hippocampus are preserved, including structural integrity, metabolic responsiveness, neuronal excitability, and synaptic transmission and plasticity. Notably, hippocampal long-term potentiation was well preserved, indicating that the cellular machinery of learning and memory remains operational. These findings extend known biophysical limits for cerebral hypothermic shutdown by demonstrating recovery after complete cessation of molecular mobility in the vitreous state. This suggests that the brain can be arrested in time and then reactivated, opening avenues for potential clinical applications. Significance StatementWhile the brain is considered exceptionally sensitive, we show that the hippocampus can resume normal electrophysiological activity after being rendered completely immobile in a cryogenic glass. The work extends known biophysical tolerance limits for the brain from the hypothermic to the cryogenic range and establishes a protocol for its long-term storage in a viable state.
Despite serious health and economic burden, borne more prominently by lower and lower middle-income countries, pharmacotherapy for common psychiatric disorders rely on drugs altering neurotransmission, with partial efficacies. The persistence of a chronic yet sub-threshold inflammation across the periphery and the brain is well documented in the patients and animal models of these disorders and can be investigated for augmenting pharmacotherapy. IL1{beta}, a pleiotropic cytokine and a key regulator of neuroinflammation has been of particular interest in this regard. Previous studies on rodent models of anxiogenic stress show activation of a large multiprotein complex - the NLRP3 inflammasome, which increases IL1{beta} production facilitated by caspase 1, through what is considered a canonical inflammasome activation pathway. However, there exists a second non canonical inflammasome activation pathway whose impact on IL1{beta} release, inflammation and behavioral consequences remain unclear. Using rat models of physical and psychosocial stress, we observed stress-induced sex-specific upregulation of activated caspase 11 and gasdermin D N-terminal fragments, the mediators of the non-canonical inflammasome pathway that facilitates IL1{beta} release through pore formations in the plasma membrane. This is the first report of non-canonical inflammasome pathway being activated in the brain and peripheral immune cells in response to psychosocial stress. Inhibition of caspase 11 with wedelolactone, or Gasdermin D cleavage with Disulfiram reduced stress-induced elevation of IL1{beta} levels, anxiety and fear acquisition, facilitated fear extinction and recall, and improved working memory. Combination treatments targeting both canonical (ibrutinib for pBTK/NLRP3 or MCC950 for NLRP3 inhibition) and non-canonical (wedelolactone for caspase 11 or disulfiram for gasdermin D) pathways proved more efficacious in reducing stress-mediated neuroinflammation, dendritic spine elimination in the CA3 region of the hippocampus and behavioral dysfunction. Furthermore, psychosocial stress drove peripheral inflammation, in peripheral blood mononuclear cells, which was mitigated by the combination treatment. Taken together, this study reveals a novel mechanism underlying psychosocial stress involving both canonical and non-canonical inflammasome signaling to facilitate IL1{beta} induction and behavioral changes. Our finding further suggests that combined targeting of the NLRP3 inflammasome and gasdermin D could contribute to the development of future transdiagnostic therapeutic targets for stress, anxiety, and depression.
Epileptic seizures result from abnormal synchronous neuronal firing caused by an imbalance between excitatory and inhibitory neurotransmission. While most seizures are self-limiting, those lasting over five minutes, termed status epilepticus, require medical intervention. Benzodiazepines, the first-line treatment, terminate seizures by enhancing GABAergic inhibition, but fail in approximately 36% of cases. In this paper, we employ a neural mass framework to investigate how different interventions influence brain dynamics and facilitate seizure termination. As seizures are characterized by persistent firing, we extend the classic Wilson-Cowan framework by introducing a term called sustenance which encodes factors that promote or discourage perpetual firing. The resulting model captures transitions between normal activity and seizure and provides a tractable framework for analysing diverse pathophysiological mechanisms. We first show how various dysfunctions - such as hyperexcitation, depletion of inhibitory neurotransmitters, and depolarizing GABAergic transmission - can all give rise to seizures, with overlapping but distinct dynamics. Building on this foundation, we turn to the central question of intervention: how different treatments act on these mechanisms to terminate seizures. We find that while enhancing GABAergic inhibition is generally effective, it fails when GABA becomes depolarizing. In such cases, interventions like levetiracetam that suppress sustained excitatory activity remain effective. These findings highlight the importance of aligning interventions to the specific underlying dysfunction for effective seizure termination.
Large-scale extracellular recording techniques represent a major advance in interrogating the structure and dynamics of neuronal circuits. However, methods that can resolve cell-type identity in a principled way, while simultaneously scaling to thousands of neurons, are currently lacking. Here, we introduce spikeMAP, a pipeline for the analysis of large-scale recordings of in vitro cortical activity that not only allows for the detection of spikes produced by single neurons (spike sorting), but also allows for the reliable distinction between genetically determined cell types by utilizing viral and optogenetic strategies as ground-truth validation. This approach tightly integrates the data analysis pipeline to an optogenetic, viral, and pharmacological protocol allowing for the dynamical probing of distinct cell-types while simultaneously recording from large populations. The novelty of spikeMAP is to combine a stream of well-established analysis techniques in an end-to-end fashion, creating a unified framework as follows. First, individual spike waveforms are fitted by spline interpolation to estimate their half-amplitude and peak-to-peak durations. These values are then entered in a principal component analysis with k-means clustering to identify uncorrelated signals from single channels on the array. Optimal separability of clusters is assessed by linear discriminant analysis. Finally, each channels source location is identified using spatiotemporal characteristics of spike waveforms across the array. We show that spikeMAP can resolve cell type identity in high-density arrays by analyzing activity monitored from mouse prefrontal cortex in vitro slices with an array of 4,096 closely-spaced channels. Using an optotagging functional strategy, we show an effective distinction of regular-spiking excitatory neurons from fast-spiking inhibitory interneurons using measures of action potential waveform, Fano factor, and spatially-dependent cross-correlations. In sum, the approach introduces a toolbox, validated by an experimental pipeline, that allows for a comprehensive characterization of neuronal activity obtained from different cell-types in high-density multielectrode recordings. This provides a scalable approach to investigate the interplay between distinct cell types in microcircuits of the brain.
It has not previously been possible to investigate the fundamental relationship between axonal structure - which dictates action potential transmission - and human neuronal function in vivo. Here, we introduce a novel metric of axonal signal speed, estimated axonal latency (EAL), derived from the relationship between axonal diameter, myelination, and length measured via MRI. We validate EAL along two pathways of the face processing network by relating it to N170 latency, an electrophysiological marker of face processing speed measured via EEG. Our results show that EAL along these pathways predicts N170 latency specifically during face processing. Moreover, we demonstrate that individuals with and without autism rely upon different pathways, potentially providing a structural account for autism-related face processing differences. By establishing this relationship between EEG-based electrical function and MRI-based axonal microstructure, we provide a non-invasive, spatially detailed estimate of neuronal processing speed that can inform our understanding of brain function, development, and disorder. TeaserEstimated axonal latency is a non-invasive, spatially detailed measure of neuronal speed to inform brain function and disorder.
Tool use is a complex motor planning problem. Prior research suggests that planning to use tools involves resolving competition between different tool-related action representations. We therefore reasoned that competition may also be exacerbated with tools for which the motions of the tool and the hand are incongruent (e.g., pinching the fingers to open a clothespin). If this hypothesis is correct, we should observe marked deficits in planning the use of incongruent as compared to congruent tools in individuals with limb apraxia following left-hemisphere stroke (LCVA), a disorder associated with abnormal action competition. We asked 34 individuals with chronic LCVA (14 females) and 16 matched neurotypical controls (8 females) to use novel tools in which the correspondence between the motions of the hand and tool-tip were either congruent or incongruent. Individuals with LCVA also completed background assessments to quantify apraxia severity. We observed increased planning time for incongruent as compared to congruent tools as a function of apraxia severity. Further analysis revealed that this impairment predominantly occurred early in the task when the tools were first introduced. Lesion-symptom mapping analyses revealed that lesions to posterior temporal and inferior parietal areas were associated with impaired planning for incongruent tools. A second experiment on the same individuals with LCVA revealed that the ability to gesture the use of conventional tools was impaired for tools rated as more incongruent by a normative sample. These findings suggest that tool-hand incongruence evokes action competition and influences the tool-use difficulties experienced by people with apraxia. Significance StatementPrior research indicates that competition between different representations associated with moving or using tools must be resolved to enable tool use. We demonstrated that competition may be exacerbated when tool and hand motions are incongruent (e.g., pinching the hand opens a clothespin), resulting in tool-use impairments particularly for individuals with greater severity of limb apraxia, a disorder known to be associated with action competition abnormalities. Lesions in posterior portions of the brains tool use network were associated with impairments in planning incongruent tool actions. This study thus demonstrates that tool-hand incongruence may invoke competition between motions of the hand and tool-tip, which individuals with limb apraxia have difficulty resolving to properly use tools.
Neurofibromatosis Type 1 (NF1) is a rare, single-gene neurodevelopmental disorder. Atypical brain activation patterns have been linked to working memory difficulties in individuals with NF1. The present work investigates if NF1 has increased inhibitory activity in the frontoparietal network during working memory tasks compared to neurotypical controls. Forty-three adolescents with NF1 and twenty-six age-matched neurotypical controls completed functional magnetic resonance imaging scans during a verbal working memory task. Dynamic causal models (DCMs) were estimated for bilateral frontoparietal network (dorsolateral and ventrolateral prefrontal cortices (dlPFC and vlPFC), superior and inferior parietal gyri (SPG and IPG)). The parametric empirical Bayes approach with Bayesian model reduction was used to test the hypothesis that NF1 diagnosis would be characterised by greater inhibitory self-connections (intrinsic connectivity). Leave-one-out cross-validation (LOO-CV) was performed to test the generalisability of group differences. NF1 participants demonstrated greater average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC. The DCM that best explained effects of working memory showed that NF1 group has increased intrinsic connectivity of left vlPFC, but weaker intrinsic connectivity of right vlPFC and left dlPFC. The parameters of these connections showed a modest but positive predictive correlation of r = 0.19 (p = 0.055) with diagnosis status, suggesting a trend toward predictive value. Overall, increased average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC in NF1, suggests reduced overall sensitivity of these regions to inputs. Working memory evoked different patterns of input processing in NF1, that cannot be characterised by increased inhibition alone. Instead, modulatory connectivity related to working memory showed less inhibitory self-connectivity of left dlPFC and left vlPFC, and more inhibitory intrinsic connectivity of right vlPFC in NF1. This discrepancy between average and modulatory connectivity suggests that overall NF1 participants are responsive to cognitive task-related inputs but may show atypical adaptation to the task demands of working memory.
AO_SCPLOWBSTRACTC_SCPLOWGrid cells in the medial entorhinal cortex (MEC) fire when an animal is located at the vertices of a hexagonal grid that extends across the environment. The population activity of grid cells serves as an allocentric representation of the current location of the animal. Recent studies have identified a class of grid cells that represent locations ahead of the animal. How do these predictive representations emerge from the wetware of the MEC? To address this question, we developed a detailed conductance-based model of the MEC network, constrained by existing data on the biophysical properties of stellate cells and the topology of the MEC network. Our model revealed two mechanisms underlying the emergence of a predictive code in the MEC. The first relied on a time scale associated with the HCN conductance. The other depended on the degree of asymmetry in the topology of the MEC network. The former mechanism was sufficient to explain predictive coding in layer II grid cells that represented locations shifted ahead of the current location. The shift was equivalent to [~]5% of the diameter of a grid field. The latter mechanism was required to model predictive representations in layer III grid cells that were shifted forward by a distance of [~]25% of the diameter of a grid field. A corollary of our model, that the extent of the predictive code changes monotonically along the dorsoventral axis of the MEC following observed changes in the properties of the HCN conductance, is borne out by recent experiments.
The olfactory bulb (OB) contains multiple, parallel projection neurons to relay the nature of a stimulus. In a mouse ex vivo slice preparation, we used patch-clamp electrophysiology to measure intrinsic properties, excitability, action potential (AP) shape, voltage-activated conductances, and neuromodulation in the newly-categorized superficial tufted cells (sTCs) compared with those of mitral cells (MCs). We propose that a marked difference in voltage- dependent current represents distinct ion channel populations that affect the kinetics of action potentials, and evokes an increase in sTC firing frequency, albeit both types of projection neurons having similar AP spiking activity. Triple-colored immunofluorescence and RNA scope were used to detect co-localization of the Kv1.3 ion channel and the insulin receptor in sTCs, with [~]73% of sTCs expressing both. The sTCs were modulated by bath application of insulin - increasing AP firing frequency by 97%, attributable to an 8% decrease in the intraburst interval, and a reduction of the latency to first spike by 37%. We conclude that there may be a range of neuromodulators of sTCs that may alter excitability and fine-tune olfactory information processing or metabolic balance. SUMMARY STATEMENTSuperficial tufted cells, as output neurons of the olfactory bulb, were electrophysiologically studied to be insulin sensitive. Brain insulin signaling represents a manner in which olfactory and metabolic circuitry are intertwined.
Vestibular hair cells (HCs) convert gravitational and head motion cues into neural signals through mechanotransduction, mediated by the hair bundle--a mechanically integrated organelle composed of stereocilia and a kinocilium. The kinocilium, a specialized form of primary cilium, remains incompletely defined in structure, molecular composition, and function. To elucidate its characteristics, we conducted single-cell RNA sequencing of adult vestibular and cochlear HCs, uncovering a selective enrichment of primary and motile cilia-associated genes in vestibular HCs, particularly those related to the axonemal repeat complex. This enrichment of orthologous axonemal-related genes was conserved in zebrafish and human vestibular HCs, indicating a shared molecular architecture. Immunostaining validated the expression of key motile cilia markers in vestibular kinocilia. Moreover, live imaging of bullfrog and mouse HCs from crista ampullaris revealed spontaneous kinociliary motion. Together, these findings define the kinocilium as a unique organelle with molecular features of primary and motile cilia and support its previously unknown role as an active, force-generating element within the hair bundle.
During infections, vertebrates develop stereotypic symptoms such as elevated body temperature, reduced appetite, and lethargy. These changes, collectively known as sickness syndrome, are orchestrated by the brain in response to immune mediators released during systemic inflammation. While the roles of subcortical regions, including the hypothalamus and brainstem nuclei, in regulating sickness symptoms are well established, the contribution of the neocortex to the encoding and modulation of the sick state remains less well understood. We examined the neuronal correlates of sickness in the neocortex of awake mice following a single intracerebroventricular (i.c.v.) injection of prostaglandin E2 (PGE2), a well-characterized mediator of sickness. Behavioral analysis revealed that PGE2 elicited a rapid and robust sickness response, characterized by fever, slower locomotion, quiescence, anorexia, and eye squinting. Whole-brain Fos mapping showed that PGE2 generates a distinct neural activation pattern encompassing much of the interoceptive network. Electrophysiological recordings using Neuropixel probes in awake mice together with dimensionality reduction and decoding analysis revealed that neuronal population dynamics in the insular cortex (IC) and the primary somatosensory cortex (SSp), two regions involved in body state representation, encode sickness-related information, such as body temperature, walking velocity, grooming, and eye squinting. However, unlike SSp, ongoing neuronal activity in IC exhibited a better decoding performance for an integrated measure of sickness rather than individual symptoms. Together, these results suggest that PGE2 induces a coordinated physiological and behavioral response akin to a sick state, which is preferentially encoded in the IC.
BackgroundContinuous theta-burst stimulation (cTBS) can perturb neural activity and behavior by inducing effects that persist beyond the relatively short stimulation period. Although widely used in basic research and clinical settings, there lacks an understanding of the neurophysiological and behavioural effects of cTBS. Objectives/HypothesisTwo assumptions motivating the use of cTBS are that it will i) inhibit neural activity in the targeted area, and ii) consequently disinhibit neural activity in the mirroring region in the contralateral cortex. Here, we test these assumptions in the oculomotor system of healthy rhesus macaques. MethodsIn two macaques, we delivered cTBS between blocks of trials where they performed a delayed pro-/anti-saccade task, delivered cTBS to the right PFC (areas 8Ar and 46, which includes the frontal eye fields; 32 cTBS-PFC sessions), to the air as a SHAM control (27 cTBS-SHAM sessions), or to the nearby primary motor cortex as a brain control (21 cTBS-M1 sessions). Across these different types of sessions, we compared changes in oculomotor behavior (reaction times, error rates, peak saccade velocity), and changes in neural activity recorded from the left, contralateral PFC. ResultsDespite multiple lines of evidence consistent with TMS influencing neural activity in the cTBS-PFC and cTBS-M1 sessions, we found no behavioral evidence for inhibition of the right PFC in the cTBS-PFC sessions, nor any evidence for contralateral disinhibition in the left PFC. ConclusionsOur results call into question some of the fundamental assumptions underlying the application of cTBS. HighlightsO_LIcTBS widely used in lab and clinic to rebalance activity across cortex C_LIO_LIWe tested this in a monkey model, delivering cTBS to the prefrontal cortex C_LIO_LINo behavioural evidence for inhibition of brain area targeted by cTBS C_LIO_LINo evidence for disinhibition of spiking activity in mirroring, contralateral cortex C_LIO_LIResults question key assumptions about how cTBS influences network activity C_LI
Precise modulation of brain networks responsible for tongue motor and sensory control (TMSC) is critical for restoring functions, such as speech and swallowing in neurodegenerative disease or in treatment-induced chronic cranial neuropathy. We present an individualized, AI-driven fMRI neuromodulation (iNM) platform that adaptively targets subject-specific TMSC networks in real time. To enhance iNM precision and encodability --critical for neurorehabilitation--we mapped each healthy participants individualized TMSC selectivity network, creating a subject-specific TMSC digital twin. iNM increased signal strength, spatial expansion, and consistency across motor, sensory, and attention regions, while it reduced signal variability. The bilateral inferior parietal lobule emerged as key sensorimotor integration hub, as it exhibited exclusive activation under iNM along with highest discriminability, and largest spatial expansion. iNM also significantly strengthened and expanded motor, sensory, and attention-related networks -- medial-middle frontal areas, insula-claustrum, S1, M1, basal ganglia, motor cerebellum, and inferior temporal-- supporting interoceptive and proprioceptive-motor integration. Machine learning and unsupervised hidden Markov modeling revealed that iNM enhanced the decodability and stability of TMSC-neural states, while it suppressed competing swallow-neural state interference. Notably, the iNM effects extended beyond the neuromodulation window, indicating functional persistence--a key requirement for rehabilitation. iNM reconfigured TMSC networks by strengthening cortico-subcortical connectivity and adaptive circuit dynamics. Our findings show iNM as a non-invasive, personalized intervention capable of selectively enhancing sensorimotor control with high spatiotemporal specificity. By demonstrating mechanistic network-precision and functional carryover, iNM offers a promising intervention for individuals with limited treatment options, including head and neck cancer survivors and early-stage neurodegenerative disease patients.
Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) and alternative splicing provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)--a fatal neurodegenerative disease characterized by disrupted RBP function. Here, we reveal enrichment of genes associated with ALS and other neurodegenerative diseases in the spinal cord cholinergic neuron rhythmic transcriptome. We demonstrate that there is circadian regulation of ALS-linked RBPs and rhythmic alternative splicing of genes involved in intracellular transport (Aftph and Mvb12a), microtubule cytoskeleton organization (Limch1 and Drc3), and synaptic function (Sipa1l2) in this neuronal sub-type. Further, we show that the cholinergic neuron clock regulates sporadic ALS-associated changes in cytoskeleton and neuromuscular junction synapse gene expression. Finally, we report that cell-type-specific Bmal1-deletion (i) increases lumbar spinal cord motor neuron loss and sciatic nerve axon degeneration, (ii) drives alternative splicing of genes encoding ALS-linked RBPs (Matr3 and Srsf7), and (iii) drives alternative splicing of genes associated with microtubule transport and postsynaptic organization. Our results establish a role for the cholinergic neuron circadian clock in RBP function and ALS disease phenotypes.
The relationship between structural properties of diverse neuronal populations in monkey primary visual cortex (V1) and their in vivo functional responses is not fully understood. We combined high-density Neuropixels recordings across cortical layers of macaque V1 with non-linear dimensionality reduction on waveform shape to delineate nine putative cell classes: 4 narrow-spiking (NS), 4 broad-spiking (BS) and 1 tri-phasic (TP). Using targeted analyses of laminar organization, spike amplitude, multichannel waveforms, functional properties, and network connectivity of these cell classes, we demonstrate four aspects of the V1 microcircuit predicted by anatomical studies but never fully demonstrated in vivo. First, NS neurons were concentrated in layer 4. Second, a large-amplitude NS cell class in layer 4B showed strong direction selectivity. Third, another layer 4B NS class exhibited robust bursting and orientation selectivity. Finally, cross-correlation analysis revealed functional interactions between cells in different layers. Our results highlight how high-resolution electrophysiology can reveal novel relationships between in vivo function of neurons and the underlying circuit. TeaserHigh-resolution electrophysiology used with machine learning reveals links between function and the underlying neural circuitry.
Animals respond to tactile stimulations of the body with location-appropriate behavior, such as aimed grooming. These responses are mediated by mechanosensory neurons distributed across the body, whose axons project into somatotopically organized brain regions corresponding to body location. How mechanosensory neurons interface with brain circuits to transform mechanical stimulations into location-appropriate behavior is unclear. We previously described the somatotopic organization of bristle mechanosensory neurons (BMNs) around the Drosophila head that elicit a sequence of location-aimed grooming movements (Eichler et al., 2024). Here, we use a serial section electron microscopy reconstruction of a full adult fly brain to identify nearly all of BMN pre-and postsynaptic partners, uncovering circuit pathways that control head grooming. Postsynaptic partners dominate the connectome, and are both excitatory and inhibitory. We identified an excitatory hemilineage of cholinergic interneurons (hemilineage 23b) that elicit aimed head grooming and exhibit varied connectivity to BMNs from different head locations, revealing lineage-based development of a somatotopic parallel circuit architecture. Presynaptic partners provide extensive BMN presynaptic inhibition, consistent with models of sensory gain control as a mechanism of suppressing grooming movements and controlling the sequence. This work provides the first comprehensive map of a somatotopically organized connectome, and reveals how this organization could shape grooming. It also reveals the mechanosensory interface with the brain, illuminating fundamental features of mechanosensory processing, including feedforward excitation and inhibition, feedback inhibition, somatotopic circuit organization, and developmental origins.
Predictive-coding like theories agree in describing top-down communication through the cortical hierarchy as a transmission of predictions generated by internal models of the inputs. With respect to the bottom-up connections, however, these theories differ in the neural processing strategies suggested for updating the internal model. Some theories suggest a coding strategy where unpredictable inputs, i.e., those not captured by the internal model, are passed on through the cortical hierarchy, whereas others claim that the predictable part of the inputs is passed on. Here, we addressed which neural coding strategy is employed in cortico-cortical connections using an information-theoretic approach. Our framework allows for quantifying two core aspects of both strategies, namely, predictability of inputs and information transfer, through local active information storage and local transfer entropy, respectively. A previous study on the neural processing of retinal ganglion cells connected to the lateral geniculate nucleus showed a coding for predictable information, captured by an increase in the information transfer with the predictability of inputs. Here, we further investigate predictive coding strategies at the cortical level. In particular, we analyzed LFP activity obtained from intracranial EEG recordings in humans and spike recordings from mouse cortex. We detected cortico-cortical connections with increasing information transfer with the predictability of inputs in recorded channels from frontal, parietal and temporal areas in human cortex. In the mouse visual system, we detected connections exhibiting both an increase and decrease in the information transfer with input predictability, although the former was predominant. Our evidence supports the presence of both predictive coding strategies at the cortical level, with a potential predominance of encoding for predictable information. SummaryThe ability of the brain to infer the hidden causes of sensory experiences has been conceptualized within the computational framework of predictive coding. This framework explains perceptual inference and learning as a process of constantly updating an internal model of the world. Predictive coding describes cortical activity as a communication of sensory evidence and predictions generated from prior expectations. While different views of predictive coding agree on the communication of prior expectations throughout cortex, they differ in how internal expectations are updated. One view states that, to update the internal model, the cortex propagates the mismatch between the expected neural activity and the actual neural response to sensory stimuli. In contrast, another view suggests that the cortex propagates the match between the expected neural activity and the actual neural response. In this work, we were able to tease apart these two views, both in human cortex and the mouse visual system, using information theory. We observed that the brain predominantly propagates expected information, i.e., the match between prior expectations and incoming sensory inputs.
Synapses are critical targets of Alzheimers disease (AD), a highly prevalent neurodegenerative disease associated with accumulation of extracellular amyloid-{beta} peptides. Although amyloidosis and aggregation of the 42-amino acid amyloid-{beta} (A{beta}42) have long been considered pathogenic triggers for AD, clinical evidence linking high levels of A{beta}42 with normal cognition challenges this hypothesis. To resolve this conundrum on the role of A{beta}42 in regulating synaptic activity, we used an adeno-associated viral vector approach that triggers extracellular accumulation of A{beta}42 and spatial memory impairment. We show that A{beta}42 leads to an early increase in excitatory and proximal inhibitory synaptic transmission onto hippocampal CA1 pyramidal cells, and an increased expression of the glutamate transporter GLT-1 in these cells. A{beta}42 accumulation does not cause early cognitive deficits unless accompanied by an increased neuronal GLT-1 expression, suggesting this transporter is a critical mediator of A{beta}42s effects. These findings unveil key molecular and cellular mechanisms implicated with AD pathogenesis.
Parental communication signals are transmitted through nursing and critically shape neurodevelopmental trajectories. Mirroring some well characterized effects of gestational challenges in rodents, maternal immune activation (MIA) during the lactational period disrupts maternal physiology, decreases milk quality, and is associated with adverse neurobehavioral outcomes in offspring. This occurs without MIA significantly affecting maternal care. While gestational MIA models are responsive to environmental interventions, which beneficially alter maternal milk composition and associated offspring outcomes, the milk-borne mediators underlying resilience remain poorly understood. Given their ability to transport and deposit biologically active cargos, we propose that milk-derived extracellular vesicles (MEVs) are vehicles that deliver environmental programming signals (e.g., miRNAs) from nursing mothers to their offspring. Using a rat model, we show that lactational MIA altered MEV miRNA cargo and expression of hippocampal miRNAs in offspring. Several miRNAs in MEVs were also found in the hippocampus of matching offspring. Remarkably, the miRNA dysregulation observed in MEVs and hippocampus was rescued when dams were raised in an enriched environment, suggesting environmental enrichment protected from the effects of MIA, as also observed in the behavioral phenotype. RNA-seq of adult offspring hippocampus showed long-term transcriptional changes associated with the gene targets of early-life regulated miRNAs. Our results position MEV miRNA cargos as dynamic programming signals by which maternal experience is communicated to offspring, encoding both stress-induced and protective cues that influence development. This suggests that breastfeeding interventions can regulate the genetic cargo of the milk, programming the life of developing infants.
Microglial dysregulation is increasingly recognized as a driver of Alzheimers disease (AD), yet how pathogen-specific cues sculpt microglial diversity remains unclear. Here we integrate high-dimensional single-cell cytometry in vitro with spatial proteomics in vivo to dissect the impact of two major periodontal pathogens on microglia. Using a 36-marker CyTOF panel, we exposed SIM-A9 microglia to wild-type Porphyromonas gingivalis (Pg) or Tannerella forsythia (Tf) and to gingipain-deficient or S-layer-deficient mutants, resolving 38 clusters. Virulence-factor "switches" redirected cells from homeostatic states toward i) oxidative, antigen-presenting programmes driven by Pg gingipains and ii) an immunosuppressive, exhausted-like state driven by the Tf S-layer. Complementary 37-marker imaging mass cytometry of 5xFAD x hTau knock-in mice chronically infected with Pg identified 21 microglial subclusters. The cortex--but not hippocampus--lost two Arg1/IL-10 immunoregulatory subsets (>2-fold decrease) while NADPH-oxidase-high microglia accumulated around amyloid-{beta} and tau aggregates. These data demonstrate pathogen-specific reprogramming of microglia across model systems and brain regions, linking virulence-factor activity to AD-relevant neuroinflammation. By pinpointing gingipains and the bacterial S-layer as molecular "switches," our study highlights tractable therapeutic targets for limiting infection-driven microglial dysfunction in Alzheimers disease.
The cerebral cortex operates in a state of restless activity, even in the absence of external stimuli. Collective neuronal activities, such as neural avalanches and synchronized oscillations, are also found under rest conditions, and these features have been suggested to support sensory processing, brain readiness for rapid responses, and computational efficiency. The rat barrel cortex and thalamus circuit, with its somatotopic organization for processing sensory inputs from the whiskers, provides a powerful system to explore such interplay. To characterize these resting state circuits, we perform simultaneous multi-electrode recordings in rats barrel cortex and thalamus. During spontaneous activity, oscillations with frequencies centered around 11.5 Hz are detected concomitantly with slow oscillations below 4 Hz, as well as power-law distributed avalanches. The phase of the lower-frequency oscillation appears to modulate the higher-frequency amplitude, and it has a role in gating avalanche occurrences. We then record neural activity during controlled whisker movements to confirm that the 11.5 Hz barrel circuit active at rest is indeed the one involved in response to whisker stimulation. We finally show how a thalamic-driven firing-rate model can describe the entire phenomenology observed at resting state and predict the response of the barrel cortex to controlled whisker movement.
Long axial field of view (LAFOV) PET imaging requires a high level of automation and standardization, as the large number of target tissues increases the manual workload significantly. We introduce an automated analysis pipeline (TurBO, Turku total-BOdy) for preprocessing and kinetic modelling of LAFOV [15O]H2O and [18F]FDG PET data, enabling efficient and reproducible analysis of tissue perfusion and metabolism at regional and voxel-levels. The approach employs automated processing including co-registration, motion correction, automated CT segmentation for region of interest (ROI) delineation, image-derived input determination, and region-specific kinetic modelling of PET data. MethodsWe validated the analysis pipeline using Biograph Vision Quadra (Siemens Healthineers) LAFOV PET/CT scans from 21 subjects scanned with [15O]H2O and 16 subjects scanned with [18F]FDG using six segmented CT-based ROIs (cortical brain gray matter, left iliopsoas muscle, right kidney cortex and medulla, pancreas, spleen and liver) representing different levels of blood flow and glucose metabolism. ResultsModel fits showed good quality with consistent parameter estimates at both regional and voxel-levels (R{superscript 2} > 0.83 for [15O]H2O, R{superscript 2} > 0.99 for [18F]FDG). Estimates from manual and automated input functions were in concordance (R{superscript 2} > 0.74 for [15O]H2O, and R{superscript 2} > 0.78 for [18F]FDG) with minimal bias (<4% for [15O]H2O and <10% for [18F]FDG). Manually and automatically (CT-based) extracted ROI level data showed strong agreement (R{superscript 2} > 0.82 for [15O]H2O and R{superscript 2} > 0.83 for [18F]FDG), while motion correction had little impact on parameter estimates (R{superscript 2} > 0.71 for [15O]H2O and R{superscript 2} > 0.78 for [18F]FDG) compared with uncorrected data. ConclusionOur automated analysis pipeline provides reliable and reproducible parameter estimates across different regions, with an approximate processing time of 1-1.5 h per subject. This pipeline completely automates LAFOV PET analysis, reducing manual effort and enabling reproducible studies of inter-organ blood flow and metabolism, including brain-body interactions.
Fiber photometry is a neuroscience technique that can continuously monitor in vivo fluorescence to assess population neural activity or neuropeptide/transmitter release in freely behaving animals. Despite the widespread adoption of this technique, methods to statistically analyse data in an unbiased, objective, and easily adopted manner are lacking. Various pipelines for data analysis exist, but they are often system-specific, only for pre-processing data, and/or lack usability. Current post hoc statistical approaches involve inadvertently biased user-defined time-binned averages or area under the curve analysis. To date, no post-hoc user-friendly tool with few assumptions for a standardised unbiased analysis exists, yet such a tool would improve reproducibility and statistical reliability for all users. Hence, we have developed a user-friendly post hoc statistical analysis package in Python that is easily downloaded and applied to data from any fiber photometry system. This Fiber Photometry Post Hoc Analysis (FiPhoPHA) package incorporates a variety of tools, a downsampler, bootstrapped confidence intervals (CIs) for analyzing peri-event signals between groups and compared to baseline, and permutation tests for comparing peri-event signals across comparison periods. We also include the ability to quickly and efficiently sort the data into mean time bins, if desired. This provides an open-source, user-friendly python package for unbiased and standardised post-hoc statistical analysis to improve reproducibility using data from any fiber photometry system.
Optogenetic activators with red-shifted excitation spectra, such as Chrimson, have significantly advanced Drosophila neuroscience. However, until recently, available optogenetic inhibitors required shorter activation wavelengths, which dont penetrate tissue as effectively and are stronger visual stimuli to the animal, potentially confounding behavioral results. Here, we assess the efficacy of two newly identified anion-conducting channelrhodopsins with spectral sensitivities similar to Chrimson: A1ACR and HfACR (RubyACRs). Electrophysiology and functional imaging confirmed that RubyACRs effectively hyperpolarize neurons, with stronger and faster effects than the widely used inhibitor GtACR1. Activation of RubyACRs led to circuit-specific behavioral changes in three different neuronal groups. In glutamatergic motor neurons, activating RubyACRs suppressed adult locomotor activity. In PPL1-{gamma}1pedc dopaminergic neurons, pairing odors with RubyACR activation during learning produced odor responses consistent with synaptic silencing. Finally, activation of RubyACRs in the pIP10 neuron suppressed pulse song during courtship. Together, these results demonstrate that RubyACRs are effective and reliable tools for neuronal inhibition in Drosophila, expanding the optogenetic toolkit for circuit dissection in freely behaving animals.
Human high-level visual cortex has been described in two seemingly opposed ways. A categorical view emphasizes discrete category-selective areas, while a dimensional view highlights continuous feature maps spanning across these areas. Can these divergent perspectives on cortical organization be reconciled within a unifying framework? Using data-driven decomposition of fMRI responses in face-, body-, and scene-selective areas, we identified overlapping activity patterns shared across individuals. Each area encoded multiple interpretable dimensions tuned to both finer subcategory features and coarser cross-category distinctions beyond its preferred category, even in the most category-selective voxels. These dimensions formed distinct clusters within category-selective areas but were also sparsely distributed across the broader visual cortex, supporting both locally selective, category-specific, and globally distributed, feature-based coding. Together, these findings suggest multidimensional tuning as a fundamental organizing principle that integrates feature-selective clusters, category-selective areas, and large-scale tuning maps, providing a more comprehensive understanding of category representations in human visual cortex.
Focal cortical dysplasia (FCD) is a leading cause of pharmacoresistant epilepsy in pediatric populations, although its contribution to epileptogenesis remains incompletely understood. Recent findings indicate that hyperexcitability might stem from peripheral areas that are not dysplastic, rather than from the malformation itself. However, consid-ering the significant variability associated with these malformations, it remains challenging to clarify whether this degree of disorganization contributes to changes in activity. In this study, we used the carmustine-induced animal model to investigate how varying degrees of cortical malformation influence neural dynamics. Local field potentials (LFP) were recorded using a multielectrode array (MEA) during both spontaneous activity and external perturbation. We developed a novel metric to quantify spatial heterogeneity in signal organization and evaluated its association with excitation-inhibition (E/I) balance. Our results reveal that alterations such as the aperiodic exponent value and the sparcity of clustering in signal classification are related to the extent and distribution of cortical abnormalities, underscoring the functional relevance of cytoarchitectural variability. This work advances the understanding of FCD-related network dysfunction and introduces analytical approaches with potential translational value for neuroscience research and pre-surgical evaluation.
BackgroundChlordecone (CLD) is a persistent organochloride pesticide formerly used against banana weevil. It is detectable in blood samples from a large proportion of the population in the French Caribbean Islands. Several experimental studies have demonstrated acute neurotoxicity of CLD, but the effect of a subchronic exposure to CLD remains to be studied. MethodsYoung adult male mice were injected intraperitoneally with 3 mg/kg CLD (n=34) or vehicle (n=22), twice a week, for eight weeks. Behavior, regional brain accumulation, and effects on the dopaminergic system were studied. In addition, functional ultrasound imaging (fUSi) was used to probe the visual, somatosensory and dopaminergic pathways. ResultsCLD was detected in all brain regions (5-15 mg/kg) after two-month exposure, without any marked impact on behavior (anxiety, motor coordination, memory). The dopaminergic system was mostly unaffected, despite slight decreases in the number of TH-positive neurons and the expression of VMAT2, quantified in a subset of animals. fUSi highlighted a decreased response to the visual stimulation in CLD-exposed animals, in contrast to the sensorimotor response, which was found unaltered. ConclusionThe two-month-long, systemic, exposure to an intermediate dose of CLD resulted in a mostly unaffected phenotype, with a normal behavior and a largely intact dopaminergic system. Interestingly, functional ultrasound imaging was able to detect an altered visual response, which has also been noted in Parkinsons disease. This study position functional ultrasound imaging as a promising technique to capture early signs of neurotoxicity, opening up opportunities for "toxico-fUS" in the field of neurotoxicology. HighlightsHigh CLD neurotropism confirmed in mice by LC-MS/MS. Sub-chronic chlordecone exposure suggests possible early signs of parkinsonism. Functional UltraSound reveals impairment of brain areas linked to vision and hearing.
Movement disorders, like Parkinson's disease, happen because of unusual patterns in the connections between the cortex and basal ganglia, often caused by timing issues in feedback pathways. This study uses a two-delay nonlinear dynamic model, based on the delayed the van der Pol oscillator, to examine how delays in the feedback loops of the direct and indirect basal ganglia pathways lead to unusual movement patterns and resonance. A thorough analysis of resonance looks at how the ratios of delays and the time it takes to respond affect the system's frequency, showing when internal resonance occurs and how frequency stabilizes under different conditions. We examine how stable the system is by looking at changes in its behavior and measuring the Lyapunov exponent across distinct types of nonlinear feedback setups. Simulations demonstrate transitions from stable oscillations to chaos with varying delays and saturation strength. Our results reproduce symptoms of Parkinson's disease, such as resting tremor, dyskinesia, and freezing, demonstrating how delayed inhibition or hyperactivity destabilizes motor function. The discussion supports these findings, indicating that early problems start in the striatum, with complex effects in the globus pallidus that worsen motor symptoms. This model explains the temporal evolution of Parkinson's disease symptoms and highlights the timing of feedback and saturation as key therapeutic targets. Overall, this research offers a biological explanation for motor problems caused by delays and supports novel approaches for brain stimulation using flexible methods.
Autobiographical memory (AM) retrieval involves goal-directed and reconstructive processes that unfold over time. A key feature of this process is the visual perspective adopted during remembering, which shapes subjective memory experience. Using fMRI, we cued participants to retrieve AMs from an own-eyes, observer, or natural perspective followed by an event probe. Our design dissociates preparatory (cue phase) and reconstructive (probe phase) mechanisms to isolate the neural signatures of retrieval orientation, the strategic use of cues to optimize retrieval. Whole-brain and ROI analyses revealed that the angular gyrus (AG) and precuneus support perspective-guided retrieval in distinct ways. During the cue phase, PGp showed greater activity for instructed perspectives than natural retrieval, consistent with preparatory perspective selection. During the probe phase, observer-perspective retrieval elicited greater activity in PGp and precuneus (7P), supporting sustained perspective maintenance. Brain-behavior models linked PGp and 7P activity to greater vividness and perspective stability, while precuneus (7M) activity was negatively associated with emotional intensity, especially in the observer condition. These findings reveal phase- and subregion-specific contributions of posterior parietal cortex to the subjective qualities of memory. AG subregions support goal-directed perspective selection and implementation, while precuneus subregions flexibly modulate phenomenological features during memory reconstruction.
Transcription factors are potent levers for neural repair, but systematic pipelines to uncover factors that unlock adult corticospinal regeneration are lacking. By intersecting developmental RNA-seq with ATAC-seq footprints, we pinpointed two nuclear-receptor transcription factors--NR2F1 and NR2F6, neither previously linked to CNS axon growth--as top candidates. Forced expression of either factor doubled neurite length in culture, and each proved highly effective in vivo: after unilateral pyramidotomy they drove robust midline sprouting, while after complete thoracic crush they supported long-tract CST regeneration that restored hip lift, partial swing trajectories and grip strength. Multi-omics dissection revealed complementary mechanisms: NR2F1 re-engaged chromatin-remodelling and cytoskeletal networks, whereas NR2F6, via a conserved corepressor domain, imposed a broad translational down-shift, bound predominantly to distal enhancers and re-packaged chromatin into new topologically associating domains that cluster growth genes with freshly activated regulatory hubs. These discoveries establish NR2F1 and NR2F6 as novel pro-regenerative TFs, demonstrate their potency across lesion types, and expose repression-driven translational control and enhancer-TAD reconfiguration as previously unrecognised axes of CNS repair.
Neuronal polarization is essential for functional compartmentalization, enabling dendritic synaptic integration and axonal action potential generation. While structural differences in mitochondria across compartments have been identified, their functional distinctions remain unclear. Here, we uncovered compartment-specific mitochondrial Ca2+ dynamics and their molecular determinants. In axonal mitochondria, Ca2+ uptake through MCU occurs independently of ER-stored Ca2+ release, with faster matrix Ca2+ clearance than dendritic mitochondria, where Ca2+ uptake predominantly originates from ER Ca2+. The ER-independent mitochondrial Ca2+ uptake in axonal mitochondria is mediated by enriched MCU-regulating proteins, MICU1 and MICU2, while higher NCLX expression facilitates rapid Ca2+ clearance. Moreover, NCLX knockdown, which functionally mimics a mental retardation-associated mutation, caused more significant axonal branching defects compared to dendrites in vivo, aligning with its enrichment in axons. These findings highlight fundamental Ca2+-modulating features and developmental importance of neuronal mitochondria in a compartment-specific manner and reveal the key underlying molecular mechanisms.
Neural oscillations at distinct frequency bands facilitate communication within and between neural populations. While single-frequency oscillations are well-characterized, the simultaneous emergence of slow (beta) and fast (gamma) oscillations within the same network remains unclear. Here, we demon-strate that multi-frequency oscillations naturally arise when the ratio of inhibitory-to-excitatory synaptic strength falls within a specific regime using a biologically plausible Izhikevich model. We show that this regime maximizes both information capacity and transmission efficiency, suggesting an optimal balance for neural communication. Deviations from this range lead to single-frequency oscillations and reduced communication efficiency, mirroring disruptions observed in neurological disorders. These findings provide mechanistic insight into how the brain leverages multiple oscillatory frequencies for efficient information processing and suggest a potential biomarker for impaired neural communication. 1. SIGNIFICANCE STATEMENTBeta (slow) and gamma (fast) oscillations often coexist in the brain, yet their origin and functional role remain unclear. Our study reveals that the inhibitory-to-excitatory synaptic strength ratio governs the emergence of this multifrequency state. Furthermore, we demonstrate that information capacity and transmission efficiency are maximized in this regime, leading to significantly enhanced neural communication. These findings provide mechanistic insight into how multiple oscillatory frequencies support efficient brain function and offer a potential framework for understanding disruptions in neural communication associated with neurological disorders.
Contemporary accounts of semantic cognition propose that conceptual knowledge is supported by a heteromodal conceptual store and controlled retrieval processes. However, it remains unclear how the neural basis of semantic control varies across modalities. Recent models of cortical organization suggest that control networks are distributed along a unimodal-to-heteromodal cortical gradient, with the semantic control network (SCN) located in more heteromodal cortex than the domain-general multiple demand network (MDN). We used fMRI to examine how these networks respond to semantic control demands in visual and auditory tasks. Participants judged the semantic relatedness of spoken and written word pairs. On half of the trials, a task cue specified the semantic feature to guide retrieval; on the remaining trials, no such cue was given. The SCN showed greater activation when task knowledge was available, consistent with a role in the top-down control of semantic retrieval across modalities. In contrast, the MDN showed greater activation for spoken words, likely reflecting increased demands in speech perception. These findings demonstrate a dissociation between control networks, with SCN involvement modulated by task structure and MDN activity influenced by input modality.
Climbing fiber (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum1-3. Paradoxically, CFs also excite molecular layer interneurons (MLIs)4,5, a cell-type that inhibits PCs and can restrict plasticity and learning6,7. However, two types of MLIs with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals, and suppress plasticity of granule cell to PC synapses2,6-9, whereas MLI2s inhibit MLI1s and disinhibit PCs8. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial EM reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 via more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s via glutamate spillover4,5. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s, and disinhibits PCs. In contrast, learning-related sensory stimulation produced more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted toward MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for LTD. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity.
AbstractFragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. While structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout (KO) mice, their developmental onset and contribution to early FXS pathophysiology remain unknown. In this study, we examined the postnatal maturation of SPN in the dorsomedial striatum (DMS) of Fmr1 KO mice, assessing glutamatergic synaptic inputs and intrinsic excitability. During postnatal development, Fmr1 deficient SPNs in DMS display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, SPNs of mice exhibit pronounced hyperexcitability, characterized by increased membrane resistance, reduced rheobase, and slower action potential kinetics. These perturbations affect both Dopamine 1 receptor-expressing (D1-SPN) and D2 receptor-expressing (D2-SPN) SPNs, though some action potential dynamics are selectively impaired in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for FXS-related symptoms, fails to normalize SPN excitability, highlighting its limited efficacy in addressing core SPN dysfunction. Our findings reveal a late-onset hyperexcitability in DMS SPNs of Fmr1 KO mice, suggesting a progressive emergence of striatal neuron abnormalities over development. These results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address striatal circuit dysfunction.
Metabolic collapse of retinal ganglion cells (RGCs) onsets glaucoma, yet no approved drug directly protects these neurons. Through a live-cell mitochondrial screen in human stem-cell-derived hRGCs we uncovered WAY-100635 (WAY), a clinically tested 5-HT1A antagonist, as a systemic neuroprotectant. WAY triggers a reversible cyclic-AMP surge that activates PGC-1-driven reversible mitochondrial biogenesis and suppresses apoptosis. In glaucoma associated OPTNE50K hRGCs, WAY restores mitochondrial fitness, dampens excitotoxicity, and reprograms metabolism toward aerobic glycolysis, while in progenitors WAY boosts mitochondrial cristae maturation, oxidative phosphorylation, and cell-cycle exit to accelerate RGC specification. Daily intraperitoneal dosing preserves RGC bodies, neural activity, promotes axon regeneration into the optic nerve and vision centers after optic-nerve crush, as well as shows RGC protection and maintenance of visual acuity in chronic ocular hypertension glaucoma. As the non-invasive neuroprotective therapy with a human safety profile, WAY addresses a critical gap in glaucoma care and potentially for other mitochondrial optic neuropathies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/659983v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@131ff3eorg.highwire.dtl.DTLVardef@16c4e6borg.highwire.dtl.DTLVardef@190724eorg.highwire.dtl.DTLVardef@4067e4_HPS_FORMAT_FIGEXP M_FIG C_FIG
Fear is a double-edged sword: it supports survival based on learned associations between environmental cues and potential threats, but its dysregulation can lead to anxiety disorders and PTSD. Many studies have addressed the roles of the hippocampus and basolateral amygdala in the storage of the fear engram, but the role of the anterior cingulate cortex (ACC), especially during and immediately after fear acquisition, remains poorly defined. To address this gap, we longitudinally recorded ACC neuronal activity using single-photon calcium imaging in freely behaving adult male mice subjected to fear conditioning. Subjects acquired a conditioned freezing response to a tone cue (conditioned stimulus, CS) paired with light foot shocks (unconditioned stimulus, US), and ACC activity was monitored during cue pre-exposure, fear acquisition, fear recall, and fear extinction. Consistent with known functions of the ACC, neuronal responses were modulated by the US and by the novelty of the CS and US. Critically, both the number of CS-responsive neurons and the CS-associated population activity rose during acquisition, peaked during recall, and decreased throughout extinction. Neuronal populations responsive to the CS overlapped at a rate consistent with chance, suggesting that the ACC operates as a flexible integrative hub rather than containing stable engrams. Together, these findings indicate that ACC neuronal populations, but not engrams, represent novelty, pain, and the dynamic valence of a CS. Our findings are consistent with a model in which the ACC plays a role in threat appraisal and provides a learning signal that dynamically updates fear representations in other regions.
Brain size measures are well-studied and often treated as a confound in volumetric neuroimaging analyses. Yet their relationship with body anthropometric measures and demographics remains underexplored. In this study, we examined those relationships alongside age- and sex-related differences in global brain volumes. Using brain magnetic resonance imaging (MRI) of healthy participants in the UK Biobank, we derived global measures of brain morphometry, including total intracranial volume (TIV), total brain volume (TBV), gray matter volume (GMV), white matter volume (WMV), and cerebrospinal fluid (CSF). We extracted these measures using the Computational Anatomy Toolbox (CAT) and FreeSurfer. Our analyses were structured in three approaches: across-sex analysis, sex-specific analysis, and impact of age analysis. Employing machine learning (ML), we found that TIV was strongly predicted by sex (across-sex r = 0.68), reflecting sexual dimorphism. On the other hand, TBV, GMV, WMV, and CSF were more sensitive to age, with higher prediction accuracy when age was included as a feature, highlighting age-related changes in the brain structure, such as fluid expansion. Sex-specific models showed reduced TIV prediction (r {approx} 0.25) but improved TBV accuracy (r {approx} 0.44), underscoring sex-specific body-brain relationships. Anthropometrics enhanced prediction but only subsidiary to age and sex. These findings advance our understanding of brain-body scaling relationships and underscore the necessity of accounting for age and sex in neuroimaging studies of brain morphology.
Primary mixed glial cultures are key tools to isolate and study astrocytes, microglia and oligodendrocytes. Cell-substrate adhesion is critical for neural cell survival and differentiation. Cationic polymers like poly-D-lysine (PDL) are widely used to promote cell adhesion to cell culture substrates, however, PDL is not stable long-term, with cultured cells often detaching (peeling) after 2-3 weeks. Dendritic polyglycerol amine (dPGA) is a synthetic polycationic non-protein polymer biomimetic of poly-lysine that is highly resistant to degradation by cellular proteases. Substrates coated with dPGA promote cell adhesion and improve survival in long-term neuronal cultures. Here we assessed dPGA as a substrate coating to provide long-term support for mixed glial cultures. Oligodendrocyte precursor cells (OPCs) were isolated weekly by differential adhesion from cultures grown in T75 flasks with PDL or dPGA-coated substrates. Following two "shake-off" isolations, the cell layer in most PDL-coated flasks fully detached, rendering these flasks unusable for further culture. In contrast, dPGA-coated flasks consistently yielded cells for six or more sequential isolations over seven weeks in culture. dPGA-coated flasks produced more cells, a greater percentage of O4+ cells, and maintained similar proportions of OPCs and MBP-positive cells as when isolated from a PDL-coated substrate. dPGA is cyto-compatible, functionally superior, easy to use, low cost and a stable alternative to conventional cell substrate coatings. The enhanced long-term stability of mixed glial cultures grown on a dPGA substrate has the capacity to increase cellular yield, reduce animal use, and facilitate studies of oligodendrocyte cell biology.
Establishing learned associations between rewarding stimuli and the context under which those rewards are encountered is critical for survival. Hippocampal input to the nucleus accumbens (NAc) is a key connection involved in integrating environmental information and reward processing to facilitate goal-directed behaviors. This connection consists of two independent pathways originating from the dorsal (dHipp) or ventral (vHipp) hippocampus, which have previously been considered functionally and anatomically distinct. Here, we show overlap in dHipp and vHipp terminal fields in the NAc, which led us to reconsider this view and raise new questions regarding the potential interactions between dHipp and vHipp pathways in the NAc. Using optogenetics, electrophysiology, and transsynaptic labeling in adult male and female mice, we investigated anatomical and functional convergence of dHipp and vHipp in the NAc. We identified a subpopulation of dually innervated cells in the NAc medial shell where dHipp and vHipp inputs are located near one another along dendritic branches. We independently manipulated dHipp and vHipp inputs via two-color optogenetic manipulation during whole-cell electrophysiology recordings to confirm functional dual innervation of individual neurons and revealed heterosynaptic interactions between the two pathways. Altogether, these results demonstrate that dHipp and vHipp dually innervate a subset of neurons in the NAc, suggesting integration of these inputs at the level of individual neurons. Exploring the physiological and behavioral implications of this convergence will offer new insights into how individual neurons incorporate information from distinct inputs and how this integration may shape learning. SIGNIFICANCE STATEMENTForming associations between rewards and the circumstances under which they are experienced is vital for survival. Hipp input to the NAc is essential for associating rewards with their environmental context to effectively guide motivated behaviors. This connection consists of two separate pathways originating from dHipp and vHipp that have long been considered distinct. Here, we reveal a subpopulation of neurons in the NAc shell innervated by both Hipp subregions as well as heterosynaptic interactions that occur between dHipp and vHipp synapses. These findings suggest that integration of distinct hippocampal information occurs at the single-neuron level, providing a critical mechanism underlying learning and motivated behavior while also opening new avenues for understanding how diverse contextual and reward signals shape decision-making.
BACKGROUNDPrevious studies have shown that cocaine-induced changes in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) differ based on dopamine receptor subtype expression, the sex of the animal, and for females, phase of the estrous cycle. These findings highlight the need to account for both sex and estrous cycle when studying drug-mediated alterations in neurophysiology. Whether MSNs of the nucleus accumbens core (NAcC), which serve different aspects of addiction, will exhibit similar sex and estrous cycle effects with cocaine administration was investigated. METHODSMice underwent a 5-day locomotor sensitization paradigm via daily cocaine administration (15 mg/kg, s.c.) followed by a 1-to 4-day drug-free abstinence period. We examined NAcC MSN excitability by obtaining ex vivo whole-cell recordings from differentially labeled dopamine D1-receptor expressing MSNs (D1R-MSNs) and dopamine D2-receptor expressing MSNs (D2R-MSNs) obtained from male mice or female mice that were either in estrus or diestrus. RESULTSIn this genetic background of mice, both male and female mice sensitized to cocaine in a similar manner. In males, there were no cocaine-induced changes in D1R-MSN or D2R-MSN excitability, with D2R-MSNs exhibiting greater excitability. In saline-treated females, D1R-MSN excitability fluctuated across the estrous cycle with increased excitability during estrus. Following cocaine, estrous cycle-dependent D1R-MSN excitability was arrested, fixed at an intermediate value between estrus and diestrus when compared to saline controls. D2R-MSNs did not change either across the estrous cycle or following cocaine. When comparing MSN subtypes, in diestrus, D2R-MSNs were more excitable under saline conditions, but indistinguishable from D1R-MSNs following cocaine. In contrast, during estrus, D1R-and D2R-MSN excitability was similar in saline treated animals, but with cocaine, D2R-MSNs displayed heightened excitability. CONCLUSIONSThere are fundamental sex differences in cocaine-induced changes to the excitability of D1R-MSNs in the NAcC. After cocaine exposure, female mice in diestrus exhibited a significant main effect change in MSN excitability, an inversion of what had previously been demonstrated in the NAcSh where no cocaine-induced changes were observed. These data suggest that there are distinct differences in the neuropharmacological effect of cocaine in males versus females that are shell and core specific. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/660420v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@fdb01corg.highwire.dtl.DTLVardef@1350b15org.highwire.dtl.DTLVardef@16aac03org.highwire.dtl.DTLVardef@433842_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSThere are sex-and estrous-cycle dependent changes to D1R-MSNs in the NAcC that are sensitive to cocaine exposure. In males, cocaine has no effect on D1R-or D2R-MSNs excitability. During the estrous cycle, D1R-MSNs exhibit increased excitability during estrus. This fluctuation is halted by cocaine, such that D1R-MSNs recorded in diestrus show increased excitability following cocaine exposure whereas female D1R-MSNs recorded in estrus have decreased excitability. PLAIN LANGUAGE SUMMARYThe nucleus accumbens core (NAcC) is a brain region associated with regulating motivated behavior. The primary neuronal populations of the NAcC are dopamine D1 receptor expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor expressing medium spiny neurons (D2R-MSNs). No studies exist which examine sex differences and estrous cycle effects in the NAcC following cocaine administration. Using ex vivo electrophysiology, we found inherent sex-and estrous-cycle differences in cocaine-induced changes in MSN neuroplasticity. D1R-MSN excitability was unaffected in males, increased in females recorded during the diestrus phase, and decreased in females recorded during estrus following cocaine exposure. This ran counter to estrous cycle effects under drug-naive conditions where D1R-MSN excitability was higher in estrus versus diestrus. The estrous cycle effects on D1R-MSNs were eliminated following cocaine administration. For both sexes, D2R-MSN excitability was not impacted following cocaine. These results highlight fundamental sex differences that might underpin differences in substance abuse.
Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS) is associated with language impairments despite seizures originating in the motor cortex, suggesting aberrant cross-network interactions. Here we tested whether functional connectivity in SeLECTS during language tasks predicts language performance. We recorded high-density EEG from right-handed children with SeLECTS (n=31) and age-matched controls (n=32) during verb generation, repetition, and resting tasks. Phonological awareness was assessed using the Comprehensive Test of Phonological Processing-2. Connectivity between bilateral motor cortices and language regions (the left inferior frontal and superior temporal cortices and their right hemisphere homologues) was measured using weighted Phase Lag Index (wPLI). Children with SeLECTS demonstrated significantly elevated connectivity between motor and language regions during language processing. Motor-to-frontal connectivity was higher in SeLECTS during both verb generation and repetition tasks. Frontal-to-temporal connectivity was elevated specifically during verb generation. Higher interhemispheric connectivity (between the left and right hemispheres) during language tasks strongly predicted worse phonological awareness in children with SeLECTS ({beta}= -40 to -61, all p<0.005), but not controls. Together, we found that children with SeLECTS exhibited pathologically elevated connectivity between motor and language networks that was strongly associated with impaired phonological awareness. These findings identify aberrant interhemispheric connectivity as a pathophysiological mechanism underlying language dysfunction and establish EEG-based connectivity measures as a potential biomarker for guiding targeted neuromodulation therapies to treat cognitive impairments in pediatric epilepsy.
Recent developments in acquisition and reconstruction of 3-dimensional magnetic-resonance spectroscopic imaging (3D-MRSI) enable the high-resolution mapping of multiple neurometabolites in the whole-brain, in vivo. Leveraging this capability, we created a voxel-based pipeline that corrects and spatially normalizes whole-brain maps of total N-acetylaspartate (tNAA), myo-inositol (Ins), choline compounds, glutamate + glutamine, and creatine + phosphocreatine. We examined a clinical cohort of adolescents and young adults at risk for psychosis (n= 21) --meeting DSM-5 criteria for Attenuated Psychosis Syndrome (APS)or Schizotypal Personality Disorder (SCZT)-- and age-/sex-matched healthy controls (n =13), as well as an independent non-clinical sample of adolescents (n = 61). We first aimed at assessing the reproducibility of MRSI measures across datasets and scanning sites, then validate the feasibility of a whole-brain voxel-based analyses on 3D-MRSI data and eventually test the sensitivity of this approach. Metabolite distributions showed reproducible regional variation in standard space between the two independent samples and scanning sites (r ranging from 0.82 to 0.99). Relative to controls, at-risk participants exhibited higher tNAA in frontal grey matter; the SCZT subgroup additionally displayed widespread cortical and subcortical Ins elevations compared with both APS and controls. Voxel-based analyses of structural (i.e., gray and white matter volumes or densities) and dijusion (i.e., generalized fractional anisotropy) parameters yielded no significant dijerences between risk participants and controls. These findings suggest the sensitivity of high-resolution 3D-MRSI for detecting subtle neurometabolic alterations at the group level in the early stages of psychotic disorders. Detailed brain metabolic mapping has the potential to help with early identification of young people at risk for psychosis or other mental disorders.
1Lie detection is important for government law enforcement. Current lie detection methods such as the polygraph test have been found to be unreliable (Meijer et al. 2017). New lie detection technology is currently arising that is based on fMRI; however, single subject tests have only been successful in detecting lies 88% of the time (Langleben et al., 2005; Wild, 2005). One of the main problems with most fMRI-based approaches is that they assume that various acts of deception involve common brain regions, (Ganis et al., 2003). In this work I propose a much more accurate fMRI lie detection method that does not make this assumption and is domain based. In my investigation, rather than trying to localize brain regions that are indicative of lying in general, I localize brain regions that indicate lying specifically about face recognition. In criminal investigations one frequently needs to establish familiar relations between a suspect, victim and/or witness. This type of information can be used as circumstantial evidence in a crime. In this work I propose to use fMRI to detect whether a suspect has any familiarity with an individual face. I find that activation in the left inferior frontal gyrus was a reliable discriminator for face familiarity.
To support robust behaviors in highly variable environments, animals rely on active sampling of their sensory surroundings. Here, we use tethered, flying Drosophila melanogaster and a multisensory behavioral apparatus simulating forward flight to determine how visual and mechanosensory information are integrated and control active movements of an important multimodal sensory organ, the antennae. We found that flies perform active antennal movements in response to varying airflow, and that the direction of these movements changes depending on the visual environment. Next, we found that antennal movements are amplified in the presence of visual motion, but only when the fly was flying. Through mechanical and optogenetic manipulation of mechanosensory input, we found that mechanosensory feedback is vital to antennal positioning at flight onset. Additionally, we observed unexpected changes in wingbeat frequency when the antenna was mechanically stabilized, suggesting that multiple antennal mechanosensors contribute to flight regulation. Finally, we show that integration of mechanosensory and visual cues for controlling antennal motion follows in a "winner-takes-all" paradigm dependent on the stimulus frequency, mirroring visuo-mechanosensory guided behaviors in other species. Together, these results reveal novel behavioral gating of sensory information and expand our understanding of the efferent control of active sensing.
The barcoded connectomics tool MAPseq enables highly multiplexed projection mapping of individual neurons by translating neuroanatomy into a DNA sequencing problem. Here we present MAPseq2, a user-friendly protocol with 3-4 fold increased barcode detection sensitivity and [~]10 fold decreased cost relative to the current MAPseq protocol. As MAPseq workflows are used across a range of barcoded connectomics methods, including BARseq, BRICseq, and ConnectID, all improvements in MAPseq2 directly transfer to these technologies.
The retrosplenial cortex (RSC) is a key integrative hub involved in spatial orientation, navigation, and cognitive processes. In rodents, RSC neurons carry rich sensory and navigational signals and are interconnected with sensory, motor, thalamic, and hippocampal circuits--supporting multimodal integration. However, the circuitry that supports this integration remain unclear. Here, we combined 2-photon calcium imaging in navigating mice with brain-wide retrograde tracing to investigate how visual and positional information are represented and distributed across RSC subregions. We found a clear anterior-posterior gradient: anterior RSC neurons exhibited sharper, more reliable position tuning and preferred fast-moving visual stimuli, while posterior RSC neurons showed broader tuning and preferential responses to slower motion. These functional differences were paralleled by distinct patterns of long-range input: anterior RSC received denser projections from motor, parietal, and hippocampal-associated areas--regions implicated in position encoding--whereas posterior RSC was more strongly innervated by visual cortices. Our findings reveal that the RSC contains functionally and anatomically distinct subregions specialized for processing different visuospatial features, suggesting a modular organization that supports integration of contextual and sensory information during navigation.
Many animals strongly rely on their sense of vision, as it provides information about the natural world with particularly high dimensionality. In insects, the first visual processing stage of the brain, the lamina, plays an important role in parallel processing of this complex information. Its main relay neurons, lamina monopolar cells (LMCs), receive information directly from the photoreceptors and shape the contrast, luminance, spatial and temporal tuning of the insect visual system in a cell-type specific manner. One of their best-investigated downstream targets is the motion vision pathway. However, how LMC types that feed into motion processing delineate contrast and luminance is only known from fruit flies, while the contribution of LMCs to spatial processing has only been described in hawkmoths. Here, we provide a novel characterization of hawkmoths lamina monopolar cells, to integrate the contrast, luminance and spatial processing properties of LMCs in the motion pathway. We used serial block-face scanning electron microscopy to reconstruct the anatomical fine structure of LMCs in a focal lamina cartridge, including their pre- and post-synaptic connections. Combining our novel LMC classification with intracellular recordings, we further investigated the functional role of hawkmoth L1 and L2 in terms of contrast and spatial processing. We show that unlike in flies, L1 and L2, the main relay neurons to the motion pathway, process contrast and luminance information in a similar manner. We further demonstrated that the spatial processing properties of these cells are highly similar as well, and can be explained by the density and the distribution of their synapses across different lamina layers. Based on these findings, we propose that the different lamina layers support distinct connectivity and functional roles in spatial processing.
SignificancePyruvate is a nodal intermediate in cellular metabolism, positioned at the crossroads between glycolysis and fermentative metabolism. It is exchanged between the intracellular and extracellular compartments through the proton-coupled monocarboxylate transporters and between the cytosol and mitochondria through the mitochondrial pyruvate carrier, where it serves as a primary carbon source for respiration. AimOur goal is to present a detailed protocol for quantifying cytosolic pyruvate concentration in neurons at single-cell resolution using a minimally invasive, two-point calibration approach with the FRET-based genetically-encoded fluorescent indicator Pyronic. ApproachThis protocol is based on a non-invasive pharmacological two-point calibration approach, where Pyronics dynamic range ({Delta}RMAX) is established by using trans-acceleration exchange to deplete intracellular pyruvate (RMIN), and by inducing Pyronic saturation (RMAX) through the combination of inhibition of pyruvate export, stimulation of its production, and blockade of its mitochondrial consumption. The protocol also incorporates the previously published KD values for Pyronic obtained from in vitro experiments. This procedure does not require the use of detergents to permeabilize the cells. ResultsImplementing this protocol enables the measurement of absolute cytosolic pyruvate concentrations. This quantitative parameter facilitates comparisons of pyruvate metabolism across different cells, samples and experimental batches, thereby enabling the comparison between a plethora of experimental conditions. ConclusionsThe FRET-based fluorescent indicator Pyronic can be reliably calibrated using a minimally invasive, pharmacology-based two-point calibration protocol in neurons, thus providing a robust and quantitative method to study pyruvate metabolism under various physiological and pathological scenarios.
From birth, individuals interpersonal dimension is underpinned by progressive learning of social interaction rules, their variations rooted in the temporal prediction of sensory events, and the inferences made about the organization of the social world. How this dimension is structured during infancy and articulated at the neural level is a critical question for cognitive and affective neurosciences. This systematic review aims to define the neural signatures of temporal prediction in newborns and infants and to discuss them in the context of the development of proximal cognitive and affective neural functions. Eight peer-reviewed studies were included, with 228 infants from birth to 9 months of age. Studies have evidenced that neural signatures of temporal prediction in infants present a broad cerebral localization, including the anterior and medial parts of the brain, especially in the frontal and central areas. Temporal prediction mechanisms emerge well before birth and evolve from early sensory-driven responses to complex top-down processing within the first year, shaped by both innate and experience-dependent factors, with influences like wakefulness and musical exposure that modulate neural integration across sensory and higher-order brain regions.
In natural language, word meanings are contextualized, that is, modified by meanings of nearby words. Inspired by self-attention mechanisms in transformer-based large language models (LLMs), we hypothesized that contextualization in the brain results from a weighted summation of canonical neural population responses to words with those of the words that contextualize them. We examined single unit responses in the human hippocampus while participants listened to podcasts. We first find that neurons encode the position of words within a clause, that they do so at multiple scales, and that they make use of both ordinal and frequency-domain positional encoding (which are used in some transformer models). Critically, neural responses to specific words correspond to a weighted sum of that words non-contextual embedding and the embedding of the words that contextualize it. Moreover, the relative weighting of the contextualizing words is correlated with the magnitude of the LLM-derived estimates of self-attention weighting. Finally, we show that contextualization is aligned with next-word prediction, which includes prediction of multiple possible words simultaneously. Together these results support the idea that the principles of self-attention used in LLMs overlap with the mechanisms of language processing within the human hippocampus, possibly due to similar prediction-oriented computational goals.
In natural language, word meanings are contextualized, that is, modified by meanings of nearby words. Inspired by self-attention mechanisms in transformer-based large language models (LLMs), we hypothesized that contextualization in the brain results from a weighted summation of canonical neural population responses to words with those of the words that contextualize them. We examined single unit responses in the human hippocampus while participants listened to podcasts. We first find that neurons encode the position of words within a clause, that they do so at multiple scales, and that they make use of both ordinal and frequency-domain positional encoding (which are used in some transformer models). Critically, neural responses to specific words correspond to a weighted sum of that words non-contextual embedding and the embedding of the words that contextualize it. Moreover, the relative weighting of the contextualizing words is correlated with the magnitude of the LLM-derived estimates of self-attention weighting. Finally, we show that contextualization is aligned with next-word prediction, which includes prediction of multiple possible words simultaneously. Together these results support the idea that the principles of self-attention used in LLMs overlap with the mechanisms of language processing within the human hippocampus, possibly due to similar prediction-oriented computational goals.
All-optical interrogation, based on high-resolution two-photon stimulation and imaging, has emerged as a potentially transformative approach in neuroscience, allowing for the simultaneous precise manipulation and monitoring of neuronal activity across various model organisms. However, the unintended excitation of light-gated ion channels such as channelrhodopsin (ChR) during two-photon calcium imaging with genetically encoded calcium indicators (GECIs) introduces artifactual neuronal perturbation and contaminates neural activity measurements. In this study, we propose an active pixel power control (APPC) approach, which dynamically adjusts the imaging laser power at each scanning pixel, to address the challenge. We aim to achieve simultaneous two-photon optogenetic manipulation and calcium imaging with a single femtosecond laser, while minimizing the crosstalk between manipulation and imaging. To study this technologys capabilities, we applied it to the larval zebrafish brain in vivo. Our results demonstrate that the APPC approach preserves GECI signal quality while suppressing optogenetic artifacts significantly. This enhances the accuracy of neural circuit dissection and advances the precision of all-optical interrogation, offering a robust framework for probing neural circuit dynamics and causality in vivo with high fidelity, potentially across various model organisms. Importantly, this technology can be seamlessly integrated with commonly used two-photon microscope systems in laboratories worldwide.
Adult hippocampal neurogenesis (AHN) is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to AHN impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-) signalling as a key driver of neurogenic dysregulation via a previously unrecognized type I interferon (IFN) autocrine/paracrine loop in human hippocampal progenitor cells (HPCs). Using a human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that TNF- induces a robust type I IFN response in HPCs, promoting chemokine and CXCR3-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in HPCs from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis. These findings uncover a key inflammatory checkpoint regulating human AHN and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.
Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) and electromyography (EMG) provides a unique window into instantaneous cortical and corticospinal excitability states. We investigated 50 healthy participants to determine how fluctuations in pre-stimulus brain activity influence single-trial TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs). We developed a novel automated source-level TEP extraction method using individualized spatiotemporal priors that is robust against poor single-trial signal-to-noise ratios (SNRs) and ongoing oscillations. TEP and MEP amplitudes were predicted with linear mixed-effects models based on pre-stimulation EEG band-powers (theta to gamma), while accounting for temporal drifts (within-session trends), coil control, and inter-subject differences. We found that higher pre-stimulus sensorimotor alpha, beta, and gamma power were each associated with larger TEPs, indicating a more excitable cortical state. Increases in alpha and gamma power immediately before stimulation specifically predicted larger MEPs, reflecting increased corticospinal excitability. These results reveal relationships between ongoing oscillatory brain states and TMS response amplitudes, identifying EEG biomarkers of high- and low-excitability states. In conclusion, our study demonstrates the feasibility of single-trial source-level TMS-EEG analysis and shows that spontaneous alpha-, beta-, and gamma-band oscillations modulate motor cortical and corticospinal responsiveness. These findings pave the way for EEG-informed, brain-state-dependent TMS protocols to optimize neuromodulatory interventions in clinical and research applications.
Understanding social difficulties in Autism Spectrum Disorder (ASD) remains challenging due to its neurobiological heterogeneity and the limited ecological validity of conventional neuroimaging methods in capturing dynamic social interactions. Hyperscanning analysis based on functional near-infrared spectroscopy (fNIRS), which measures inter-brain synchrony (IBS) during dyadic interaction, offers a novel avenue to address these challenges. However, prior studies on ASD have reported inconsistent findings, primarily focusing on intra-regional synchronization while overlooking cross-regional network dynamics. To bridge this gap, we proposed an interpretable graph neural network (GNN) model to systematically identify ASD-specific IBS modular network between child-caregiver dyads during naturalistic cooperative puzzle-solving and free-talking tasks. We identified distinctive key IBS sub-networks for the cooperative puzzle-solving task and free-talking task, with the frontal eye field (FEF) of caregivers, the dorsal lateral prefrontal cortex (DLPFC) and the motor region of children highlighted. Furthermore, the key IBS sub-networks were found to be able to predict multiple domains of the core ASD symptoms. By integrating hyperscanning with GNN-driven analysis, this work uncovers task-dependent inter-brain neural mechanisms underlying social difficulties in ASD. These findings advance the field by proposing a data-driven framework to identify IBS biomarkers tied to clinical profiles, paving the way for personalized interventions that integrate computational neuroscience with clinical practice.
Perceptual illusions are widely used to study brain processing, and are essential for elucidating underlying function. Successful brain models should then also be able to reproduce these illusions. Some of the most successful models for vision are several variants of Deep Neural Networks (DNNs). These models can classify images with human-level accuracy, and many behavioral and activation measurements correlate well with humans and animals. For several networks it was also shown that they can reproduce some human illusions. However, this was typically done for a limited number of networks. In addition, it remains unclear whether the presence of illusions is linked to either how accurate or brain-like the DNNs are. Here, we consider the scintillating grid illusion, to which two DNNs have been shown to respond as if they are impacted by the illusion. We develop a measure for measuring Illusion Strength based on model activation correlations, which takes into account the difference in Illusion Strength between illusion and control images. We then compare the Illusion Strength to both model performance (top-1 ImageNet), and how well the model explains brain activity (Brain-score). We show that the illusion was measurable in a wide variety of networks (41 out of 51). However, we do not find a strong correlation between Illusion Strength and Brain-Score, nor performance. Some models have strong illusion scores but not Brain-Score, or vice-versa, but no model does both well. Finally, this differs strongly between model types, particularly between convolutional and transformer-based architectures, with transformers having low illusion scores. Overall, our work shows that Illusion Strength measures an important metric to consider for assessing brain models, and that some models could still be missing out on some processing important for brain functioning.
Task context affects stimulus representations in human visual cortex, suggesting that visual representations are flexible. However, this interpretation is at odds with a major computational goal of the human visual system: creating a perceptually stable representation of the external visual environment. How does the visual system balance stability and flexibility? Here, human participants (71 percent females) categorized object images and written words according to different task rules, while brain responses were measured with fMRI. Using an ANOVA-based modeling strategy, we precisely quantified the relative contributions of stimulus, task, and their interaction in explaining representational variance across the cortical hierarchy. Our results show that stimulus effects account for the overwhelming majority of explainable representational variance across the ventral visual system: > 95 percent in V1 and V2, and > 90 percent in higher-level visual cortex. In prefrontal cortex, the relative contributions reverse: task effects dominate stimulus effects, accounting for 80 percent of explainable representational variance. In parietal cortex, contributions of stimulus and task are approximately equal. Our findings suggest that population coding in sensory cortex is optimized for representational stability to allow a consistent interpretation of the external environment. Population coding in parietal and frontal multiple-demand cortex, by contrast, is optimized for representational flexibility to accommodate changing behavioral goals and support flexible cognition and action. Significance statementStimulus representations in human visual cortex are affected by behavioral goals and are therefore thought to be flexible. However, this view is inconsistent with a major computational goal of the human visual system: creating a perceptually stable representation of the external environment. Here, we show that modulatory effects of behavioral goals on stimulus representations in visual cortex are surprisingly small. In contrast, behavioral goals strongly affect representations in parietal and frontal multiple-demand cortex. Our findings suggest that population coding in sensory cortex is optimized for stable perception, while population coding in parietal and frontal multiple-demand cortex is optimized for flexible cognition.
Botulinum neurotoxin type A1 (BoNT/A1) is an effective treatment for chronic migraine, but its direct mechanism of action on human sensory neurons has not been fully elucidated. While rodent studies on dorsal root ganglion (DRG) and trigeminal ganglion (TG) show that BoNT/A1 inhibits neurotransmission, including calcitonin gene-related peptide (CGRP) release, by cleaving SNAP-25, only one previous study has assessed its effect on human DRG neurons. The objective of this study was to understand the mechanism of action of BoNT/A1 in cultured human sensory neurons and assess, using RNA sequencing, the transcriptomic consequences of BoNT/A1 treatment. Using DRGs obtained from organ donors the expression of key targets, including SNAP25, SV2C, & CALCA, was validated by mining existing transcriptomic datasets as well as immunohistochemistry. Cultured dissociated human DRG neurons treated with BoNT/A1 were used to examine cleavage of SNAP25, release of CGRP and transcriptomic changes after BoNT/A1 treatment. SV2C was found to be widely expressed in human DRG neurons in a pattern that completely overlapped with CGRP expression. Consistent with this finding, BoNT/A1 disrupted SNARE protein complexes in human DRG neurons as demonstrated by SNAP-25 cleavage in most somatosensory neurons and a reduction in capsaicin-evoked CGRP release, indicating impaired vesicle fusion. Moreover, Bulk RNA sequencing experiments revealed downregulated expression of a large subset of genes responsible for neurotransmitter and neuropeptide release from neurons suggesting a novel mechanism through which BoNT/A regulates neurotransmission. These results provide new insight into the molecular mechanisms by which BoNT/A may exert its pain-relieving effects in humans.
BackgroundSocial stress--particularly when experienced during adolescence, can have a lasting impact on health and well-being. Among other key biological pathways, inflammatory and innate immune signaling appear to play important roles in linking stress to physical and mental health problems. Individual differences in sensitivity to social threats may leave certain people more vulnerable to stress and its harmful sequelae than others, and a growing body of research has found that stress sensitivity is reflected in neural activity throughout the threat network. However, few studies have investigated whether heightened neural sensitivity to social threats is related to acute changes in immune and neuroendocrine pathways relevant to health, particularly among those for whom the effects of stress may be especially impactful. MethodIn the current research, 52 adolescent females (MAge = 14.90, SD = 1.35) participated in a functional magnetic resonance imaging study to examine brain activity and functional connectivity during a social evaluation task. Nearly half of the sample (n = 22) were identified as having a maternal history of depression. Blood samples were collected prior to the task, as well as 35 and 65 min. after the task began, and were used for transcriptional profiling. ResultsThe primary analyses tested whether threat network activity and connectivity predicted the magnitude of change in gene expression from baseline to the follow-up time points. Results revealed robust shifts in expression of genes in innate immune pathways in response to the task (e.g., hypoxia inducible factor-1, interferon signaling). Although activity across the entire threat network was related to individual differences in gene expression, anterior cingulate cortex-insula and insula-ventromedial prefrontal cortex connectivity were most consistently related to up- and down-regulation of immune pathways, respectively. These patterns were further moderated by differences in maternal depression history. ConclusionResults demonstrate that individual differences in threat network activity may have important implications for biological responses to social threat among adolescent females. In turn, these findings both provide insights into neural signatures of social stress vulnerability and the biological pathways that may contribute to poorer health outcome among those most vulnerable to stress.
Attention plays a crucial role in maintaining precision and effectiveness in goal-directed actions. Although there is evidence that dividing attention across tasks impairs performance in various domains, the impact of attention on sensorimotor adaptation remains inconclusive, with some studies reporting deficits and others showing no effects. Because sensorimotor adaptation arises from the interaction of explicit and implicit processes, this discrepancy may reflect differential effects of attention on each process. Here, we investigate how divided attention influences implicit sensorimotor adaptation using an error-clamp paradigm, coupled with a random dot kinematogram (RDK) motion coherence discrimination task. We also assessed whether the timing of the secondary task affects error processing during sensorimotor adaptation by presenting the RDK either during the outward movement (coinciding with error feedback), or the inward movement (following error feedback). We observed that attentional manipulation influenced implicit sensorimotor adaptation only when the RDK was presented on the outward movement, not the inward movement. Remarkably, implicit sensorimotor adaptation was enhanced when attention was divided, compared to when attention was focused entirely on the adaptation task. This suggests that implicit sensorimotor adaptation is sensitive to attentional demand, particularly during the time window where error feedback is received.
Xylazine is a veterinary sedative and widespread adulterant of illicit opioids, where it is commonly combined with the highly potent synthetic {micro} opioid receptor (MOR) agonist fentanyl. Xylazine adulteration of fentanyl is associated with increased risk of lethal overdose and decreased efficacy of reversal by the MOR antagonist naloxone. Here we use whole body plethysmography in mice to show that xylazine produces profound respiratory depression at subanesthetic doses. Xylazine rapidly and dose-dependently suppressed minute ventilation, tidal volume, and respiratory frequency. These effects were dependent on -2 adrenergic receptors and were fully blocked by coadministration of the -2 adrenergic antagonist atipamezole. Atipamezole, administered alone, produced only modest reversal of fentanyl-induced respiratory depression. Xylazine, when combined with a dose of fentanyl with modest respiratory effects, suppressed breathing with greater efficacy than when administered alone. Strikingly, doses of naloxone sufficient to completely reverse fentanyl-induced respiratory depression were ineffective in reversing the respiratory suppression induced by xylazine-adulterated fentanyl. By contrast, combinations of naloxone with atipamezole rapidly and fully reversed the suppression of breathing induced by xylazine-adulterated fentanyl. Our results show that xylazine suppresses breathing via activation of -2 receptors, an effect enhanced by coadministration with the MOR agonist fentanyl. Respiratory suppression inflicted by the mixture of xylazine and fentanyl resisted reversal by naloxone but was fully reversible by subsequent coadministration of both naloxone and atipamezole. These observations have profound implications for the current opioid epidemic.
In biological systems, survival is predicated on an animal being able to perform computations quickly on a minimal energy budget. What is the energy consumption of non-equilibrium brain computation, i.e., what is the cost of cognition? Previous literature has estimated the metabolic cost using neuroimaging measures of glucose consumption but complementary to these findings, here we directly estimate the computational costs by combining the new field of stochastic thermodynamics with whole-brain modelling. We developed the COCO (COst of COgnition) framework using an analytical expression quantifying the links between energy cost, non-equilibrium and information processing for any given brain state measured with neuroimaging. Importantly, this key relationship also holds at the level of individual brain regions. We used this to quantify the benefits of information processing on the highly anatomically, interconnected hierarchical systems of the brain. Crucially, in empirical neuroimaging data we demonstrate that the human brain uses significantly less energy overall than other mammals (including non-human primates and mice), suggestive of an evolutionary optimisation of the effectiveness of computation. Focusing on the cost of cognition, using large-scale human neuroimaging data of 970 healthy human participants, we show that the resting state uses significantly less energy that seven different cognitive tasks. Furthermore, different kinds of tasks require different amounts of non-equilibrium, information processing and energy consumption. We found that tasks requiring more distributed computation also use more energy. Overall, these results directly quantify the cost of cognition, i.e., the non-equilibrium and energetic demands of information processing, allowing a deeper understanding of how the brain compute in a way that is far more energy efficient than current generations of digital computers and artificial intelligence.
In biological systems, survival is predicated on an animal being able to perform computations quickly on a minimal energy budget. What is the energy consumption of non-equilibrium brain computation, i.e., what is the cost of cognition? Previous literature has estimated the metabolic cost using neuroimaging measures of glucose consumption but complementary to these findings, here we directly estimate the computational costs by combining the new field of stochastic thermodynamics with whole-brain modelling. We developed the COCO (COst of COgnition) framework using an analytical expression quantifying the links between energy cost, non-equilibrium and information processing for any given brain state measured with neuroimaging. Importantly, this key relationship also holds at the level of individual brain regions. We used this to quantify the benefits of information processing on the highly anatomically, interconnected hierarchical systems of the brain. Crucially, in empirical neuroimaging data we demonstrate that the human brain uses significantly less energy overall than other mammals (including non-human primates and mice), suggestive of an evolutionary optimisation of the effectiveness of computation. Focusing on the cost of cognition, using large-scale human neuroimaging data of 970 healthy human participants, we show that the resting state uses significantly less energy that seven different cognitive tasks. Furthermore, different kinds of tasks require different amounts of non-equilibrium, information processing and energy consumption. We found that tasks requiring more distributed computation also use more energy. Overall, these results directly quantify the cost of cognition, i.e., the non-equilibrium and energetic demands of information processing, allowing a deeper understanding of how the brain compute in a way that is far more energy efficient than current generations of digital computers and artificial intelligence.
White matter injury (WMI) is a major cause of morbidity in premature infants, contributing to 5%-10% of cerebral palsy cases and up to 50% of cognitive and behavioral deficits in the United States. Two commonly used preclinical models, intermittent hypoxia (IH) and hypoxia-ischemia (HI) are widely employed to investigate the effects of WMI. The internal capsule (IC) and corpus callosum (CC) are major white matter tracts undergoing active myelination during the neonatal period, making them particularly vulnerable to hypoxic insults. This study aims to compare the effects of IH and HI models on myelination as well as the involvement of inflammatory cells in the IC and CC. We evaluated five oligodendrocyte (OL) subtypes, along with astrocytes, microglia, and activated microglia in IC and CC at postnatal day 12 (P12) and day 20 (P20) using spatial transcriptomics (CosMx, Novogene). For the HI model, C57BL/6 mice at P10 underwent permanent ligation of the left carotid artery followed by 45 minutes of hypoxia (8% O2 / 92% N2). For the IH model, P3 mice were exposed to 5% O2 / 95% N2, twice daily for five consecutive days. Animals were euthanized at P12 and P20, perfused transcardially, and brains were post-fixed in 4% paraformaldehyde, dehydrated in an ethanol series, embedded in paraffin, and coronally sectioned at 7 m. Slides were submitted for CosMx spatial transcriptomic analysis (NanoString Technologies), and data analysis was performed using the Seurat package in RStudio. Our results demonstrate that IH and HI models affect OL populations differently, and these effects vary by brain region. In the IC, the IH model caused earlier and more pronounced changes in OL differentiation-related gene expression compared to HI. In contrast, the CC was more affected by HI. Moreover, in the HI group, mature OL s in both regions showed reduced expression of myelination-associated genes. This was accompanied by greater activation of inflammatory cells and increased intercellular communication between these cells and mature OLs, potentially contributing to the observed hypomyelination. Overall, our study provides critical insights into how each model of neonatal hypoxia differentially impacts white matter development. This knowledge can help refine preclinical strategies and guide therapeutic research tailored to the underlying pathology of each model.
Human infants begin life with limited visual capacities, such as low acuity and poor color sensitivity, due to gradual sensory maturation. In contrast, machine learning models are trained on high-fidelity inputs from the outset, often leading to shortcut learning and overfitting to spurious correlations. Here, we show that early sensory immaturity plays a critical role in shaping bias-resistant, abstract visual representations that conventional models struggle to develop. Using neural network simulations and human psychophysics experiments, we demonstrate that gradual sensory development supports the emergence of robust and generalizable internal representations, reduces reliance on superficial cues, and promotes disentangled representations that enable compositional reconstruction and visual imagination. Comparative analyses of human and model behavior reveal shared patterns of bias resistance and adaptive generalization, including resilience to misleading information. Our findings suggest that gradual sensory maturation is not merely a developmental constraint, but rather a key mechanism that enables abstract representation learning. One sentence summaryEarly-stage sensory immaturity guides the development of abstract, bias-resistant representations that enable generalization and compositionality, providing a functional account of gradual sensory maturation. HighlightsO_LIThe essential yet overlooked role of gradual sensory maturation was explored C_LIO_LIEarly sensory immaturity promotes abstract representations resistant to shortcut learning C_LIO_LIEmergent representations support compositional reconstruction of novel visual attributes C_LIO_LIHuman and model behaviors show similar bias resistance and adaptive generalization C_LI
Singing to infants is a universal human practice that has beneficial effects on infants cognitive and affective development. Children born preterm have impaired brain development, and their perception of maternal speech is known to be affected by the atypical hospital auditory environment. Understanding how preterm infants perceive maternal singing is of critical importance, yet it remains largely unexplored. Using high-density EEG, we examined neural responses to the same melody presented through maternal singing, stranger singing, and instrument, and compared the responses in 12 preterm infants. Moreover, to examine their processing of spatialisation, auditory stimuli were presented under monaural and binaural conditions. Preterm newborns are able to discriminate the same melody when sung by their mother, a stranger, or played by an instrument. When presented monaurally, the mothers singing voice enhances widespread brain synchrony across the entire scalp. In contrast, this synchrony diminishes with binaural spatialization. These findings suggest that maternal singing constitutes a highly salient auditory stimulus for preterm newborns, eliciting a distinct neural signature. Given that brain synchrony is a critical component of healthy brain function and development, harnessing maternal singing may offer a promising, natural intervention to support neurodevelopment--particularly in vulnerable populations such as preterm infants.
Singing to infants is a universal human practice that has beneficial effects on infants cognitive and affective development. Children born preterm have impaired brain development, and their perception of maternal speech is known to be affected by the atypical hospital auditory environment. Understanding how preterm infants perceive maternal singing is of critical importance, yet it remains largely unexplored. Using high-density EEG, we examined neural responses to the same melody presented through maternal singing, stranger singing, and instrument, and compared the responses in 12 preterm infants. Moreover, to examine their processing of spatialisation, auditory stimuli were presented under monaural and binaural conditions. Preterm newborns are able to discriminate the same melody when sung by their mother, a stranger, or played by an instrument. When presented monaurally, the mothers singing voice enhances widespread brain synchrony across the entire scalp. In contrast, this synchrony diminishes with binaural spatialization. These findings suggest that maternal singing constitutes a highly salient auditory stimulus for preterm newborns, eliciting a distinct neural signature. Given that brain synchrony is a critical component of healthy brain function and development, harnessing maternal singing may offer a promising, natural intervention to support neurodevelopment--particularly in vulnerable populations such as preterm infants.
The hippocampus has long been regarded as a neural map of physical space, with its neurons categorized as spatially or non-spatially tuned according to their response selectivity. However, growing evidence suggests that this dichotomy oversimplifies the complex roles hippocampal neurons play in integrating spatial and non-spatial information. Through computational modeling and in-vivo electrophysiology in macaques, we show that neurons classified as spatially tuned primarily encode linear combinations of immediate behaviorally relevant factors, while those labeled as non-spatially tuned rely on nonlinear mechanisms to integrate temporally distant experiences. Furthermore, our findings reveal a temporal gradient in the primate CA3 region, where spatial selectivity diminishes as neurons encode increasingly distant past events. Finally, using artificial neural networks, we demonstrate that nonlinear recurrent connections are crucial for capturing the response dynamics of non-spatially tuned neurons, particularly those encoding memory-related information. These findings challenge the traditional dichotomy of spatial versus non-spatial representations and instead suggest a continuum of linear and nonlinear computations that underpin hippocampal function. This framework provides new insights into how the hippocampus bridges perception and memory, informing on its role in episodic memory, spatial navigation, and associative learning.
Proteins are the functional effectors of virtually all biological processes, and accurately measuring their abundance and dynamics is essential for understanding development and disease. Although mRNA levels have historically been used as proxies for protein expression, growing evidence, especially from studies of the human cerebral cortex, has revealed widespread discordance between transcript and protein abundance. To directly address this limitation, we developed a rigorously optimized workflow that combines single-cell mass spectrometry with precise sample preparation to resolve, for the first time, quantitative proteomes of individual cells from the developing human brain. Our platform achieved deep proteomic coverage ([~]800 proteins per cell) even in immature prenatal human neurons (5-10 m diameter, [~]100 pg of protein per cell), capturing major brain cell types and enabling proteome-wide characterization at single-cell resolution. This approach revealed extensive transcriptome-proteome discordance across cell types, with particularly strong discrepancies in genes associated with neurodevelopmental disorders, a finding validated through orthogonal experiments. Proteins exhibited markedly higher cell-type specificity than their mRNA counterparts, underscoring the importance of proteomic-level analysis for resolving cellular identity and function. By reconstructing developmental trajectories from radial glia to excitatory neurons at the proteomic level, we identified dynamic stage-specific protein co-expression modules and pinpointed the intermediate progenitor-to-neuron transition as a molecularly vulnerable phase linked to autism. Altogether, by enabling single cell proteomics, this study establishes a foundational resource and technological advance for developmental neuroscience. It demonstrates that single-cell proteomics can capture critical developmental events and disease mechanisms that are undetectable at the transcript level. As this technology continues to improve in sensitivity and scalability, single-cell proteomics will become an indispensable tool for uncovering the molecular logic of brain development and for illuminating pathophysiological processes underlying neurodevelopmental disorders.
Humans spend time contemplating the minds of others. But this ability is not limited to external agents - we also turn the lens for reading minds inward, reflecting on our own thoughts, emotions, and sense of self. Some processes involved in reasoning about minds may rely on shared mechanisms, while others may be specific to the agent under consideration. We developed a paradigm where participants performed either a mental state inference task or a control task targeting either another person presented onscreen or their own mind. Using fMRI and multi-voxel pattern analysis, we replicate a well-established self-other axis along the medial wall of prefrontal cortex: ventral regions selectively decoded mental state inference patterns for self, but not other, whereas more dorsal regions decoded mental state inference for both self and other, compared to control conditions. Posterior cingulate cortex, on the other hand, differentiated the target of mental state inference. Using a cross-classification analysis, we also found patterns in the dorsomedial prefrontal cortex, ventromedial prefrontal cortex, and right temporoparietal junction were sensitive to mental state reasoning in general, regardless of the target agent. These findings highlight one process reflecting reasoning specific to the agent and another reflecting the reasoning process itself.
When a visual stimulus is repeated, the cortex has the opportunity to adjust its processing. Indeed, repeated stimuli induce reduced neuronal spike rates and increased neuronal gamma-band synchronization. Previous studies found the repetition-related gamma increase to occur both in human and non-human primates, for artificial and natural stimuli, to persist for minutes and to not transfer between strongly differing stimuli. Here, we further investigated the repetition-related effects using laminar recordings of multi-unit activity and local field potentials from awake macaque areas V1 and V2. We find that the effects on spike rate and gamma occur in all laminar compartments of V1 and V2. We quantify the degree of stimulus specificity with oriented gratings and find that the repetition-related gamma increase does not transfer to gratings differing by merely 10 {degrees}, the smallest difference tested. Furthermore, we find that the repetition-related effects are robust to stimulus set size, occurring both when one stimulus was repeated and when eighteen different interleaved stimuli were repeated. Finally, we show that alpha-beta activity increases and remains elevated when a stimulus is repeated, and decreases sharply when an unexpected stimulus is presented. These results suggest that repetition-related plasticity leads to changes in spike rates and rhythmic neuronal synchronization in different frequency bands that adjust the cortical processing of repeated stimuli.
Reactive astrocytes shape central nervous system (CNS) inflammation and participate in myelin damage and repair mechanisms in multiple sclerosis (MS). Through the activation of cannabinoid CB1 receptors (CB1R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promote remyelination in preclinical MS models. However, despite accumulating evidence that supports a crucial role for these receptor populations in brain physiology and pathology, the implications of astrocyte CB1R signaling in MS initiation and progression remain uncertain. Using complementary in vivo disease models, here we investigated the effects of targeted genetic deletion of astrocytes CB1R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB1R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB1R inactivation displayed unaltered oligodendrocyte populations both in EAE lesions and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that astrocyte CB1R modulate myelin repair processes. Conversely, inactivation of CB1R in astroglial cells restricted humoral and leukocyte parenchymal infiltration and reduced the expression of vascular effectors in EAE lesions. Finally, loss of blood-brain barrier (BBB) function induced by cortical microinjection of VEGF-A was less severe in GFAP-CB1R-KO mice. These results show that astrocyte CB1R signaling constitutes a significant pro-inflammatory mechanism in MS and bring to light a deleterious role for endocannabinoid-mediated modulation of astroglial cells with potential implications in the etiopathology and therapy of neuroinflammatory disorders.
Learning to detect and respond to threats is fundamental for survival and is often modeled through threat conditioning (TC) paradigms. While these paradigms reliably produce implicit memories that elicit physiological and behavioral responses to conditioned stimuli (CS), less is explored about how TC influences cognitive and emotional biases, particularly those implicated in anxiety disorders, such as threat overestimation and negative stimulus representation. In this study, we investigated the dynamic interaction between the reactivation of the implicit threat memory and these cognitive biases using a validated TC paradigm in humans. In Experiment 1, participants underwent TC on Day 1, followed by a memory reactivation session (incomplete reminder: one unreinforced CS+) and a highly demanding working memory (HWM) task, used as an amnesic manipulation, or a control condition on Day 2. On Day 3, memory retention was tested using a simplified, single-trial protocol (one CS+, one CS-, and one neutral CS), followed by tasks assessing threat valuation and representation. Results indicated that the HWM task administered post-reactivation significantly reduced skin conductance responses (SCRs) and attenuated cognitive biases, without altering expectancy of the unconditioned stimulus (US). In Experiment 2, we evaluated the effect of varying reactivation frequency (none, one, or two reminders) on implicit memory and cognitive biases. While repeated reactivations generalized the conditioned response to other stimuli, cognitive and emotional biases remained stable, suggesting a dissociation between memory generalization and evaluative processing. These findings demonstrate that implicit threat memories can be selectively modified through post-reactivation interventions, affecting both physiological and cognitive-emotional domains. Importantly, the distinct effects of memory reactivation and reconsolidation on physiological versus cognitive outcomes support the existence of temporally and functionally dissociable mechanisms. This research highlights the need to consider cognitive biases alongside physiological responses when evaluating memory-based interventions and offers novel insight into mechanisms underlying anxiety maintenance and treatment.
Chlamydia pneumoniae (Cp), an obligate intracellular bacterium, has been implicated in Alzheimers disease (AD), yet its role in retinal pathology remains unexplored. We analyzed postmortem tissues from 95 human donors and found 2.9-4.1-fold increases in Cp inclusions in AD retinas and brains, with no significant elevation in mild cognitive impairment (MCI). Proteomics revealed dysregulation of retinal and brain bacterial infection-related proteins and NLRP3 inflammasome pathways. NLRP3 expression was markedly elevated in MCI and AD retinas, and its activation was evident by increased N-terminal gasdermin D (NGSDMD) and mature interleukin-1{beta}. Retinal Cp strongly correlated with A{beta}42 and NLRP3 inflammasome components, which tightly linked to cleaved caspase-3-apoptotic and NGSDMD-pyroptotic cell death. Although retinal microgliosis was elevated in AD, Cp-associated microglia were reduced by 62%, suggesting impaired Cp phagocytosis. Higher retinal Cp burden correlated with APOE{varepsilon}4, Braak stage, and cognitive deficit. Machine learning identified retinal Cp or NLRP3 combined with A{beta}42 as strong predictors of AD diagnosis, staging, and cognitive impairment. Our findings suggest that Cp infection contributes to AD dementia but not initiating pathology, whereas early NLRP3 activation may promote disease development, warranting studies on Cps role in AD pathogenesis and early antibiotic or inflammasome-targeted therapies.
Neural fluctuations exhibit rich spectral profiles that reflects both local dynamics and structural (or anatomical) embedding. Yet, standard models of resting-state effective connectivity neglect structural embedding and assume uniformity in the timescales of regions endogenous fluctuations. We introduce a chromatic dynamic causal model (DCM) in which structural valency (or degree) modulates the spectral color of endogenous fluctuations. Specifically, we assume a linear mapping between regional structural valency and the spectral exponent of scale-free auto-spectra. Simulations show this mapping can emerge as a generic consequence of structural embedding under minimal coupling in a non-equilibrium regime. We show chromatic DCM reliably recovers ground-truth parameters across network sizes and noise conditions, outperforming standard spectral DCM. Applied to empirical data, chromatic DCM reveals that valency-exponent mappings vary across a cortical hierarchy, and that its parameters are conserved across a homologous network in humans, macaques, marmosets, and mice. These findings advance a generative account of structure-function coupling and expand the repertoire of biophysical mechanisms available for inference in effective connectivity modeling.
Predictive processing theories propose that the brain continuously generates expectations about incoming sensory information. Discrepancies between these predictions and actual inputs, sensory prediction errors, guide perceptual inference. A fundamental yet largely unresolved question is which stimulus features the brain predicts, and therefore, what kind of surprise drives neural responses. Here, we investigated this question using EEG and computational modelling based on deep neural networks (DNNs). Participants viewed object images whose identity was probabilistically predicted by preceding cues. We then quantified trial-by-trial surprise at both low-level (early DNN layers) and high-level (late DNN layers) visual feature representations. Results showed that stimulus-evoked responses around 200ms post-stimulus onset over parieto-occipital electrodes were increased by high-level, but not by low-level visual surprise. These findings demonstrate that high-level visual predictions are rapidly integrated into perceptual inference, suggesting that the brains predictive machinery is finely tuned to utilize expectations abstracted away from low-level sensory details to facilitate perception.
Neuroimaging techniques produce vast amounts of data, capturing brain activity in a high-dimensional space. However, brain dynamics are consistently shown to reside in a rather lower-dimensional space, which contains relevant information for cognition and behavior. This dimensionality reduction reflects distinct types of interactions between brain regions, such as redundancy -shared neural information distributed across regions- and synergy, where information emerges only when regions are considered collectively. Significant efforts have been devoted to developing linear and non-linear algorithms to reveal these low-dimensional dynamics, often termed "brain modes." Here, we apply various dimensionality reduction techniques to resting-state functional magnetic resonance imaging (fMRI) data from 100 healthy participants to examine how synergistic interactions in brain dynamics are preserved by these techniques. We first demonstrate that biologically informed brain parcellation modulates and preserves synergy-dominated interactions. Next, we show that synergy among low-dimensional modes enhances functional-connectivity reconstruction: nonlinear autoencoders not only achieve the lowest reconstruction error but also maximally preserve synergy, outperforming principal component analysis, diffusion maps, and Laplacian eigenmodes. Finally, we confirm previous results suggesting that global signal regression helps to identify synergistic interactions between regions. Our findings establish synergy preservation as a complementary criterion to reconstruction accuracy, highlighting autoencoders as a nonlinear tool for uncovering synergistic low-dimensional brain modes from high-dimensional neuroimaging data.
ObjectiveCranial nerve stimulation (CNS) uses electric current to modulate higher-order brain activity and organ function via nerves, including the vagus and trigeminal, with applications in migraine, epilepsy, and pediatric ADHD. The trigeminal nerve is an emerging target for non-invasive neuromodulation due to the superficial trajectory of its branches, the supraorbital (SON), infraorbital (ION), and mental nerves (MN), and the predominantly sensory composition of the SON and ION. However, the parameters and outcomes of trigeminal nerve stimulation (TNS) remain varied. ApproachThis study characterizes the anatomical course, tissue composition, and activation profiles of the SON, ION, and MN using five human donors. CT imaging was utilized to localize each nerves exit foramen and distance to midline. Microdissections quantified nerve circumference and depth relative to the skin surface. Histological analysis described the number of fascicles and fascicular tissue area. Nerve depths were incorporated into computational models to illustrate the activation function across tissue layers, comparing expected nociceptor and nerve trunk activation functions as a measure of neural engagement. Main ResultsThe SON was found to be significantly more superficial than the ION and MN and had a higher nerve-to-connective tissue ratio relative to the MN. Computational modeling demonstrated that the activation function at the depths of nociceptors was orders of magnitude greater than within the main nerve trunks, suggesting preferential recruitment of cutaneous nociceptors, dependent on nociceptor density. SignificanceThe SON presents the most accessible and anatomically favorable target for transcutaneous trigeminal nerve stimulation among the branches examined due to its superficial location. However, preferential activation of low-threshold nociceptors compared to nerve trunks may lead to treatment-limiting off-target side effects, favoring strategies that target fibers of interest within the skin. These findings offer an anatomically informed framework to guide further computational modeling and electrode design for targeted trigeminal neuromodulation.
IntroductionPatients with mild cognitive impairment (MCI) have shown disruptions in both brain structure and function, often studied separately. However, understanding the relationship between brain structure and function can provide valuable insights into this early stage of cognitive decline for better treatment strategies to avoid its progression. Network Control Theory (NCT) is a multi-modal approach that captures the alterations in the brains energetic landscape by combining the brains functional activity and the structural connectome. Our study aims to explore the differences in the brains energetic landscape between people with MCI and healthy controls (HC). MethodsFour hundred ninety-nine HC and 55 MCI patients were included. First, k-means was applied to functional MRI (fMRI) time series to identify commonly recurring brain activity states. Second, NCT was used to calculate the minimum energy required to transition between these brain activity states, otherwise known as transition energy (TE). The entropy of the fMRI time series as well as PET-derived amyloid beta (A{beta}) and tau deposition were measured for each brain region. The TE and entropy were compared between MCI and HC at the network, regional, and global levels using linear models where age, sex, and intracranial volume were added as covariates. The association of TE and entropy with A{beta} and tau deposition was investigated in MCI patients using linear models where age, sex, and intracranial volume were controlled. ResultsCommonly recurring brain activity states included those with high and low amplitude activity in visual (+/-), default mode (+/-), and dorsal attention (+/-) networks. Compared to HC, MCI patients required lower transition energy in the limbic network (adjusted p = 0.028). Decreased global entropy was observed in MCI patients compared to HC (p = 7.29e-7). There was a positive association between TE and entropy in the frontoparietal network (p = 7.03e-3). Increased global A{beta} was associated with higher global entropy in MCI patients ({rho} = 0.632, p = 0.041). ConclusionLower TE in the limbic network in MCI patients may indicate either neurodegeneration-related neural loss and atrophy or a potential functional upregulation mechanism in this early stage of cognitive impairment. Future studies that include people with AD are needed to better characterize the changes in the energetic landscape in the later stages of cognitive impairment.
Background and HypothesisTraditional fMRI analyses often ignore regions that fail to reach statistical significance, assuming they are biologically unimportant. We tested the accuracy of this assumption using causal discovery based-analysis that go beyond associations/correlations to test the causality of one regions influence over the other. We hypothesized that the network of statistically significant (active network, AN) and non-significant regions (silent network, SN) causally interact and their features will causally influence psychopathology severity and working memory performance. Study DesignWe examined AN and SN during N-BACK task on 25 FHR and 37 controls. Clusters with significantly different activations were juxtaposed to 360 Glasser atlas parcellations. The PC algorithm for causal discovery was implemented. Connectivity of regions with the highest alpha-centrality (HAC) were examined. ResultsSeventy-seven Glasser regions were in the AN and the rest were silent nodes. Two regions showed HAC for FHR and HC. Among controls, one HAC region was silent (auditory association cortex) and the other one was active (insula). Among FHR, both were silent nodes (early auditory cortex). These HAC regions in both groups had bidirectional directed edges between each other forming a reciprocal circuit whose edge-weights causally "increased" magical ideation severity. ConclusionCausal connectivity between SN and AN suggests that the statistically non-significant and significant regions influence each other. Our findings question the merit of ignoring statistically non-significant regions and exclusively including statistically significant regions in the pathophysiological models. Our study suggests that causality analysis should receive greater attention.
Mild brain trauma from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance after a CHI models. Analyzing single-cell RNA sequencing data from cortical cells from a model of CHI, we found that Pycard (Asc), the gene encoding for a common inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), is expressed particularly in microglial clusters. Sustained upregulation of inflammasome-related proteins persisted up to 21 days in a model for mild CHI, with this pattern significantly reduced in Asc-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2 expression is elevated in the hippocampus of PS19 tauopathy mice and in postmortem brains of dementia patients, particularly in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2 levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2 depletion also enhanced synaptic gene expression, synaptic density, and LTP, while attenuating microglial activation, synaptic engulfment, and pro-inflammatory cytokine levels. Importantly, CK2 depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways. Our findings highlight CK2 as a key node at the intersection of tau pathology, synaptic dysfunction, and neuroimmune signaling. Targeting CK2 may offer a novel and selective therapeutic strategy for modifying disease progression in tauopathies.
We tested whether the same principles of actuation and control that support steady-state walking are sufficient for robust, rapid gait adaptation over a wide range of step lengths and frequencies. We begin by demonstrating that periodic limit cycle gaits exist at combinations of step frequency and step length that span the full range of gaits achievable by humans. We demonstrate that open-loop local stability is not enough to rapidly transition to target gaits because some gaits in the gait space are unstable and the stable gaits have slow convergence rates. Next, we show that actuating with only one push-off and one hip spring of fixed stiffness cannot fully control the walker in the entire gait space. We solve this by adding a second hip spring with an independent stiffness with respect to the first one to actuate the second half of the swing phase. This allowed us to design local feedback controllers that provided rapid convergence to target gaits by making once-per-step adjustments to push-off and hip spring stiffnesses. To adapt to a range of target gaits that vary over time, we interpolated between local controllers. This policy performs well, accurately tracking rapidly varying combinations of target step length and step frequency with human-like response times across a wide range of human achievable gaits. To test whether this policy is biologically plausible, we use it with supervised learning to train an artificial neural network to perform nearly identical control. Author SummaryPeople can rapidly adapt their walking gaits. In this study, we used a modeling approach to study whether control of walking adaptation is identical to control of steady state walking. We first demonstrate that the model can produce human-like gaits over a wide range of step lengths and step frequencies. However, we found that unlike steady state walking, the model does not transition between gaits quickly or reliably. To address this, we introduced an additional actuation to control the swing leg and used feedback control that applies once-per-step adjustments to the actuations. This enabled the model to rapidly converge to target gaits, even when the targets changed from one step to the next. To test whether this policy is biologically plausible, we use it with supervised learning to train an artificial neural network to perform nearly identical control. This work provides insights into the mechanisms of walking adaptation and has potential implications for the design of adaptive control in robotic and wearable assistive systems.
Inferring the underlying computational processes from behavioral measurements is a fundamental approach in cognitive science and neuroscience. Although Bayesian decision theory has become a major normative framework for modeling cognition, it is unclear to what extent its modeling components (i.e., prior belief, likelihood function, and the loss function) can be recovered from behavioral data. Here, we systematically investigated the problem of inferring such Bayesian models from behavioral tasks. In contrast to a pessimistic picture often painted in previous research, our analytical results guarantee in-principle identifiability under broadly applicable conditions, without any a priori knowledge of prior or encoding. Simulations and applications on the basis of behavioral datasets validate that the predictions of this theory apply in realistic settings. Importantly, our results demonstrate that reliable recovery of the model often requires having data from multiple noise levels. This is a crucial insight that will guide future experimental design.
Along the gut-brain axis, visceral pain demonstrably evokes emotional learning and memory processes shaping behavior in clinically relevant ways. Avoidance motivated by learned fear may constitute a major obstacle to treatment success in extinction-based interventions. However, the effects of avoidance on visceral pain-related fear extinction remain poorly understood. By implementing an ecologically valid experimental protocol, we investigated how costly avoidance affects the modulation and extinction of visceral pain-related fear. Thirty-three healthy volunteers underwent conditioning with visual cues (conditioned stimuli; CS+,CS-) consistently followed by visceral pain or remaining unpaired. During avoidance, participants decided to avoid or receive pain upon confronting CS+. Avoidance decisions resulted in pain omission in some trials, while in others, participants experienced unpredictable pain. During extinction, CS were presented unpaired. CS valence, fear, and trial-by-trial decisions were analyzed. Avoidance decisions depended on prior experiences, with the highest probability of avoidance following successful pain omission. Negative CS+ valence and fear remained elevated across avoidance and extinction. Learned fear and more avoidance decisions explained 57% variance in sustained CS+ fear. Our findings indicate that avoidance, which provides short-term absence of pain even when followed by unpredictable pain, motivates its maintenance. However, it perpetuates pain-related fear and may impede extinction, with implications for persisting symptoms and therapeutic outcomes in chronic visceral pain.
Vasomotion, vascular oscillations at [~]0.1 Hz, may serve as a biomarker and therapeutic target for neurodegenerative diseases, but its origins, structure across brain vasculature, and correlation with neural activity remain unclear. This study examined the spatiotemporal characteristics of cerebral vasomotion and its relationship to neural activity in anaesthetised Hooded Lister rats using simultaneous recordings of neuronal activity and haemodynamics in motor and whisker barrel cortices. In a subset of rats, tissue oxygen was also measured. Blood pressure was pharmacologically modulated to alter vascular oscillations. We found that vasomotion was driven by the arterial tree. Two prominent activity patterns emerged: global vasomotion across the entire hemisphere and phasic vasomotion seen as a travelling wave running through the surface arteries. Moreover, vasomotion was associated with low tissue oxygen and was largely independent of spontaneous neural activity and therefore not a product of neurovascular coupling.
Understanding the principle of information flow across distributed brain networks is of paramount importance in neuroscience. Here, we introduce a novel neuroimaging framework, leveraging integrated effective connectivity (iEC) and unconstrained signal flow mapping for data-driven discovery of the human cerebral functional hierarchy. Simulation and empirical validation demonstrated the high fidelity of iEC in recovering connectome directionality and its potential relationship with histologically defined feedforward and feedback pathways. Notably, the iEC-derived hierarchy revealed a monotonically increasing level along the axis where the sensorimotor, association, and paralimbic areas are sequentially ordered - a pattern supported by the Structural Model of laminar connectivity. This hierarchy was further demonstrated to flexibly reorganize across brain states: flattening during an externally oriented condition, evidenced by a reduced slope in the hierarchy, and steepening during an internally focused condition, reflecting heightened engagement of interoceptive regions. Our study highlights the unique role of macroscale directed functional connectivity in uncovering a biologically interpretable state-dependent signal flow hierarchy.
Spinal cord injury (SCI) causes irreversible loss of motor, sensory, and autonomic functions and currently has no cure. Beyond local damage, SCI induces systemic inflammation, including cerebral inflammation that impairs neurogenesis. While cell therapies show promising effects in animal models, such as scar reduction and neuroprotection, their benefits in humans remain limited. One key difference lies in the transplantation strategy: animals receive healthy donor cells, whereas humans require autologous transplants. This led us to investigate how the lesion context affects the neuro-reparative potential of olfactory ensheathing cells (OECs) harvested from olfactory bulbs. To this end, we cultured OECs from healthy animals and from animals that had undergone SCI one week earlier. We then transplanted both types of OECs into recipient animals after SCI for therapeutic purposes. Using functional sensory-motor studies, histological and gene expression analyses, we were able to demonstrate for the first time that the lesion negatively affects the therapeutic properties of cells used to treat SCI. Indeed, transplantation of cells from previously injured animals does not modulate the fibrotic and glial scar, or the demyelinated areas at the lesion site, and therefore fails to improve functional recovery; unlike cells derived from healthy donors. Moreover, our in vitro studies show that cells derived from SCI animals secrete pro-inflammatory molecules that promote the polarization of microglia toward a pro-inflammatory phenotype. Altogether, these innovative findings provide new insights into the potential of cell transplantation in the context of autologous therapy after SCI. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/660789v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2e9b52org.highwire.dtl.DTLVardef@1d75bfaorg.highwire.dtl.DTLVardef@1d7af58org.highwire.dtl.DTLVardef@138f1b8_HPS_FORMAT_FIGEXP M_FIG C_FIG
Cognitive flexibility, the ability to switch behavior in response to changing rules in an uncertain environment, is crucial for adaptive decision making. Prior research has hypothesized a key role of prediction error and theta oscillations in medial frontal cortex in this process. However, the causal link between such processes remains to be established. To address this, we combined neural stimulation, EEG, behavioral measurement, and computational modelling. Specifically, we applied high-definition transcranial direct current stimulation (HD-tDCS) to modulate theta oscillations as measured via EEG followed by a probabilistic reversal learning task. We find that anodal stimulation reduces theta power and rule prediction error, and it increases the number of trials needed to reliably switch between rules. These findings support the role of rule prediction error signaling as a key mechanism linking neural oscillations to behavioral adaptation and highlight the importance of theta power and rule prediction error for cognitive flexibility. Significance statementCognitive flexibility--the ability to adjust behavior when rules change--is critical for adaptive behavior in uncertain environments. Although prediction error signaling and theta oscillations in medial frontal cortex have been proposed as key mechanisms, their causal relationship remains unclear. Here, we combine high-definition transcranial direct current stimulation (HD-tDCS), EEG, behavioral assessment, and computational modeling to establish a mechanistic link. We show that anodal stimulation reduces frontal theta power and rule-level prediction errors, leading to less efficient rule switching. These findings provide causal evidence that supports behavioral flexibility, advancing our understanding of the neural computations underlying adaptive decision making.
Echo state networks are well-known for their ability to learn temporal patterns through simple feedback to a large recurrent network with random connections. However, the learning process itself remains poorly understood. We develop a quantitative theory that explains learning in a regime where the network dynamics is stable and the feedback is weak. We show that the dynamics is governed by a finite number of master modes whose nonlinear interactions can be described by a normal form. This formulation provides a simple picture of learning as a Fourier decomposition of the target pattern with amplitudes determined by nonlinear interactions that, remarkably, become independent of the network randomness in the limit of large network size. We further show that the description extends to moderate feedback and recurrent networks with multiple unstable modes.
Pathogenic DNMT3A mutations cause Tatton-Brown-Rahman Syndrome (TBRS), a disorder characterized by intellectual disability and overgrowth of multiple somatic tissues including the brain. However, the functions of DNMT3A during human cortical development remain poorly understood. Here, we utilized newly developed human pluripotent stem cell models of TBRS-associated DNMT3A mutation to define DNMT3A requirements and consequences of mutation during human cortical neuron development. Profiling changes to epigenetic gene regulation across both GABAergic and glutamatergic neuron development, we identified GABAergic cortical interneurons as particularly sensitive to TBRS-associated mutation. During GABAergic neuron development, TBRS-associated DNMT3A mutations resulted in reduced DNA methylation and were associated with concomitant de-repression of gene expression, causing precocious neuronal differentiation. By contrast, the consequences of DNMT3A mutation on glutamatergic neuron development were less pronounced, due in part to compensatory repressive histone methylation, and resulted in increased expression of early neurodevelopmental genes during glutamatergic neuron differentiation. Assessing the consequences of these molecular phenotypes by patch-clamp electrophysiology, we found that DNMT3A deficient GABAergic neurons were hyperactive, while glutamatergic neuron function was largely unaffected by these DNMT3A loss of function mutations. Finally, we used both low density and high density multi electrode array techniques in conjunction with glutamatergic-GABAergic neuron co-cultures to assess how TBRS-associated GABAergic neuron hyperactivity affected the emergence and development of neuronal networks. We found that TBRS GABAergic neuron hyperactivity was sufficient to drive abnormal neuronal network development, increasing the neuronal activity consolidated into neuronal bursting and networks. Ultimately, this work elucidated new roles for DNMT3A-mediated repression in human cortical development, identifying critical requirements in regulating neuronal and synaptic gene expression during GABAergic differentiation, with these TBRS-associated molecular changes driving alterations of neuronal network function likely to contribute to TBRS etiology.
Dementia is a defining feature of Lewy body disease: its timing and onset distinguish different clinical diagnoses, and its effect on quality of life is profound. However, it remains unclear whether processes leading to cognitive and motor symptoms in Lewy body disease differ. To clarify this, we used in-vivo neuroimaging to assess spatial gradients of inter-regional differences in structural and functional connectivity in 108 people across the Lewy body disease spectrum (46 Parkinsons with normal cognition (PD-NC), 62 Lewy body dementia (LBD)) and 23 controls. We found divergent structural gradient differences with cognitive impairment: PD-NC showed increased inter-regional differentiation, whilst LBD showed overall gradient distribution similar to controls despite widespread organisational differences at the regional level. We then assessed cellular and molecular underpinnings of these organisational changes. We reveal similarities and also important differences in the drivers of cortical organisation between LBD and PD-NC, particularly in layer 4 excitatory neurons.
Decision-making stems from a sequence of information processing steps between the choice onset and the response. Despite extensive research, uncertainty remains about the actual cognitive sequence involved in the reaction time. Using the hidden multivariate pattern method we modeled the single-trial electroencephalogram of participants performing a decision task as a sequence of an unknown number of events estimated as trial-recurrent, time-varying, stable topographies. We provide evidence for three events occurring during participants decision making, respectively representing encoding, attention orientation, and decision. This interpretation is supported by the observation that a targeted manipulation of stimulus intensity yields Pierons law in the interval between encoding and attention orientation, and Fechners law in the interval between attention orientation and decision. This final, decision-related, event is represented in the brain as a positive burst in parietal areas whose timing, amplitude and build-up predict the participants decision accuracy.
Premature birth has known impacts on brain development, leading to sustained differences in cognitive function throughout the lifespan. Despite known deficits in executive functioning (EF) within individuals born premature, the extent to which neural engagement during executive functioning tasks differs between those born preterm and full-term is not fully understood. Additionally, it is unknown whether regions of differential engagement are the same in children and adults. This meta-analysis synthesizes fMRI results of activation differences between preterm and full-term subjects during executive functioning tasks in adult and child groups separately. Our results indicate that differences in neural engagement during EF tasks differ between pre-term (PT) and full term (FT) individuals in both age groups. Moreover, the regions affected contribute to well-known brain networks, including the fronto-striatal circuitry, the default mode network (DMN), and the salience network, all of which subserve broad EF capabilities. We found no differences between child and adult maps in a direct contrast, suggesting that effects of prematurity on executive functioning may persist from childhood into adulthood, although these findings should be interpreted in context of methodological limitations and potential confounding factors. This meta-analysis provides greater insight into the neural mechanisms behind EF disruption following premature birth. HighlightsO_LIDifferences in neural activation during executive function tasks exist in both children and adults with a history of premature birth. C_LIO_LIPT children show hyperactivity in fronto-striatal regions while PT adults show differential engagement of default mode network regions. C_LI
Prion diseases are fatal neurodegenerative diseases of humans and other mammals with no current treatment options. Here, we describe the characterization of a novel anti-prion compound, elacridar (GW120918), which has sub-micromolar activity in assays of prion infection, propagation and toxicity. Elacridar acts at an early step in the prion infection process, enhancing degradation of newly formed PrPSc. The lysosome is the likely site of elacridars anti-prion effects, based on transcriptomic analysis and the use of functional lysosomal probes. Elacridar alters gene expression networks controlling lysosomal sterol and lipid metabolism but, unlike other lysosomotropic drugs, it prominently upregulates genes that control lysosomal pH. Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to -synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for the treatment of protein misfolding neurodegenerative diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/661349v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@6280dorg.highwire.dtl.DTLVardef@2f8723org.highwire.dtl.DTLVardef@512492org.highwire.dtl.DTLVardef@1381569_HPS_FORMAT_FIGEXP M_FIG C_FIG
While the neuroprotective effects of vitamin D (Vit-D) have been demonstrated pre-clinically in a wide range of neurologic conditions, its potential use in the treatment of spontaneous intracerebral hemorrhage (ICH) has not been fully explored. We previously reported that Vit-D could expedite hematoma clearance in experimental ICH by inducing the conversion of M1 to M2 macrophage to enhance erythrophagocytosis1,2. Here, we provide new evidence on the dose-dependent effects of Vit-D on neuronal survival and functional recovery, lending further support for the clinical testing of Vit-D in the management of ICH.
Pain perception is modulated by expectations and learning processes, but the influence of uncertainty in this relationship is not well established. We aimed to examine the relationship between uncertainty, pain learning and perception using hierarchical Bayesian modeling. In an aversive learning task, fifty participants learned contingencies between auditory cues and painful stimulations under changing levels of uncertainty to create periods of stability and volatility. Model-free analysis of our data suggested unexpected trials resulted in reduced accuracy and greater response times. In unexpected trials, high pain perception was reduced, while low pain perception was increased, in line with documented effects of expectations on pain perception. Computational model fitting revealed participants learning was best described by a two-level hierarchical gaussian filter model, suggesting participants adapted their beliefs at multiple levels during the task. Uncertainty influenced pain perception in opposite patterns for high and low pain stimulations: high pain perception was greater under high levels of uncertainty, while there was a non-significant trend for low pain perception to be reduced. Analyses of individual differences suggested depressive symptoms were associated with a reduced learning rate throughout the task. These results shed light on processes involved in pain learning in changing environments. They also suggest a possible relationship between learning alterations and psychological traits commonly found in chronic pain, such as depressive symptoms.
Electroencephalography (EEG) is a widely applied method for decoding neural activity, offering insights into cognitive function and driving advancements in neurotechnology. However, decoding EEG data remains challenging, as classification algorithms typically require large datasets that are expensive and time-consuming to collect. Recent advances in generative artificial intelligence have enabled the creation of realistic synthetic EEG data, yet no method has consistently demonstrated that such synthetic data can lead to improvements in EEG decodability across diverse datasets. Here, we introduce EEG-GAN, an open-source generative adversarial network (GAN) designed to augment EEG data. In the most comprehensive evaluation study to date, we assessed its capacity to generate realistic EEG samples and enhance classification performance across four datasets, five classifiers, and seven sample sizes, while benchmarking it against six established augmentation techniques. We found that EEG-GAN, when trained to generate raw single-trial EEG signals, produced signals that reproduce grand-averaged waveforms and time-frequency patterns of the original data. Furthermore, training classifiers on additional synthetic data improved their ability to decode held-out empirical data. EEG-GAN achieved up to a 16% improvement in decoding accuracy, with enhancements consistent across datasets but varying among classifiers. Data augmentations were particularly effective for smaller sample sizes (30 and below), significantly improving 70% of these classification analyses and only significantly impairing 4% of analyses. Moreover, EEG-GAN significantly outperformed all benchmark techniques in 69% of the comparisons across datasets, classifiers, and sample sizes and was only significantly outperformed in 3% of comparisons. These findings establish EEG-GAN as a robust toolkit for generating realistic EEG data, which can effectively reduce the costs associated with real-world EEG data collection for neural decoding tasks.
Focal cortical dysplasia type II (FCDII), a leading cause of pediatric drug-resistant focal epilepsy, results from brain somatic variants in genes of the mTOR pathway, including germline and somatic second-hit loss-of-function variants in the mTOR repressor DEPDC5. Here, we investigated the effects of mosaic DEPDC5 two-hit variants on cortical development and neuronal activity using patient-derived human cortical organoids (hCOs). Mosaic hCOs displayed increased mTOR activity and altered neural rosette densities, which were both rescued by treatment with the mTOR inhibitor rapamycin. In addition, mosaic hCOs presented dysmorphic-like neurons and increased neuronal excitability, recapitulating FCDII pathology. Longitudinal single-cell transcriptomics at three developmental stages revealed altered neuronal differentiation, dysregulated expression of genes associated with the Notch and Wnt pathways in neural progenitors, and of synaptic- and epilepsy-associated genes in excitatory neurons. We further identified cell-autonomous alterations in metabolism and translation in mosaic two-hit hCOs. This study provides novel insights into the consequences of mosaic biallelic DEPDC5 deficiency on corticogenesis in the context of FCDII, highlighting both autonomous and non-cell autonomous effects.
It has been suggested that humans and other animals are driven by a fundamental desire to acquire information about opportunities available in their environments. Not only might such a desire explain pathological behaviors, but it may be needed to account for how everyday decisions are resolved. Here, we combine artificial neural networks (ANNs) with symbolic regression to extract an expressive yet interpretable model that specifies how human participants evaluate decision-relevant information during choice. This model accounts for behavior in our own data and in previous work, outperforming existing accounts of information sampling such as the Upper Confidence Bound heuristic. This modelling approach has broad potential for uncovering novel patterns in behavior and cognitive processes, while also specifying them in human-interpretable formats. We then used the value of information derived by our model, together with ultra-high field neuroimaging, to examine activity across a suite of subcortical neuromodulatory nuclei and two cortical regions that influence these nuclei. This established roles for midbrain dopaminergic nuclei, anterior cingulate cortex, and anterior insula in mediating the influence of value of information on behavior.
Flexible cognition depends on the ability to represent and apply context, allowing the brain to interpret sensory input and guide behavior in a context-dependent manner. Recent work has proposed Spatial Computing as a mechanism for this flexibility, suggesting that contextual signals organize information processing through spatial patterns of oscillatory activity across the cortical surface. These patterns act as "inhibitory stencils" that constrain where information (the "content" of cognition) can be expressed in spiking activity. Here, we provide a comprehensive empirical test of Spatial Computing Theory using multi-electrode recordings from the lateral prefrontal cortex in non-human primates performing a range of cognitive tasks (object working memory, sequence working memory, categorization). We found that alpha/beta oscillations encoded contextual information, reorganized their spatial patterns with context and task demands, and spatially gated the expression of content-related spiking activity. Furthermore, we found that alpha/beta oscillations reflected misattributions of task context and correlated with subjects trial-by-trial decisions. These findings validate core predictions of Spatial Computing by showing that oscillatory dynamics not only gate information in time but also shape where in the cortex cognitive content is represented. This framework offers a unifying principle for understanding how the brain flexibly coordinates cognition through structured population dynamics.
Parkinsons disease is projected to rise to pandemic proportions by 2050, which has resulted in an urgent need for disease-modifying treatments. In this regard, we previously showed that in a mouse model of parkinsonism with unilateral 6-hydroxydopamine (6-OHDA) injection into the dorsolateral striatum (DLS), low doses of the neuronal nicotinic acetylcholine receptor (nAChR) partial agonist and smoking cessation drug, cytisine exerts sex-specific neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of only female mice by reducing apoptotic endoplasmic reticulum (ER) stress. Although these data suggest that neuroprotection might occur via cytisine-mediated upregulation of {beta}2 subunit-containing ({beta}2*) nAChRs in SNc DA neurons, there is no direct evidence to support this idea. Therefore, this study asks the critical question of whether upregulation of {beta}2* nAChRs in SNc DA neurons alone is sufficient to reduce apoptotic ER stress and exert neuroprotection in a preclinical unilateral DLS mouse model of 6-OHDA-induced parkinsonism. To address this question, we generate and characterize a novel {beta}2-upregulated transgenic mouse line. These transgenic mice possess mutations in the M3-M4 intracytoplasmic loop of {beta}2 subunits that cause constitutive upregulation of {beta}2* nAChRs without nicotinic ligands. Surprisingly, when compared to wild-type littermates, only female {beta}2-upregulated transgenic mice demonstrate upregulation of {beta}2* nAChRs in SNc DA neurons as assessed by significant increases in Sec24D-containing ER exit sites (Sec24D-ERES). Using the optogenetic calcium and dopamine sensors, GCaMP6f and GRABDA respectively, we found significant increases in dihydro-beta-erythroidine (Dh{beta}E)-sensitive {beta}2* nAChR-mediated calcium influx in SNc DA neuron dendrites and Dh{beta}E-sensitive acetylcholine (ACh)-evoked dopamine release at SNc DA neuron terminals of the DLS in female transgenic mice. We then used four independent readouts to assess neuroprotection of SNc DA neurons following unilateral 6-OHDA injection into the DLS, viz., contralateral apomorphine-induced rotations, preservation of SNc DA neurons, inhibition of a major proapoptotic ER stress protein, C/EBP homologous protein (CHOP) and glial fibrillary acid protein (GFAP) expression in SNc astrocytes. In all four readouts, female {beta}2-upregulated transgenic mice showed significant neuroprotection. From a clinical perspective, this study shows that upregulation without nicotinic ligand-mediated activation of {beta}2* nAChRs in SNc DA neurons can be a translationally viable disease-modifying strategy for Parkinsons disease. In addition, we envision that the novel transgenic {beta}2-upregulated mice created in this study will provide a valuable tool for understanding the role of nAChR upregulation in major neurological disorders such as addiction, anxiety, depression and dementia.
Monoacylglycerol lipase (MAGL) inhibitors are considered as drug candidates for epilepsy. In order to determine the level of MAGL and evaluate changes in the epileptic brain, we have validated and used autoradiography and the MAGL radiotracer [3H]T-401 on resected temporal neocortex specimens obtained from patients with temporal lobe epilepsy and in brains from mice with chronic reoccurring seizures. Saturation experiments revealed a KD around 4 nM for the human temporal cortex and 7 nM for the mouse brain. In the human brain, binding of [3H]T-401 was detected mostly in the grey matter, and in the subcortical white matter in lower amounts. The levels were strongly correlated in the two cortical compartments. The level of [3H]T-401 binding in the human temporal cortex varied about a 4-fold among the patients, but was not correlated to either epilepsy duration or the age of the patients. In the epileptic mouse brain, a significant reduction was observed bilaterally in the hippocampus, as well as in other cortical regions, including the temporal cortex. Interestingly, a highly significant negative correlation was seen between MAGL and binding to the translocator protein 18 kDa (TSPO) expressed in glia. These data support the presence of MAGL in neuronal and non-neuronal cells, and indicate that MAGL levels in the brains of either patients with epilepsy or mice after intra-hippocampal kainite injection are reduced not only in the epileptic zone in the hippocampus, but more widespread in the brain.
The paravertebral sympathetic chain ganglia (SCG) are autonomic ganglia critical for regulating the "fight-or-flight" response. Symptoms of sympathetic dysfunction are prevalent in diabetes, affecting up to 90% of patients. The molecular and cellular composition of the human SCG and its alteration in diabetes remains poorly defined. To address this gap, we performed spatial transcriptomic profiling of lumbar SCGs from diabetic and non-diabetic organ donors. We identified 3 three distinct neuronal populations, two noradrenergic (NA1 and NA2) and one cholinergic (CHO), based on tyrosine hydroxylase (TH) and SLC18A3 expression, respectively. We also characterized 9 non-neuronal populations consisting of Schwann cells, immune cells, fibroblasts, adipocytes, and endothelial cells. In diabetic SCGs, we observed a significant loss of myelinating Schwann cells and a phenotypic shift of cholinergic neurons toward a noradrenergic identity. Additionally, diabetes was associated with a significant reduction in the transcripts of vasodilatory neuropeptides, such as VIP and CALCA, suggesting a mechanism for impaired vascular control. Upstream regulator analysis highlighted altered neurotrophic signaling in diabetes, with enhanced NGF/TRKA and diminished BDNF/TRKB activity, potentially driven by target-derived cues. Comparison between SCG and dorsal root ganglia (DRG) neurons revealed ganglia-specific genes, like SCN3A and NPY (SCG) versus SCN10A and GPX1 (DRG), offering specific therapeutic targets for autonomic dysfunction or pain. Our findings provide a transcriptomic characterization of human SCG, revealing molecular signatures that underlie diabetic autonomic dysfunction. This work lays a foundation for the development of therapies to restore sympathetic function and avoid unintended autonomic effects in the development of analgesics. Significance StatementAutonomic dysfunction affects up to 90% of people with diabetes, yet the human sympathetic nervous system remains poorly molecularly defined. To address this gap, we present a spatial transcriptomic profile of the human sympathetic chain ganglia (SCG), revealing how diabetes affects the human autonomic nervous system. We show that diabetes shifts the cholinergic neuronal population to a noradrenergic phenotype and reduces vasodilation neuropeptide expression, potentially explaining impaired vascular control and thermoregulation. Comparative analysis of sympathetic and sensory ganglia reveals distinct gene profiles that may inform novel therapeutic strategies. These findings offer critical insight into the molecular drivers of diabetic autonomic neuropathy and lay the groundwork for safer, more precise treatments that selectively modulate autonomic or sensory function in chronic disease.
Huntingtons disease (HD) is a monogenic autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene, yielding a gain-of-toxic-function mutant Huntingtin protein mHTT. CRISPR/Cas9 is a potentially powerful therapeutic tool for treating HD by eliminating mutant HTT (mHTT) gene. We developed a specific SaCas9 guide RNA to target human mHTT, and a self-inactivating gene editing system that abolishes SaCas9 after a short transient expression for high gene editing efficiency and maximal safety to prevent off-target effects. Both conventional and the new self-inactivating gene editing systems achieved successful elimination of mHTT gene, 60-90% mHTT protein and 90% of mHTT aggregation in BAC226Q HD mouse brains, which resulted in significant long-term rescue of neural pathology, motor deficits, weight loss and shortened lifespan. These beneficial effects were observed when gene editing was applied before, at and well after the on-set of pathological and behavioral abnormalities. These proof-of-concept data demonstrate that gene editing can be a highly effective therapeutic approach for HD and other inherited neurodegenerative diseases. One Sentence SummarySelf-inactivating CRISPR for mutant huntingtin in HD mice achieved long-term rescue of neural pathology, motor deficits, weight loss and survival.
The acquisition of temporally proximate information can impair the brains ability to consolidate earlier experiences, resulting in retroactive interference (RI). Recognition-based behavioral paradigms are well-suited for investigating RI in rodents, particularly those involving sequential learning episodes. The medial prefrontal cortex (mPFC) integrates multimodal information relevant to the regulation of memory interference and is strongly modulated by the serotonergic system. Serotonin 2A receptors (5-HT2AR), which are densely expressed in the mPFC, have been shown to influence the retrieval of competing object-recognition memories. However, their role in other phases of memory processing, particularly in modulating RI, remains unclear. Using a novel object recognition task designed to induce RI, combined with pharmacological manipulation of 5-HT2AR, we demonstrate that RI specifically impairs the object-related component of memory. Moreover, serotonin signaling through 5-HT2AR is necessary to prevent RI. Strikingly, the activation of 5-HT2AR before retrieval can rescue the expression of memories affected by RI, suggesting that RI may not erase memory traces but rather hinder access to them.
The acquisition of temporally proximate information can impair the brains ability to consolidate earlier experiences, resulting in retroactive interference (RI). Recognition-based behavioral paradigms are well-suited for investigating RI in rodents, particularly those involving sequential learning episodes. The medial prefrontal cortex (mPFC) integrates multimodal information relevant to the regulation of memory interference and is strongly modulated by the serotonergic system. Serotonin 2A receptors (5-HT2AR), which are densely expressed in the mPFC, have been shown to influence the retrieval of competing object-recognition memories. However, their role in other phases of memory processing, particularly in modulating RI, remains unclear. Using a novel object recognition task designed to induce RI, combined with pharmacological manipulation of 5-HT2AR, we demonstrate that RI specifically impairs the object-related component of memory. Moreover, serotonin signaling through 5-HT2AR is necessary to prevent RI. Strikingly, the activation of 5-HT2AR before retrieval can rescue the expression of memories affected by RI, suggesting that RI may not erase memory traces but rather hinder access to them.
Aging leads to alterations in the sensorimotor system and balance control but it is not well understood how changes in sensorimotor function affect how people respond to postural disturbances. Elucidating the relationships between balance control and sensorimotor function is crucial for developing effective rehabilitations. Here, we compared the kinematic responses to platform translations and rotations during standing in 10 young and 30 older adults and explored relationships between sensorimotor function and balance responses. We found that older adults were less able to withstand perturbations without stepping, not because their non-stepping strategies were less effective but because they chose to step at smaller deviations of the extrapolated center of mass. Older adults performed worse than young adults on measures of sensory and motor function but lower stepping thresholds were associated with susceptibility to unreliable visual information and not with reduced sensory acuity or reduced strength. Poor sensory reweighting may contribute to and combine with age-related cognitive rigidity, leading to a higher priority on safer strategies. Older adults may resort to stepping, even if a step is not necessary, rather than rely on potentially inaccurate sensory signals to inform a corrective response. Our results provide initial evidence that sensory reweighting could be a potential target for fall prevention methods. NEW & NOTEWORTHYThe relationship between age-related changes in sensorimotor function and postural control is poorly understood. Here, we did a comprehensive assessment of sensorimotor function and reactive standing balance. We found that healthy older adults chose safer strategies, i.e. they step at smaller disturbances, than young adults. Although we found many differences in sensorimotor function, only a reduced ability to suppress conflicting sensory information was related to the use of a safer strategy.
In neuroprosthetics, intracortical microstimulation (ICMS) recruits cortical networks to evoke brain responses and sensory perceptions. However, multi-electrode ICMS often generates suboptimal percepts compared to single-electrode ICMS, suggesting nonlinear neuromodulation rather than simple summation by multi-electrode ICMS. Yet, the factors and mechanisms underlying this modulation remain poorly understood. To investigate multi-electrode ICMS, we combined two-photon calcium imaging with a well-controlled dual-electrode ICMS in the mouse visual cortex to investigate how neurons integrate converging ICMS inputs at varying intensities. We found that stimulation intensity significantly shapes neuromodulation at both single-cell and population levels. Specifically, low intensities (5-7 {micro}A) have a minimal effect on neural responses. At intermediate intensities (10-15 {micro}A), we observed diverse, nonlinear bipolar modulation--both enhancement and attenuation--at the single-cell level. However, we achieved net enhancement at the population level. At higher intensities (15-20 {micro}A), although the proportion of modulated neurons increased in both enhancement and attenuation directions, the net effect at the population level was neutral (zero modulation). Furthermore, neurons strongly responsive to single-electrode ICMS were more likely to be attenuated, while weaker responding cells exhibited enhanced modulation. The strongest neuromodulatory effects occur at intermediate spatial distances in between the two electrodes. Computational modeling based on spiking neural network composed of adaptive exponential integrate-and-field neurons implicated the importance of inhibitory network dynamics and network variability as key mechanisms. Our experimental data was used to train an advanced deep learning approach, which successfully predicted the neuromodulation patterns induced by dual-electrode ICMS. Our findings reveal intensity- and spatial-dependent rules of neuromodulation by ICMS, providing necessary insights to optimize multi-electrode ICMS for neuroprosthetic applications. Significance statementUnderstanding how cortical neurons integrate concurrent inputs from multi-electrode intracortical microstimulation (ICMS) is essential for advancing neuroprosthetic technologies. We show that dual-electrode ICMS evokes distinct, predictable neuromodulatory effects that depend on (i) stimulation intensity, (ii) a neurons baseline responsiveness to single electrode input, and (iii) its proximity to the electrodes. Low and intermediate intensity dual-electrode ICMS amplifies neural activity compared to single-electrode ICMS, whereas high-intensity stimulation leads to attenuation, limiting net activation.
1.Sleep is critical for brain plasticity during early development, yet the individual maturation of sleep neurophysiology in infancy remains poorly characterized. In particular, slow wave activity (SWA) has emerged as a key marker of both cortical maturation and experience-dependent plasticity. Understanding the regional dynamics of sleep neurophysiology early in life could yield critical insights into neurodevelopmental health. We conducted a longitudinal high-density EEG study in 11 healthy infants (3-6 months) assessing non-rapid eye movement (NREM) sleep. We analyzed the maturation of SWA (0.75-4.25 Hz), theta power (4.5-7.5 Hz), and sigma power (9.75-14.75 Hz) across scalp regions and examined their association with behavioral development. From 3 to 6 months, SWA increased maximally in occipital regions, while theta power exhibited a global increase. Sigma power, initially concentrated centrally, dispersed towards frontal regions. Greater power increases over frontal regions correlated with higher motor (theta) and personal-social skill scores (sigma) at 6 months. These findings establish a framework for typical infant sleep EEG maturation, highlighting frequency-specific and regionally distinct developmental patterns. This study provides the first longitudinal evidence that early changes in sleep EEG topography reflect individual developmental trajectories, supporting its utility as a non-invasive and yet precise biomarker for early identification of atypical neurodevelopment at preverbal ages.
Altered sensory perception is a hallmark of autism and determines how autistic individuals engage with their environment. These sensory differences are shaped by top-down cognitive processes--such as categorization, attention, and priors--which themselves exhibit characteristic atypicalities in the condition. Among sensory modalities, tactile perception is particularly critical for daily functioning and social interactions. However, the dynamic interplay between tactile and cognitive processes remains poorly understood. In this study, we investigated the influence of top-down cognitive processes on tactile perception in the Fmr1-/y genetic mouse model of autism. We developed a translational, forepaw-based decision-making task designed to dissociate stimulus-driven tactile responses from those modulated by cognitive factors. This approach enabled us to assess multiple aspects of perceptual processing, including perceptual learning, stimulus categorization and discrimination, as well as the influence of prior experience and attention. Mice were initially trained to distinguish between high- and low-salience stimuli and were subsequently tested with a continuum of intermediate stimulus intensities. Our results revealed salience-dependent cognitive alterations that significantly influenced sensory performance. During the training phase, Fmr1-/y mice exhibited an increased choice consistency bias in low-salience trials, resulting in impaired perceptual learning. In the testing phase, Fmr1-/y mice demonstrated enhanced tactile discrimination under low-salience conditions, driven by a reduced influence of categorization. Moreover, under conditions of high cognitive load, Fmr1-/y mice displayed attentional deficits that were dissociable from their enhanced tactile sensitivity. Together, our findings reveal that cognitive context critically shapes sensory phenotypes in autism. They advocate for a shift beyond traditional sensory-cognitive dichotomies to better capture the dynamic interplay between perceptual and cognitive alterations in autism.
BackgroundThe use of methamphetamine has continued to rise in the US. In addition to facilitating dopamine neurotransmission, methamphetamine indirectly increases glutamate release which activates N-methyl-D-aspartate receptors (NMDARs). Ketamine is a noncompetitive NMDAR antagonist. Ketamine also has actions on -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and promotes synaptogenesis. Thus, we hypothesized that ketamine may be a potential therapeutic to reduce methamphetamine-seeking behaviors and associated negative affect in a rat model. MethodsMale and female rats underwent methamphetamine or saline intravenous self-administration for 10 sessions, followed by extinction training. Rats received ketamine or saline treatment either prior to 10 daily extinction sessions or only prior to the last extinction session. Anxiety-like behaviors were measured 24 hours after extinction, followed by cue-induced and drug-primed reinstatement two and six days later respectively. ResultsMethamphetamine withdrawal increased anxiety-like behaviors in male rats on the elevated plus maze test compared to rats that self-administered saline. Moreover, anxiety-like behaviors were significantly attenuated by daily ketamine treatment during extinction. Drug-primed but not cue-induced reinstatement, tested six days after the last extinction session, was significantly attenuated in male rats that received ten or one ketamine treatments during extinction compared with rats receiving vehicle during extinction. Ketamine was ineffective in female rats in reducing cue-induced or drug-primed reinstatement. ConclusionsKetamine may confer sex-specific benefits during methamphetamine withdrawal and relapse vulnerability, particularly by reducing anxiety-like behaviors and attenuating drug-primed reinstatement in males. These results support the potential of ketamine as a targeted adjunct therapy during early methamphetamine abstinence in males.
We introduce Generative Phenomenology: making viewable images of peoples perceptions (Perceptograms) and generating the images from neural models, as a powerful technique for understanding the neural bases of perception. Amblyopia, a disorder of spatial vision, provides a perfect case because signals from the two eyes go through partly different cortical neurons, and many amblyopes report phantom forms when viewing sinusoidal gratings through their amblyopic eye (AE) but not through the fellow eye (FE). Using a dichoptic display, we acquired high-fidelity perceptograms for 24 gratings shown to AE while sums-of-gratings plaids were shown to FE with contrast, frequency, phase, and orientation of the plaid gratings adjusted to match the two percepts exactly. Plaids provided exact matches to 92.6% of distortions. A formal equation that the signals generated in visual cortex by the test gratings seen through AE match the signals generated by their matched perceptograms seen through FE for each observer, was used to analytically derive cortical filters processing AE signals as linear transforms of standard steerable filters modeling normal V1 neurons for FE. Passing gratings through AE filters accurately generated the measured perceptograms. The filter transformations reflected complex changes in V1 receptive fields and possibly in cross-correlations. The AE filters also explained amblyopic deficits in perceiving sinusoidally modulated circular contours and were consistent with orientation perceptive fields estimated from reverse-correlation experiments. Changes in neuronal receptive fields thus have profound effects on perception, to the extent that observers can see more features than are present in the viewed stimulus. SIGNIFICANCE STATEMENTWhat we see is generated by our cortical neurons processing sensory input. With their amblyopic eye, whose signals are processed by deficiently developed cortical cells, many amblyopes see phantom forms that contain more features than the viewed stimulus, providing a perfect case for studying the neural generation of percepts (Generative Phenomenolog)y). We acquired computer aided perceptograms (viewable records of perceived images) of the phantom forms and then derived a cortical model that accurately generated the perceptograms by using linear transforms of normal V1 receptive fields. The modifications also explained amblyopic deficits at discerning departures from circularity and were validated with reverse-correlation experiments. These results show that small changes in cortical neuronal properties can cause major differences in what people perceive.
We introduce Generative Phenomenology: making viewable images of peoples perceptions (Perceptograms) and generating the images from neural models, as a powerful technique for understanding the neural bases of perception. Amblyopia, a disorder of spatial vision, provides a perfect case because signals from the two eyes go through partly different cortical neurons, and many amblyopes report phantom forms when viewing sinusoidal gratings through their amblyopic eye (AE) but not through the fellow eye (FE). Using a dichoptic display, we acquired high-fidelity perceptograms for 24 gratings shown to AE while sums-of-gratings plaids were shown to FE with contrast, frequency, phase, and orientation of the plaid gratings adjusted to match the two percepts exactly. Plaids provided exact matches to 92.6% of distortions. A formal equation that the signals generated in visual cortex by the test gratings seen through AE match the signals generated by their matched perceptograms seen through FE for each observer, was used to analytically derive cortical filters processing AE signals as linear transforms of standard steerable filters modeling normal V1 neurons for FE. Passing gratings through AE filters accurately generated the measured perceptograms. The filter transformations reflected complex changes in V1 receptive fields and possibly in cross-correlations. The AE filters also explained amblyopic deficits in perceiving sinusoidally modulated circular contours and were consistent with orientation perceptive fields estimated from reverse-correlation experiments. Changes in neuronal receptive fields thus have profound effects on perception, to the extent that observers can see more features than are present in the viewed stimulus. SIGNIFICANCE STATEMENTWhat we see is generated by our cortical neurons processing sensory input. With their amblyopic eye, whose signals are processed by deficiently developed cortical cells, many amblyopes see phantom forms that contain more features than the viewed stimulus, providing a perfect case for studying the neural generation of percepts (Generative Phenomenolog)y). We acquired computer aided perceptograms (viewable records of perceived images) of the phantom forms and then derived a cortical model that accurately generated the perceptograms by using linear transforms of normal V1 receptive fields. The modifications also explained amblyopic deficits at discerning departures from circularity and were validated with reverse-correlation experiments. These results show that small changes in cortical neuronal properties can cause major differences in what people perceive.
Peroxisomes are critical organelles that detoxify wastes while also catabolizing and anabolizing lipids. How peroxisomes coordinate protein import and support metabolic functions across complex tissues and timescales remains poorly understood in vivo. Using the Drosophila brain, we discover a striking enrichment of peroxisomes in the neuronal soma and the cortex glia that enwrap them. Unexpectedly, import of peroxisomal proteins into cortex glia, but not neurons, dramatically oscillated across time and peaked in the early morning. Rhythmic peroxisomal import in cortex glia autonomously required the circadian clock and Peroxin 5 (Pex5; peroxisomal biogenesis factor 5 homolog), with endogenous Pex5 protein peaking in the morning. Notably, removing Pex5 in cortex glia severely reduced sleep while concomitantly causing aberrant lipid metabolism characterized by ectopic lipid droplets and increases across multiple lipid families. Thus, the circadian import of peroxisomal proteins via Pex5 in cortex glia is essential for lipid homeostasis and organismal behavior. HighlightsO_LIPeroxisomal membrane and importer proteins are enriched in cortex glia (CG). C_LIO_LIThe circadian clock autonomously decreases peroxisomal import in CG. C_LIO_LIThe cytosolic importer Pex5 controls circadian peroxisomal import in CG. C_LIO_LILoss of Pex5 in CG disrupts brain lipid metabolism and sleep behavior. C_LI
Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neurodevelopmental disorders, including congenital malformations and autism spectrum disorder. In animal models and neural organoids, VPA has been shown to alter signaling pathways, such as Wnt pathway, providing insights into VPA-induced neurodevelopmental defects. Here, we exposed dorsal forebrain organoids to VPA for 30 days and examined effects at the tissue, cellular, and molecular level. VPA treatment disrupted ventricular-like regions, indicating defects in cell-cell and cell-matrix interactions. Transcriptomics analysis confirmed altered expression of extracellular matrix (ECM) genes and single cell RNA sequencing analysis identified genes involved in microenvironment sensing, such as cellular mechanosensing and Hippo-YAP/TAZ signaling pathway. Finally, proteomics analysis corroborated that VPA alters the microenvironment of the human dorsal forebrain organoids by disrupting the secretion of ECM proteins. Altogether, our study suggests that VPA-treated dorsal forebrain organoids serve as a model to investigate the role of extracellular processes in brain development and to understand how their disruptions might contribute to neurodevelopmental disorders.
Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABAA synapses on dopamine neurons (LTPGABA) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. We optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTPGABA. Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTPGABA. Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTPGABA at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTPGABA that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.
Tuberous Sclerosis Complex (TSC) is a genetic disease which manifests as a range of neurological symptoms, including benign brain tumors, epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Among the latter, according to recent reports, anxiety and mood disorders affect over 50% of patients. We have previously demonstrated anxiety-like behavioral symptoms in the zebrafish model of TSC, which were rescued by treatment with the TrkB antagonist ANA-12. Here, we aimed to investigate the mechanism of how ANA-12 regulates behavior by analyzing brain activity in the telencephalon of TSC zebrafish larvae, and we identified the affected regions as corresponding to the known mammalian circuitry involved in anxiety processing. Due to differences in development, the identification of telencephalic territories that are homologous between zebrafish and mammals remains challenging, particularly at early, dynamic stages of development. However, we were able to identify populations of neurons in the zebrafish habenula and ventral subpallium whose involvement in anxiety parallels that of mammals. Those regions were dysregulated in the TSC mutant. This dysregulation correlated with aberrant anxiety behavior and was rescued by treatment with ANA-12. Our results suggest that hyperactivation of TrkB in those regions is a major contributor to anxiety-like behavior as seen in TSC fish, and that those mechanisms could be evolutionarily conserved between zebrafish and mammals.
Approximately 14% of U.S. households are estimated to be food insecure. The neurocognitive and metabolic impacts of unpredictable food access during early-life periods of development are poorly understood. To address these gaps we devised a novel rat model of food insecurity to control the timing, type, and quantity of accessible food using programmable feeders. Male rats were divided into 3 groups: Secure-chow (SC), a control group given 100% of daily caloric needs, distributed evenly across 4 daily meals of standard chow at set mealtimes; Secure-mixed (SM), a 2nd control group identical to the SC group except that the food type predictably alternated daily between chow and a high-fat, high-sugar diet (HFHS); and Insecure-mixed (IM), the experimental group given randomly alternating daily access to either chow or HFHS at either 85% or 115% of daily caloric needs, distributed evenly across 3 daily meals with unpredictable mealtimes. These feeding schedules were implemented from postnatal days (PNs) 26-45, after which all groups received chow ad libitum. Metabolic assessments performed in adulthood revealed no group differences in caloric intake, body weight, or body composition when maintained on either chow (PN46-149) or a cafeteria diet (PN150-174). Behavioral measures (PN66-126) revealed no group differences in anxiety-like, exploratory, or impulsive behavior (zero maze, open field, differential reinforcement of low rates of responding procedures). However, the IM group exhibited hippocampus-dependent memory impairments compared to both control groups in the novel location recognition test. These findings suggest that early-life food insecurity may contribute to long-term impairments in memory function.
Lysosomal dysfunction and mitochondrial health are intricately connected, playing essential roles in cellular homeostasis. Lysosomes are acidic membrane-bound organelles responsible for degrading and recycling cellular waste, while mitochondria generate the energy required for cellular functions. Growing evidence implicates roles for lysosomal and mitochondrial dysfunction in neurodegenerative diseases, including Alzheimers and Parkinsons disease. With novel therapeutics targeting both the lysosomal and mitochondrial functions, robust assays for compound screening are becoming critical to evaluate modulation of both organelles in disease-relevant cellular models. Here, we investigated human fibroblasts derived from healthy donors, as well as patients with Alzheimers and Parkinsons disease, to assess their capacity to model key aspects of lysosomal and mitochondrial dysfunction. Lysosomal function was evaluated using various assays, including quantification of lysosomal proteins (TMEM175 and LAMP1), LysoTracker staining, measurement of lysosomal pH, and lysosomal enzymatic activity. Autophagic flux was assessed by measuring p62 levels as a marker of autophagy. Mitochondrial function was investigated by measuring mitochondrial calcium levels, membrane potential, oxidative stress, and mitochondrial content using MitoTracker. To explore the potential of using human fibroblasts for in vitro compound screening, we validated these assays in a 384-well high-throughput format using compounds such as chloroquine and ammonium chloride. Our findings demonstrate that human fibroblasts faithfully recapitulate lysosomal and mitochondrial dysfunctions characteristic of neurodegenerative diseases. Moreover, the use of robust assays positions these cells as a valuable platform for high-throughput screening to identify novel therapeutics targeting lysosomal and mitochondrial pathways.
Cerebral aneurysm (CA) rupture is the most common cause of nontraumatic subarachnoid hemorrhage. Recent data suggests that tortuosity is associated with aneurysm formation and rupture risk. We aimed to determine if tortuosity correlates with CA development and rupture in a mouse CA model and to develop a novel tortuosity scale to be used for in vivo CA studies. A highly validated, elastase-mouse CA model was used to assess cerebral vessel tortuosity with CA formation and rupture in sham and elastase groups. A 4-point ordinal scale was created to evaluate predictive capacity for vessel tortuosity level and CA formation and rupture. Nearly all sham animals (92%) had little to no vessel tortuosity on the visual scale (median, IQR: 1, [1-2]), compared to 24% in the elastase groups (2, [2-3]) (p=0.001). Sham cohorts had zero animals with highly tortuous vessels, while 3.5mU and 35mU cohorts had >35% of animals with significant visual tortuosity, p=0.003 and p<0.000, respectively. CA formation and rupture was higher in the elastase groups compared to the sham group (p=0.002). Both the visual scale and tortuosity index significantly predicted CA formation (p<0.001) and rupture (p<0.001). A novel tortuosity scale is highly predictive of CA formation and rupture in vivo. It may offer a new measurement to better understand vessel stress in the pathogenesis and progression of CAs.
Brain-computer interface (BCI) is a system that translates neural activity into commands, allowing direct communication between the brain and external devices. Despite its clinical application, BCI systems fail to robustly capture subjects intent due to a limited understanding of the neural mechanisms underlying BCI control. To address this issue, we introduce a biophysical modeling approach that leverages a linear neural mass model to investigate the associated neural mechanisms of motor imagery-based BCI experiments. We tailor this model to simulate both motor imagery task and resting state. We apply this approach to a cohort of 19 healthy subjects trained along four sessions where magnetoencephralography (MEG) and electroencephalography (EEG) signals were simultaneously recorded. The neural synaptic gain and time scale of the modeled excitatory and inhibitory neural mass populations capture changes in neural activity across conditions and sessions. Those changes appear in important areas of the sensorimotor cortex, relevant for motor imagery tasks. We observed these effects in both EEG and MEG modalities. These findings provide insights into the underlying neural mechanisms in a motor imagery task in BCI, paving the way to tailored BCI training protocols.
The central nervous system (CNS) has a limited intrinsic capacity for axonal regeneration, making functional recovery after injury extremely challenging. Numerous strategies have been explored to overcome this blockade, among others, molecular interventions or modulation of the inhibitory extracellular environment. Despite some advances, effective regeneration remains elusive, particularly in adult CNS neurons. To investigate these mechanisms in a controlled and reproducible setting, we employ organotypic slice cultures (OSCs), which retain key structural and cellular features of the intact brain while allowing for long-term in vitro experimentation. In particular, the entorhino-hippocampal (EH) co-culture model preserves the anatomical and functional connectivity of the perforant pathway, providing an excellent platform for studying axonal degeneration and regeneration. This model reproduces laminar specificity, axonal myelination, and inhibitory signaling after axotomy, closely mimicking in vivo conditions. Furthermore, EH co-cultures facilitate the application of optogenetic tools to monitor and manipulate neuronal activity. Our study explores whether enhancing activity in entorhinal cortex neurons can promote axonal regeneration after a EH lesion. Our results show that increased activity in entorhinal neurons alters the development of the EH connection and fails to enhance the regrowth of injured mature entorhinal axons. These findings suggest that both extrinsic and intrinsic factors shape the regenerative response and highlight the utility of EH OSCs as a versatile model for testing future pro-regenerative interventions.
Variants in GBA1 are common genetic risk factors for several synucleinopathies. The increased risk has been attributed to the toxic effects of misfolded glucocerebrosidase (GCase) (gain-of-function), and the accumulation of lipid substrates due to reduced enzyme activity (loss-of-function). To delineate GBA1 pathogenicity, an iPSC line was generated from a patient with both type 1 Gaucher disease (GBA1: N370S/N370S; p.N409S/p.N409S) and Parkinson disease (PD). From this line, we created a reverted wild-type (WT) line and a GBA1 knockout (KO) line to eliminate misfolded GCase and intensify lipid accumulation. N370S/N370S and KO dopaminergic neurons (DANs) exhibited decreasing GCase levels and progressive accumulation of lipid substrates compared to WT DANs. Notably, the expression of GPNMB, whose levels correlate with PD risk, was upregulated by the mild lipid accumulation in N370S/N370S DANs but disrupted in KO DANs. These findings refine the loss-of-function mechanism by associating PD risk levels of GPNMB with lipid levels specific to GBA1 risk variants.
Inhibitory control is essential for adaptive behaviour and declines with age, yet the underlying neural dynamics remain poorly understood. The {beta}-rhythm (15-29 Hz) is thought to reflect inhibitory signalling within the fronto-basal ganglia network. Recent evidence suggests that transient {beta}-bursts support inhibitory performance, often masked by conventional analyses of trial-averaged {beta}-power. To reveal the link between trial-by-trial {beta}-bursting and inhibition, we applied a recently developed analysis framework combining linear mixed-effects modelling (LMM) with threshold-free cluster enhancement (TFCE) during response inhibition and initiation in older adults. Twenty healthy older adults performed a bimanual anticipatory response inhibition task, while electroencephalography and electromyography were recorded to capture {beta}-activity ({beta}-burst rate/duration; averaged {beta}-power) and muscle bursting dynamics, respectively. Our analysis revealed distinct {beta}-bursting signatures absent in averaged {beta}-power data. Following the stop-signal, parieto-occipital {beta}-bursting presented before a temporal cascade from attentional to inhibitory processes. In addition to expected right fronto-central and bilateral sensorimotor activity, we observed left prefrontal {beta}-bursting, indexing broader inhibitory network engagement during bimanual response inhibition. Moreover, we established a functional link between right sensorimotor {beta}-bursting and muscle bursts during stopping, indicating rapid cortical suppression of initiated motor output. These results help clarify the mechanistic role of {beta}-oscillations and underscore the sensitivity of {beta}-bursting to both the timing and context of inhibitory demands in healthy older adults. Future research will help establish the potential of {beta}-bursting, combined with LMM-TFCE analysis, as a clinically relevant marker of impulse control dysfunction. Significance statementOur novel application of an advanced statistical framework revealed distinct spatiotemporal {beta}-bursting patterns during response inhibition and response withholding in healthy older adults, which were not captured by averaged {beta}-power. Identifying a further link between cortical {beta}-bursting and muscle-level suppression, the findings offer a mechanistic account of how the brain halts action in real time in older adults. This work provides a sensitive, trial-level framework for studying {beta}-bursting measures in general, as well as inhibitory control across aging and clinical populations.
Brain function relies on energy supplied by mitochondrial energy transformation, but how cellular energetics constrain neurological function and cognition remains poorly understood. Genetic defects in mitochondrial DNA cause rare mitochondrial diseases (MitoD) that offer a unique window into the energetic foundations of cognition, shedding light on the neural processes that are most energetically constrained. In this study, we assessed functional magnetic resonance imaging (fMRI) on 29 participants with MitoD and 62 matched controls during resting state and tasks probing cognitive (N-back task), affective (cold pain), and sensory (multisensory visual and auditory perception) functions. MitoD individuals exhibited significant cognitive deficits across a range of functions, including executive function and working memory, mental and physical fatigability, low exercise tolerance, and low mood. These deficits were accompanied by markedly elevated blood levels of metabolic stress markers, including GDF15 and FGF21. Surprisingly, overall BOLD fMRI activity and connectivity were largely intact across all tasks in MitoD individuals. However, those with more severe cognitive impairment and higher GDF15 levels showed reduced working memory-related activity, which in turn mediated poorer task performance. Conversely, individuals with relatively preserved cognitive function exhibited hyperactivation in working memory regions and working memory performance compared to controls, suggesting compensatory engagement of cortical systems in high-functioning MitoD individuals. These effects were weaker in the sensory domain and absent during affective (cold pain) processing, suggesting an energy hierarchy in the brain that prioritizes essential functions such as affective responses while downregulating more energy-demanding, complex cognitive processes when resources are limited.
Brain function relies on energy supplied by mitochondrial energy transformation, but how cellular energetics constrain neurological function and cognition remains poorly understood. Genetic defects in mitochondrial DNA cause rare mitochondrial diseases (MitoD) that offer a unique window into the energetic foundations of cognition, shedding light on the neural processes that are most energetically constrained. In this study, we assessed functional magnetic resonance imaging (fMRI) on 29 participants with MitoD and 62 matched controls during resting state and tasks probing cognitive (N-back task), affective (cold pain), and sensory (multisensory visual and auditory perception) functions. MitoD individuals exhibited significant cognitive deficits across a range of functions, including executive function and working memory, mental and physical fatigability, low exercise tolerance, and low mood. These deficits were accompanied by markedly elevated blood levels of metabolic stress markers, including GDF15 and FGF21. Surprisingly, overall BOLD fMRI activity and connectivity were largely intact across all tasks in MitoD individuals. However, those with more severe cognitive impairment and higher GDF15 levels showed reduced working memory-related activity, which in turn mediated poorer task performance. Conversely, individuals with relatively preserved cognitive function exhibited hyperactivation in working memory regions and working memory performance compared to controls, suggesting compensatory engagement of cortical systems in high-functioning MitoD individuals. These effects were weaker in the sensory domain and absent during affective (cold pain) processing, suggesting an energy hierarchy in the brain that prioritizes essential functions such as affective responses while downregulating more energy-demanding, complex cognitive processes when resources are limited.
Eye movements directed to high-valued objects in the environment are executed with greater vigor. Superior Colliculus (SC) - a subcortical structure that controls eye movements - contains multiple subtypes of neurons that have distinct functional roles in generating saccades. How does value-related information processed in other parts of the brain affect the responses of these different subtypes of SC neurons to facilitate faster saccades? To test this, we recorded four subtypes of neurons simultaneously while the monkey made saccades to objects they had been extensively trained to associate with large or small rewards (i.e., good or bad). In three subtypes of neurons (visual, visuomotor, and motor), the good objects elicited more spikes than bad objects. More importantly, using a bootstrapping procedure, we identified three separable phases of activity: 1) early visual response (EVIS), 2) late visual response (LVIS), and 3) pre-saccadic (PreSAC) motor response in these neuronal subtypes. In each subtype of neurons, the value of objects (good vs. bad) was positively correlated with the activity in the LVIS and PreSAC phases but not the EVIS phase. These data suggest that the value information from other brain regions modulates the visual (LVIS) and the motor (PreSAC) responses of visual, visuomotor, and motor neurons. This enhanced activation facilitates the faster initiation and execution of the saccade based on the value of each object. In addition, we found a novel class of tonically active neurons that decrease their activity in response to object onset and remain inhibited till the end of the saccade. We suggest that these tonic neurons facilitate the saccade to objects by disinhibiting the interactions between the other three SC neurons.
The state of neural dynamics prior to the presentation of an external stimulus significantly influences its subsequent processing. This neural preparatory mechanism might be of particular importance for crossmodal memory formation. The integration of stimuli across different sensory modalities is a fundamental mechanism underlying the formation of episodic memories. However, the causal role of pre-stimulus neural activity in this process remains largely unclear. In this preregistered study, we investigate the direct relationship between transient brain states induced by sensory entrainment and crossmodal memory encoding. Participants (n = 105) received rhythmic visual stimuli at theta (5 Hz) or alpha (9 Hz) frequencies to evoke specific brain states. EEG recordings confirmed successful entrainment, with sustained increases in neural activity within the stimulated frequency bands persisting until stimulus onset. Notably, induced alpha oscillatory activity enhanced recognition memory performance reflected by increased sensitivity, and suggesting that alpha oscillations prepare the brain for optimal multisensory integration. These findings highlight the functional significance of distinct oscillatory brain states in facilitating memory encoding by increasing cortical excitability before stimulus presentation. Overall, our results emphasize the importance of pre-stimulus brain states in shaping the efficiency of memory formation across sensory modalities and shed light on how dynamic neural preparations support learning. Impact StatementBy using sensory entrainment of pre-stimulus oscillations we could show thatalpha-band stimulation in particular enhanced crossmodal memory. These findings reveal a frequency-specific functional dissociation and highlight the potential of targeting preparatory brain rhythms to improve crossmodal memory formation.
The state of neural dynamics prior to the presentation of an external stimulus significantly influences its subsequent processing. This neural preparatory mechanism might be of particular importance for crossmodal memory formation. The integration of stimuli across different sensory modalities is a fundamental mechanism underlying the formation of episodic memories. However, the causal role of pre-stimulus neural activity in this process remains largely unclear. In this preregistered study, we investigate the direct relationship between transient brain states induced by sensory entrainment and crossmodal memory encoding. Participants (n = 105) received rhythmic visual stimuli at theta (5 Hz) or alpha (9 Hz) frequencies to evoke specific brain states. EEG recordings confirmed successful entrainment, with sustained increases in neural activity within the stimulated frequency bands persisting until stimulus onset. Notably, induced alpha oscillatory activity enhanced recognition memory performance reflected by increased sensitivity, and suggesting that alpha oscillations prepare the brain for optimal multisensory integration. These findings highlight the functional significance of distinct oscillatory brain states in facilitating memory encoding by increasing cortical excitability before stimulus presentation. Overall, our results emphasize the importance of pre-stimulus brain states in shaping the efficiency of memory formation across sensory modalities and shed light on how dynamic neural preparations support learning. Impact StatementBy using sensory entrainment of pre-stimulus oscillations we could show thatalpha-band stimulation in particular enhanced crossmodal memory. These findings reveal a frequency-specific functional dissociation and highlight the potential of targeting preparatory brain rhythms to improve crossmodal memory formation.
Smartphone use varies ranging from rapid, rhythmic tapping (e.g., texting) to slower, irregular scrolling (e.g., browsing), resulting in diverse temporal patterns of inter-touch intervals. The underlying brain processes may dynamically align to these behaviors. We investigated population neural signals captured by using EEG during hour long smartphone use sessions (n = 53 subjects, accumulating 136869 interactions). We grouped the brain signals according to the transition patterns between consecutive touchscreen intervals (next-interval statistics), resulting in a matrix of EEG signals. Using data-driven dimensionality reduction on this matrix, we identified low-dimensional neuro-behavioral clusters that captured brain signal features associated with specific next-interval statistics. These neuro-behavioral clusters were found for diverse cortical locations spanning occipital, parietal and frontal cortices, suggesting a cortex-wide alignment to the next-interval statistics. Notably, these clusters were observed predominantly before rather than after the touchscreen interactions and they varied across individuals, suggesting personalized strategies for planning and executing smartphone use. Our findings indicate that the brain tracks and adapts to the fine-grained temporal patterns in touchscreen behavior, likely to support efficient smartphone interactions. More broadly, this work demonstrates how naturalistic smartphone use can reveal dynamic, individualized cortical adaptations to real-world temporal structure.
Acute stress triggers the release of stress hormones such as cortisol, increasing stress reactivity and aiding post-stress recovery. Prior work in rodents revealed the modulating role of the gut microbiota in stress reactivity, but whether this is also the case in humans is unclear. Additionally, to what degree stress reactivity is tied to ones capacity to produce microbial metabolites such as short-chain fatty acids (SCFAs) is untested. To close this gap, we invited 80 healthy human adults to the laboratory who were either exposed to a well-established, standardized intervention that induced acute stress or to a non-stressful control condition (n = 40 per group). Changes in stress hormones were assessed from repeated saliva sampling. Stool samples were obtained at baseline, and the gut microbiota were characterized through 16S rRNA gene amplicon sequencing. We found that higher gut microbiota diversity was associated with lower cortisol stress reactivity and lower levels of subjectively experienced stress, but not faster post-stress recovery, across the individuals of the stress group. Moreover, lower cortisol stress reactivity was associated with a higher relative abundance of taxa that encode metabolic pathways for the production of butyrate, a key SCFA. These results are the first to highlight the role of gut microbial diversity and inferred butyrate production capacity in modulating stress reactivity in healthy adults, underscoring the microbiotas potential to buffer against the detrimental effects of acute stress.
Visceral pain-related fear, shaped by associative learning, drives maladaptive emotional reactions and may contribute to the chronicity of pain in disorders of gut-brain interaction. However, the role of contingency awareness remains unclear. In a translational model of pain-related conditioning, we investigated the brain-behavior relationships underlying contingency awareness in shaping the neural circuitry involved in visceral pain-related fear and safety learning. Data from 75 healthy individuals undergoing differential conditioning were acquired in two functional magnetic resonance imaging studies. Visceral pain as unconditioned stimulus (US) was paired with a visual cue as conditioned stimulus (CS+) while another cue (CS-) remained unpaired. Differential neural responses to predictive cues were analyzed using a full factorial model and regression analyses to evaluate the predictive value of neural activation patterns based on contingency awareness. Analyses revealed a significant interaction between CS-type and contingency awareness involving dorsolateral prefrontal cortex (dlPFC) and parahippocampus, driven by an enhanced CS+>CS- differentiation in highly aware participants. The reverse contrast revealed widespread activation in fronto-parietal and limbic networks, more pronounced in the highly aware group. Regression analyses showed that enhanced CS--related were associated with increased contingency awareness and CS- valence change, while no activation clusters predictive of behavioral responses were found for CS+. The recruitment of emotional arousal and executive control networks as a function of contingency awareness highlights its relevance in shaping pain- and, particularly, safety-predictive cue properties. These results suggest distinct processes for fear acquisition and inhibition, with significant implications for exposure-based treatments of disorders of gut-brain interaction.
Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a progressive inherited retinal degenerative disorder currently lacking effective treatments. A recurrent 3-base pair deletion in the RHO gene, resulting in the loss of isoleucine at codon 255 or 256 (RHO{Delta}I255 or RHO{Delta}I256), has been identified in patients from the United Kingdom, Germany, Belgium, China, and Korea, suggesting a broad geographic distribution. This mutation leads to rhodopsin (RHO) misfolding, its retention in the endoplasmic reticulum (ER), and aggregation with wild-type (WT) RHO, ultimately triggering ER stress and photoreceptor degeneration. These aggregates are primarily cleared via the ER-associated degradation (ERAD) pathway, with valosin-containing protein (VCP) playing a key role in their retrotranslocation and proteasomal degradation. Pharmacological or genetic inhibition of VCP has shown neuroprotective effects in other models of adRP, but the poor aqueous solubility of VCP inhibitors and challenges in retinal drug delivery hinders clinical translation. To overcome these limitations, we evaluated and compared three VCP-targeted therapeutic strategies in Rho{Delta}I255 knock-in mouse retinae: (1) small-molecule inhibitors (ML240, NMS-873) solubilized in DMSO, (2) ML240 encapsulated in monomethoxy-polyethylene glycol (mPEG)-cholane nanoparticles, and (3) small interfering RNA (siRNA) targeting VCP, delivered via magnetic nanoparticles. Neuroprotective effects were assessed in vitro in retinal explants and in vivo following intravitreal injection. Our findings provide the first evidence that VCP inhibition restores RHO trafficking to the outer segments and prevents photoreceptor cell death in the Rho{Delta}I255 model. Among the three approaches, nanocarrier-encapsulated ML240 exhibited superior efficacy, enabling sustained drug delivery and enhanced photoreceptor protection. These results establish a preclinical proof-of-concept for nanocarrier-mediated VCP inhibition as a promising therapeutic strategy for RHO-adRP and potentially other ER-stress-related retinal degenerations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/661245v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@12f9366org.highwire.dtl.DTLVardef@76437dorg.highwire.dtl.DTLVardef@48dd6corg.highwire.dtl.DTLVardef@1c11812_HPS_FORMAT_FIGEXP M_FIG C_FIG
Frontal Cortex (FC) plays a pivotal role in controlling actions and their dynamics in response to incoming sensory stimuli. We explored FC representations of the same stimuli when signifying diametrically opposite behavioral meanings depending on task context. Two groups of ferrets performed Go-NoGo auditory categorization tasks with opposite contingencies and rewards, and varied stimuli. Remarkably, despite the opposite stimulus-action associations, single-unit responses were similar across all tasks, being more sustained and stronger to (Target) sounds signaling a change in action, than to (Reference) sounds indicating maintenance of ongoing actions, especially during task engagement. Three major dynamic response profiles were extracted from the overall responses, and their combination defined separate neuronal clusters that exhibited different roles in relation to task events. Decoding based on the temporal structure of the population responses revealed distinct decoders that were aligned to different task events. Furthermore, the {beta}-band power, extracted from the FC local field potentials, was similarly and strongly modulated during Target stimuli in all tasks despite opposite behavioral actions. Based on these findings, we propose a model of pathway-specific functional projections from the tripartite FC neuronal clusters to the basal ganglia that is consistent with previous evidence for the conjoint roles of the FC and striatum in adaptive motor control.
Sensory operators are classically modelled using small circuits involving canonical computations, such as energy extraction and gain control. Notwithstanding their utility, circuit models do not provide a unified framework encompassing the variety of effects observed experimentally. We develop a novel, alternative framework that recasts sensory operators in the language of intrinsic geometry. We start from a plausible representation of perceptual processes that is akin to measuring distances over a sensory manifold. We show that this representation is sufficiently expressive to capture a wide range of empirical effects associated with elementary sensory computations. The resulting geometrical framework offers a new perspective on state-of-the-art empirical descriptors of sensory behavior, such as first-order and second-order perceptual kernels. For example, it relates these descriptors to notions of flatness and curvature in perceptual space.
Efforts to restore vision via neural implants have outpaced the ability to predict what users will perceive, leaving patients and clinicians without reliable tools for surgical planning or device selection. To bridge this critical gap, we introduce a computational virtual patient (CVP) pipeline that integrates anatomically grounded phosphene simulation with task-optimized deep neural networks (DNNs) to forecast patient perceptual capabilities across diverse prosthetic designs and tasks. We evaluate performance across six visual tasks, six electrode configurations, and two artificial vision models, positioning our CVP approach as a scalable pre-implantation method. Several chosen tasks align with the Functional Low-Vision Observer Rated Assessment (FLORA), revealing correspondence between model-predicted difficulty and real-world patient outcomes. Further, DNNs exhibited strong correspondence with psychophysical data collected from normally sighted subjects viewing phosphene simulations, capturing both overall task difficulty and performance variation across implant configurations. While performance was generally aligned, DNNs sometimes diverged from humans in which specific stimuli were misclassified, reflecting differences in underlying decision strategies between artificial agents and human observers. The findings position CVP as a scientific tool for probing perception under prosthetic vision, an engine to inform device development, and a clinically relevant framework for pre-surgical forecasting.
The healthy human eyes optical components are misaligned. Although important in studying vision quality, it has been overlooked in research on binocular and oculomotor vision. This study presents the construction of ocular torsion in the binocular system that incorporates the fovea displaced from the posterior pole and the lens tilted away from the eyes optical axis. When the eyes binocular posture changes, each eyes torsional position transformations, computed in the framework of Rodrigues vector, are visualized in GeoGebra simulations. Listings law, important in oculomotor control by constraining a single eye redundant torsional degree of freedom, is ab initio formulated for bifoveal fixations in the binocular system with misaligned optical components for the fixed upright head. It leads to the configuration space of binocularly constrained eyes rotations, including the noncommutativity rule. This formulation modifies the Listing plane of the straight-ahead eyes primary position by replacing it with the binocular eyes posture corresponding to the empirical horopters abathic distance fixation, a unique bifoveal fixation for which the longitudinal horopter is a straight frontal line. Notably, it corresponds to the eye muscles natural tonus resting position, which serves as a zero-reference level for convergence effort. Supported by ophthalmology studies, it revises the elusive neurophysiological significance of the Listing plane. Furthermore, the binocular constraints couple 3D changes in the eyes orientation and, hence, torsional positions during simulations with GeoGebras dynamic geometry. The binocular Listings law developed here can support this coupling, which is important in oculomotor control. The results obtained in this study should be a part of the answers to the questions posted in the literature on the relevance of Listings law to clinical practices. Author summaryOur eye optical components are misaligned: the fovea is displaced from the eyes posterior pole, and the lens is tilted away from the optical axis. Listings law, important in oculomotor control, has not only overlooked the misaligned eyes optics but was also formulated for a single eye, with a later ad hoc extension added for binocular vision. The purpose of Listings law is to constrain the eyes redundant torsional degrees of freedom, thereby supporting neural processing in the development of our spatial understanding by controlling the noncommutativity of the eyes rotations. This goal cannot be fully met because Listings law is monocular, but we acquire an understanding of the scene through bifoveal fixations on objects. In this work, I construct ocular torsion that accounts for the eyes misaligned optics and incorporate it into Listings law. It directly leads to its first ab initio consistent binocular formulation, which is visualized in a computer simulation. Supported by ophthalmological studies, it revises the still elusive neurophysiological significance of the Listing plane, the basic ingredient of Listings law. It also resolves the persistent lack of a generally accepted explanation for Listings law. The results of this study are likely to be important in the ongoing discussion in the literature regarding the relevance of Listings law to clinical practices.
Rhythmic ability has been studied for more than a century in laboratory settings testing timed finger taps. While robust results emerged, it remains unclear whether these findings reflect behavioral limitations in realistic scenarios. This study tested the synchronization-continuation task in a museum with 455 visitors of a wide variety of ages (5-74yrs), musical experiences (0-40yrs) and educational and cultural backgrounds. Adopting a dynamic systems perspective, three metronome pacing periods were anchored around each individuals preferred tempo, and 20% faster and 20% slower. Key laboratory findings were replicated and extended: timing error and variability decreased during childhood and increased in older adults and were lower, even with moderate musical experience. Consistent with an oscillator perspective, timing at non-preferred tempi drifted toward their preferred rate. Overall, these findings demonstrate that timing limitations may reflect attractor properties of a neural oscillator and its signature is still present even in noisy, naturalistic settings.
Interoceptive attention--the ability to selectively focus on internal bodily signals--has been linked to distinct neural responses, yet the contribution of oscillatory dynamics to this process remains underexplored. This study investigates the neural mechanisms underlying interoceptive attention by examining beta-band power suppression during heartbeat and auditory discrimination tasks. Fifty-one healthy participants engaged in interoceptive (heartbeat detection) and exteroceptive (auditory discrimination) tasks while their brain activity was measured using magnetoencephalography (MEG). The results revealed significant beta suppression time-locked to the R-peak in the somatosensory cortex, anterior cingulate cortex, mid-cingulate cortex, and dorsolateral prefrontal cortex from 310 to 530 ms post-R-peak. Beta suppression was more pronounced during interoceptive attention, correlating positively with interoceptive accuracy. The findings support the notion that beta suppression in fronto-cingulo- somatosensory network may serve as a neural marker of interoceptive processing, contributing to predictive coding models of interoception. This study highlights the potential for using beta suppression as an objective measure of interoceptive accuracy and suggests that neural oscillations play a critical role in the brains regulation of heartbeat-related information. Furthermore, the study proposes that interoceptive attention involves a top-down mechanism that dynamically adjusts the brains response to cardiac afferent signals, enhancing the precision of interoceptive processing. These findings have implications for understanding how the brain integrates interoceptive signals and may provide insights into clinical applications targeting interoceptive dysfunctions.
Alzheimers disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimers disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1{Delta}E9/WT, PSEN1M146V/WT, or APPswe/WT. Our CO model reveals time-progressive accumulation of amyloid beta (A{beta}) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of A{beta} and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.
Study ObjectivesTo investigate associations between social jetlag and developing brain circuits and structures in adolescents. MethodsN = 3507 youth (median (IQR) age = 12.0 (1.1) years; 50.9% females) from the Adolescent Brain Cognitive Development (ABCD) cohort were studied. Social jetlag (adjusted for sleep debt (SJLSC) versus non-adjusted (SJL)), topological properties and intrinsic dynamics of resting-state networks, and morphometric characteristics were analyzed. ResultsOver 35% of participants had SJLSC [≥]2.0 h. Boys, Hispanic and Black non-Hispanic youth, and/or those at later pubertal stages had longer SJLSC ({beta}=0.06 to 0.68, CI=[0.02, 0.83], p[≤]0.02), which was also associated with higher BMI ({beta}=0.13, CI=[0.08, 0.18], p<0.01). SJLSC and SJL were associated with weaker thalamic projections ({beta}=- 0.22, CI=[-0.39, -0.05], p=0.03), potentially reflecting a disrupted sleep-wake cycle. Longer SJLSC was also associated with less topologically resilient and weakly connected salience network ({beta}=-0.04, CI=[-0.08, -0.01], p=0.04), and lower thickness and/or volume of cortical and subcortical structures overlapping with this and other networks supporting emotional and reward processing and regulation, and social function ({beta}=- 0.08 to -0.05, CI=[-0.12, -0.01], p<0.05). SJLSC and SJL were associated with alterations in spontaneous brain activity and coordination that indicate disrupted neural maturation and plasticity. SJL was associated with lower information transfer between regions supporting sensorimotor integration, social function and emotion regulation ({beta}=-0.07 to-0.05, CI=[-0.12, -0.01], p<0.04). ConclusionsMisaligned sleep may have detrimental effects on adolescent brain circuit organization and dynamics, and structural characteristics of regions that play critical roles in cognitive function and regulation of fundamental biological processes.
Adolescence is a critical period that requires balancing exploration of uncertain and novel environments while maintaining safety. This task requires sophisticated neural integration of threat and safety cues to guide behavior. Yet little work has been conducted on threat and safety processing outside of conditioning paradigms, which, while valuable, lack the complexity to identify how the adolescent brain supports distinguishing threat from safety when both are present and as task contingencies change. In the current study, we take an approach that expands on elements of differential conditioning as well as conditioned inhibition. We recorded brain responses to external threat and self-oriented protection cues to examine how the adolescent brain supports threat-safety discrimination using 7-Tesla functional magnetic resonance imaging (fMRI). Our findings reveal an adolescent transition in the neural mechanisms supporting accurate threat-safety discrimination, with younger adolescents (12-14 years) relying predominantly on the hippocampus and older adolescents (15-17 years) utilizing a more integrated circuit involving the hippocampus and anterior ventromedial prefrontal cortex (vmPFC) connectivity. Our results clarify how competition between threat and safety cues is resolved within the visual cortex, demonstrating enhanced perceptual sensitivity to protection that is independent of threat. By examining the dynamic encoding of safety to different stimuli, the current study advances our understanding of adolescent neurodevelopment and provides valuable insights into threat-safety discrimination beyond conventional conditioning models. HighlightsO_LIProtection is more strongly weighted than threat in adolescent safety estimation. C_LIO_LIHippocampus aids accurate safety detection in younger adolescents. C_LIO_LIHippocampal-vmPFC connectivity aids accurate safety detection in older adolescents. C_LIO_LIProtection enhances visual processing, reflecting perceptual prioritization. C_LI
Normative modeling provides a principled framework for quantifying individual deviations from typical brain development and is increasingly used to study heterogeneity in neuropsychiatric conditions. While widely applied to structural phenotypes, functional normative models remain underdeveloped. Here, we introduce MEGaNorm, the first normative modeling framework for charting lifespan trajectories of resting-state magnetoencephalography (MEG) brain oscillations. Using a large, multi-site dataset comprising 1,846 individuals aged 6-88 and spanning three MEG systems, we model relative oscillatory power in canonical frequency bands using hierarchical Bayesian regression, accounting for age, sex, and site effects. To support interpretation at multiple scales, we introduce Neuro-Oscillo Charts, visual tools that summarize normative trajectories at the population level and quantify individual-level deviations, enabling personalized assessment of functional brain dynamics. Applying this framework to a Parkinsons disease cohort (n = 160), we show that normative deviation scores reveal disease-related abnormalities and uncover a continuum of patients in theta-beta deviation space. This work provides the first lifespan-encompassing normative reference for MEG oscillations, enabling population-level characterization and individualized benchmarking. All models and tools are openly available and designed for federated, continual adaptation as new data become available, offering a scalable resource for precision neuropsychiatry.
Traditional models of brain connectivity have primarily focused on pairwise interactions, over-looking the rich dynamics that emerge from simultaneous interactions among multiple brain regions. Although a plethora of higher-order interaction (HOI) metrics have been proposed, a systematic evaluation of their comparative properties and utility is missing. Here, we present the first large-scale analysis of information-theoretic and topological HOI metrics, applied to both resting-state and task fMRI data from 100 unrelated subjects of the Human Connectome Project. We identify a clear taxonomy of HOI metrics -- redundant, synergistic, and topological--, with the latter acting as bridges along the redundancy-synergy continuum. Despite methodological differences, all HOI metrics align with the brains overarching unimodal-to-transmodal functional hierarchy. However, certain metrics show specific associations with the neurotransmitter receptor architecture. HOI metrics outperform traditional pairwise models in brain fingerprinting and perform comparably in task decoding, underscoring their value for characterizing individual functional profiles. Finally, multivariate analysis reveals that -- among all HOI metrics -- topological descriptors are key to linking brain function with behavioral variability, positioning them as valuable tools for linking neural architecture and cognitive function. Overall, our findings establish HOIs as a powerful framework for capturing the brains multidimensional dynamics, providing a conceptual map to guide their application across cognitive and clinical neuroscience.
This research challenges the traditional localizationist view that brain tumors affect only regions directly associated with the lesion, by examining whether they also induce macrostructural alterations in the contralesional hemisphere. We applied Voxel-Based Morphometry, linear regression, and Principal Component Analysis (PCA) to a cohort of 107 adults, including patients with gliomas in the language-dominant left hemisphere and healthy participants. Unlike previous studies, a subset of the clinical population was followed longitudinally for up to four months after oncological treatment, allowing us to describe the temporal progression of structural grey matter changes. Interestingly, a principal component model based on anomaly detection enabled robust differentiation between patients and controls. Patients exhibited significantly greater grey matter volume in the contralesional hemisphere compared to healthy participants, and these structural differences evolved over time, improving the models AUC-ROC metrics. Although exploratory, a correlation analysis revealed that these structural changes were negatively associated with postsurgical cognitive performance. Together with the PCA findings, these results suggest that brain tumors induce extensive and dynamic adaptive mechanisms in the contralateral, unaffected hemisphere, likely reflecting altered patterns of structural covariance rather than simple regional volume increases. Understanding whether these changes could represent potential predictors of postoperative cognitive recovery is crucial for developing comprehensive clinical strategies. Key PointsO_LILeft-hemisphere tumors induce contralesional grey matter increases pre- and post-sugery C_LIO_LIPCA detects altered structural covariance and distinguishes patients from healthy participants C_LIO_LIContralesional grey matter volume changes correlate with postoperative cognitive performance C_LI Importance of the StudyThis study challenges the traditional view that brain tumors cause only localized effects by demonstrating widespread macrostructural alterations in the contralesional hemisphere. We reveal increased grey matter volume and altered patterns of structural covariance outside the tumor region. Longitudinal follow-up after surgery shows these changes are dynamic and evolve over time. Further, we identify moderate associations between contralesional grey matter alterations and cognitive performance, suggesting a link between large-scale neuroplastic responses and functional outcomes. These findings offer new insights into tumor-related neuroplasticity and position structural covariance as a promising marker for tracking brain-wide adaptation in this population. The study has translational relevance for developing predictive tools to monitor recovery and guide personalized rehabilitation.
Rett Syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in the X-linked MECP2 gene, results in profound life-long neurological dysfunction. RTT patients live an apparently normal initial life until 12-18 months of age following which, a progressive accumulation of a wide range of phenotypic manifestations sets in. While MeCP2 is known to regulate chromatin, its impact on global histone composition and dynamics remains poorly understood. Here, we combine mass spectrometry imaging (MSI) and laser capture microdissection (LCM) coupled to LC-MS/MS to systematically profile histone proteoforms in three key brain regions: the dentate gyrus (DG) and cornu ammonis (CA) of the hippocampus, and the cerebellum (Cb). Our analysis reveals striking neuron-specific differences in histone composition between Mecp2-deficient and wildtype (WT) mice. Interestingly, the expression of a pathogenic Mecp2 missense mutant (Y120D) results in subtler changes in histone composition that are distinct from the null mutations. This study provides the first spatially resolved epigenetic atlas of histone proteoforms in RTT and suggests that Mecp2 loss perturbs chromatin homeostasis in a neuron- and mutation-dependent manner. Our findings underscore the critical need for cell-type-resolved analyses to unravel the mechanistic underpinnings of RTT and emphasize the importance of personalised therapeutic strategies that consider both the affected cell-type and particular Mecp2 mutation.
Huntingtons disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Two major molecular drivers--somatic expansion of inherited CAG repeats and toxic mutant HTT (mHTT) variants--lead to neuronal dysfunction. Despite multiple trials, HTT-lowering strategies have not shown meaningful clinical benefit. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MSH3 (a key regulator of somatic expansion), HTT, or both. In Q111 HD mice (>110 CAGs), which exhibit robust expansion, mHTT inclusions, and transcriptional dysregulation by 12 months, long-term MSH3 silencing blocked expansion, reduced inclusions, and reversed gene expression changes. HTT silencing alone had limited effect, but combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based co-silencing of MSH3 and HTT as a disease-modifying strategy for HD.
Retinal degenerative diseases are a major cause of blindness in humans that often result in permanent and progressive loss of vision. Unlike humans, zebrafish possess the remarkable ability to regenerate lost retinal neurons through Muller glia (MG) reprogramming and asymmetric cell division to produce multipotent retinal progenitor cells (RPCs). While most studies on the molecular mechanisms underlying this regeneration process have focused on intracellular mechanisms, the role of the microenvironment surrounding retinal cells, the extracellular matrix (ECM), has been understudied. Laminins are heterotrimeric glycoproteins, are principal components of the ECM basement membrane, and play important roles in vertebrate retinal development. Here, we examine the role of {beta}1b chain-containing laminins in the regenerative response of the zebrafish retina. We found that the zebrafish lamb1b gene is differentially expressed during MG reprogramming and MG and NPC proliferation during retinal regeneration. Further, we found that {beta}1b-containing laminins play important roles in regulating MG and NPC proliferation and neuroprotection of photoreceptors in light-damaged zebrafish retinas. Finally, Lam{beta}1b plays an important role in regulating the expression of integrin receptors and other laminin genes during the regeneration response. Taken together, Lam{beta}1b, and likely other ECM components, play a critical role in the MG-dependent neuronal regeneration response in the zebrafish retina.
Sensory perception often relies on the brains integration of multiple noisy inputs (cues), a process known as cue combination. Cue combination within the sense of touch has been understudied. Here, we investigated whether humans optimally combine haptic cutaneous and hand configuration cues when discerning the size (e.g., diameter) of a disk held edge-on between the thumb and index fingers. When these two fingers span the diameter of a disk to contact its perimeter, a hand configuration cue (relating to the perceived distance between the fingers) provides information about the disks size. Less obviously, cutaneous cues to disk size may be provided simultaneously from the indentation of the skin caused by the curvature of the disk (smaller disks cause greater indentation). It is unknown whether humans make use of all these cues when perceiving the size of the held object, and if so, whether they integrate the cues optimally. We considered three hypotheses for how humans might use these cues: they might rely solely on the least noisy cue (Winner-Take-All Model, WTA), combine cues based on a simple arithmetic average (Average-Measurement Model, AVG), or combine cues via an optimal weighted average (Optimally-Weighted Model, OPT). In three experiments involving 34 participants, we measured the reliabilities of these cues and compared participant performance to the predictions of the three models. Each experiment tested participants using a two-interval forced-choice (2IFC) paradigm with 3D printed disk stimuli. On each trial, under occluded vision, participants felt two disks sequentially and responded which felt larger. Participants were tested with each fingers cutaneous cue alone, the configuration cue alone, and all three cues together. In two experiments, the disks presented were circular. In a third experiment, unknown to participants, some of the presented disks were oval-like cue-conflict stimuli. The improvement of accuracy observed in multi-cue conditions over single-cue conditions, and the Point of Subjective Equality (PSE) shifts observed in cue-conflict conditions, were consistent with optimal cue combination. We conclude that humans are capable of combining haptic cutaneous and configuration cues optimally to judge the sizes of held objects.
The brains resting-state activity can serve as an indicator of cognitive flexibility and predict the likelihood of an upcoming Aha experience. This suggests that spontaneous neural dynamics reflect a persons readiness for creative insight and underscore the potential of resting-state measures as biomarkers for anticipating creative breakthroughs. However, solutions accompanied by an Aha experience are not always truly creative, so it may be more valuable to identify biomarkers specifically linked to novelty and usefulness--two key dimensions of creative performance. To achieve this, we recruit 49 participants to complete the Alternative Uses Test, in which unconventional uses for everyday items are generated. We evaluate the responses for both novelty and feasibility using automated GPT-based methods and analyze resting-state EEG prior to the test. We find that creative performance is better predicted by interactions between different brain areas than by the activation of individual regions. Specifically, the degree centrality of theta-band functional connectivity in the right parietal and occipital areas correlates with novelty, while connectivity in the right middle and inferior frontal areas is associated with more feasible answers. These findings highlight distinct resting-state brain networks underlying the "creative potential" for novelty and feasibility, which could be leveraged to monitor and enhance brain flexibility. Significance statementOur study introduces the Creativity Potential Network (CPN), a resting-state brain network that can predict the novelty and feasibility of the upcoming solution in creative problem-solving. We show that the CPN is represented by communication between brain areas, and that the networks for novelty and feasibility are spatially distinct. This work provides a potential method to assess the potential to be creative without relying on behavioral measures and could be combined with neurofeedback to monitor and enhance brain flexibility.
In glaucoma, the optic nerve head (ONH) is exposed to increased biomechanical strain, impacting the resident astrocytes that maintain neural homeostasis. After injury, astrocytes exhibit morphologic and metabolic shifts; however, the specific impact of glaucoma-related biomechanical strains on astrocyte behavior remains poorly understood. To address this, we utilized our previously established 3D cell-encapsulated ECM hydrogel to elucidate ONH astrocyte transcriptomic and cellular responses to varying biomechanical strain levels over time. Murine ONH astrocyte-encapsulated hydrogels were subjected to 0, 3, or 10% cyclic strain for 4h and 24h. Using confocal reflectance microscopy, we observed that hydrogel porosity was adequate for nutrient supplementation, while bulk hydrogel stiffness and cell viability remained unchanged after biomechanical strain. Mechanotranscriptional responses were robustly altered within 4h in a hydrogel region-, strain-, and time-dependent manner. RNA sequencing revealed changes in gene expression related to cell morphology, division, senescence, hypoxia, metabolism, and ECM regulation. Morphometric analyses of strained ONH astrocytes showed reduced F-actin area coverage, increased GFAP, HIF-1, fibronectin, and collagen fibril reorganization. Our findings demonstrate that ONH astrocyte transcriptional responses are highly dependent on duration/magnitude of biomechanical strain and surrounding ECM density, corresponding with altered cell morphology, hypoxia, and ECM modification. This ONH astrocyte-encapsulated hydrogel provides a valuable platform for nuanced future manipulation of porosity, ECM composition, and cellularity to study the impact of biomechanical strain on ONH pathophysiology.
Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) as one of the key imaging biomarkers. Our understanding of its pathophysiology remains limited due to the lack of appropriate animal models. We report a novel mouse CMB model created by disrupting collagen IV, a core component of the vascular basement membrane (BM), specifically within brain microvessels. Targeted deletion of Col4a1 was achieved in adult mice using brain endothelial-specific AAV vectors with CRISPR/Cas9. MRI revealed numerous CMBs with distributions similar to those of human CMBs. CMB burden increased progressively over six months following Col4a1 deletion in a dose-dependent manner, accompanied by cognitive decline and motor incoordination. Histological examination revealed hemosiderin deposits corresponding to MRI-detected CMBs without evidence of macroscopic hemorrhage or white matter lesions, while ultrastructural analysis demonstrated significant BM thinning in Col4a1-depleted microvessels. Analysis of human MRI and genomic data identified significant associations between CMB susceptibility and genetic variants in TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2, underscoring the clinical relevance of our model. These findings establish a direct causal relationship between microvessel COL4A1 and CMB, suggesting that dysregulated collagen IV homeostasis in BM underlies CMB development.
Cocaine addiction is marked by high relapse rates, often triggered by drug-associated cues. These cues can be conditioned stimuli (CSs), which occur after drug intake and are paired with drug effects, and discriminative stimuli (DSs), which signal drug availability, regardless of ongoing drug-seeking behaviour. While projections from the infralimbic cortex (IL) to the nucleus accumbens (NAc) shell are known to regulate CS-induced cocaine relapse, their role in DS-triggered relapse is not known. To investigate this, we examined how activating IL[->]NAc shell projections influences relapse driven by DSs and CSs during abstinence from intermittent cocaine use. Female Sprague-Dawley rats received viral-mediated gene expression of excitatory designer receptors exclusively activated by designer drugs in the IL. Rats then self-administered cocaine during 12 intermittent-access sessions (5-min cocaine ON/25-min cocaine OFF, 4h/day). A discrete light (DS+) signalled drug-available periods, while a different light (DS-) signalled drug non-availability. During each DS+ period, cocaine infusions were paired with a compound light-tone (CS+). Four weeks later, rats were tested for cue-induced cocaine seeking following response-independent presentation of DS+, CS+ or both. Immediately prior to testing, rats received intra-NAc shell clozapine N-oxide or aCSF to activate IL terminals. DS+ alone and DS+/CS+ combined triggered greater cocaine seeking than did the CS+. Activation of IL[->]NAc shell projections suppressed relapse behaviour in DS+ and DS+/CS+ conditions. These findings highlight the distinct and powerful influence of DSs on relapse and identify the IL[->]NAc shell circuit as a promising target for relapse prevention.
Amyloid-{beta} (A{beta}) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE {varepsilon}4, a key genetic risk factor for Alzheimers disease (AD). Although the presence of A{beta}, tau, and APOE {varepsilon}4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9{+/-}5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. A{beta} was measured using CSF A{beta}42/A{beta}40 or Florbetaben-PET imaging and tau was measured using CSF pTau181. Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE {varepsilon}4 was independently associated with greater A{beta} and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE {varepsilon}4. Among APOE {varepsilon}4 non-carriers, A{beta} burden was linked to a pattern of hippocampal hyperactivity. Among APOE {varepsilon}4 carriers, CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE {varepsilon}4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD. Significance StatementHippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimers disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by APOE {varepsilon}4 in cognitively unimpaired older adults. Amyloid-{beta}-related hyperactivity was observed in the hippocampus among APOE {varepsilon}4 non-carriers, while CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE {varepsilon}4 carriers. Our findings highlight synergistic effects of APOE and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.
The reproduction of a perceived stimulus, such as a distance or a duration, is often influenced by two biases. Central tendency indicates that reproductions are biased toward the mean of the stimulus distribution. Serial dependence reflects that the reproduction of the current stimulus is influenced by the previous stimulus. Although these biases are well-documented, their origins remain to be determined. Studies on duration reproduction suggest that autocorrelation within a stimulus sequence may play a role. In this study, we explored whether the level of autocorrelation in a stimulus sequence affects central tendency and serial dependence in vestibular path integration. Participants (n = 24) performed a vestibular distance reproduction task in total darkness by actively replicating a passively moved stimulus distance with a linear motion platform. We compared two conditions: a high-autocorrelation condition, where stimulus distances followed a random walk, and a no-autocorrelation condition, where the same distances were presented in a randomly shuffled order. We quantified both biases using two approaches: separate simple linear regressions and a joint multiple linear regression model that accounts for the autocorrelation in the stimulus sequence. Simple linear regressions revealed that central tendency was weaker and serial dependence reversed in the high-autocorrelation condition compared to the no-autocorrelation condition. However, these differences were no longer observed in the multiple linear regression analysis, indicating that these biases were independent of the specific stimulus sequence protocol. We conclude that these perceptual biases in vestibular path integration persist regardless of stimulus autocorrelation, suggesting that they reflect robust strategies of the brain to process vestibular information in self-motion perception. Author summaryHow are we able to successfully navigate our surroundings? An essential part of navigation is distance estimation based on self-motion signals. We previously found that distance reproductions based on vestibular self-motion signals were affected by stimulus history. Reproductions showed a central tendency toward the mean of the stimulus distribution and an attractive serial dependence toward the immediately preceding stimulus distance. The stimulus distances were presented in a low-autocorrelation, randomized order. Here we ask whether reproductions show the same central tendency and serial dependence when consecutive stimulus distances are similar (i.e., in a high-autocorrelation, random-walk order). Participants performed a distance reproduction task in the dark: a linear motion platform first passively moved the participant over a stimulus distance, after which they actively reproduced this distance by steering the platform back to the estimated start position. We found that the reproductions showed similar central tendency and attractive serial dependence in both a no- and high-autocorrelation condition, but only if the analysis accounted for the covariation of the two effects in the high-autocorrelation condition. In conclusion, our findings indicate that central tendency and serial dependence of vestibular distance reproductions are not a result of the stimulus sequence protocol, but have neurocognitive origins.
Ultrahigh-density electrocorticography (ECoG) provides unprecedented spatial resolution for recording cortical electrical activity. This study uses simulated scalp projections from an ECoG recording to challenge the assumption that channel-level electroencephalography (EEG) reflects only local field potentials near the recording electrode. Using a 1024-electrode ECoG array placed on the primary motor cortex during finger movements, we applied Adaptive Mixture Independent Component Analysis (AMICA) to decompose activity into maximally independent grid activity components and projected these to 207 simulated EEG scalp electrode channels using a high-definition MR image-based electrical forward-problem head model. Our findings demonstrate how cortical surface-recorded potentials propagate to scalp electrodes both far from and near to the generating location. This work has significant implications for interpreting both EEG and ECoG data in clinical and research applications. Clinical RelevanceThis study provides insights for interpreting scalp EEG data, demonstrating that scalp channel activity represents a complex mixture of distributed cortical source activities rather than primarily activity generated nearest to the scalp electrodes. These findings may hopefully spur improvement in EEG-based diagnostics for neurological disorders.
Amphetamine and nicotine are two widely used and abused drugs that are taken for legitimate pharmaceutical purposes but are also highly abused through illicit recreational use. Both of these drugs have been widely shown to decrease food intake in both humans and pre-clinical models, and although amphetamine and nicotine clearly affect food intake under normal baseline ( homeostatic) conditions, there has been limited examination of the ability of these drugs to affect reward-related ( hedonic) aspects of feeding. Furthermore, there are sex differences in the behavioral responses to both drugs, but it is unclear if these sex differences also translate to their effects on feeding. This study examined whether nicotine and amphetamine regulate sucrose intake in a food self-administration paradigm in a sex-dependent manner across both fixed and progressive schedules of reinforcement. Amphetamine reduced operant responding for sucrose pellets and decreased acute intake of sucrose during ad libitum free-feeding access in a dose-dependent manner, whereas nicotine reduced sucrose self-administration and free intake only at higher doses that also impaired locomotor activity in open field tests. The effects of both amphetamine and nicotine did not differ by sex for either drug. Overall, these results suggest that the mechanisms mediating the addictive qualities of these drugs and their appetite suppressing effects may be distinct and therefore could be a potential target for future obesity therapeutics.
BackgroundThe discovery and development of therapeutics for Parkinsons disease (PD) requires preclinical models and an understanding of the disease mechanisms reflected in each model is crucial to success. ObjectiveTo illuminate disease mechanisms and translational value of two commonly utilized rat models of synucleinopathy - AAV-delivered human mutant hA53T alpha synuclein (-Syn) and -Syn preformed fibril (PFF) injection - using a top-down, unbiased, large-scale approach. MethodsTandem mass tag mass spectrometry (TMT-MS), RNA sequencing, and bioinformatic analyses were used to assess proteins, genes, and pathways disrupted in rat striatum and substantia nigra. Comparative analyses were performed with PD drug candidate targets and an existing human PD and dementia with Lewy body (DLB) proteomics dataset. ResultsUnbiased proteomics identified 388 proteins significantly altered by hA53T--Syn and 1550 by PFF--Syn compared to sham controls. Pathway and correlation analyses of these revealed common and distinct pathophysiological processes altered in each model: dopaminergic signaling/metabolism, mitochondria and energy metabolism, and motor processes were disrupted in AAV-hA53T--Syn, while immune response, intracellular/secretory vesicles, synaptic vesicles, and autophagy were more impacted by PFF--Syn. Synapses, neural growth and remodeling, and protein localization were prominently represented in both models. Analyses revealed potential biomarkers of disease processes and proteins and pathways also altered in patients, elucidating drug targets/ disease mechanisms the models best reflect. ConclusionsAlignment of unbiased multi-omics analyses of AAV-hA53T and PFF--Syn models of synucleinopathy with PD and DLB patient data and PD drug development pipeline candidates identifies optimal models for testing novel therapeutics based on biological mechanisms.
The growing channel count of silicon probes has substantially increased the number of neurons recorded in electrophysiology (ephys) experiments, rendering traditional manual spike sorting impractical. Instead, modern ephys recordings are processed with automated methods that use waveform template matching to isolate putative single neurons. While scalable, automated methods are subject to assumptions that often fail to account for biophysical changes in action potential waveforms, leading to systematic errors. Consequently, manual curation of these errors, which is both time-consuming and lacks reproducibility, remains necessary. To improve efficiency and reproducibility in the spike-sorting pipeline, we introduce here the Spike-sorting Lapse Amelioration System (SLAy), an algorithm that automatically merges oversplit spike clusters. SLAy employs two novel metrics: (1) a waveform similarity metric that uses a neural network to obtain spatially informed, time-shift invariant low-dimensional waveform representations, and (2) a cross-correlogram significance metric based on the earth-movers distance between the observed and null cross-correlograms. We demonstrate that SLAy achieves[~] 85% agreement with human curators across a diverse set of animal models, brain regions, and probe geometries. To illustrate the impact of spike sorting errors on downstream analyses, we develop a new burst-detection algorithm and show that SLAy fixes spike sorting errors that preclude the accurate detection of bursts in neural data. SLAy leverages GPU parallelization and multithreading for computational efficiency, and is compatible with Phy and NeuroData Without Borders, making it a practical and flexible solution for large-scale ephys data analysis.
Spatial long-read technologies are becoming more common but lack nanometer- and therefore often single-cell resolution. This leaves the question unanswered whether spatially variable isoforms represent spatial variability within one cell type or differences in cell-type abundance between different regions. Here, we develop Spl-ISO-Seq2 with 220nm spot size and 500nm resolution, and the accompanying software packages Spl-IsoQuant-2 and Spl-IsoFind and apply it to the adult mouse brain. We compare spatial variability within a fixed cell type by examining (a) differential isoform abundance between known brain regions and (b) spatial isoform patterns that do not align with predefined regions. The former reveals larger numbers of spatial isoform differences, e.g. Rps24 in oligodendrocytes. For the previously appreciated gene with spatially-variable isoforms Snap25, we can now show that this variability exists in excitatory neurons. However, the latter approach reveals patterns that the former cannot conceptually model, e.g., Tnnc1 in excitatory neurons. Taken together, our experimental and analytical methods enrich spatial transcriptomics with a so-far elusive isoform view of spatial variation for individual cell types.
Deep brain stimulation of the temporal cortex can enhance learning and memory in the face of cognitive impairment. Despite the potential of such therapies, the neural and genetic mechanisms underlying the effect of stimulation on human brain circuits are not understood. To explicate direct mechanisms of neural modulation elicited by brain stimulation, we developed an ex vivo approach utilizing microelectrode array stimulation and recording of resected temporal cortex from neurosurgical patients. We find that stimulation preferentially increases firing rates in pyramidal cells compared to interneurons and also strengthens cell assemblies. Using single cell multiomics, we link the observed physiological changes to cell type-specific gene expression patterns. We detail gene regulatory networks that indicate preferential involvement of specific excitatory neuron subtypes and the response of non-neurons. We conclude that the overall impact of stimulation on the human temporal cortex is activation of specific excitatory neurons and enhanced cell assembly activity, and that these changes are supported by gene networks involving immediate early, synaptic, and ion channel genes. Our findings establish a foundation to identify targetable cell type-specific genetic signatures that may be harnessed for therapeutic benefit in future neuromodulation strategies.
Single-cell transcriptomics has uncovered the enormous heterogeneity of cell types that compose each region of the mammalian brain, but describing how such diverse types connect to form functional circuits has remained challenging. Current methods for measuring the probability and strength of cell-type specific connectivity motifs principally rely on low-throughput whole-cell recording approaches. The recent development of optical tools for perturbing and observing neural circuit activity, now notably including genetically encoded voltage indicators, presents an exciting opportunity to employ optical methods to greatly increase the throughput with which circuit connectivity can be mapped physiologically. At the same time, advances in spatial transcriptomics now enable the identification of cell types in situ based on their unique gene expression signatures. Here, we demonstrate how long-range synaptic connectivity can be assayed optically with high sensitivity, high throughput, and cell-type specificity. We apply this approach in the motor cortex to examine cell-type-specific synaptic innervation patterns of long-range thalamic and contralateral input onto more than 1000 motor cortical neurons. We find that even cell types occupying the same cortical lamina receive vastly different levels of synaptic input, a finding which was previously not possible to uncover using lower-throughput approaches that can only describe the connectivity of broad cell types.
Variation in over 100 genes are now associated with increased risk for autism and related neurodevelopmental condition, but how this variation results in distinct and overlapping behavioral changes is still not well understood. Recent efforts have focused on screening many autism genes at once for functional and phenotypic convergence, and identified subsets that are crucial for many early steps of neurodevelopment. Few studies have screened later steps of neurodevelopment, circuit function, circuit plasticity, or behaviors. We screened twenty conserved autism-associated genes for impact on experience-dependent neuron remodeling in C. elegans. Loss of unc-44/ANK2, set-4/KMT5B, daf-18/PTEN, gap-2/SYNGAP1, and chd-1/CHD8 increased, while CACNA2D3/unc-36 decreased, neurite outgrowth of the GABAergic DVB neuron in adults. Although daf-18/PTEN, set-4/KMD5B, and unc-44/ANK2 had convergent phenotypes, they arise from distinct temporal trajectories with differential impact on DVB pre-synaptic morphology. Screening for the DVB regulated spicule protraction behavior identified multiple autism genes involved, but only unc-44/ANK2 and CACNA2D3/unc-36 were shared between screens. Application of a metric geometry computational framework (CAJAL) to the DVB morphology dataset identified 5 additional genes that impact DVB morphology, including unc-2/CACNA1A and unc-10/RIMS1, which also significantly impacted behavior. This work defines new regulators and molecular mechanisms of experience-dependent neuron remodeling and circuit plasticity, and further links these processes with conserved autism genes. It also demonstrates the utility of using intact, behavior generating circuits in C. elegans, to screen for novel roles for conserved autism genes.
Variation in over 100 genes are now associated with increased risk for autism and related neurodevelopmental condition, but how this variation results in distinct and overlapping behavioral changes is still not well understood. Recent efforts have focused on screening many autism genes at once for functional and phenotypic convergence, and identified subsets that are crucial for many early steps of neurodevelopment. Few studies have screened later steps of neurodevelopment, circuit function, circuit plasticity, or behaviors. We screened twenty conserved autism-associated genes for impact on experience-dependent neuron remodeling in C. elegans. Loss of unc-44/ANK2, set-4/KMT5B, daf-18/PTEN, gap-2/SYNGAP1, and chd-1/CHD8 increased, while CACNA2D3/unc-36 decreased, neurite outgrowth of the GABAergic DVB neuron in adults. Although daf-18/PTEN, set-4/KMD5B, and unc-44/ANK2 had convergent phenotypes, they arise from distinct temporal trajectories with differential impact on DVB pre-synaptic morphology. Screening for the DVB regulated spicule protraction behavior identified multiple autism genes involved, but only unc-44/ANK2 and CACNA2D3/unc-36 were shared between screens. Application of a metric geometry computational framework (CAJAL) to the DVB morphology dataset identified 5 additional genes that impact DVB morphology, including unc-2/CACNA1A and unc-10/RIMS1, which also significantly impacted behavior. This work defines new regulators and molecular mechanisms of experience-dependent neuron remodeling and circuit plasticity, and further links these processes with conserved autism genes. It also demonstrates the utility of using intact, behavior generating circuits in C. elegans, to screen for novel roles for conserved autism genes.
Energy expenditure (EE) is essential for metabolic homeostasis, yet its central regulation remains poorly understood. Here, we identify arcuate Kiss1 neurons as key regulators of EE in male mice. Ablation of these neurons induced obesity, while their chemogenetic activation increased brown adipose tissue (BAT) thermogenesis without affecting food intake. This action is mediated by glutamatergic projections from Kiss1ARC neurons to CART/Lepr-expressing neurons in the dorsomedial hypothalamus, which activate the raphe pallidus-BAT pathway. CRISPR-mediated deletion of the vesicular glutamate transporter 2 (Vglut2) from Kiss1ARC neurons replicated the obesogenic effect. Furthermore, deletion of the melanocortin 4 receptor (MC4R) from Kiss1 neurons resulted in obesity, reduced energy expenditure and impaired thermogenesis. Optogenetic stimulation of pro-opiomelanocortin (POMC) fibers evoked inward currents in Kiss1 neurons, that were attenuated by MC4R antagonism. Our findings reveal a previously unrecognized neural circuit that mediates melanocortin action on energy expenditure, offering new insights into central mechanisms of metabolic control.
An axiomatic view in contemporary neuroscience is that EEG components such as event-related brain potentials (ERPs) and oscillations are directly interpretable as manifestations of biological processes that support sensory, motor, and cognitive constructs of interest. This premise justifies and propels research programs in laboratories worldwide, but with a substantial social and economic cost, warranted by the potential for basic-science discovery and the resulting bench-to-bedside transfer for health and disease. But a different premise would be more fruitful. This article proposes that EEG components in psychophysiological experiments relate to cognition indirectly through their more direct relationship with oculomotor action. The common experimental design that includes a baseline ocular fixation period preceding stimulus presentation provides an excellent template with which to develop the present proposal. Electrophysiological and eye-tracking evidence (3 published and 3 new data sets: 6 experiments, Ntotal = 204, in the context of face and affective picture viewing, reading, listening, rest, and microsleep) demonstrates how and why common conclusions, and reliance on them in clinical practice/treatment efficacy and drug development studies, are at best premature. Results indicate that the oculomotor system plays a mediating role between such EEG phenomena and cognition. Present evidence supports a complementary view of how EEG can shape the development of a broader thought horizon in psychophysiological theory and practice.
It has been suggested that hierarchical synchronization of theta and gamma oscillations coordinates neural activity during sequence memory. Yet, the role of gamma oscillations and their interaction with theta and single-unit activity (SUA) has not been directly examined in humans. We analysed simultaneous micro wire recordings of single-unit activity (N = 1417) and local field potentials (N = 917 channels) from the medial temporal lobe (MTL) of epilepsy patients performing a visual multi-item sequence memory task. During encoding, both spiking activity and gamma power contained item-specific information and were temporally coupled. During memory maintenance, stimulus-specific gamma was characterized by recurring bursts during which spiking was tightly synchronized and both, gamma and spiking, were preferentially aligned to similar theta phases predictive of sequential stimulus position. These findings demonstrate that theta-gamma-spike interactions support a phase-based multiplexed code for sequential memories in the human MTL.
Neuroimaging research has identified focal differences in the cerebral cortex of individuals with autism spectrum disorder (ASD), particularly in the cortical folds (sulci) within higher-level association cortices. The present study investigated the sulcal patterning and morphology of the anterior cingulate cortex (ACC) in individuals with ASD compared to neurotypical (NT) individuals for the first time. We used neuroimaging data from 50 NT and 50 ASD participants. All participants were under 20 years old and male. The two groups were age-matched. Using established criteria and cortical reconstructions generated from each participants T1-weighted magnetic resonance imaging scans with FreeSurfer, we identified the defining sulcal feature of ACC, the variably present paracingulate sulcus (PCGS): its presence in the left and right hemispheres, and asymmetry in PCGS presence between hemispheres. Finally, multiple quantitative morphological features (length, depth, and cortical thickness mean and standard deviation) were extracted from the PCGS using FreeSurfer tools. Analyses revealed that NT participants were more likely to have asymmetrical PCGS patterns than ASD participants (controlling for age and scanner site). However, none of the quantitative morphological features differed between groups. These findings suggest the presence of a variation in the prenatal neurodevelopment of ACC in young males with ASD; however, further research is necessary to uncover the role of this observed difference in the pathogenesis of ASD. The present study also adds to the growing literature implicating variations in PCGS patterning as a trait marker across multiple disorders. Lay SummaryThis study found that young males with autism spectrum disorder (ASD) show less hemispheric asymmetry in the presence of a notoriously variable brain structure (paracingulate sulcus (PCGS)) compared to neurotypical individuals. Considering that this feature of the PCGS develops before birth, the reduced asymmetry may indicate focal differences in brain development in ASD. These findings further enhance our understanding of the neurodevelopmental characteristics of ASD and highlight growing findings indicating that the PCGS may be a useful transdiagnostic marker for various psychiatric conditions.
Evidence accumulation models have been successfully applied to decision-making in sensory and cognitive domains; however, it remains unclear how this process is regulated when perceptual ambiguity arises from social-affective content. Here, we integrate computational modeling with multimodal neuroscience to characterize how perceptual ambiguity in emotion judgment shapes decision dynamics. Participants viewed perceptually ambiguous stimuli - morphed images of two categories, such as happy and fearful facial expression - and made binary categorization decisions. Using drift diffusion modeling (DDM), we first demonstrate that drift rate, a key index of evidence accumulation, decreases as perceptual ambiguity increases. Scalp electroencephalography (EEG) data reveal that the magnitude of the late positive potential (LPP) tracks the speed of evidence accumulation in both emotional and non-emotional stimulus categories, but only when the ambiguous dimension is relevant to the categorization decision. Similar to LPP magnitude, single-unit recordings from the dorsomedial prefrontal cortex (dmPFC) and amygdala show that neuronal firing rates in both regions also encode drift rate during the emotion categorization task. Moreover, fMRI-based functional connectivity reveals that the strength of connectivity between the amygdala and dmPFC correlates with individual differences in drift rate. To establish the causal role of the dmPFC, we applied anodal transcranial direct current stimulation (tDCS) targeting the dmPFC in patients with schizophrenia and found that stimulation enhanced evidence accumulation speed in emotion categorization under perceptual ambiguity. These findings identify a distributed corticolimbic circuit that dynamically modulates evidence accumulation during social-affective decision-making under perceptual ambiguity. Our results bridge social-affective and perceptual neuroscience, offering a translational framework for understanding emotion recognition and decision-making impairments.
BACKGROUNDNerve growth factor (NGF), a key mediator of pain and inflammation, is increased in joints with osteoarthritis (OA). Neutralizing NGF with monoclonal antibodies has shown analgesic effects in painful knee OA, but clinical development was stopped due to side effects in the joints. Knowledge about the biological effects of long-term exposure of joint tissues to NGF is limited. Therefore, we aimed to explore the effects of repeated intra-articular (IA) injections of NGF into the knee joints of healthy mice on pain and sensitization, as well as joint innervation and structure. METHODSWe conducted five experiments in male C57BL/6 mice. In Experiment 1, NGF (50ng or 500ng) or vehicle was injected IA into the knee of naive wildtype (WT) mice, twice a week for 4 weeks. We assessed knee swelling, knee hyperalgesia and histopathology. In Experiment 2, mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks and microCT of the knee was performed. In Experiment 3, NaV1.8-tdTomato reporter mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks, and joint innervation was assessed. In Experiment 4, WT mice received 500ng NGF or vehicle twice a week for 4 weeks and were used for single cell RNA sequencing (scRNAseq) of the synovium. In Experiment 5, L3-L5 DRGs of mice that received 3 IA injections of 500ng NGF or vehicle twice a week were used for bulk RNA sequencing. RESULTSRepeated bi-weekly IA injections of NGF caused knee hyperalgesia in naive mice. NGF caused dose-dependent knee swelling, synovial pathology, increased bone mineral density and trabecular bone thickness in the medial subchondral bone, growth of pre-osteophytes in the medial compartment, but no cartilage degeneration. NGF injection caused sprouting of NaV1.8+ neurons in the medial but not the lateral synovium. ScRNAseq of the synovium revealed upregulated genes related to neuronal sprouting, synovial fibrosis and ossification, confirming histopathological findings. Bulk RNA seq of DRG showed upregulated pathways related to axonal growth. CONCLUSIONSIn healthy mouse knees, NGF induced mechanical sensitization, synovitis, neoinnervation in the medial synovium, subchondral bone changes and pre-osteophyte growth in the medial compartment, thus capturing many pathological changes observed in OA, except cartilage damage.
Left ventral occipitotemporal cortex (vOT) is crucial in reading, yet its functional role remains debated. Competing theories paint it as either a prelexical feedforward hub or a bidirectional interface between sensory and higher-order linguistic systems. To address the debate, we investigated the temporal and spectral dynamics of information flow involving left vOT during visual word and pseudoword reading using magnetoencephalography (MEG). The pseudowords varied in the degree to which they orthographically resembled real words. By combining two directed connectivity metrics, i.e., phase slope index (PSI) and Granger causality (GC), we converged on a hybrid model of left vOT function that reconciles the competing perspectives. Feedforward connectivity from low-level visual areas to vOT emerged at around 100 ms post stimulus similarly across all conditions, spanning a wide frequency range. Subsequently, feedforward orthographic information flowed from left vOT to higherorder areas, especially left superior temporal cortex (ST), at the low gamma band. This flow strength was modulated by word-likeness, being stronger for real words and word-like pseudowords than complete pseudowords. Conversely, feedback flow from left ST to vOT was observed in the low beta band for pseudowords, and occurred later for word-like than complete pseudowords. This indicates that greater processing demands modulate the direction of information flow, necessitating top-down linguistic constraints to facilitate reading. Our findings clarify the functional role of left vOT and explain when and why its connectivity may show as feedforward or bidirectional depending on time and task.
Contextual fear conditioning is an experimental framework widely used to investigate how aversive experiences affect the valence an animal associates with an environment. While the initial formation of associative context-fear memories is well studied - dependent on plasticity in hippocampus and amygdala - the neural mechanisms underlying their subsequent consolidation remain less understood. Recent evidence suggests that the recall of contextual fear memories shifts from hippocampal-amygdalar to amygdalo-cortical networks as they age. This transition is thought to rely on sleep. In particular, neural replay during hippocampal sharp-wave ripple events seems crucial, though open questions regarding the involved neural interactions remain. Here, we propose a biologically informed neural network model of context-fear learning. It expands the scope of previous models through the addition of a sleep phase. Hippocampal representations of context, formed during wakefulness, are replayed in conjunction with cortical and amygdalar activity patterns to establish long-term encodings of learned fear associations. Additionally, valence-coding synapses within the amygdala undergo overnight adjustments consistent with the synaptic homeostasis hypothesis of sleep. The model reproduces experimentally observed phenomena, including context-dependent fear renewal and time-dependent increases in fear generalisation. Few neural network models have addressed fear memory consolidation and to our knowledge, ours is the first to incorporate a neural mechanism enabling it. Our framework yields testable predictions about how disruptions in synaptic homeostasis may lead to pathological fear sensitization and generalisation, thus potentially bridging computational models of fear learning and mechanisms underlying anxiety symptoms in disorders such as PTSD. Author SummaryHow do we learn to fear certain environments? Why do some fear memories fade while others persist or even grow stronger over time? Scientists have long used laboratory experiments to study how animals associate danger with a particular context. These studies have helped identify brain regions involved in fear learning, including the amygdala, hippocampus, and cortex, and have inspired many computational models of how fear is acquired in the brain. However, most models focus only on what happens when fear is first learned, overlooking how these memories evolve in the days that follow and the role of sleep in this process. In this work, we present a neural network model that captures how fear memories are strengthened or reshaped during sleep. It builds on earlier models by incorporating memory replay and synaptic homeostasis, two brain processes believed to support emotional memory consolidation. Our model identifies neural processes that help make fear memories persistent, suggests that sleep is necessary to maintain adaptive behaviour after threatening experiences, and proposes that sleep disruptions mediate the harmful impact of stress on emotional regulation. By extending amygdala-based models of fear learning to include post-learning dynamics, our work offers new insight into how emotional memories are stabilised.
Brain-wide neural circuits are formed by the diverse axonal branching patterns of many individual neurons. Here we introduce POINTseq (projections of interest by sequencing), a high-throughput and user-friendly barcoded connectomics method that uses cell type specific barcoding and sequencing to rapidly map single-cell projections of a cell type of interest for thousands of neurons per animal. POINTseq leverages pseudotyping of Sindbis virus and a specific alphavirus-cellular receptor pair to make Sindbis infections cell type specific. It thus integrates MAPseq-style high-throughput barcoded projection mapping with the established viral-genetic neural circuit analysis toolbox. We validated POINTseq by mapping genetically and projection-defined cell populations in the mouse motor cortex. We then applied POINTseq to midbrain dopaminergic neurons and reconstructed the brain-wide single-cell projections of 3,813 dopaminergic neurons in ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). We define over 30 connectomic cell types, vastly exceeding the known diversity of dopaminergic cell types, and identify stereotyped projection motifs that may mediate parallel dopamine signaling. This data constitutes the anatomical substrate on which the diverse functions of dopamine in the brain are built. HIGHLIGHTSO_LIWe develop POINTseq, which uses pseudotyped Sindbis virus and cell type-specific expression of a viral receptor for cell type-specific barcoding. C_LIO_LIPOINTseq enables massively multiplexed single-cell projection mapping of cell types of interest. C_LIO_LIWe map the brain-wide projections of 3,813 individual VTA and SNc dopaminergic neurons. C_LIO_LIVTA and SNc dopaminergic neurons form over 30 connectomic cell types. C_LIO_LIProjections organize into stereotyped motifs that may mediate parallel dopamine signalling. C_LI
In computational neuroscience, simulation platforms generally do not have adequate tools to model the brain, body and environment simultaneously. We demonstrate a method for simulating neuromechanical models using a novel combination of widely used software platforms: NEURON and MuJoCo. Different neural models are used to control a realistic musculoskeletal model in both open-loop and closed-loop configurations. Three models are presented: (1) an open-loop model using simple spiking neurons from the NEURON model library; (2) an open-loop model using realistic, spiking motoneurons; and (3) a closed-loop central pattern generator with feedback from the physics engine.
A growing number of magnetic resonance imaging (MRI) studies are examining brain changes across pregnancy and early motherhood, gaining fundamental insight into the neural adaptations of motherhood, with critical clinical and policy implications for supporting mother, child, and family unit. As the field takes off, now is the time to take stock of the current literature and neuroscience practices, to ensure that the field is based on studies that are robust, representative, and transparent. Here, we conducted a scoping review to understand the racial and ethnic diversity of participants reported in MRI studies of the maternal brain, guided by the Joanna Briggs Institute methodology. Our findings highlight three key issues in the 185 identified studies of the maternal brain using MRI: (1) the widespread underreporting of participant racial and ethnic data, with only 38.38% of studies reporting race and/or ethnicity demographics; (2) the overrepresentation of white participants, with 46.83% of the samples that report race and/or ethnicity identifying as white/Caucasian; and (3) the disproportionate geographical locations of studies, with 68.65% of studies from North America or Europe and Central Asia. These findings raise concerns about the generalizability of existing research beyond WEIRD (western, educated, industrialized, rich and democratic) populations, and underscore the urgent need for concerted structural change in neuroscience research practices. While identifying a lack of diversity is only the first step, this scoping review serves as a call to action for greater representation in future research, for our own research group as well as others.
Biophysical models of diffusion tailored to characterize gray matter (GM) microstructure are gaining traction in the neuroimaging community. NEXI, SMEX, SANDI, and SANDIX represent recent efforts to incorporate different microstructural features,such as soma contributions and inter-compartment exchange, into the diffusion MRI (dMRI) signal. In this work, we present a comparative evaluation of these four gray matter models on a single, publicly available in vivo human dataset, the Connectome Diffusion Microstructure Dataset (CDMD), acquired with two diffusion times. Using the open-source Gray Matter Swiss Knife toolbox, we estimate cortical microstructure metrics in 26 healthy subjects and evaluate goodness of fit, anatomical patterns and consistency with previous studies. CDMD data yielded GM parameter estimates consistent with values reported in previous studies. This retrospective cross-model analysis establishes the feasibility of estimating exchange models from only two diffusion times and highlights trade-offs in biological specificity, model complexity, and fitting robustness, critical considerations when choosing a model for future clinical and research applications.
In younger adults, newly formed procedural memories are weakened by the subsequent formation of episodic memories (E[->]P interference) and vice versa (P[->]E interference; "cross-memory interference"). Older adults experience significant decline in episodic memory but maintain relatively intact procedural memory. This asymmetric decline in memory may also cause an asymmetric change in cross-memory interference compared to younger adults. For example, older adults may experience a significant increase in one type of cross-memory interference while leaving the other unchanged. Additionally, decline in episodic memory may cause E[->]P interference to either increase or decrease depending on how the episodic and procedural memory systems interact. However, no study to our knowledge has compared cross-memory interference between younger and older adults. We investigated cross-memory interference in younger and older adults by measuring E[->]P (Exp. 1) and P[->]E (Exp. 2) interference in 40 younger (18-40 years old) and 40 older ([≥] 55 years old) adults. Compared to younger adults, the results show that older adults experience significantly stronger E[->]P interference while P[->]E interference was statistically indistinguishable between groups. These results confirm that older adults experience an asymmetric increase in cross-memory interference and suggest that the increase in E[->]P interference is related to the asymmetric decline in episodic memory relative to procedural memory.
Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations. Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have [~]50% of cells expressing either a mutant or wild-type copy of MECP2 (mosaic) and males have 100% of cells expressing a mutant MECP2 (non-mosaic). Typical RTT females have a short window of normal early development until [~]6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males. How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female (Mecp2+/-) and male (Mecp2-/y) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice. We identified a core disease signature consisting of 12 genes consistently dysregulated only in MeCP2-cells across RTT models. Moreover, we uncovered non-cell-autonomous effects exclusively in female MeCP2+ excitatory neurons, but not inhibitory neurons, suggesting excitatory circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed that a previously underappreciated MeCP2-interneuron subtype had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and non-mosaic environment that appear early in RTT pathogenesis.
Monte Carlo diffusion simulations in numerical substrates are valuable for exploring the sensitivity and specificity of the diffusion MRI (dMRI) signal to realistic cell microstructure features. A crucial component of such simulations is the use of numerical phantoms that accurately represent the target tissue, which is in this case, cerebral white matter (WM). This study introduces CATERPillar (Computational Axonal Threading Engine for Realistic Proliferation), a novel method that simulates the mechanic of axonal growth using overlapping spheres as elementary units. CATERPillar facilitates parallel axon development while preventing collisions, offering user control over key structural parameters such as cellular density, tortuosity, beading and myelination. Its uniqueness lies in its ability to generate not only realistic axonal structures but also realistic glial cells, enhancing the biological fidelity of simulations. We showed that our grown substrates feature distributions of key morphological parameters that agree with those from histological studies. The structural realism of the astrocytic components was quantitatively validated using Sholl analysis. Furthermore, the time-dependent diffusion in the extra- and intra-axonal compartments accurately reflected expected characteristics of short-range disorder, as predicted by theoretical models. CATERPillar is open source and can be used to (a) develop new acquisition schemes that sensitise the MRI signal to unique tissue microstructure features, (b) test the accuracy of a broad range of analytical models, and (c) build a set of substrates to train machine learning models on. 1 HighlightsO_LICATERPillar generates realistic axons and glial cells that may co-exist within numerical substrates. C_LIO_LISynthetic axons had similar morphologies to those segmented from human electron microscopy in previous works. C_LIO_LIThe morphological features of synthetic astrocytes closely matched those observed in rodent histology. C_LIO_LIThe functional form of diffusion time-dependence in the intra- and extra-axonal spaces agreed with experimentally observed disorder power laws in voxels composed of synthetic axons. C_LI
The mechanical stiffness of brain parenchyma varies across physiological states and pathophysiological conditions, such as during normal and abnormal development, in degenerative diseases and disorders, like Alzheimers disease and traumatic brain injury (TBI), neuronal activation, and sleep via the glymphatic brain waste clearance mechanism. Despite its biological and clinical importance, relatively few techniques exist to measure and map mechanical properties of brain tissue non-invasively and in vivo. MR elastography (MRE) is an established method that has been widely used to estimate tissue stiffness in the liver by applying mechanical waves using an external tamper and measuring their resulting deformations. However, applying MRE in the brain is more challenging due to the skull and cerebrospinal fluid (CSF), which impede mechanical wave propagation, and tissue mechanical anisotropy, which requires a 4th-order tensor description. In this study, we propose using the intrinsic deformation of brain tissue caused by periodic cardiac pulsation to measure the 4th-order stiffness tensor throughout the brain while simultaneously estimating the 2nd-order diffusion tensor in each voxel throughout the cardiac cycle, which we use as a priori information in the reconstruction of the stiffness tensor. While the DTI-derived mean diffusivity (MD) appears uniform throughout brain parenchyma, stiffness maps obtained at about 1 Hz (i.e., at the fundamental cardiac frequency) show contrast within gray matter, and within white matter pathways such as along the corpus callosum, internal capsule, corona radiata, etc. Generally, stiffness differences at internal tissue boundaries are expected to lead to local stress concentration, which may predispose tissues to damage in TBI. Therefore, our novel tamperless MRE method has the potential to not only identify such interfaces, but assess changes in tissue stiffness there that might occur following injury.
Machine learning algorithms are affording new opportunities for building bio-inspired and data-driven models characterizing neural activity. Critical to understanding decision making and behavior is quantifying the relationship between the activity of neuronal population codes and individual neurons. We leverage a SHallow REcurrent Decoding (SHRED) architecture for mapping the dynamics of population codes to individual neurons and other proxy measures of neural activity and behavior. SHRED is a robust and flexible sensing strategy which allows for decoding the diversity of neural measurements with only a few sensor measurements. Thus estimates of whole brain activity, behavior and individual neurons can be constructed with only a few neural time-series recordings. This opens up the potential for using non-invasive, or minimally invasive, measurements for estimating difficult to achieve, or invasive, large scale brain and neural recordings. SHRED is constructed from a temporal sequence model, which encodes the temporal dynamics of limited sensor data in multiple scenarios, and a shallow decoder, which reconstructs the corresponding high-dimensional neuronal and/or behavioral states. We demonstrate the capabilities of the method on a number of model organisms including C. elegans, mouse, zebrafish, and human biolocomotion.
Meditation encompasses diverse practices that train attention inward, in contrast to externally oriented task states. However, the neurodynamic features distinguishing meditative states from non-meditative states across traditions remain unclear. We analyzed high-density EEG data (N=170; 121 advanced meditators, 49 controls) across four traditions: Vipassana, Brahma Kumaris Raja Yoga, Heartfulness, and Isha Yoga. EEG features spanned oscillatory, aperiodic, nonlinear, and timescale components. Using random forest classifiers, we distinguished meditative from non-meditative states with robust classification performance (91%). Nonlinear features contributed the most, suggesting a core neurodynamic profile. Classification performance was higher in advanced meditators (92%) than in controls (85%), with distinct feature importance: nonlinear and aperiodic features dominated in meditators, and oscillatory and timescale features in controls. Each tradition showed distinct neurodynamic profiles, indicating technique-specific constellations. Our findings revealed shared yet distinct neurodynamic signatures across meditation techniques, suggesting that multiple neurodynamic pathways lead to meditative states.
Introduction: Canine Cognitive Dysfunction (CCD) is an increasingly prevalent naturally occurring neurodegenerative condition in senescent dogs that share neuropathological and clinical features with human Alzheimers disease (AD). Metabolic profiling allows for identification of new candidates for AD biomarkers, diagnostics, and therapeutics. Despite its translational potential, plasma metabolomic profiling of dogs with CDD has not been previously characterized. Methods: This case control study analyzed plasma samples from ten client owned geriatric dogs, including five with severe CCD and five age matched, clinically healthy controls. Untargeted plasma metabolomics was performed using ultra-performance liquid chromatography mass spectrometry (UPLC-MS). Multivariate and univariate statistical analyses identified significant metabolic differences between the groups. Metabolites were considered significant based on a variable importance in projection (VIP) score > 1.5, fold change (FC) > 2.0, and adjusted p-value < 0.05. Results: Fifteen metabolites across seven chemical classes were significantly altered in CCD dogs compared to controls, including glycerophospholipids, steroid derivatives, indoles, and mitochondrial-related compounds. Notably, elevated lysophosphatidic acid (LPA 20:2/0:0) and reduced ubiquinone-2 levels suggest dysregulation in neuroinflammatory and oxidative stress pathways. Cholesterol exhibited the highest FC and VIP scores, further reinforcing its role in AD pathogenesis. Hierarchical clustering and pathway enrichment analyses supported distinct metabolic signatures in CCD that mirror those observed in human AD. Discussion: This is the first untargeted plasma metabolomic profiling of dogs with CCD, revealing systemic metabolic disturbances that align with AD pathophysiology. Data was collected from senescent community-dwelling companion dogs, which enhances the studys ecological and translational relevance. It supports the utility of CCD as an AD model and highlight candidate plasma biomarkers that warrant further investigation. Future longitudinal studies integrating metabolomics with neuroimaging, histopathology, and behavioral assessments are required to validate these findings and contribute to AD biomarker discovery and therapeutic development
Humans rapidly update the control of an ongoing movement following changes in contextual parameters. This involves adjusting the controller to exploit redundancy in the movement goal, such as when reaching for a narrow or wide target, and adapting to dynamic changes such as velocity-dependent force fields (FFs). Although flexible control and motor adaptation are computationally distinct, the fact that both unfold within the same movement suggests they may share common neural resources for task-specific adjustments. To test this hypothesis, we conducted a series of experiments combining changes in the target structure and a force field presented separately or in combination. Seventy-six human participants (both sexes) took part in this study, with each experiment involving different participants. They were asked to reach for a target that could change from a narrow square to a wide rectangle between or during trials. Step loads were used to assess whether participants exploited target redundancy. In a separate experiment, we added a force field in addition to target changes and step loads. Our results revealed a reduced ability to exploit target redundancy when sudden target changes occurred concurrently with FF adaptation. Furthermore, the magnitude of adaptation was reduced when step loads were added to the FF. Crucially, this interference emerged specifically when all perturbations impacted motor execution simultaneously. These results indicate that flexible control and motor adaptation interact in a non-trivial manner, suggesting possible overlap between their underlying neural mechanisms, and a clear identification of the timescale at which they are engaged - namely, during movement. Significant statementHumans rapidly adapt to changes in task demands, such as target structure changes or exposure to force fields (FFs). These two types of adjustments occur within a single movement, suggesting potential interactions between them. Our experiments revealed that the combination of FF exposure with online target shape changes selectively reduced participants ability to exploit target redundancy, while the combination of FF and step loads led to a reduced extent of motor adaptation. These findings confirm that motor adaptation occurs not only between trials but also during movement. The selective nature of the observed interference highlights an interplay between flexible control and motor adaptation, underscoring the importance of understanding the timing of these processes to better characterise their underlying neural circuits.
NLRP3 plays an essential role in secondary neuroinflammatory damage following traumatic brain injury (TBI). However, the specific mechanisms mediating NLRP3s effects in TBI remain poorly understood, and it is unknown whether its pharmacological inhibition with oral compounds during initial phases confers long-term protection. In this study, we investigated the role of the NLRP3 inflammasome pathway in TBI-induced neuroinflammation and long-term neurobehavioral impairment, as well as the impact of its pharmacological inhibition. Following controlled cortical impact (CCI), most NLRP3 inflammasome-related proteins and key inflammatory markers were elevated during the first week post-injury. Genetic Nlrp3 deletion and treatment with oral NLRP3-specific inhibitors preserved microglial homeostatic architecture, reduced ASC aggregation, and enhanced neurological and cognitive recovery after CCI. Repeated intravital imaging confirmed that NLRP3 inhibition prevents microglial activation post-TBI. These findings suggest NLRP3 inflammasome targeting represents a viable translational strategy for clinical trials and may mitigate long-term neurocognitive decline following TBI.
Memory-related transcriptional events in brain remain poorly understood. Visual imprinting is a form of learning in which young animals develop preferences through early exposure to specific stimuli. In chicks, visual imprinting memory is stored in the intermediate medial mesopallium (IMM) of the forebrain. To investigate learning-associated molecular changes, we performed single-nucleus RNA sequencing of the left IMM in strongly imprinted chicks and untrained controls. This analysis identified over 30 cell clusters with distinct transcriptional differences putatively linked to memory formation, nearly half of them in long non-coding RNAs (lncRNAs). Expression levels of two lncRNAs and four protein-coding genes FOXP2, RORA, LUC7L, and ROBO1 correlate with memory strength, reflecting either innate learning potential or imprinting experience. Notably, the brain- and avian-specific lncRNA ENSGALG00010007489 is enriched in the nuclei of specific glutamatergic clusters. These findings offer the first single-cell resolution map of transcriptional changes underlying memory formation in the avian brain.
While early life sets the stage for later learning, comparatively less is known about newborns cognition than that of older infants. A striking example is the lack of consensus regarding the extent to which newborns spontaneously mimic gestures, and whether such behavior drives bonding and learning. Despite the theoretical importance of these questions, practical challenges limit researchers ability to engage newborns in behavioral research. Webcam-based, asynchronous online studies have expanded developmental sciences capacity to reach older infants. However, such scalable and replicable methods have yet to be deployed with younger infants. Taking a commonly-used neonatal mimicry paradigm as a test case, we assessed the feasibility of leveraging an open-source online platform (Children Helping Science) for asynchronous research with 0-6-week-olds and their caregivers. Caregivers modeled face movements to their 4-45 days-old infants (N = 29, N = 17 included) while webcams filmed their infants responses; 13 dyads participated more than once (72 included test videos). There was preliminary, moderate evidence against group-level neonatal mimicry of caregivers tongue protrusions (Bayes Factor [~] [1/3]), and inconclusive evidence for or against mimicry of caregivers mouth openings ([1/3] < BF < 3). Simulations identified a target sample size for more conclusive evidence. Finally, we asked whether caregivers perceived their newborns behavior as imitative. Caregivers perceptions of mimicry reflected infants behaviors but did not align with an often-used metric of mimicry ("imitators"). These results demonstrate the feasibility of asynchronous online behavioral studies with newborns and provide a foundation for future research on neonatal mimicry of caregivers.x1
While simulating compartmental dynamics in response to various input patterns is the prevalent technique for understanding dendritic computation, a great deal can be learned from classical analytical methods that provide solutions for the dendritic voltage. For example, such solutions are needed to simplify spatially extended neuron models, to understand frequency-dependent response properties, to elucidate the interaction between synaptic inputs, and hence to reveal the effective compartmentalization of dendrites into functional subunits. Nevertheless, these methods have not been implemented in modern software tools. This works describes the NEural Analysis Toolkit (NEAT), a Python toolbox that implements classical algorithms to compute response properties of spatially extended neuron models, and that leverages these algorithms to simplify them. Packaged with this are a range of useful utilities to plot morphologies and spatial quantities defined on the morphology, to distribute locations on the morphology, and to select parts of the morphology to e.g. apply morphological ablations or alter the membrane properties. The resulting models can be exported to NEURON and NEST, two commonly used simulators, the former focused on detailed single neuron model simulations, and the latter geared towards distributed network simulations. As a consequence, this toolbox provides a missing link between single neuron computation and large-scale network analysis, substantially facilitating the study of the role of dendritic computation in shaping emergent network dynamics. NEAT is available through pip under the name nest-neat, or from its source code (https://github.com/nest/NEAT), which is provided under the GNU General Public License. Furthermore, support for NEAT is provided on its GitHub page and through the NEST user mailing list (users@nest-simulator.org).
Extant research has implicated functional connectivity of the subgenual anterior cingulate cortex (sgACC) in major depressive disorders or depressive traits in neurotypical populations. However, prior studies have not distinguished the inputs and outputs of the sgACC, and the diagnostic accuracy of these connectivity metrics remains elusive. Here, we analyzed data of 890 subjects (459 women, age 22 to 35) from the Human Connectome Project using Granger causality analyses (GCA) with the sgACC as the seed and 268 regions of interest from the Shen atlas as targets. Individual connectivities were assessed with an F test and group results were evaluated with a binomial test, both at a corrected threshold. We identified brain regions with significant input to and output from the sgACC. Clustering analyses of Granger causality input, but not Granger causality output or resting state connectivity features revealed distinct subject clusters, effectively distinguishing individuals with severe and mild depressive symptoms and those with comorbidities. Specifically, weaker projections from the fronto-parietal and orbitofrontal cortices, anterior insula, temporal cortices, and cerebellum to the sgACC characterized five clusters with low to high scores of depression as well as comorbid internalizing and externalizing problems. Machine learning using a logistic classifier with the significant GCA-in features and 5-fold cross-validation achieved 87% accuracy in distinguishing subject clusters, including those with high vs. low depression. These new findings specify the functional inputs and outputs of the sgACC and highlight an outsized role of sgACC inputs in distinguishing individuals with depressive and comorbid problems.
Cognitive control is believed to arise from interactions among multiple brain networks depending on task demands. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Because the claustrum possesses widespread connections with cortex and can synchronize distant cortical regions, we tested whether the claustrum activates task-dependent network states using fMRI during working memory (n = 420) and autobiographical memory (n = 35), tasks which elicit opposing responses from key cognitive control networks. In both tasks, the claustrum exhibited increased activity and excitatory influence on task-associated cognitive control network nodes, with corroborating underlying structural connectivity. The claustrum also displayed stronger excitatory effective connectivity during task performance and greater structural connectivity with task-related network nodes than regions prominently implicated in directing network states - the anterior insula and pulvinar. These findings establish a role for the claustrum in initiating network states for cognitive control.
For maximizing survival, animals must accurately memorize the structure of their environment. This is achieved by stabilizing and enriching hippocampal place cells near salient features, while the representation of neutral locations incrementally drifts with time. However, the circuit mechanisms by which top-down and bottom-up inputs selectively embed saliency into the hippocampal spatial map remain poorly understood. Here we identified a specific top-down input from the anterior cingulate cortex (ACC) to the dysgranular zone of the retrosplenial cortex (RSCd) that becomes active exclusively at reward locations. Activity of these ACC neurons is both necessary and sufficient for shaping the hippocampal saliency map. Unlike dopaminergic neurons in the ventral tegmental area, which respond to reward irrespective of the context, this class of ACC neurons encodes reward-context associations. Their optogenetic activation induces a reduction in locomotor speed, a behavioral correlate of saliency detection, while their inhibition disrupts the formation of the hippocampal place map. This work not only provides the first mechanistic insight into how context-dependent saliency is integrated in a top-down fashion into the hippocampal map to guide adaptive behavior but also challenges the classical view of memory consolidation theory where memory unidirectionally moves in bottom-up fashion from the hippocampus to the neocortex.
Sensory inputs are progressively transformed into internal representations of the environment along the cortical hierarchy. How does the behavioral relevance of these inputs affect this encoding? Using two-photon calcium imaging in mice navigating virtual-reality environments, we found that visual cortex maintained high sensory discrimination regardless of behavioural engagement, whereas the hippocampal dentate gyrus required active navigation for effective discrimination. These findings suggest that sensory cortices act as general-purpose sensory discriminators, while the hippocampus filters information based on task relevance.
The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptomically-defined identity programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naive neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.
Auditory cortex connectivity extends beyond the processing of acoustic stimuli, playing a crucial role in cognitive and emotional regulation through its interactions with higher-order brain regions. Although the neural mechanisms underlying acoustic information processing along the auditory pathway are well-documented, the connections supporting auditory-related cognitive and emotional processing, particularly in comparative studies between mice and human adults, are not yet fully clarified. In this study, we aim to investigate connections between the auditory cortex and brain regions involved in cognitive and emotional processing using retrograde fluoro-gold (FG) tracer in mice and 3-tesla high-resolution diffusion tensor tractography (DTI) in human adults. The FG injections into the primary (AI)/ secondary (AII) auditory cortices showed afferent connections with cortical (olfactory bulb, piriform, orbitofrontal, cingulate, motor, primary somatosensory, insular, visual, parietal, entorhinal and perirhinal cortices), subcortical (amygdala, hippocampus, globus pallidus, claustrum, bed nucleus of stria terminalis, diagonal band of the Broca and medial septal nucleus) and brainstem (raphe nuclei, pedunculopontine nucleus and locus coeruleus) structures. The DTI data obtained from human adults mostly corresponded with the experimental findings. Auditory cortical processing integrates auditory signals with other sensory, limbic and motor inputs. The connections collectively may suggest its role in cognitive and emotional functions. The auditory cortex is likely a critical hub within the neural circuitry underlying multisensory integration, decision-making, prediction, learning and memory functions. Understanding the connectivity of the auditory cortex can deepen our insight into its contribution to cognitive/emotional functions, offering new perspectives on the underlying mechanism linking hearing deficits with cognitive/emotional disorders.
The two main cell types in the striatum, dopamine receptor 1 and adenosine receptor 2a spiny projection neurons (D1-SPNs and A2A-SPNs), have distinct roles in regulating motor- and reward-related behaviors. Cre-selective CRISPR-dCas9 systems allow for cell-type specific, epigenomic-based manipulation of gene expression with gene-specific single guide RNAs (sgRNAs) and have potential to elucidate molecular mechanisms underlying striatal subtype mediated behaviors. Conditional transgenic Rosa26:LSL-dCas9-p300 mice were recently generated to allow for robust expression of dCas9-p300 expression with Cre-driven cell-type specificity. This system utilizes p300, a histone acetyltransferase which regulates gene expression by unwinding chromatin and making that region of the genome more accessible for transcription. Rosa26-LSL-dCas9-p300 mice were paired with Drd1-Cre and Ador2a-Cre mice to generate Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 mouse lines and underwent behavioral phenotyping when sgRNAs were not present. Both Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 have cell-type specific expression of spCas9 mRNA. Baseline behavioral assessments revealed that, under a sgRNA absent nontargeted state, Drd1-Cre:dCas9-p300 mice display repetitive spinning behavior, hyperlocomotion and enhanced acquisition of reward learning in comparison to all genotypic littermates. In contrast, Ador2a-Cre:dCas9-p300 do not exhibit any changes in behavior in comparison to their littermates. Electrophysiological recordings of dorsal striatum D1-SPNs revealed that Drd1-Cre:dCas9-p300 mice have increased input resistance and increased spontaneous excitatory postsynaptic current amplitude, together suggesting greater excitatory drive of D1-SPNs. Overall, these data demonstrate the necessity to validate CRISPR-dCas9 lines for research investigations. Additionally, the Drd1-Cre:dCas9-p300 line has the potential to be used to study underlying mechanisms of stereotypy and reward-learning.
Synaptic dysfunction resulting from pathogenic variants in genes encoding synaptic proteins is a major contributor to brain and behavioural disorders, collectively termed synaptopathies. To facilitate research into the genetic basis and clinical manifestations of synaptopathy we have created SynaptopathyDB, an online resource that integrates data from 64 mammalian synapse proteomic studies and multiple genetic and phenotypic resources. We identified a consensus set of 3,437 mammalian synapse proteins from presynaptic and postsynaptic compartments, which have wide application in genetic and omic studies. Mutations in 954 genes encoding 28% of the consensus synapse proteome were associated with 1,266 OMIM diseases of the central and peripheral nervous system. We present findings that underscore the pervasive role of synaptic gene variants in the phenotypes of neurological, psychiatric, developmental, and systemic disorders highlighting the significant burden they impose on individuals and healthcare systems. SynaptopathyDB is a versatile platform and discovery tool for understanding the role of synapse proteins and genetic variants in human disease phenotypes.
Understanding how emotional and general vocabulary develop across the lifespan offers key insights into cognitive and socioemotional processes. While emotional vocabulary is foundational for emotion regulation and social interaction, general vocabulary underpins broader cognitive functions such as reasoning and reading comprehension. In this study, we modeled the growth trajectories of emotional and general vocabulary using Gompertz functions in a large cross-sectional sample (N = 820; age range = 12 - 84 years). To control for item difficulty, we selected a subset of vocabulary items with similar and low difficulty in adulthood. Both vocabulary types showed non-linear growth patterns, with emotional vocabulary exhibiting earlier and faster development, reaching near-asymptotic levels by early adulthood. General vocabulary showed a more gradual increase and later inflection point. A joint nonlinear mixed-effects model confirmed significant differences in developmental timing, with emotional vocabulary peaking approximately four years earlier than general vocabulary. These findings support theoretical models emphasizing the early emergence and adaptive relevance of emotional concepts and highlight adolescence as a sensitive period for emotional vocabulary acquisition. The Gompertz model proved effective in capturing asymmetric vocabulary growth, providing interpretable parameters aligned with developmental theory. Implications for education and emotional development interventions are discussed.
A ventral tectal longitudinal column (TLCv) has been described in rats and is hypothesized to provide multisensory modulation of acoustic processing in the superior olivary complex (Saldana et al., 2007, J Neurosci 27, 13108-16). The TLCv is a column of cells in the dorsomedial tectum extending rostro-caudally through the inferior and superior colliculi. It receives ascending auditory input and projects to the superior olivary complex. Further insight into TLCv function has been hampered by limited information on its connections. Here, we provide evidence that a TLCv is recognizable in mice and that it has more extensive connections than previously believed. Deposit of retrograde tracer into the superior olivary complex labels cells bilaterally in the TLCv, comparable to results seen in rats. Viral labeling of neuronal projections demonstrate input to the TLCv from the superior olivary complex and from the inferior colliculus. Thus, the TLCv in mice has inputs and outputs similar to those described in rats. Additional experiments with retrograde tracers revealed more extensive outputs from the TLCv. Neurons in the TLCv are labeled after deposit of retrograde tracers into the cochlear nucleus or into the inferior colliculus. The projections from the TLCv to these targets, like those to the superior olivary complex, are bilateral. These projections are much broader than those described previously. The results suggest that the TLCv could exert modulation over a wide expanse of the auditory brainstem, from the cochlear nucleus through the inferior colliculus.
Peripheral nociceptive sensory neurons integrate various noxious inputs, resulting in local depolarization that triggers the firing of action potentials and thus the sensation of pain. We recently reported that nociceptor depolarization itself initiates signaling by the calcium channel CaV1.2 causing acute hyperalgesia in vivo. However, whether this mechanism initiates excitation-transcription (E-T) coupling and thereby leads to long-lasting modulation of nociceptor activity remains poorly understood. Using high content imaging of dorsal root ganglion (DRG) neurons, we here found that depolarization of nociceptors induces phosphorylation of the transcription factor (TF) cAMP-response element binding protein (CREB), which was affected by inhibition of protein kinase A (PKA) and calcineurin, but not Ca2+/calmodulin-dependent protein kinases. Genetic deletion or pharmacological inhibition of CaV1.2 confirmed its role in calcium-dependent kinase signaling and CREB phosphorylation after depolarization. In line with this, pharmacological modulation of CaV1 channels affected the expression of a subset of depolarization-regulated immediate early genes known to orchestrate a broader transcriptional response. Indeed, RNA-Seq analysis of DRG neurons from mice with a tissue-specific deletion of CaV1.2 in nociceptive sensory neurons (SNS-Cacna1c-/- mice) revealed downregulation of multiple calcium and potassium channel subunits as well as proteins involved in synaptic vesicle release and cell adhesion. Furthermore, repetitive firing of action potentials and release of the neuropeptide CGRP was impaired in CaV1.2-deficient sensory neurons. SNS-Cacna1c-/- mice showed increased sensitivity to noxious heat and exacerbated inflammatory but not neuropathic pain. In conclusion, our data suggest a CaV1.2-dependent E-T coupling mechanism in nociceptors that counteracts nociception in vivo.
Internal bodily signals, notably the heartbeat, influence our perception of the external world - but the nature of this influence remains unclear. One line of evidence (Competition) indicates that interoceptive and exteroceptive inputs compete for neural resources. Another line (Self-related Facilitation) shows a link between interoceptive and self-related processing, that might also include computing the self-relevance of exteroceptive inputs. We tested these seemingly opposing views within a single experimental task. Measuring heartbeat-evoked potentials (HEPs, a measure of cardiac interoception) with EEG, we manipulated the self-relevance of an audio-tactile stimulus by placing the audio source either inside or outside the peripersonal space immediately around the body. This design ensured that Competition and Self-related Facilitation accounts yielded contrasting predictions. On the one hand, pre-stimulus HEP amplitudes over somatosensory cortex were linked to slower reaction times, and affected audio-tactile stimulus-evoked responses in the same area, indicating competition for shared neural resources. On the other hand, pre-stimulus HEPs over integrative sensorimotor and default-mode network regions facilitated subsequent self-relevance encoding, both in reaction times and audio-tactile stimulus evoked responses. Importantly, Competition and Facilitation effects were spatially and statistically independent from each other. We thereby reconcile the two views by showing the co-existence of two independent mechanisms: one that allocates neural resources to either internal bodily signals or the external world, and another by which interoception and exteroception are combined to determine the self-relevance of external signals. Our results highlight the multi-dimensionality of HEPs as neurophysiological markers, and thus of internal states more generally.
Theory of Mind (ToM) refers to the capacity to infer others' latent mental states, such as intentions, beliefs, and strategies, and use these inferences to predict behavior. A defining characteristic of ToM is its recursive nature: individuals reason not only about what others are thinking, but also about what others think about them. Most computational models of ToM adopt a hierarchical structure in which Level-0 (L0) agents are assumed to follow simple, fixed heuristics (e.g., Win-Stay-Lose-Shift, WSLS) without mentalizing. However, this assumption overlooks the diversity of non-mentalizing strategies exhibited in human behavior, such as imitation or tit-for-tat, which do not conform to WSLS yet require no recursive reasoning. To address this limitation, we introduce a novel ToM framework (BELIEFS) that flexibly infers latent L0 strategies from behavior rather than relying on predefined heuristics. We evaluated the model in four classic dyadic games: Matching Pennies, Prisoner's Dilemma, Bach or Stravinsky, and Stag Hunt, manipulating model's learning rates and the volatility of L0 strategy switching. Predictive accuracy was assessed using cumulative negative log-likelihood (NLL) of opponent's next choice and compared against both a ToM model that assumes only WSLS at L0 and chance-level performance. Our model outperformed both baselines, particularly under low-volatility conditions and at intermediate learning rate. Moreover, to evaluate strategy inference, we computed trial-wise confusion matrices and Cohen's k; between inferred and true L0 strategies, reaching significantly above-chance classification. We further tested the model's ability to distinguish between action sequences generated by the opponent's true Theory of Mind (ToM) level (L0 vs. L1) and those generated using an incorrect ToM level. The model assigned lower negative log-likelihoods (NLLs) to sequences from the true level, suggesting an indirect method for identifying the opponent's actual ToM level. Finally, we assessed whether the model effectively tracks behaviorally distinguishable action probabilities across ToM levels. Using Fisher-transformed correlations between model-generated action probabilities at L0, L1, and L2, we found significant dissimilarities, especially in competitive games. In summary, our model introduces a flexible, probabilistic approach to Theory of Mind that captures both surface-level strategy use and recursive reasoning depth. By jointly tracking dynamic beliefs over L0 strategies and ToM levels, the model adapts to behavioral shifts and outperforms static heuristics. These advances provide a powerful framework for modeling human behavior in interactive contexts, with implications for both human-human and human-machine interaction research.
The triceps surae, composed of the soleus (SOL) and medial (MG) and lateral (LG) gastrocnemii, are anatomically-derived synergists which act as a functional unit to plantarflex the ankle. However, anatomical differences suggest that each muscle is capable of generating distinct torques at the ankle, raising the possibility that each can be independently controlled to suit the needs of a given task. This possibility was explored by investigating the activation patterns of the triceps surae during two balance tasks that use different neuromechanical control strategies to maintain equilibrium. High-density surface EMG was recorded from the triceps surae of 14 healthy young adults during multiple trials of dual- and single-legged standing. Newly developed analyses examined how each muscle tuned its activity with center of pressure (COP) movement throughout 2-D space. During dual-legged standing, only the SOL and MG were active and both tuned their activity uniformly with anteroposterior COP movement. By contrast, during single-legged standing, each muscle showed robust activation and significantly different directional tuning, with the LG most active before medial COP movement, while SOL and MG were most active before lateral COP movement. Further analyses demonstrated the LG could be activated entirely independent of the SOL and MG, and vice versa, with independent activation of each muscle causing different angular deflections of the COP during single-, but not dual-legged standing. These observations reveal a sophisticated level of neural control, whereby the nervous system exploits subtle differences between highly similar muscles to tune balance corrective adjustments in a task-dependent manner.
Neuropeptides are a highly conserved and diverse class of intercellular signaling molecules that regulate a broad range of neural and hormonal processes across animal phyla. The American lobster, Homarus americanus, has long served as a powerful invertebrate model for the discovery and functional investigation of neuropeptides. Among common post-translational modifications (PTMs) found in neuropeptides, glycosylation remains underexplored due to the inherently low in vivo abundance and intrinsically complex structural heterogeneity. In this study, we employed hydrophilic interaction liquid chromatography (HILIC) enrichment coupled with oxonium-ion triggered EThcD fragmentation strategy to simultaneously profile novel endogenous and glycosylated neuropeptides across eight distinct neural tissues and neuroendocrine organs of Homarus americanus. This integrative mass spectrometry-based approach led to the identification of 154 endogenous neuropeptides derived from 25 families, approximately one-third of which are newly reported, and uncovered 28 O-linked glycosylated neuropeptides in this species for the first time. These peptides exhibit strong tissue-specific expression, distinct proteolytic cleavage patterns, and confidently localized glycosylation sites. Our results highlight the utility of integrated sampling enrichment and hybrid fragmentation strategies for deep neuropeptidomic profiling and provide a valuable resource for future studies on the functional roles of newly identified neuropeptides and glycosylation in crustacean neuromodulation and peptidergic signaling.
Septic encephalopathy (SE) is a devastating complication of sepsis, marked by neuroinflammation and metabolic dysfunction, with the cerebellum being among the most affected brain regions. Progress in the field has been hindered by: (1) the incomplete characterization of cerebellar metabolic disruption in SE, (2) the limited understanding of the therapeutic mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) treatments in SE, and (3) the absence of reliable biomarkers for detecting SE. To address these gaps, we employed a murine sepsis model and performed metabolomic analyses of cerebellar tissue and plasma with and without MSC-sEV treatment. Sepsis induced profound cerebellar metabolic dysfunction, suppression of oxidative energy metabolism, and redox imbalance. MSC-sEVs mitigated these effects through their cargo, restoring cellular energetics and rebalancing antioxidant pathways. Cross-compartment analyses identified six plasma metabolites with strong diagnostic potential. These findings define key cerebellar metabolic mechanisms of SE and MSC-sEV treatment and propose plasma biomarkers for SE diagnostics.
Our fMRI study investigates dependencies between brain areas during resting and working memory states using directed spillover indices estimated from vector autoregressive models that recognize dynamics in the network. A dorsolateral prefrontal centered system (DLPFC) demonstrates spillover memory capacity at rest, labeled resting memory, which facilitates self-referential thinking. Resting memory contains roughly 9 times more neurocognitive dependencies (spillover) as the difference in spillover between working and resting brains, suggesting that resting brains are highly active. The transitioning from resting memory to working memory is initiated by a right inferior fontal (IFG) centered system which connects to the DLPFC centered system when relevant information is detected in the outside world and also inhibits self-referential feedback in parietal cortices. Spillover between the IFG and DLPFC centered systems facilitate a smooth transition in attention from events that take place outside the brain to (sustained) representations of external events within the brain.
The global spread and increasing populations of disease vector mosquitoes expose hundreds of millions of people to mosquito-borne illnesses each year. Female Aedes aegypti mosquitoes, global vectors of dengue, require protein from host blood to support egg development and undergo repeated cycles of blood-feeding and egg-laying. After biting, females temporarily alter their behavioral state and suppress host-seeking while using blood-derived nutrients to develop eggs. Host-seeking suppression ends once eggs are laid. While this period has generally been thought of as one of behavioral inactivity, we reveal that it instead reflects behavioral reprogramming, during which females transition from post-blood-meal inactivity into active searching for egg-laying sites. Females with mature eggs show a distinct behavioral state characterized by increased locomotor activity and a shift in circadian behavioral timing, leading to nocturnal humidity-seeking and egg-laying in an otherwise diurnal species. We show that the circadian clock gene cycle is critical for regulating this transition; its absence disrupts the timing of oviposition behaviors, leading to poor site selection and reduced predicted offspring survival. These findings suggest that during egg development, circadian clock-dependent behavioral reprogramming triggers nocturnal hyperactivity and oviposition site search, an essential process for mosquito reproduction and population viability.
Astrocytes adapt to injury and disease by entering a reactive state defined by transcriptomic, morphological, and functional changes. Using a combination of human cortical organoids (hCOs) and primary fetal brain tissue, we investigated the plasticity of human astrocyte reactivity. We observed robust inflammatory transcriptomic and chromatin signatures following cytokine exposure, which varied with duration. To assess reversibility, we withdrew cytokines after acute or chronic exposure. In both cases, astrocytes returned to a quiescent genomic state within days. Chronic exposure induced MHC class II gene ex-pression, normally restricted to professional antigen-presenting cells. We validated MHCII protein in primary tissue and hCOs and used co-immunoprecipitation and mass spectrometry to identify candidate antigens. Finally, we showed that exogenous peptides from fetal neurons could be presented by astrocytic MHCII.
Our brains dynamically adapt to a multisensory world by orchestrating diverse inputs across sensory streams. This process engages multiple brain regions, but it remains unclear how audiovisual stimuli are represented and evolve over time, especially in naturalistic scenarios. Here, we employed movie-watching to explore this question. We recorded intracranial electrocorticography (iEEG) to measure brain activity in 19 participants watching a short multilingual movie. Using unsupervised clustering and supervised encoding models, we identified a robust modality-specific gradient in the frontal cortex, wherein the ventral division primarily processes auditory information and the dorsal division processes visual inputs. Further, we found that this cortical organization dynamically changed, adapting to different movie contexts. This result potentially reflects flexible audiovisual-resource assignment to construct a coherent percept of the movie. Leveraging behavioral ratings, we found that the frontal cortex is the primary site in this modality assignment process. Together, our findings shed new light on the functional architecture of the frontal cortex underlying flexible multisensory representation and integration in natural contexts.
Contingent learning, the process by which specific courses of action become associated with subsequent outcomes, is dependent on the amygdala and ventrolateral prefrontal cortex (vlPFC). The amygdala and vlPFC are bidirectionally connected but it is unclear what the contribution of individual feedforward and feedback pathways is to contingent learning. Here we tested the role of amygdala projections to vlPFC in mediating two key components of contingent learning: signaling the outcome (reward/no reward) that follows a choice and maintaining representation of the choice that was made prior to outcome delivery. To test for these two aspects of contingent learning, we trained macaques to perform a probabilistic reward learning task where for separate stimulus pairs reward was either delivered immediately or after a trace interval. Inhibiting vlPFC-projecting amygdala neurons impacted contingent learning irrespective of whether there was a trace interval or not, and this effect was primarily driven by maladaptive learning on unrewarded trials. Notably, deficits in contingent learning caused by manipulating activity in the amygdala-vlPFC pathway were distinct from impairments in motivation and the ability to update the value of specific rewards in a reinforcer devaluation task. Thus, vlPFC-projecting amygdala neurons appear to play a specific role in contingent learning through signaling the outcomes of a choice, but not in maintaining a memory of the prior choice.
During typical development, non social visual object recognition emerges in the first year of life, engaging both low level cues (e.g., color, orientation) and higher level mechanisms involving inference and prior knowledge. Little is known about how these processes function in minimally verbal children with autism (mvASD). We studied 22 children with mvASD using touchscreen based oddball and contour detection tasks, targeting low level (e.g., shape, orientation) and mid level (e.g., Kanizsa figures, 3D shapes) visual stimuli, measuring both pointing and eye gaze responses. All children detected the oddball in the easiest condition with faint distractors, and approximately half succeeded across all low level tasks. Notably, some high performers showed reduced accuracy under mid level conditions with greater stimulus complexity. Strikingly, and not originally anticipated, several low performers who failed to point correctly nonetheless fixated on the correct target. In the Kanizsa oddball task, several mvASD participants, unlike typically developing (TD) peers, consistently pointed to local inducers rather than to the center of the illusory triangle. While the overall deterioration in performance with increased visual complexity suggests that mvASD visual perception may rely on low level representations with attenuated inference based processing, the dissociation between gaze and pointing, along with atypical local pointing behavior, indicates that performance depends not only on what is perceived, but also on how they use the visual signal to drive their behavior. They may, see the point, but not point to what they see.
Alzheimer's Disease (AD) disrupts neural circuits vital for memory and cognition. We used two-photon microscopy to investigate these disruptions in behaving mice, focusing on the link between amyloid plaques - a hallmark of AD - and aberrant neural activity. Using the 5xFAD mouse model, we observed significant changes in hippocampal neurons, including elevated baseline activity and reduced locomotion-driven firing, leading to a diminished neuronal dynamic range. These abnormalities were more pronounced near amyloid plaques. We also found degraded spatial coding, reduced synchrony, and increased variability in neuronal responses. Furthermore, place fields emerged more slowly in both familiar and novel environments, indicative of recall and learning impairments respectively. By showing a specific link between plaque vicinity and neural coding deficits including reduced dynamic range in mice performing spatial tasks, our study offers new insights into the circuit basis of progressive cognitive degradation in AD.
In both vertebrates and invertebrates, the developing brain becomes electrically active before it is ready to process sensory input. During neural circuit maturation, developmental activity is thought to refine synaptic connections by driving neuronal co-activation in rhythmic patterns. Here we describe cellular interactions that shape brainwide developmental activity and their molecular basis. In Drosophila, patterned stimulus independent neural activity (PSINA) engages the entire brain in highly stereotyped, globally coordinated cycles of activity. A molecularly-defined population of ~2,000 neurons (Transient Receptor Potential Gamma, Trp{gamma}+ neurons) act as an activity template for PSINA. We show that this activity template is patterned by four neurons expressing the neuropeptide SIFamide (SIFa). Signaling through the SIFa Receptor, SIFa modulates the activity of both SIFa and Trp{gamma}+ neurons to establish the brainwide activity cycles of PSINA. In turn, Trp{gamma}+ neurons sustain SIFa neuron activity through a recurrent interaction. Neuropeptides modulate neuronal activity through synapse-free, or wireless, signaling; a fitting mode of communication for a process tasked with refining on-going synapse formation. By placing neuropeptide signaling at the core of developmental activity, this work highlights the rich neurophysiological potential of the chemical connectome in shaping the developing brain.
Context. The cerebral substrates of fatigue in patients with Multiple Sclerosis (pwMS) are not elucidated yet. This study aims at exploring the disease-specific functional brain substrates of fatigue in pwMS with a recent disease history. Methods. Sixteen pwMS (disease history < 5 years) and 17 matched Healthy Controls (HC) performed a N-Back task with three difficulty levels during fMRI acquisitions following high vs. low fatigue induction. Measures of subjective trait and state fatigue were also recorded. Behavioral performance at n-back task and evolution of subjective fatigue states were analyzed by means of Bayesian repeated measures analyses of variance. Functional MRI data were analyzed to determine between-group differences (1) in task-related brain activity, independently of trait fatigue score; (2) in the association between trait fatigue and brain activity. Results. A similar trajectory was observed in the two groups for subjective and task-related measures following fatigue induction. No between-group difference was observed in brain activity unrelated to fatigue score. However, negative associations between trait fatigue score and brain activity were observed in pwMS, while the associations are positive in HC. Specifically, interactions between group and task difficulty were observed in regions belonging to the Striato-Thalamo-Cortical (STC) network and the fronto-parietal cortex. Conclusion. Group-specific patterns of brain activity related to fatigue were identified in pwMS and HC in the STC circuitry, despite similar behavioral performance and subjective fatigue level. This confirms the implication of the STC loops in fatigue pathophysiology, occurring from the early stages of the disease.
Adolescent opioid use in the United States commands attention: millions of twelve- to nineteen-year-olds are exposed to opioids each year by prescription and misuse. Recent findings show that opioids bind not only to canonical opioid receptors but also interact with receptors on immune cells within both the central and peripheral nervous systems. The potential for early life opioid exposure to induce long-term changes in the neuroimmune system is not fully understood, particularly given the adolescent brains high susceptibility to neuroplastic changes. The goal of this study was to investigate the hypothesis that adolescent opioid use potentiates physiological and behavioral responses to pathogen-induced sickness later in life. To achieve this, we treated adolescent mice (PND 35-42) with bi-daily escalating doses of morphine to model dependence and then administered a low dose of lipopolysaccharide (LPS, 0.1 mg/kg) in adulthood (PND 60-76) to induce an immune response. In contrast to our hypotheses, we found that adolescent morphine exposure had no additive effect on low-dose LPS-induced sickness measures when assessed in adulthood. These data suggest that adolescent opioid exposure may have minimal effects on future immune challenges, although further research is needed to confirm this.
Visual information from the retina is sent to diverse targets throughout the brain by different retinal ganglion cells (RGCs). Much of our knowledge about the different RGC types and how they are routed to these brain targets is based on mice, largely due to the extensive library of genetically modified mouse lines. To alleviate the need for using genetically modified animal models for studying retinal projections, we developed a high-throughput approach called projection targeting with phototagging that combines retrograde viral labeling, optogenetic identification, functional characterization using multi-electrode arrays, and morphological analysis. This method enables the simultaneous investigation of projections, physiology, and structure-function relationships across dozens to hundreds of cells in a single experiment. We validated this method in rats by targeting RGCs projecting to the superior colliculus, revealing multiple functionally defined cell types that align with prior studies in mice. By integrating established techniques into a scalable workflow, this framework enables comparative investigations of visual circuits across species, expanding beyond genetically tractable models.
Aggregation of TAR DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases with FTLD-TDP, as well as FTLD-MND and MND-TDP cases subclassified neuropathologically into PLS, ALS, and PMA. All FTLD-TDP type C cases had ANXA11 proteinopathy. However, ANXA11 proteinopathy was present in over 40% of FTLD-MND and in 38 out of 40 FTLD-PLS cases (95%), of which 80% had TDP type B or an unclassifiable TDP-43 proteinopathy and 15% had TDP type C. Genetic analyses excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated novel forms of ANXA11 proteinopathy strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship of ANXA11 in TDP-43 proteinopathies, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises the molecular pathology of cases with abundant inclusions that are co-immunoreactive for both proteins and we subclassify three types of TAP based on distinct clinical and neuropathologic features.
Our visual capabilities depend on neural response properties in visual areas of our brains. Neurons exhibit a wide variety of selective response properties, but the reasons for this diversity are unknown. Here, we related the distribution of neuronal tuning properties to the information capacity of the population. Our results from theory, simulations, and analysis of recordings from macaque primary visual cortex (V1) reveal that diversity of amplitude and bandwidth drive complementary changes to the representational geometry of a population. Amplitude diversity pushes the centers of the representations further apart, whereas bandwidth heterogeneity decorrelates the center locations. These geometric changes separate out representations for distinct stimuli, creating more efficient encoding. We study how both types of diversity affect the population code for two different perceptual tasks: discrimination and identification. While both types of diversity improve encoding for both tasks, their distinct impacts on geometry make each more beneficial for one of the two tasks. Amplitude diversity impacts coding efficiency more for discrimination than it does for identification, while bandwidth diversity has a stronger impact on identification. These complementary effects indicate the importance of both types of diversity for perception. Finally, because tuning diversity exists across species and brain areas, our results suggest a fundamental neural coding strategy that may be applicable to a wide range of behavior.
The basal ganglia, particularly the striatum, are critical for orchestrating skilled behavioral sequences, yet the precise mechanisms underlying this process remain unclear. Using high-resolution kinematic tracking and neural recordings in mice performing a water-reaching task, we found spatially distributed modules of striatal projection neurons whose activity corresponded to the generation of each element in the sequence (aiming, reaching, and drinking). They are activated sequentially and exhibit reciprocal inhibition, ensuring a strict serial order. Optogenetic activation of the direct pathway of the orofacial module promoted licking while suppressing reaching. Reaching could in turn suppress stimulation-evoked licking, revealing bidirectional inhibitory interactions. Our findings demonstrate that the modular organization in the striatum, coupled with reciprocal inhibition, sculpts the temporal progression of actions, providing a mechanistic framework for understanding how the basal ganglia coordinate complex behaviors.
Parameterizing electroencephalography (EEG) signals in the spectral domain reveals physiologically relevant components of neural stochastic processes, yet the linearity or nonlinearity of these components remains debated and could not solved by the current Spectral Parameter Analysis (SPA). We address this using BiSCA (BiSpectral EEG Component Analysis), a likelihood-based model unifies EEG spectrum and bispectrum analysis to identify inter-frequency harmonic relationships and distinguish signal components. Simulations demonstrate BiSCA's ability to separate nonlinearity from non-Gaussianity (e.g., linear non-Gaussian systems exhibit diffuse bicoherence, while nonlinear Gaussian systems show localized peaks). Analyzing 1,771 intracranial EEG (iEEG) channels and a large scalp EEG dataset, we uncover a clear organizational principle: the brain's aperiodic ({xi}) activity is predominantly linear, whereas its resonant ({rho}) oscillations, including Alpha () rhythms and other peaks, are the primary source of cortical quadratic nonlinearity. This finding challenges the long-held notion of widespread linearity in large-scale brain signals, as our analysis reveals that over two-thirds of EEG and iEEG channels exhibit significant nonlinear characteristics. Spatially, we uncover a striking dissociation between signal power and nonlinearity: while the occipital Alpha () rhythm dominates in power, the parietal Mu () rhythm generates the strongest nonlinear signature. These findings highlight that nonlinearity is present across the brain, arising from resonant activity.
While glutamatergic synaptic plasticity is believed to be a fundamental mechanism mediating learning, the behavioral significance of plasticity at cortical GABAergic synapses remains less well understood. Furthermore, despite recent discoveries of long-range projections from neocortical GABAergic neurons, details about how they function are also sparse. Here we combine behavioral optogenetics with patch-clamp electrophysiology to link plasticity at long-range GABAergic synapses with higher-order cognitive functions. Specifically, learning extradimensional rule shifts potentiates callosal GABAergic synapses from prefrontal parvalbumin-expressing (PV) neurons onto corticothalamic neurons. Disrupting this potentiation by inhibiting callosal PV terminals during rule shifts induces perseveration, whereas reinstating this potentiation with subsequent gamma-frequency callosal PV terminal stimulation restores flexible behavior. This shows how a novel plasticity locus can regulate brain circuits underlying normal cognition and pathological states.
Accurate motor behavior relies on our ability to refine movements based on errors. While sensory prediction errors (SPEs), mismatches between expected and actual sensory feedback, predominantly drive such adaptation, task performance errors (TPEs), or failures in achieving movement goals, also appear to contribute. However, whether and how TPEs interact with SPEs to shape net learning, remains controversial. This controversy stems from difficulties in experimentally decorrelating these errors, ambiguity related to possible interpretations of task instructions, and inconsistencies between theory and computational models. To try and resolve this issue, we employed variants of an ''error-clamp'' adaptation paradigm across four reaching experiments (N = 144). Addressing the ambiguity of whether or not the TPE is indeed ignored in standard error-clamp designs as assumed in theoretical (but not computational) models, Experiment 1 explicitly manipulated TPE magnitude by shifting the endpoint feedback location while holding SPE constant. We found that learning was uninfluenced by TPE size. Experiment 2 assumed that the TPE is in fact disregarded under clamp instructions. To then study SPE-TPE interactions, we induced TPEs of varying magnitudes by shifting the target location (''target jump'') while always clamping feedback to the original target location. Here, instructions to reach the new target also induced an SPE. Crucially, learning driven by this SPE was again unaffected by TPE magnitude, a result validated by two additional experiments. Our findings consistently demonstrate that SPE-mediated learning remains impervious to variations in task performance feedback, and point to a distinction in learning mechanisms triggered by these two error signals.
The human brain is sensitive to temporal regularities across bodily and environmental signals. Here, we investigated the pupil and neural correlates of regularity encoding established across cardiac and auditory stimuli. Auditory sequences were presented in synchrony with the heartbeat (synchronous), at a fixed pace, or without temporal regularity while recording pupillometry, electroencephalography, and electrocardiography in healthy participants. Sounds evoked typical pupil dilation in all conditions. However, only in the synchronous condition, pupil dilation progressively decreased over the course of the sequence, possibly reflecting adaptation to the repeated cardio-auditory alignment. A concurrent increase in global EEG activity suggested enhanced cortical processing in response to the synchronous sequence. Pupil constriction was driven by participants with higher heart rate, indicating that pupil adaptation mostly occurs in response to fast auditory sequences. Cardio-audio regularity encoding manifests as a pupil adaptation and an amplification of global EEG activity, likely reflecting improved temporal prediction precision.
The locus coeruleus-norepinephrine (LC-NE) system has been implicated in perceptual decision-making, but its causal contribution and underlying mechanisms in humans remain unclear. Here, we used transcutaneous vagus nerve stimulation (tVNS) to modulate LC-NE activity during a random dot motion task, with stimulation delivered at three distinct time points across groups, each targeting different stages of LC-NE engagement during the task. tVNS reliably increased pupil-linked LC-NE activity across all groups. Notably, early stimulation, at a time when LC-NE activity was still at baseline, elicited a more sustained pupil dilation that extended into the decision phase, resulting in comparable pupil responses during decision-making across groups. For behavior, tVNS selectively improved decision accuracy in contexts characterized by initially low performance, without affecting response times. Drift diffusion modeling revealed that this improvement was specifically associated with increased drift rate, consistent with more efficient evidence accumulation with tVNS. These effects were consistent across groups but most pronounced when tVNS was applied at the early time point. Our results provide causal evidence that tVNS enhances decision-making in a state-dependent manner, likely by stabilizing attentional engagement and facilitating evidence accumulation when endogenous control is suboptimal.
Epilepsy is a brain disorder, characterized by recurrent seizures due to abnormal neuronal activity originating from a population of cortical neurons. It is known that seizures are often associated with abnormal glial cell function at the seizure focus. Recent studies have shown that each glial type such as astrocytes display significant degree of heterogeneity in their development, molecular signatures, and function depending on the brain region in which they are located. It is unknown if such heterogeneity differentially influence/cause seizures. Previous studies in Drosophila have shown that aberrant cortex glial function led to light inducible seizures in Ceramide phosphoethanolamine synthase (cpes) and temperature inducible seizures in zyd mutants. Here, we have optimized Gal4/Split-Gal4/Gal80/LexA drivers to specifically express a gene of interest throughout development in cortex glial subpopulations in different parts of the brain including optic lobe (OL), central brain (CB) and ventral nerve cord (VNC). Using these tools, we performed brain region specific cortex glial rescue experiments in cpes and zyd mutants. We found that OL and CB, but not VNC specific cortex glial expression of UAS CPES, were able to significantly suppress light inducible seizures in cpes mutants. In contrast, VNC but not OL or CB specific cortex glial expression of UAS Zyd suppressed temperature sensitive seizures. Further, in a third model, expression and activation of transient receptor potential (dTrpA1) just in the VNC specific cortex glia was sufficient to induce temperature sensitive seizures in wild type flies. Our findings suggest that regionally specialized cortex glial subtypes differentially regulate seizure susceptibility in seizure models.
The brain excels at extracting meaning from noisy and degraded input, yet the computational principles that underlie this robustness remain unclear. We propose a theory of spatiotemporal abstraction (STA), in which neural networks integrate inputs across space and time to produce multi-scale, concept-level representations that remain stable despite loss of detail. We demonstrate this principle using spectrograms of spoken sentences and their degraded analogs from cochlear implants, showing that as integration kernels widen, distorted input converges toward the original representation. This mechanism may explain how cochlear implant users comprehend speech despite severely scrambled afferent signals. STA provides a unified framework for understanding abstraction as an emergent property of cortical architecture, with implications for memory, neuroprosthesis design, and robust artificial systems.
Adult stem cells inhabit specialized niches where local and systemic cues regulate their behavior. In the mouse ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) dynamically transition between quiescence and activation and reside amidst unique deposits of extracellular matrix (ECM) known as fractones. We show that NSCs that enter quiescence in response to BMP4 secrete a complex ECM that, on its own, is capable of inducing NSC quiescence. This specific ECM triggers the nuclear translocation of Yes-associated protein (YAP), to induce further ECM remodeling and adhesion. Together, the BMP-ECM-YAP pathway creates a two-step mechanism where a soluble and transient quiescence-inducing signal leads to the formation of a physical niche to maintain the quiescent state. In the intact niche, YAP and its paralog TAZ (Transcriptional coactivator with PDZ-binding motif) essentially sustain quiescence by preserving fractones and the characteristic structural organization. Moreover, our findings reveal a previously unrecognized role for YAP/TAZ in quiescence.
Respiration dynamically modulates sensory perception by orchestrating transient states of the brain and the body. Using simultaneous recordings of high-density magneto-encephalography (MEG), respiration, and pupillometry, we show that human perceptual sensitivity to near-threshold visual stimuli was enhanced during inspiration, coinciding with respiration-modulated increases in arousal neuromodulation and cortical excitability. Participants adapted their breathing patterns to align with predictable stimulus onset, and this adaptive respiratory control correlated with improved performance. We further reveal that respiration-modulated changes in alpha and beta oscillations reflect distinct shifts in sensory and motor excitability, respectively. Crucially, respiration-resolved multivariate Granger causality analyses demonstrate that the breathing rhythm systematically shapes directed information flow within a widespread interoceptive network. This respiration-brain coupling was flexibly adjusted based on stimulus predictability, highlighting a novel mechanism for active sensing which integrates internal bodily rhythms with external sensory demands to optimize perception.
Functional improvement following traumatic spinal cord injury (SCI) remains limited, therefore, it is necessary to develop therapeutic interventions such as cell transplantation to replace lost cells and promote connectivity. While transplantation typically focuses on neurons, it is important to include other neural cells, such as immature astrocytes, to provide a permissive environment, promote neuroprotection and regeneration, and ultimately restore connectivity. In this study, we leveraged cellular engineering using human induced pluripotent stem cells (hiPSCs) to generate astrocyte progenitor cells (hAPCs). We tested two hiPSC lines (WTC11 and KOLF2.1J) to characterize the fate of the hAPCs in vitro and following transplantation at the cervical level of the intact spinal cord for up to 3 weeks. Our results demonstrated efficient and consistent differentiation of the hiPSCs into hAPCs, their survival and integration with the adult spinal cord, with no signs of tumors, deleterious outcomes, and unexpected locations. The ability to survive and the absence of adverse effects indicate that hAPC transplantation could be a safe element of therapy in treating spinal cord injuries.
Adverse childhood experiences significantly increase the risk of developing alcohol use disorder (AUD) in adulthood. We used a model of combined limited bedding/nesting and maternal separation (LBN+MS) in C57BL/6J background mice to investigate how early life stress (ELS) modulates behavioral sensitivity to alcohol, long-term alcohol drinking patterns, and the effects of alcohol on social behaviors. Our findings reveal that ELS increased sensitivity to the stimulatory locomotor effects of alcohol (1.75 g/kg) selectively in females and reduced sensitivity to the sedative effects of alcohol (4.0 g/kg) particularly in males. This pattern of enhanced stimulation and diminished sedation is consistent with phenotypes observed in human subjects at high risk for developing AUD. ELS also significantly enhanced escalation of voluntary alcohol intake and preference over eight weeks of two-bottle choice intermittent access drinking particularly in males. Additionally, social behavior assessments revealed that ELS impaired sociability selectively in females with a history of alcohol drinking, highlighting the detrimental interactive effects of ELS and alcohol exposure on adaptive behaviors. These results underscore the complex interplay between ELS, alcohol responses, and sex differences, suggesting that ELS creates a high-risk phenotype for AUD through altered alcohol behavioral sensitivity. Our study highlights the importance of future studies that seek to identify the neurobiological mechanisms underlying these interactions, which may pave the way for targeted interventions in populations affected by childhood adversity and excessive alcohol consumption.
Adaptive circuit plasticity plays crucial roles in the brain during development, learning, sensory experience, and after injury. During chronic whisker trimming, a well-studied paradigm for inducing experience dependent plasticity, whisker representations in the somatosensory barrel cortex (S1BF) undergo remapping, with expansion of maps for spared whiskers and contraction of maps for trimmed whiskers. At the cellular level, excitatory pyramidal cells in Layer 2/3 shift their whisker tuning, increasing selectivity to spared whiskers and away from deprived whiskers. While these changes are well documented, the circuit mechanisms regulating experience-dependent plasticity remain incompletely characterized. Parvalbumin (PV) interneurons play important roles in regulating the spatial and temporal dynamics of sensory evoked activity in Pyr cells and have been implicated in the regulation of experience dependent plasticity in other cortical regions. However, there is little evidence as to how the sensory evoked activity of PV cells change in S1BF during whisker trimming or how those changes might affect cortical remapping. To address these questions, we used longitudinal in vivo two-photon (2P) calcium imaging of PV cells in S1BF before, during, and after inducing experience-dependent plasticity by whisker trimming. At baseline, we found that PV cells have spatially distributed responses to whisker deflections, responding best to the principal whisker of a given barrel and less frequently to surround whiskers in a distance-dependent manner. After whisker trimming, there is a substantial recruitment of PV cells responsive to the spared whisker in deprived, but not spared, barrels. Upon whisker regrowth, this recruitment is reversed, but changes in individual PV cell whisker selectivity can persist for weeks. To probe the potential casual effects of increased PV activity during whisker trimming, we used chemogenetics to acutely manipulate the activity of PV cells and found that modulating PV cell activity strongly affects sensory evoked responses in local Pyr and PV cells, as well as Somatostatin (SST) interneurons. In particular, increased PV cell activity strongly suppressed activity in all three cell types. Together, our results reveal dynamic changes in the spatial distribution and tuning of PV cells during experience dependent plasticity and suggest that increased PV cell activity could constrain the extent of potential cortical remapping in the adult S1BF.
The psychostimulant methylphenidate may exert its effects on cognition and associated brain signals via action on the dopamine or noradrenaline transporter (DAT/NET). A recently developed and increasingly popular dual-regression approach (REACT; Dipasquale et al. (2019)) attempts to hone in on the molecular mechanisms underlying (drug-induced) changes in fMRI signal by enriching the analysis with information about the spatial distribution of molecular targets of interest. This method has great potential, but hitherto lacked validation of its molecular specificity and functional relevance. Here we leverage a unique pharmaco-fMRI dataset with established dopamine-dependent methylphenidate effects on neural reward prediction error (RPE) signaling, the canonical functional signature of dopamine. Using REACT we found that methylphenidate significantly modulated both DAT and NET-related functional connectivity networks, but only the effect on the DAT network varied with interindividual differences in striatal dopamine synthesis capacity, as measured with [18F]FDOPA PET. Furthermore, methylphenidate affected DAT-related connectivity in the prefrontal cortex in the same location where it affected neural RPE signaling. Together, these findings firmly establish the validity of REACT as a tool for isolating the role of dopamine from that of noradrenaline in methylphenidate's effects on brain function.
Infarct-induced neurodegeneration increases dementia risk for at least a decade in humans. It can be modeled in wildtype mice, where a cortical stroke results in chronic lymphocytic infiltration into the infarct and delayed cognitive decline. Vascular cell adhesion molecule 1 (VCAM1) on endothelial cells is increased by stroke and facilitates immune cell diapedesis by binding very late antigen 4 (VLA4) on immune cells. We report here that after stroke, chronic but not acute treatment with a VCAM1 blocking antibody reduces B and T lymphocyte infiltration and prevents chronic cognitive dysfunction in wildtype male and female mice. Preservation of cognitive function also occurred after chronic anti-VLA4 treatment despite anti-VLA4s lack of effect on lymphocyte infiltration. High-depth single-cell RNA sequencing of the chronic infarct and peri-infarct cortex revealed an infarct-induced decrease in expression of blood vessel growth and maturation genes in endothelial cells that was reversed by both anti-VLA4 and anti-VCAM1. Plasma proteomics also support a vasculoprotective mechanism of anti-VCAM1. Finally, immunostaining demonstrated that both antibodies improve pericyte coverage of the vasculature and prevent extravascular fibrinogen leakage. Together, our findings indicate that vascular structure and function remain abnormal long after stroke and that the VLA4/VCAM1 axis is a promising treatment target for infarct-induced neurodegeneration as blockade of either molecule restores cerebrovasculature and prevents cognitive decline.
Maternal infection during pregnancy is a well-established risk factor for neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain poorly understood. Lipocalin-2 (Lcn2), an innate immune protein that is highly upregulated during infection, also affects neuronal and glial function. This study investigates the role of Lcn2 in shaping brain development, particularly after maternal immune activation (MIA). To mimic maternal infection, pregnant mice received intraperitoneal injections of either lipopolysaccharide (LPS) or saline on embryonic days 16 to 18 to model infection during the second trimester of pregnancy in humans. We first showed that Lcn2 mRNA is expressed in the fetal brain and that MIA significantly upregulates Lcn2 mRNA and protein in the hippocampus and neocortex of both sexes. To assess functional relevance, we employed Lcn2 heterozygous females to generate wild-type and Lcn2 KO offspring from the MIA and control groups. Both female and male offspring underwent a battery of behavioral assays. Lcn2 deletion and MIA independently induced deficits in social behavior and increased repetitive behavior phenotypes relevant to NDDs in adult animals. However, their combination did not exacerbate these effects, suggesting an occlusion effect. Interestingly, no deficits were observed in the learning and memory task. To investigate potential shared molecular mechanisms, we performed RNA sequencing of the fetal forebrain 4 hours after the final LPS injection. This analysis revealed an overlapping group of differentially expressed genes in the Lcn2 KO and MIA groups, indicating convergence on similar transcriptional pathways that may underlie the observed behavioral phenotypes. These results suggest that while Lcn2 may not mediate the pathological effects of prenatal immune challenge, it plays a critical role in normal brain development.
This study used variations of a sensory preconditioning protocol in male and female rats to test a theory that the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) represent focal and peripheral states of attention, respectively. It specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required activation of NMDAR in the BLA and not the PRh (Experiments 2A and 2B) regardless of whether the stimulus-shock pairings were contiguous or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required activation of NMDAR in the BLA and not the PRh (Experiments 1A, 1B, 3A and 3B). However, when a pre-exposed stimulus was indirectly paired with shock - because it was associatively activated at the time of shock or separated from the shock by another stimulus - its conditioning required activation of NMDAR in the PRh and not the BLA (Experiments 1A, 1B, 3A and 3B). These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.
The vomeronasal system (VNS) plays a central role in mammalian chemical communication, mediating critical social and reproductive behaviors. In the wapiti (Cervus canadensis), a cervid species with complex social structures and pronounced chemical signaling during the rut, the VNS had not been previously characterized. This study provides the first comprehensive anatomical and neurochemical analysis of the VNS in wapiti using histological, lectin-histochemical, and immunohistochemical techniques. The vomeronasal organ (VNO) exhibited clear rostrocaudal differentiation, with distinct sensory and respiratory epithelia, a complex glandular distribution, and region-specific expression of neural markers. Lectin binding patterns confirmed functional compartmentalization along the epithelium, and immunoreactivity for markers such as OMP, PGP9.5, CR, and G-protein subunits (Gi2, G{gamma}8, and G0) revealed detailed molecular organization. Notably, G0-positive neurons in the epithelium did not project to the accessory olfactory bulb (AOB), suggesting alternative targets, possibly within transitional zones. The AOB showed all canonical layers, including well-defined glomeruli and expression of markers such as calbindin, CR, GFAP, and LEA lectin. Novel findings include the presence of large white matter tracts and region-specific lectin distribution. Confocal double immunofluorescence and autofluorescence imaging were also employed, allowing high-resolution visualization of neuroepithelial architecture and glomerular domains. Altogether, our results demonstrate that the vomeronasal system in wapiti is highly developed and functionally specialized. These findings contribute to a better understanding of chemosensory communication in wild ungulates and provide a comparative framework for future studies in cervid behavior, reproduction, and conservation.
Sleep regulation depends on the complex interplay between homeostatic and circadian processes synchronized by the light/dark cycle. Sleep is also directly regulated by light via projections from the retina to the preoptic area (POA). Although the light-responsive POA neurons project to several wake-promoting neurons, including histaminergic neurons in the tuberomammillary nucleus (TMn), there is no functional evidence for their involvement in light-induced sleep. To bridge this gap, we used histidine decarboxylase (HDC, the histamine-synthetizing enzyme) knockout mice (HDC-/-, n=7) and hM4Di-HDC-cre mice (HDC+/+, n=8) subjected to an ultradian light/dark protocol (LD 1h:1h over 24h), and another group of hM4Di-HDC-cre mice (n=8) exposed to a 1-h light pulse. We found that light pulses during the biological night enhanced slow wave sleep and increased cortical EEG power in the delta range (0.5-3Hz), and that these effects were significantly attenuated both in HDC-/- (83 vs 23 min/6h, p=0.005) under LD 1h:1h condition and in hM4Di-HDC-cre mice after acute chemogenetic silencing of histamine neurons by the DREADD ligand deschloroclozapine (15 vs 6 min/h, p=0.0016) under a 1-h light pulse. In addition, the sleep-inducing effect of light was circadian dependent, with the strongest effect at the beginning and end of the night but no effect at all during the biological day in HDC+/+ mice. The response dynamics to light were slowed down when lacking histamine neurotransmission. Our study provides functional evidence that the acute sleep-inducing effects of light on sleep require histamine neurotransmission in mice.
The ability of the brain to briefly retain information, in processes ranging from sensory perception to complex cognition, is believed to be supported by persistent neural firing. Historically, such firing has been attributed to recurrent synaptic networks, in which neural activity reverberates. Here, we present in vivo evidence challenging this view, demonstrating that individual neurons can sustain persistent firing in behaving mice. Disruption of this capability in hippocampal neurons via silencing of TRPC4 channels significantly and selectively reduces persistent firing in vivo, impairs the maintenance of spatial representations, and compromises spatial working memory performance. These findings redefine neurons as active contributors to information retention beyond their conventional role as passive input-output units, potentially reshaping our general understanding of brain computation.
Odorants stimulate olfactory sensory neurons (OSNs) to create a bilateral sensory map defined by a set of glomeruli present in the left and right olfactory bulbs. Using Xenopus tropicalis tadpoles we challenged the notion that glomerular activation is exclusively determined ipsilaterally. Glomerular responses evoked by unilateral stimulation were potentiated following transection of the contralateral olfactory nerve. The gain of function was observed as early as 2 hours after injury and faded away with a time constant of 4 days. Potentiation was mediated by the presence of larger and faster calcium transients driving glutamate release from OSN axon terminals. The cause was the reduction of the tonic presynaptic inhibition exerted by dopamine D2 receptors. Inflammatory mediators generated by injury were not involved. These findings reveal the presence of a bilateral modulation of glomerular output driven by dopamine that compensates for imbalances in the number of operative OSNs present in the two olfactory epithelia. Considering that the constant turnover of OSNs is an evolutionary conserved feature of the olfactory system and determines the innervation of glomeruli, the compensatory mechanism here described may represent a general property of the vertebrate olfactory system to establish an odor map.
Emotional processing is a crucial adaptive function. Research suggests that sleep, particularly rapid eye movement (REM) sleep, may have a role in processing the emotional load of past events. Notably, dream experiences may offer insight into this nighttime process. Some studies have reported increased emotionality in dreams as the night progresses, possibly reflecting ongoing emotional processing in the sleeping brain. However, findings on how dream affect evolves throughout the night remain mixed. In this study, we investigated how emotional intensity in conscious experiences during sleep changes across the night and sleep stages. Participants (Nsubjects = 20) were subjected to a multiple awakening paradigm, where they were awakened 4-5 times throughout the night and asked to recall their dreams (Ndreams = 61). Additionally, they rated the emotional intensity of their experiences using a structured cued questionnaire. Emotional intensity in dreams increased significantly throughout the night, with late-night dreams being more emotional than dreams collected during earlier sleep. Contrary to our expectation, this increase was not driven by dream reports obtained from REM sleep awakenings. Moreover, late-night dream reports were also significantly longer than those from early sleep, yet the length of the dream reports did not correlate with their emotional intensity. This suggests that the emotionality of dreams is not directly linked to the ability to recall the dream or its narrative complexity. Instead, it could be driven by emotional processes occurring independently throughout the night, or by other factors that regulate our access to dream experiences and their emotional content.
Cannabis use during pregnancy is increasing, often to alleviate stress and anxiety, yet the long-term effect of prenatal cannabis exposure alone or in combination with psychosocial stress on offspring neurodevelopment or maternal behaviors remains unclear. Here, we developed a translational rodent model combining prenatal {Delta}-tetrahydrocannabinol (THC) exposure with chronic psychosocial stress using the maternal witness defeat stress (MWDS) paradigm. Pregnant C57BL/6 mice were exposed to MWDS from gestational day (GD) 3-12 and received daily subcutaneous THC (2 mg/kg) or vehicle until birth. All exposure groups showed impaired maternal behavior, with negative postnatal outcomes and caregiving, with additive effects observed in the combined exposure group. In adolescence, male and female offspring exhibited exposure-specific behavioral alterations. Prenatal stress and combined exposures led to increased anxiety-like behavior and reduced motivated behavior in both sexes, while THC alone primarily impacted female self-care and social behavior. Transcriptomic profiling of the prefrontal cortex (PFC) and nucleus accumbens (NAc) of adolescent offspring revealed sex- and region-specific gene expression changes across all exposure groups. Prenatal THC-, stress-, and combined exposures each altered distinct molecular pathways related to mitochondrial function, synaptic organization, and glial signaling. Comparative analysis with a perinatal fentanyl model revealed shared transcriptional substrates involved in synaptic signaling and circadian regulation. These findings indicate that THC and stress independently and additively impair maternal behaviors with lasting neurodevelopment signatures in offspring.
The different aspects of a face, like sex or identity, can be decoded from the cortical patterns related to its processing. Many studies have investigated this phenomenon with similar outcomes. These studies usually utilize a low number of facial identities and high repetition numbers, which affects the recognizability and familiarity of a face, thus altering the processing. We propose that this commonly employed paradigm influences cortical patterns associated with features seemingly unrelated to identity, such as the sex of a face. In the first experiment, we recreated the findings of previous studies using a few identities and a high presentation number for decoding facial sex. In the second experiment, the identity-presentation ratio was switched. This change resulted in a narrower time window where facial sex related cortical patterns were detected. Decoding accuracy was also diminished, yielding lower values and suggesting a reduced signal-to-noise ratio in the cortex. After expanding the sample size with balanced gender representation, we identified shared cortical patterns related to face-sex processing both within the population and across gender-based subpopulations. These results provide further evidence that familiarity impacts face processing and suggest that previous findings on sex information decoding were likely influenced by the experimental paradigms employed.
One of the major characteristics of sleep is homeostatic sleep rebound following sleep loss. While the molecular mechanisms of baseline sleep regulation have been intensively studied, a specific molecular understanding of sleep rebound remains elusive. Here, we show that a constitutively active form of the Munc13-family presynaptic release factor Unc13A, which lacks the inhibitory Ca2+/calmodulin interaction domain (Unc13AWRWR), dominantly suppressed sleep rebound upon acute sleep deprivation, leading to a nearly complete elimination of recovery sleep (''reboundless''). In contrast, baseline sleep remained largely normal. Through a genetic modifier screen, we found that this dominant ''reboundless'' phenotype of Unc13AWRWR was rescued by a partial loss of Snap, a cofactor of NSF required for disassembly and recycling of post-fusion cis-SNARE complex. Given that Unc13A promotes fusion-competent trans-SNARE complex formation, these findings suggest that sleep rebound may depend on a delicate balance between SNARE complex assembly and recycling. Additionally, we found that expression of a human disease-associated active Unc13A (Unc13APL) variant attenuated baseline and rebound sleep. Since both Unc13AWRWR and Unc13APL were shown to promote presynaptic release probability (Pr), we speculate that Unc13A suppresses recovery sleep likely by increasing Pr and subsequently enhancing synaptic transmission, probably through elevated trans-SNARE formation and efficient cis-SNARE recycling. Taken together, our data demonstrate a fundamental role of Unc13A and SNARE dynamics in sleep homeostasis.
During sleep, ensemble activity patterns encoding recent experiences are reactivated in the hippocampus and cortex. This reactivation is coordinated by hippocampal sharp-wave ripples (SWRs) and is believed to support the early stages of memory consolidation. However, only a minority of sleep SWRs are associated with memory reactivation in the hippocampus and its downstream areas. Whether that subset of SWRs have specific physiological characteristics and directly contribute to memory performance is not known. We identified a specific subset of large SWRs linked to memory reactivation in both the hippocampus and prefrontal cortex (PFC) of mice, and found that their occurrence selectively increased during sleep following new learning. Closed-loop optogenetic SWR boosting during sleep was sufficient to enhance ensemble memory reactivation in hippocampus and PFC. This manipulation also improved subsequent memory retrieval and hippocampal-PFC coordination, causally linking both phenomena to SWR-associated ensemble reactivation during sleep.
Cough is a hallmark sign of tuberculosis and key driver of transmission. While traditionally attributed to host-driven inflammation, we previously demonstrated that Mycobacterium tuberculosis lipid extract (Mtb extract) and its component sulfolipid-1 (SL-1) directly activate nociceptive neurons to induce cough in guinea pigs. However, the cellular mechanisms by which Mtb extract and SL-1 modulate nociceptive sensory neurons remain incompletely understood. Here, we show that Mtb extract enhances action potential (AP) generation in mouse nodose nociceptors via an SL-1-dependent mechanism. Using calcium imaging, we found that Mtb extract and SL-1 increased intracellular calcium; signals in TRPV1-positive; neurons from both mouse nodose and human dorsal root ganglia (hDRG). These calcium; signals were attenuated by the Galpha;q/11 pathway inhibitor YM254890, even in the absence of extracellular calcium;, suggesting involvement of intracellular calcium; stores. Together, these findings indicate that SL-1 engages Galphaq/11 coupled pathways to sensitize nociceptors via intracellular calcium release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention.
Transcranial magnetic stimulation (TMS) has transformed non-invasive brain therapies but faces challenges due to variability in outcomes, likely stemming from inter-individual differences in brain function. This study aimed to address this challenge by integrating personalized functional networks (PFNs) derived from functional magnetic resonance imaging (fMRI) with a neural network-based decoder to optimize stimulation in real time during a working memory (WM) task. After identification of individualized stimulation targets, participants completed a TMS/fMRI session, performing a WM task while receiving rTMS at randomized frequencies. Decoder outputs and behavioral data during this session guided selection of optimal and suboptimal stimulation frequencies. Participants then underwent six stimulation sessions (three optimal, three suboptimal) in a randomized crossover design, performing WM and control tasks. The optimal stimulation improved WM performance by the final session, with no improvement observed in the control task. Additionally, the decoder output predicted behavioral performance on the WM task, both during the TMS/fMRI and neuromodulation sessions. These findings show that neural network-guided closed-loop neuromodulation can improve TMS effectiveness, marking a step forward in personalized brain stimulation.
Ethanol rapidly produces widespread neuronal apoptosis during early development, but this susceptibility declines as the brain matures. In previous research, we found Myt1l (a proneuronal transcription factor) mutations can cause precocious differentiation, neuronal immaturity, and transcriptomic alterations, including many in apoptotic regulators. Therefore, we used a recently developed Myt1l haploinsufficient mouse model to examine this gene\'s effects on ethanol-induced apoptosis across different developmental stages. We discovered that haploinsufficiency can moderately influence vulnerability to ethanol in a complex, age- and cell type-specific manner: apoptosis was reduced on P7, increased P21, but unaffected on P60. Remarkably, we also discovered the previously unrecognized ability of a single binge of ethanol to rapidly increase apoptosis within six hours in early adolescent and adult wild-type mice occurring in microglia and the newborn granule neurons in the hippocampus. This suggests apoptosis is an underappreciated contributor to ethanol\'s neuropathology at older ages and, translated to human use, occurs far more frequently than previously recognized.
Many newly encoded memories are labile when acquired but then consolidate to more stable states. Reconsolidation theory posits that reactivating a consolidated memory again destabilizes it, increasing its vulnerability to interference from competing memories. In a series of 3-day experiments, we investigated the fate of a motor memory when it is reactivated and challenged with a competing one. We pursued a modular design in which humans adapted to a visuomotor rotation A (day 1), then an opposite rotation B (day 2), followed by a retest on A (day 3). We first found that reactivating A before learning B (A-AB-A) caused no greater impairment in A retention than non-reactivation (A-B-A). That is, while interference occurred, it appeared to be uninfluenced by reactivation, contradicting reconsolidation predictions. We then tested an alternate idea, that reactivation might serve to protect the original memory from interference. In subsequent experiments, we introduced no rotation (N) trials either prior to A relearning (A-AB-NA and A-B-NA groups), or immediately after B learning (A-ABN-A and A-BN-A groups). Here, we observed that reactivation served a protective function, but only when B was washed out immediately, preventing its consolidation (A-ABN-A group). Collectively, our results show that reactivation does not necessarily increase the susceptibility of a motor memory to interference but may rather shield it from degradation by competing learning. Our findings align with theories positing memory transitions between active and inactive states, and hold implications for strategies focused on improving memory retention in rehabilitation, sports and skills training.
A fundamental feature of the visual system is its ability to detect image contrast. The contrast processing starts in the first synapse of the retina where parallel pathways are established to compute contrast to bright (ON pathway) and dark (OFF pathway) objects, separately transferred to morphologically identified ON and OFF cells throughout the visual system. Here, we found that response polarity in ON and OFF neurons is not fixed but rather switches dynamically to the opposite sign. The switch was not observed in rod-knockout mice, indicating that rods generate the polarity switch. We determined that neither horizontal cells nor rod-signaling pathways were responsible for the switch. Instead, we discovered that EAAT5 glutamate transporters located at photoreceptor terminals were required to produce the polarity switch. Our findings provide a new perspective on the adaptive properties of neural networks and their ability to encode contrast across the visual dynamic range.
Central post-stroke pain (CPSP) is a highly distressing condition that develops in 50% of people who suffer a thalamic stroke, and is typically unresponsive to current clinical treatments. Hypoxic damage to the ventral posterolateral (VPL) and ventral posteromedial (VPM) sensory thalamic nuclei, in particular, precipitates CPSP. One barrier to developing treatments for CPSP is the lack of preclinical models of thalamic ischemic stroke. In this study, we present a novel mouse model of CPSP induced through targeted photothrombotic ischemia. After eliciting hypoxia in the sensory thalamus of male mice, we assessed pain behaviors over a four-week period. Stroke-affected mice exhibited a persistent spontaneous facial grimace from day four to week four post-stroke, indicative of pain. Hind-paw mechanical hypersensitivity indicative of altered nociception, characteristic of VPL and VPM hemorrhagic CPSP models, was not detected in our model. Immunofluorescence analysis revealed increased activated microglia (Iba1) and reactive astrocytes (GFAP). Iba1 fluorescence intensity in the VPL thalamus, but not the VPM thalamus, correlated with the severity of facial grimace at four weeks post-stroke. Clustering based on behavioral phenotypes identified a subpopulation of mice in which grimace pain spontaneously resolved, by four weeks post-stroke, relative to sham controls, suggesting that this model can be used to understand how stroke recovery may influence pain chronification. This model provides a valuable tool to investigate the cellular and circuit mechanisms underlying CPSP after an ischemic thalamic stroke.
Most insects, including agricultural pests and disease vectors, rely on olfaction for key innate behaviors. Consequently, there is growing interest in studying insect olfaction to gain insights into odor-driven behavior and to support efforts in vector control. Calcium imaging using GCaMP fluorescence is widely used to identify olfactory receptor neurons (ORNs) responsive to ethologically relevant odors. However, accurate interpretation of GCaMP signals in the antenna requires understanding both response uniformity within an ORN population and how calcium signals relate to spike activity. To address this, we optimized a dual-modality recording method combining single-sensillum electrophysiology and widefield imaging for Drosophila ORNs. Calcium imaging showed that homotypic ab2A neurons exhibit similar odor sensitivity, consistent with spike recordings, indicating that a single ORN\'s response can reliably represent its homotypic counterparts. Furthermore, concurrent dual recordings revealed that peak calcium responses are linearly correlated with spike activity, regardless of imaging site (soma or dendrites), GCaMP variant, odorant, or fly age. These findings validate the use of somatic calcium signals as a reliable proxy for spike activity in fly ORNs and provide a foundation for future large-scale surveys of spike vs. calcium response relationships across diverse ORN types.
Background: Synthetic Cannabinoids Receptor Agonists (SCRAs) are the largest group of new psychoactive substances monitored worldwide. 5F-MDMB-PICA is a recent SCRA classified as a potent full agonist at CB1/CB2 receptors able to activate the mesolimbic dopamine (DA) transmission in adolescent but not in adult mice. Here, we have studied its reinforcing effects in adolescent mice and characterized the neurochemical and behavioral effects induced in the same animals in adulthood. Methods: We utilized an intravenous self-administration (IVSA) protocol in adolescent (PND 40-56) CD-1 male mice. In adulthood (PND 66-78), we conducted several behavioral and neurobiological assessments including: Sucrose Preference Test (SPT); Resident Intruder Test (RIT); Olfactory Reactivity Test (ORT); brain microdialysis to quantify DA levels in the medial Prefrontal Cortex (mPFC); and fiber photometry analysis using the GCaMP calcium sensor to monitor excitatory neural dynamics in the mPFC after exposure to an aversive odorant. Results: We found that 5F-MDMB-PICA, administered through IVSA in adolescent mice, produced an inverted U-shaped dose-response curve. The dose of 2.5 g/kg/25ul elicited behavior consistent with drug seeking. Adult mice exposed to 5F-MDMB-PICA during adolescence exhibited significant behavioral and neurochemical changes in adulthood compared to control mice. These behaviors included increased aggression, reduced social interaction, an anhedonic state, and an abolishment of mPFC DA response to an aversive odorant, as measured by in vivo brain microdialysis. Moreover, fiber photometry analysis of excitatory neuronal activity in the mPFC showed diminished calcium activity in response to the same aversive odorant in 5F-MDMB-PICA-exposed mice compared to controls. Conclusions: Notably, this study is the first to demonstrate that adolescent mice can acquire and sustain IVSA of 5F-MDMB-PICA. Furthermore, it highlights the long-term behavioral and neurochemical changes associated with adolescent exposure to 5F-MDMB-PICA, underscoring the potential detrimental effects of its use during this critical developmental period.
Our ability to transfer motor skills across tools and contexts is what makes modern technology usable. The success of motor augmentation devices, such as supernumerary robotic limbs, hinges on users\' capacity for generalised motor performance. We trained participants over seven days to use an extra robotic thumb (Third Thumb, Dani Clode Design), worn on the right hand and controlled via the toes. We tested whether motor learning was confined to the specific tasks and body parts involved in controlling and interacting with the Third Thumb, or whether it could generalise beyond them. Participants showed broad skill generalisation across tasks, body postures, and even when either the Third Thumb or the controller was reassigned to a different body part, suggesting the development of abstract, body-independent motor representations. Training also reduced cognitive demands and increased the sense of agency over the device. However, participants still preferred using their biological hand over the Third Thumb when given the option, suggesting that factors beyond motor skill generalisation, cognitive effort, and embodiment must be addressed to support the real-world adoption of such technologies.
Animals rely on both sensory perception and memory when navigating relative to learned allocentric locations. Incoming sensory stimuli, which arrive from an egocentric perspective, must be integrated into an allocentric reference frame to allow neural computations that direct an animal toward a learned goal. This egocentric-allocentric spatial transformation has been proposed to involve projections from the rodent postrhinal cortex (POR), which receives strong visual input, to the medial entorhinal cortex (MEC), which contains allocentric spatial cell types such as grid and border cells. A major step toward understanding this transformation is to identify how POR and MEC spatial representations differ during place navigation, which is currently unknown. To answer this question, we recorded single neurons from POR and MEC as rats engaged in a navigation task that required them to repeatedly visit a learned uncued allocentric location in an open field arena to receive a randomly scattered food reward. While neurons in both regions displayed strong tuning to the spatial structure of the environment, neither showed bias toward the goal location despite strongly biased behavior. Critically, when local visual landmarks were manipulated to place the visual scene in conflict with the learned location, POR neurons adjusted their tuning preferences to follow the visual landmarks, while MEC neurons remained in register with the true global reference frame. These findings reveal a strong dissociation between POR and MEC spatial reference frames during place navigation and raise questions regarding the mechanisms underlying integration of POR egocentric signals into the MEC allocentric spatial map.
Background: Optic flow is vital for locomotor control and is often perturbed to study the impact of optic flow on balance control. However, it remains unclear whether gait speed influences responses to such perturbations. This study aims to examine the effects of gait speed on gait parameters following immediate and prolonged exposure to mediolateral optic flow perturbations. Methods: Twenty-one young adults (23.43 +/- 4.19 years) walked on an instrumented treadmill, including 3 phases: baseline (3 min), perturbation with mediolateral optic flow (8 min), and post-perturbation (3 min). Trials were conducted at 0.6, 1.2, and 1.8 m/s. Ground reaction forces and 3D motion data were collected to calculate mediolateral margin of stability (MoS), mean step length (SL), step width (SW) and their variabilities. Three repeated-measures ANOVAs (Speed by Phase) were used to compare: baseline vs. early perturbation, early vs. late perturbation, and baseline vs. post-perturbation. Results: The responses to immediate and prolonged exposure to optic flow perturbation were speed dependent. Walking at slow speeds induced greater immediate responses in mediolateral gait parameters (SW and mediolateral MoS, both p < 0.001) compared to walking at faster speeds. During the perturbation phase, the adaptations were larger at faster vs. slower speeds for gait parameters in the direction of movement (SL, p = 0.007). Conclusion: Immediate responses and adaptations to mediolateral optic flow perturbations are speed-dependent and larger at slower gait speeds. The responses to prolonged perturbation are interpreted as step-to-step adaptations that may inform future interventions and studies on gait speed selection.
The steroid hormone 5-androstene-3{beta},17{beta}-diol (ADIOL) was discovered in humans nearly a century ago, yet its physiological roles remain poorly defined. Here, we show that fasting and caloric restriction, two forms of dietary restriction, induce transcriptional upregulation of genes encoding CYP11A1, CYP17A1, and 17{beta}-hydroxysteroid dehydrogenase family enzymes, promoting ADIOL biosynthesis. ADIOL, in turn, acts on the nervous system to reduce levels of kynurenic acid, a neuroactive metabolite linked to cognitive decline and neurodegeneration. This effect requires NHR-91, the C. elegans homolog of estrogen receptor {beta}, specifically in the RIM neuron, a key site of kynurenic acid production. Consistent with the known benefits of fasting and caloric restriction on healthspan, enhancing ADIOL signaling improves multiple healthspan indicators during aging. Conversely, animals deficient in ADIOL signaling exhibit reduced healthspan under normal conditions and in genetic models of caloric restriction, underscoring the functional significance of this pathway. Furthermore, ADIOL suppresses cellular stresses induced by the Alzheimer\'s-associated APOE4 variant, highlighting its potential as a neuroprotective agent. Notably, ADIOL does not significantly impact lifespan, indicating that its healthspan benefits are not simply a byproduct of lifespan extension. Together, these findings establish a physiological role for ADIOL in mediating the neuroprotective and pro-healthspan effects of fasting and caloric restriction and suggest that boosting ADIOL signaling may help narrow the gap between lifespan and healthspan. This positions ADIOL as a promising mimetic of dietary restriction effects on healthspan that could be used as a therapeutic strategy for age-related neurodegenerative conditions.
Progress at the intersection of artificial intelligence and pediatric neuroimaging necessitates large, heterogeneous datasets to generate robust and generalizable models. Retrospective analysis of clinical brain magnetic resonance imaging (MRI) scans offers a promising avenue to augment prospective research datasets, leveraging the extensive repositories of scans routinely acquired by hospital systems in the course of clinical care. Here, we present a systematic protocol for identifying scans with limited imaging pathology through machine-assisted manual review of radiology reports. The protocol employs a standardized grading scheme developed with expert neuroradiologists and implemented by non-clinician graders. Categorizing scans based on the presence or absence of significant pathology and image quality concerns, facilitates the repurposing of clinical brain MRI data for brain research. Such an approach has the potential to harness vast clinical imaging archives exemplified by over 250,000 brain MRIs at the Childrens Hospital of Philadelphia to address demographic biases in research participation, to increase sample size, and to improve replicability in neurodevelopmental imaging research. Ultimately, this protocol aims to enable scalable, reliable identification of clinical control brain MRIs, supporting large-scale, generalizable neuroimaging studies of typical brain development and neurogenetic conditions.
A role for the trafficking receptor SORLA in reducing A{beta} levels has been well-established, however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo. Here, we show that transgenic SORLA upregulation (SORLA TG) can reverse pathological effects in aged PS19 (P301S tau) mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, LTP impairment and glial hyperactivation. Proteomic analysis indicates reversion of PS19 profiles in PS19/SORLA TG hippocampus, including pathological changes in synapse-related proteins as well as key drivers of synaptic dysfunction such as Apoe and C1q. snRNA-seq analysis reveals suppression of PS19- signatures with SORLA upregulation, including proinflammatory induction of Plxnb1/Plxnb2 in glia. Tau seeding and aggregation, neuroinflammation, as well as PlxnB1/B2 induction are exacerbated in PS19 hippocampus with SORLA deletion. These results implicate a global role for SORLA in neuroprotection from tau toxicity in PS19 mouse brain.
TAR DNA-binding protein 43 kDa (TDP-43) is an essential splicing repressor whose loss of function underlies the pathophysiology of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Nuclear clearance of TDP-43 disrupts its function and leads to the inclusion of aberrant cryptic exons. These cryptic exons frequently introduce premature termination codons resulting in the degradation of affected transcripts through nonsense-mediated mRNA decay (NMD). Conventional RNA sequencing approaches thus may fail to detect cryptic exons that are efficiently degraded by NMD, precluding identification of potential therapeutic targets. We generated a comprehensive set of neuronal targets of TDP-43 in human iPSC-derived i3Neurons (i3N) by combining TDP-43 knockdown with inhibition of multiple factors essential for NMD, revealing novel cryptic targets. We then restored expression of selected NMD targets in TDP-43 deficient i3Ns and determined which genes improved neuronal viability. Our findings highlight the role of NMD in masking cryptic splicing events and identify novel potential therapeutic targets for TDP-43-related neurodegenerative disorders.
There are many sources of heterogeneity in the CA1 network, including plasticity, connectivity and cell properties, yet the extent and functional consequences of this diversity remains poorly understood. We used patterned optogenetic stimulation of CA3 pyramidal neurons and whole-cell patch clamp recordings from CA1 pyramidal neurons in acute mouse hippocampal slices, to characterize the contributions of different forms of heterogeneity to information flow. We found pronounced heterogeneity in synaptic responses and short-term plasticity (STP), influenced by the neurotransmitter identity, input pattern, and size of the activated presynaptic ensemble. Inhibitory synapses exhibited greater diversity in both response variability and depression profiles than excitatory synapses. We incorporated these readings in a molecule-to-network multiscale model of the CA3->CA1 circuit. The reference model shows strong decorrelation of autocorrelated input, but removal of STP makes the decorrelation frequency dependent. Removal of stochasticity and heterogeneity in connections makes the output periodic. Thus heterogeneity, short-term plasticity, and stochasticity each have distinct effects on cellular information transmission.
Memory-based inference allows individuals to integrate information acquired across separate episodes to support novel decisions and reasoning. Although prior knowledge, such as schemas, is known to influence learning and memory, its impact on the neural mechanisms underlying inference remains unclear. In this study, we investigated how schema congruency affects the encoding and retrieval of overlapping events and how these processes contribute to memory-based inference. Thirty-nine participants encoded AB associations, consisting of picture-word pairs presented on either schema-congruent or schema-incongruent backgrounds. These were followed by BC associations involving the same word paired with a new picture on a neutral background. At test, participants were asked to infer the indirect AC association. While overall inference accuracy did not differ as a function of schema congruency, behavioral and neural data revealed distinct mechanisms. Inference for schema-incongruent events depended on accurate retrieval of both AB and BC associations, whereas schema-congruent inferences did not. To investigate the neural processes involved, we trained hierarchical multivariate pattern classifiers on EEG data to detect schema and context reinstatement during task performance. For schema-congruent events, successful inference was predicted by schema reinstatement during BC encoding, consistent with integrating overlapping information into a unified memory trace. In contrast, successful inference for schema-incongruent events was predicted by context reinstatement during AC retrieval, reflecting a reliance on flexible recombination of separate memory representations. These findings demonstrate that schema congruency modulates the neural basis of memory-based inference. Congruent events are integrated during encoding, whereas incongruent events rely on retrieval-based inference. Keywords: memory integration, schema, congruency, context, MVPA, EEG
Visual, vestibular, proprioceptive and cutaneous sensory information is important for posture control during quiet stance. When the reliability of one source of sensory information used to detect self-motion for posture control is reduced, there may be a reweighting of inputs within and/or across the remaining sensory systems determining self-motion for postural control. Muscle vibration, which creates an illusion of muscle stretch and a compensatory movement to shorten the vibrated muscle, may be used to determine the weighting of muscle spindle Ia proprioception for posture control. The objective of this study was to determine the effect of vision occlusion on triceps surae muscle Ia proprioceptive weighting for postural control during quiet stance, utilizing 80 Hz muscle vibration and a quantitative measure of the bodys anterior to posterior ground center of pressure response to triceps surae muscle vibration in freely standing subjects. Subjects (N = 41; mean(standard deviation), 19.6(2.0) years) were examined as they stood with eyes open or eyes closed. Ground center of pressure was measured during quiet standing with, and without, bilateral vibration of the triceps surae muscles. The mean backward center of pressure shift induced by triceps surae vibration was significantly greater during the eyes closed condition compared to eyes open (eyes closed: -4.93(1.62) centimeters; eyes open: -3.21(1.33) centimeters; p = 6.85E-10; Cohens d = 1.29). Thirty-seven subjects increased, and two subjects decreased, their vibration induced center of pressure backward shift in the eyes closed condition compared to eyes open, although the magnitude of the change varied. Results support the idea that for most subjects, during an eyes closed stance there is an increased triceps surae muscle Ia proprioceptive weighting for postural control, due to the need for posture control to depend more on non-visual feedback.
Insect proprioception, vibration and sound detection rely on the scolopidium--a mechanosensory unit enclosing the sensory cilium of chordotonal organ neurons. The cilium contains mechanosensitive ion channels, and is enclosed by a scolopale cell with its tip embedded in a cap. Despite knowledge of the scolopidium\'s structure in multiple insects, the mechanism by which mechanical force elicits the transduction current remains speculative. We examined scolopidia in the auditory Muller\'s organ of the desert locust and present a comprehensive three-dimensional ultrastructure of a scolopidium using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). Next, we characterised sound-evoked motions of Muller\'s organ and the scolopidium using Optical Coherence Tomography (OCT) and high-speed light microscopy. We further measured transduction currents via patch clamp electrophysiology during mechanical stimulation of individual scolopidia. By combining ultrastructure, sound-evoked motions, and transduction current recordings, our finding suggests that the scolopidium is activated best by stretch along the ciliary axis.
Purpose To identify the origin of out-of-voxel (OOV) signals based on the coherence transfer pathway (CTP) formalism using signal phase conferred by the acquisition phase cycling scheme. Knowing the CTP driving OOV artifacts enables optimization of crusher gradients to improve their suppression without additional data acquisition. Theory and Methods A phase cycle systematically changes the phase of RF pulses across the transients of an experiment, encoding phase shifts into the data that can be used to suppress unwanted CTPs. We present a new approach, phase cycle inversion (PCI), which removes the receiver phase originally applied to the stored transients, replacing it with new receiver phases, matching the phase evolutions associated with each unwanted CTP, to identify the OOV signals. We demonstrated the efficacy of PCI using the MEGA-edited PRESS sequence in simulations, phantom and in vivo experiments. Based on these findings, the crusher gradient scheme was optimized. Results The simulation results demonstrated that PCI can fully separate signals originating from different CTPs using a complete phase cycling scheme. PCI effectively identified the CTP responsible for OOV signals in phantom experiments and in vivo, though with reduced specificity in vivo due to phase instabilities. Re-optimization of the gradient scheme based on the identified OOV-associated CTP to suppress these signals, resulted in cleaner spectra in six volunteers. Conclusion PCI can be broadly applied across pulse sequences and voxel locations, making it a flexible and generalizable approach for diagnosing the CTP origin of OOV signals.
Alpha-synuclein (asyn) fibril accumulation is the defining feature of Parkinson disease and is a target for disease-modifying treatments. One therapeutic strategy to reduce fibril accumulation is inhibition of asyn fibril growth. We developed a sensitive fluorescence-based fibril growth assay to screen for small molecule inhibitors. After validating the inhibition assay using a previously identified inhibitor, epigallocatechin-3-gallate, we identified compound 1 as a lead for inhibition of fibril growth. We analysed structure-activity relationships with analogs of 1 to optimize inhibition potency. Our results identified two dimethoxyphenyl piperazine analogs with more potent inhibition of in-vitro assembled fibrils. These analogs also inhibited the growth of asyn fibrils amplified from Lewy Body Disease brain tissue, further validating the inhibitor screening assay. Molecular docking studies indicate that these compounds can bind to the fibril ends, suggesting a potential capping mechanism through which these compounds inhibit the sequential association of monomeric asyn required for fibril growth.
The vomeronasal system (VNS) is critical for detecting pheromonal cues that modulate sociosexual behaviors. Despite its central role in chemical communication, our understanding of its anatomical and functional variability across mammals remains incomplete. This study provides the first detailed characterization of the VNS in the Iberian mole (Talpa occidentalis), a fossorial species endemic to the Iberian Peninsula. We performed a morphofunctional and neurochemical analysis of the vomeronasal organ (VNO) and the accessory olfactory bulb (AOB) using histology, immunohistochemistry, and lectin histochemistry. The VNO in T. occidentalis exhibited an unusual circular lumen lined by a uniform sensory epithelium, lacking the dual epithelial organization seen in most species. The vomeronasal cartilage was limited in extent and did not form the typical J-shaped structure. Importantly, no evidence of a vomeronasal pump was found, suggesting alternative mechanisms for semiochemical entry, likely facilitated by the anatomical position of the organ and continuous receptor distribution. Immunohistochemical analysis revealed strong expression of Gai2 and Gg8 in sensory neurons, with weaker Ga0 expression, suggesting predominance of V1R-type signal transduction. The AOB, though small, exhibited clear lamination and specific marker localization (Gai2, OMP, CR, MAP2), indicating robust functional organization. Lectin binding revealed specific glycosylation patterns in the glomerular layer, with STL and LEA marking synaptic regions. These findings uncover unprecedented anatomical and molecular features in the VNS of T. occidentalis, positioning this species as a valuable model for studying vomeronasal diversity and evolution among Laurasiatherian mammals.
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AbstractThe Tweety homologues (TTYHs) constitute a family of eukaryotic membrane proteins that, on the basis of structural features, were recently proposed to contribute to lipid transfer between soluble carriers and cellular membranes1. However, in the absence of supporting data, this function was hypothetical. Here through pull-down of endogenous proteins, we identify APOE as the interaction partner of human TTYH2. Subcellular fractionation and immunocytochemistry assays showed that both proteins colocalize in endosomal compartments. Characterization of the specific interaction between APOE and TTYH2 through binding assays and structural studies enabled us to identify an epitope in an extended domain of TTYH2 that faces the endosomal lumen. Structures of complexes with APOE-containing lipoprotein particles revealed a binding mode that places lipids in a suitable position to facilitate their diffusion into the membrane. Moreover, in vitro studies revealed that lipid transfer is accelerated by TTYH2. Collectively, our findings indicate that TTYH2 has a role in the unloading of APOE-containing lipoproteins after they are endocytosed. These results define a new protein class that facilitates the extraction of lipids from and their insertion into cellular membranes. Although ubiquitous, this process could be of particular relevance in the brain, where APOE is involved in the transfer of lipids between astrocytes and neurons.
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AbstractThe brain represents sensory variables in the coordinated activity of neural populations, in which tuning curves of single neurons define the geometry of the population code1,2. Whether the same coding principle holds for dynamic cognitive variables remains unknown because internal cognitive processes unfold with a unique time course on single trials observed only in the irregular spiking of heterogeneous neural populations3–8. Here we show the existence of such a population code for the dynamics of choice formation in the primate premotor cortex. We developed an approach to simultaneously infer population dynamics and tuning functions of single neurons to the population state. Applied to spike data recorded during decision-making, our model revealed that populations of neurons encoded the same dynamic variable predicting choices, and heterogeneous firing rates resulted from the diverse tuning of single neurons to this decision variable. The inferred dynamics indicated an attractor mechanism for decision computation. Our results reveal a unifying geometric principle for neural encoding of sensory and dynamic cognitive variables.
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AbstractLanthanides have shown magnetic memory at both the atomic1,2and molecular3,4level. The magnetic remanence temperatures of lanthanide single-molecule magnets can surpassd-transition metal examples5,6, and since 2017, energy barriers to magnetic reversal (Ueff) from 1,237(28) cm–1to 1,631(25) cm–1and open magnetic hysteresis loops between 40 K and 80 K have typically been achieved with axial dysprosium(III) bis(cyclopentadienyl) complexes7–17. It has been predicted that linear dysprosium(III) compounds could deliver greatermJ(the projection of the total angular momentum,J, on a quantization axis labelledz) state splitting and therefore higherUeffand hysteresis temperatures18–21, but as lanthanide bonding is predominantly ionic22,23, so far dysprosium bis(amide) complexes have shown highly bent geometries that promote fast magnetic reversal24,25. Here we report a dysprosium bis(amide)–alkene complex, [Dy{N(SiiPr3)[Si(iPr)2C(CH3)=CHCH3]}{N(SiiPr3)(SiiPr2Et)}][Al{OC(CF3)3}4] (1-Dy), that showsUeff= 1,843(11) cm–1and slow closing of soft magnetic hysteresis loops up to 100 K. Calculations show that theUeffvalue for1-Dyarises from the charge-dense amide ligands, with a pendant alkene taking a structural role to enforce a large N–Dy–N angle while imposing only a weak equatorial interaction. This leads to molecular spin dynamics up to 100 times slower than the current best single-molecule magnets above 90 K.
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AbstractMaterials emitting circularly polarized light (CPL) are highly sought after for applications ranging from efficient displays to quantum information technologies1–7. However, established methods for time-resolved CPL (TRCPL) characterization have notable limitations8–17, generally requiring a compromise between sensitivity, accessible timescales and spectral information. This has limited the acquisition of in-depth photophysical insight necessary for materials development. Here we demonstrate a high-sensitivity (noise level of the order of 10−4), broadband (about 400–900 nm), transient (nanosecond resolution, millisecond range) full-Stokes (CPL and linear polarizations) spectroscopy setup. The achieved combination of high-sensitivity, broad wavelength response and flexible time ranges represents a substantial advancement over previous TRCPL approaches. As a result, TRCPL measurements are shown to be applicable to hitherto inaccessible material systems and photophysical processes, including systems with low (10−3) dissymmetry factors and luminescence pathways spanning nanosecond to millisecond time ranges. Finally, full-Stokes measurements allow tracking the temporal evolution of linear polarization components, of interest by themselves, but especially relevant in the context of controlling for associated CPL artefacts18,19in the time domain.
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AbstractA key virtue of spin qubits is their sub-micron footprint, enabling a single silicon chip to host the millions of qubits required to execute useful quantum algorithms with error correction1–3. However, with each physical qubit needing multiple control lines, a fundamental barrier to scale is the extreme density of connections that bridge quantum devices to their external control and readout hardware4–6. A promising solution is to co-locate the control system proximal to the qubit platform at milli-kelvin temperatures, wired up by miniaturized interconnects7–10. Even so, heat and crosstalk from closely integrated control have the potential to degrade qubit performance, particularly for two-qubit entangling gates based on exchange coupling that are sensitive to electrical noise11,12. Here we benchmark silicon metal-oxide-semiconductor (MOS)-style electron spin qubits controlled by heterogeneously integrated cryo-complementary metal-oxide-semiconductor (cryo-CMOS) circuits with a power density sufficiently low to enable scale-up. Demonstrating that cryo-CMOS can efficiently perform universal logic operations for spin qubits, we go on to show that milli-kelvin control has little impact on the performance of single- and two-qubit gates. Given the complexity of our sub-kelvin CMOS platform, with about 100,000 transistors, these results open the prospect of scalable control based on the tight packaging of spin qubits with a ‘chiplet-style’ control architecture.
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AbstractMirroring the complex structures and diverse functions of natural organisms is a long-standing challenge in robotics1–4. Modern fabrication techniques have greatly expanded the feasible hardware5–8, but using these systems requires control software to translate the desired motions into actuator commands. Conventional robots can easily be modelled as rigid links connected by joints, but it remains an open challenge to model and control biologically inspired robots that are often soft or made of several materials, lack sensing capabilities and may change their material properties with use9–12. Here, we introduce a method that uses deep neural networks to map a video stream of a robot to its visuomotor Jacobian field (the sensitivity of all 3D points to the robot’s actuators). Our method enables the control of robots from only a single camera, makes no assumptions about the robots’ materials, actuation or sensing, and is trained without expert intervention by observing the execution of random commands. We demonstrate our method on a diverse set of robot manipulators that vary in actuation, materials, fabrication and cost. Our approach achieves accurate closed-loop control and recovers the causal dynamic structure of each robot. Because it enables robot control using a generic camera as the only sensor, we anticipate that our work will broaden the design space of robotic systems and serve as a starting point for lowering the barrier to robotic automation.
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AbstractMitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis1–3. Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown4–8. Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin–CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin–CDK acts as a ‘signal relayer’. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm.
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AbstractGastrointestinal (GI) motility disorders represent a major medical challenge, with few effective therapies available. These disorders often result from dysfunction of inhibitory nitric oxide (NO)-producing motor neurons in the enteric nervous system, which are essential for regulating gut motility. Loss or dysfunction of NO neurons is linked to severe conditions, including achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation1,2. Here we introduce a platform based on human pluripotent stem cells (hPSCs) for therapeutic development targeting GI motility disorders. Using an unbiased screen, we identified drug candidates that modulate NO neuron activity and enhance motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define developmental programs driving the specification of NO neurons and found that inhibition of platelet-derived growth factor receptors (PDGFRs) promotes their differentiation from precursors of the enteric nervous system. Transplantation of these neurons into NO-neuron-deficient mice led to robust engraftment and improved GI motility, offering a promising cell-based therapy for neurodegenerative GI disorders. These studies provide a new framework for understanding and treating enteric neuropathies.
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AbstractEmergence of universal collective behaviour from interactions within a sufficiently large group of elementary constituents is a fundamental scientific concept1. In physics, correlations in fluctuating microscopic observables can provide key information about collective states of matter, such as deconfined quark–gluon plasma in heavy-ion collisions2or expanding quantum degenerate gases3,4. Mesoscopic colliders, through shot-noise measurements, have provided smoking-gun evidence on the nature of exotic electronic excitations such as fractional charges5,6, levitons7and anyon statistics8. Yet, bridging the gap between two-particle collisions and the emergence of collectivity9as the number of interacting particles increases10remains a challenging task at the microscopic level. Here we demonstrate all-body correlations in the partitioning of electron droplets containing up toN= 5 electrons, driven by a moving potential well through a Y-junction in a semiconductor device. Analysing the partitioning data using high-order multivariate cumulants and finite-size scaling towards the thermodynamic limit reveals distinctive fingerprints of a strongly correlated Coulomb liquid. These fingerprints agree well with a universal limit at which the partitioning of a droplet is predicted by a single collective variable. Our electron-droplet scattering experiments illustrate how coordinated behaviour emerges through interactions of only a few elementary constituents. Studying similar signatures in other physical platforms such as cold-atom simulators4,11or collections of anyonic excitations8,12may help identify emergence of exotic phases and, more broadly, advance understanding of matter engineering.
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AbstractAll contemporary Eurasians trace most of their ancestry to a small population that dispersed out of Africa about 50,000 years ago (ka)1–9. By contrast, fossil evidence attests to earlier migrations out of Africa10–15. These lines of evidence can only be reconciled if early dispersals made little to no genetic contribution to the later, major wave. A key question therefore concerns what factors facilitated the successful later dispersal that led to long-term settlement beyond Africa. Here we show that a notable expansion in human niche breadth within Africa precedes this later dispersal. We assembled a pan-African database of chronometrically dated archaeological sites and used species distribution models (SDMs) to quantify changes in the bioclimatic niche over the past 120,000 years. We found that the human niche began to expand substantially from 70 ka and that this expansion was driven by humans increasing their use of diverse habitat types, from forests to arid deserts. Thus, humans dispersing out of Africa after 50 ka were equipped with a distinctive ecological flexibility among hominins as they encountered climatically challenging habitats, providing a key mechanism for their adaptive success.
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AbstractEach spring, billions of Bogong moths escape hot conditions across southeast Australia by migrating up to 1,000 km to a place that they have never previously visited—a limited number of cool caves in the Australian Alps, historically used for aestivating over summer1,2. At the beginning of autumn, the same individuals make a return migration to their breeding grounds to reproduce and die. Here we show that Bogong moths use the starry night sky as a compass to distinguish between specific geographical directions, thereby navigating in their inherited migratory direction towards their distant goal. By tethering spring and autumn migratory moths in a flight simulator3–5, we found that, under naturalistic moonless night skies and in a nulled geomagnetic field (disabling the moth’s known magnetic sense4), moths flew in their seasonally appropriate migratory directions. Visual interneurons in different regions of the moth’s brain responded specifically to rotations of the night sky and were tuned to a common sky orientation, firing maximally when the moth was headed southwards. Our results suggest that Bogong moths use stellar cues and the Earth’s magnetic field to create a robust compass system for long-distance nocturnal navigation towards a specific destination.
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AbstractSexual reproduction relies on meiotic chromosome pairing to form bivalents, a process that is complicated in polyploids owing to the presence of multiple subgenomes1. Uneven ploidy mostly results in sterility due to unbalanced chromosome pairing and segregation during meiosis. However, pentaploid dogroses (Rosasect.Caninae; 2n= 5x= 35) achieve stable sexual reproduction through a unique mechanism: 14 chromosomes form bivalents and are transmitted biparentally, while the remaining 21 chromosomes are maternally inherited as univalents2,3. Despite being studied for over a century, the role of centromeres in this process has remained unclear. Here we analyse haplotype-resolved chromosome-level genome assemblies for three pentaploid dogroses. Subgenome phasing revealed a bivalent-forming subgenome with two highly homozygous chromosome sets and three divergent subgenomes lacking homologous partners, therefore explaining their meiotic behaviour. Comparative analyses of chromosome synteny, phylogenetic relationships and centromere composition indicate that the subgenomes originated from two divergent clades of the genusRosa. Pollen genome analysis shows that subgenomes from different evolutionary origins form bivalents, supporting multiple origins of dogroses and highlighting variation in subgenome contributions. We reveal that bivalent-forming centromeres are enriched withATHILAretrotransposons, contrasting with larger tandem-repeat-based centromeres mainly found in univalents. This centromere structural bimodality possibly contributes to univalent drive during female meiosis. Our findings provide insights into the unique reproductive strategies of dogroses, advancing our understanding of genome evolution, centromere diversity and meiotic mechanisms in organisms with asymmetrical inheritance systems.
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AbstractRepresentation learning in neural networks may be implemented with supervised or unsupervised algorithms, distinguished by the availability of instruction. In the sensory cortex, perceptual learning drives neural plasticity1–13, but it is not known whether this is due to supervised or unsupervised learning. Here we recorded populations of up to 90,000 neurons simultaneously from the primary visual cortex (V1) and higher visual areas (HVAs) while mice learned multiple tasks, as well as during unrewarded exposure to the same stimuli. Similar to previous studies, we found that neural changes in task mice were correlated with their behavioural learning. However, the neural changes were mostly replicated in mice with unrewarded exposure, suggesting that the changes were in fact due to unsupervised learning. The neural plasticity was highest in the medial HVAs and obeyed visual, rather than spatial, learning rules. In task mice only, we found a ramping reward-prediction signal in anterior HVAs, potentially involved in supervised learning. Our neural results predict that unsupervised learning may accelerate subsequent task learning, a prediction that we validated with behavioural experiments.
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AbstractBrain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems1–3. Here we establish long-term, live light-sheet microscopy on unguided brain organoids generated from fluorescently labelled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviours and subcellular features over weeks of organoid development4. We provide a novel dual-channel, multi-mosaic and multi-protein labelling strategy combined with a computational demultiplexing approach to enable simultaneous quantification of distinct subcellular features during organoid development. We track actin, tubulin, plasma membrane, nucleus and nuclear envelope dynamics, and quantify cell morphometric and alignment changes during tissue-state transitions including neuroepithelial induction, maturation, lumenization and brain regionalization. On the basis of imaging and single-cell transcriptome modalities, we find that lumenal expansion and cell morphotype composition within the developing neuroepithelium are associated with modulation of gene expression programs involving extracellular matrix pathway regulators and mechanosensing. We show that an extrinsically provided matrix enhances lumen expansion as well as telencephalon formation, and unguided organoids grown in the absence of an extrinsic matrix have altered morphologies with increased neural crest and caudalized tissue identity. Matrix-induced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signalling pathways, including spatially restricted induction of the WNT ligand secretion mediator (WLS) that marks the earliest emergence of non-telencephalic brain regions. Together, our work provides an inroad into studying human brain morphodynamics and supports a view that matrix-linked mechanosensing dynamics have a central role during brain regionalization.
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AbstractModern colour image sensors face challenges in further improving sensitivity and image quality because of inherent limitations in light utilization efficiency1. A major factor contributing to these limitations is the use of passive optical filters, which absorb and dissipate a substantial amount of light, thereby reducing the efficiency of light capture2. On the contrary, active optical filtering in Foveon-type vertically stacked architectures still struggles to deliver optimal performance owing to their lack of colour selectivity, making them inefficient for precise colour imaging3. Here we introduce an innovative architecture for colour sensor arrays that uses multilayer monolithically stacked lead halide perovskite thin-film photodetectors. Perovskite bandgap tunability4is utilized to selectively absorb the visible light spectrum’s red, green and blue regions, eliminating the need for colour filters. External quantum efficiencies of 50%, 47% and 53% are demonstrated for the red, green and blue channels, respectively, as well as a colour accuracy of 3.8% in ΔELaboutperforming the state-of-the-art colour-filter array and Foveon-type photosensors. The image sensor design improves light utilization in colour sensors and paves the way for the next generation of highly sensitive, artefact-free images with enhanced colour fidelity.
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AbstractTrace elements and isotopes (TEIs) are important to marine life and are essential tools for studying ocean processes1. Two different frameworks have arisen regarding marine TEI cycling: reversible scavenging favours water-column control on TEI distributions2–5, and seafloor boundary exchange emphasizes sedimentary imprints on water-column biogeochemistry6,7. These two views lead to disparate interpretations of TEI behaviours8–10. Here we use rare earth elements and neodymium isotopes as exemplar tracers of particle scavenging11and boundary exchange6,7,12. We integrate these data with models of particle cycling and sediment diagenesis to propose a general framework for marine TEI cycling. We show that, for elements with greater affinity for manganese oxide than biogenic particles, scavenging is a net sink throughout the water column, contrary to a common assumption for reversible scavenging3,13. In this case, a benthic flux supports increasing elemental concentrations with water depth. This sedimentary source consists of two components: one recycled from elements scavenged by water-column particles, and another newly introduced to the water column through marine silicate weathering inside sediment8,14,15. Abyssal oxic diagenesis drives this benthic source, and exerts a strong influence on water-column biogeochemistry through seafloor geometry and bottom-intensified turbulent mixing16,17. Our findings affirm the role of authigenic minerals, often overshadowed by biogenic particles, in water-column cycling18, and suggest that the abyssal seafloor, often regarded as inactive, is a focus of biogeochemical transformation19,20.
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Highlights from theSciencefamily of journals
Nanostructured reflecting plates in squid cells enable a rapid switch between colored and near-transparent states
In Thailand, the wordBaiKhao(ใบข้าว)—meaning “rice leaf”—embodies a quiet agricultural revolution. For generations, farmers gauged crops’ nitrogen fertilizer needs by visually assessing leaf greenness, a method vulnerable to variations in lighting conditions and human error. Today, the “BaiKhaoNK” mobile app transforms smartphones into optical sensors. Using built-in cameras, it quantifies chlorophyll levels through spectral analysis and recommends precise fertilizer doses. This innovation epitomizes agriphotonics, a field dedicated to harnessing light-based tools to monitor, analyze, and diagnose crops and their environments.
A scholar confronts how powerful groups use food as a means of control
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The evolution of soft-bodied squids, which provide a major part of the biomass in modern oceans globally, is poorly understood owing to their patchy fossil record. We provide a comprehensive evolutionary history of squids through “digital fossil-mining” techniques, revealing a new lagerstätte. The more than 250 fossil beaks of 40 species show that squids originated and rapidly radiated by 100 million years ago. Our data suggest that the radical shift from heavily shelled, slowly moving cephalopods to soft-bodied forms did not result from the end-Cretaceous mass extinction (66 million years ago). Early squids had already formed large populations, and their biomass exceeded that of ammonites and fishes. They pioneered the modern-type marine ecosystem as intelligent, fast swimmers.
Editors’ selections from the current scientific literature
Our experience of the world is a continuous stream of events that must be segmented and organized at multiple timescales. The neural mechanisms underlying this process remain unknown. In this work, we simultaneously recorded hundreds to thousands of neurons in the lateral entorhinal cortex of freely behaving rats. Neural population activity drifted continuously along a one-dimensional manifold during all behaviors and behavioral states, including sleep, which points to an intrinsic origin of the drift. In awake animals, boundaries between events were associated with discrete shifts in population dynamics, which segmented the neural activity into temporal units. During tasks with recurring temporal structure, activity traveled additionally in directions orthogonal to the drift, encoding event information across multiple timescales. The results identify a hierarchical coding scheme for organizing events in time.
Combining 131 paleogenomes with bioarchaeological and archaeological data, we studied social organization and gendered practices in Çatalhöyük East Mound (7100 to 5950 BCE), a major Neolithic settlement in Central Anatolia. In early Çatalhöyük, burials in the same building were frequently close genetic relatives, suggesting that houses were used by biological family members. In later periods, however, individuals buried in the same building were often genetically unrelated, despite sharing similar diets. We found no indication of sex-biased mobility into Çatalhöyük. Meanwhile, in all periods, within-building genetic connections were predominantly maternal rather than paternal. Burials of female subadults also received a higher frequency of gifts than male subadults. Our results reveal how kinship practices changed while specific practices prioritizing female lines persisted for 1000 years at Neolithic Çatalhöyük.
The manipulation of light by means of materials with varying refractive index distributions is widespread among natural systems and modern technologies. However, understanding how animals leverage refractive index differences for dynamic color changes and then translating such insight into tunable optical devices remains challenging. We experimentally and computationally demonstrated that iridescent cells (iridophores) containing Bragg reflectors with sinusoidal-wave (rugate) refractive index profiles enable squid dorsal mantle tissues to reversibly transition between nearly transparent and vibrantly colored states. We then drew inspiration from these findings for the design and development of iridophore-inspired multispectral composite materials with tunable visible and infrared functionalities. Our study provides insight into squid dynamic structural coloration mechanisms and furnishes a technology for camouflage, heat management, display, and sensing applications.
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FOXA1 is altered in 10 to 40% of prostate cancers, yet its oncogenic mechanisms remain uncharacterized in vivo. We developed knock-in mouse models representing distinct classes of FOXA1 mutations. Histopathological and multi-omic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction withp53inactivation, drive androgen-dependent adenocarcinomas through co-activation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. In contrast, Class 2 mutations induce intra-luminal plasticity by reprogramming differentiated luminal cells into a progenitor-like state through activation of KLF5 and AP-1 neo-enhancer circuitries, which enables enhanced survival and proliferation even under castrate androgen levels. Our findings establish FOXA1 as a multifaceted oncogene, with distinct mutational classes divergently evolving to drive prostate tumorigenesis or therapy-resistant progression.
Using Global Navigation Satellite System data, we investigated the interplate slip before, during, and after the 2024 Hyuga-nada earthquake in Japan. Before the earthquake, a moment magnitude (Mw) 6.0 slow-slip event (SSE) was observed from late 2023 in a downdip extension of the mainshock. The coseismic slip was adjacent to the 1996 Hyuga-nada earthquake source. The afterslip resolved near the hypocenter area and in the downdip extension of the mainshock, reachingMw6.7 on 16 September 2024. Leading up to the earthquake, the recurrence interval for SSEs in the preslip area shortened from an average of 2 years, estimated from observations over the past 30 years, to 1 year, consistent with simulations in which the weakening of the Nankai megathrust was attributed to the cause.
Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching onAldh1a2or RA supplementation reactivated regeneration. Evolutionary inactivation of multipleAldh1a2-linkedregulatory elements accounted for the deficientAldh1a2expression upon injury in mice and rats. Furthermore, the activation ofAldh1a2by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration.
In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively prepared by de novo synthesis; the existing approach to swap carbon with sulfur is inefficient and involves stoichiometric mercury reagents. In this study, we report a two-step carbonyl-to-sulfur (CO-to-S) atom swap approach, enabled by a rationally designedN′-alkyl-hydrazonamide (NAHA) reagent that promotes forming pre-aromatic intermediates twice sequentially by different mechanisms, thereby achieving homolytic cleavage of both α-C−C bonds of the ketone substrates. A Ts−S−Ts (Ts,p-toluenesulfonyl) reagent mediates this process through successive intermolecular and intramolecular alkyl radical trapping by the central sulfur. This method shows a broad substrate scope and excellent chemoselectivity, providing a streamlined route to sulfur-containing scaffolds from readily available ketones.
A field scientist candidly reflects on navigating personal and institutional challenges
Stable zeolites with extra-large pores and nano dimensions that are capable of processing large molecules are in high demand but have been difficult to produce. Their complex structures and nanoscale crystal sizes present challenges for analysis using conventional x-ray diffraction techniques, leading to inefficiencies in material development. We report NJU120-1 and NJU120-2, two robust and fully connected aluminosilicate nano zeolites featuring interconnected channel systems with extra-large 22-ring pores. NJU120-1 is a nanosheet with only about 8-nanometer thickness, corresponding to 1.5 unit cells, and NJU120-2 is a nanorod with 50 by 250 nanometer dimensions. Their synthesis optimization was greatly accelerated through rapid structure determination with MicroED, revealing their multidimensional pore structures. Their very large largest-free-sphere diameters of approximately 1.2 nanometers coupled with nano morphologies enabled catalytic cracking of large molecules.
West Anatolia has been a crucial yet elusive element in the Neolithic expansion from the Fertile Crescent to Europe. In this work, we describe the changing genetic and cultural landscapes of early Holocene West Anatolia using 30 new paleogenomes. We show that Neolithization in West Anatolia was a multifaceted process, characterized by the assimilation of Neolithic practices by local foragers, the influx of eastern populations, and their admixture, with their descendants subsequently establishing Neolithic Southeast Europe. We then coanalyzed genetic and cultural similarities across early Holocene Anatolian and Aegean Neolithic villages using 58 material culture elements. Cultural distances among villages correlate with their spatial distances but not with their genetic distances after controlling for geography. This suggests that cultural change was often decoupled from genetically visible mobility.
The United States reneged on its foreign aid commitments. Nepal’s malnourished children and their families are paying the price
Federal judge decries NIH’s rationale for killing blacklisted grants as capricious and arbitrary
As the Trump administration systematically defunds the American research ecosystem, while disingenuously promising a return to so-called “gold standard science,” hope can be drawn from the new bipartisan initiative from Senators Martin Heinrich (Democrat, New Mexico) and Michael Rounds (Republican, South Dakota). Their American Science Acceleration Project (ASAP) seeks to make science in the United States “ten times faster by 2030” through five pillars: data, computing, artificial intelligence (AI), collaboration, and process improvement. But simply accelerating will exacerbate historical weaknesses in our innovation system and reproduce the damaging Silicon Valley ethos of “move fast and break things.” Faster is not necessarily better when it comes to innovation and discovery. Supercharging a research ecosystem that already struggles with accessibility and public trust risks more than it achieves.
This Review synthesizes progress and outlines a new framework for understanding how land surface hazards interact and propagate as sediment cascades across Earth’s surface, influenced by interactions among the atmosphere, biosphere, hydrosphere, and solid Earth. Recent research highlights a gap in understanding these interactions on human timescales, given rapid climatic change and urban expansion into hazard-prone zones. We review how surface processes such as coseismic landslides and post-fire debris flows form a complex sequence of events that exacerbate hazard susceptibility. Moreover, innovations in modeling, remote sensing, and critical zone science can offer new opportunities for quantifying cascading hazards. Looking forward, societal resilience can increase by transforming our understanding of cascading hazards through advances in integrating data into comprehensive models that link across Earth systems.
Matriarchs and foragers emerge as important players in early farming villages
Realignment of major program units aims to improve efficiency and make up for loss of federal contracts
Adjacent slow slip events affect megathrust earthquakes
Organic self-assembled molecules (SAMs), widely used in perovskite solar cells (PSCs), should exhibit enhanced performance to support the ongoing advancement of perovskite photovoltaics. We designed diradical SAMs through a coplanar-conjugation of donor-acceptor strategy to facilitate hole transport across the SAMs. The diradical SAMs exhibited high photothermal and electrochemical stability, as well as improved assembly uniformity and large-area solution processability attributed to molecular steric hindrance design. An advanced scanning electrochemical cell microscopy-thin-layer cyclic voltammetry technique was used to accurately determine the carrier transfer rate, stability, and assembly properties of SAMs. Ultimately, the efficiencies of PSCs exceeded 26.3%, mini-modules (10.05 cm2) reached 23.6%, and perovskite-silicon tandem devices (1 cm2) surpassed 34.2%. PSCs maintained > 97% after 2000 hours tracking at 45°C.
Study shows the organelles traveling through “bridges” into nearby cancer cells
Rapid evolution through small shifts in allele frequencies at thousands of loci is a long-standing neo-Darwinian prediction but is hard to characterize in the wild. European ash tree (Fraxinus excelsior) populations have recently come under strong selection by the invasive fungal pathogenHymenoscyphus fraxineus. Using genomic prediction models based on field trial phenotypes and 7985 loci, we show a shift in genomically estimated breeding values in an ancient woodland, between adult trees established before the epidemic started and juvenile trees established since. Using simulations, we estimate that natural selection has eliminated 31% of the juvenile population. Thus, we document a highly polygenic heritable microevolutionary adaptive change over a single generation in the wild.
Many questions remain regarding Earth’s earliest crust owing to the rarity of Hadean (>4.03 billion-year-old) rocks and minerals. The Nuvvuagittuq Greenstone Belt (NGB) in Canada may be the only known remnant of Hadean crust, although its age is debated, ranging from ≥3.75 to 4.3 billion years old. Mafic intrusions within this belt were specifically sampled and analyzed to investigate the timing of their magmatic differentiation. Correlations between samarium/neodymium (Sm/Nd) and143Nd/144Nd and142Nd/144Nd ratios correspond to ages of 4157 ± 174 and4196−81+53million years for the long-lived147Sm-143Nd and the short-lived146Sm-142Nd systems, respectively. The age agreement between both extant and extinct radiogenic systems, in rocks related through igneous fractionation, is compelling evidence for preservation of Hadean rocks in the NGB, opening a rare window into Earth’s earliest times.
Urea is a key molecule in the search for the origin of life and a basic chemical produced in large quantities by industry. Its formation from ammonia and carbon dioxide requires either high pressures and temperatures or, under milder conditions, catalysts or additional reagents. In this study, we observed the spontaneous formation of urea under ambient conditions from ammonia and carbon dioxide in the surface layer of aqueous droplets. Single, optically trapped droplets were probed by using Raman bands as markers. We found the surface layer to act like a microscopic flow reactor, with chemical gradients providing access to unconventional reaction pathways. This observation revealed a general mechanistic scheme for distinctive droplet chemistry. Interfacial chemistry is a possible nonenergetic route for urea formation under prebiotic conditions.
“GlycoCaging” uses gut bacteria to activate drugs for inflammatory bowel disease
During apoptosis, cytosolic BAX monomers are translocated to the mitochondria to permeabilize the outer membrane. Here, we identified a dimer of BAX dimers as the basic repeating unit of its various oligomeric forms: arcs, lines, and rings. Cryo–electron microscopy structure of the BAX repeating unit at 3.2-angstrom resolution revealed the interactions within and between dimers. End-to-end stacking of the repeating units through the protruding α9 pairs yielded lines, arcs, polygons, and rings. We structurally characterized the tetragon, pentagon, hexagon, and heptagon, which comprise 16, 20, 24, and 28 BAX protomers, respectively. Missense mutations at the BAX inter-protomer interface damage pore formation and cripple its proapoptotic function. The assembly principle of the various BAX oligomers reported here provides the structural basis of membrane permeabilization by BAX.
Seafloor monitoring is revealing how “slow slip” earthquakes can lead to big ones
Patterns of strain accumulation and release offshore in subduction zones are directly linked to the potential for shallow coseismic slip and tsunamigenesis, but these patterns remain elusive. In this work, we analyze formation pore pressure records from three offshore borehole observatories at the Nankai subduction zone, Honshu, Japan, to capture detailed slip-time histories of two slow slip events (SSEs) along the outermost reaches of the plate boundary. Slip initiates ~30 kilometers landward of the trench; migrates seaward at 1 to 2 kilometers per day to within a few kilometers of, and possibly breaching, the trench; and coincides with the onset and migration of tremor and/or very-low-frequency earthquakes. The SSE source region lies in a zone of high pore fluid pressure and low stress, which provides clear observational evidence linking these factors to shallow slow earthquakes.
Science can help to target climate finance at better-quality adaptation
The gut microbiota of mammals possess distinctive metabolic pathways with untapped therapeutic potential. Using molecular insights into dietary fiber metabolism by the human gut microbiota, we designed a targeted drug delivery system, called GlycoCaging, that is based on bespoke glycoconjugates of a complex plant oligosaccharide. GlycoCaging of exemplar anti-inflammatory drugs enabled release of active molecules triggered by specific glycosidases of autochthonous gut bacteria. GlycoCaging ensured that drug efficacy was potentiated, and off-target effects were eliminated in murine models of inflammatory bowel disease. Biochemical and metagenomic analyses of gut microbiota of individual humans confirmed the broad applicability of this strategy.
Through two grassroots efforts, approximately 200 op-eds showcasing federally funded science have been published across the country
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Taste is crucial in shaping animal perception. Sourness, one of the primary tastes, is aversive in mammals, whereas many birds frequently consume acidic fruits, suggesting a potential tolerance. Our study uncovers a mechanism enabling avian sour tolerance that involves changes to the sour receptor [otopetrin 1 (OTOP1)]. We demonstrate that sour tolerance is a conserved trait in birds, with avian OTOP1 exhibiting acid-induced inhibition and OTOP1 modulation affecting sour perception and tolerance. Ancestral reconstruction reveals that the increase in acid tolerance may have evolved at the same point in the songbird phylogeny as the regain of sweet sensing in this clade. This shift might have enabled songbirds to feed on a wider range of fruits, affecting the evolution and diversification of the songbird radiation.
FDA’s anticipated approval of lenacapavir comes at a time of global health cuts
Prolonged wakefulness leads to persistent, deep recovery sleep (RS). However, the neuronal circuits that mediate this process remain elusive. From a circuit screen in mice, we identified a group of thalamic nucleus reuniens (RE) neurons activated during sleep deprivation (SD) and required for sleep homeostasis. Optogenetic activation of RE neurons leads to an unusual phenotype: presleep behaviors (grooming and nest organizing) followed by prolonged, intense sleep that resembles RS. Inhibiting RE activity during SD impairs subsequent RS, which suggests that these neurons signal sleep need. RE neurons act upstream of sleep-promoting zona incerta cells, and SD triggers plasticity of this circuit to strengthen their connectivity. These findings reveal a circuit mechanism by which sleep need transforms the functional coupling of a sleep circuit to promote persistent, deep sleep.
Lawmakers reject some cuts, question others
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Editors’ selections from the current scientific literature
Canceled and curtailed grants from federal agencies have hit research projects, collections, and training
Neurons in the thalamus drive restorative sleep
Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.
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Highlights from theSciencefamily of journals
Shifts in phytoplankton populations could affect marine ecology and fisheries around the world
The constraints that govern the evolution of gene expression patterns across development remain unclear. Single-cell RNA sequencing can detail these constraints by systematically profiling homologous cells. The conserved invariant embryonic lineage ofCaenorhabditis elegansandC. briggsaemakes them ideal for comparing cell type gene expression across evolution. Measuring the spatiotemporal divergence of gene expression across embryogenesis, we find a high level of similarity in gene expression programs between species despite tens of millions of years of evolutionary divergence. Nonetheless, thousands of genes show divergence in their cell type specific expression patterns, with enrichment for functions in environmental response and behavior. Neuronal cell types show higher divergence than others such as the intestine and germline. This work identifies likely constraints on the evolution of developmental gene expression.
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Mystery signals used to locate gases in the spaces between galaxies
The brain’s response to injury includes the activation of intrinsic microglia and the influx of leukocytes, collectively constituting neuroinflammation, the “flame” of the brain. Although details differ and matter, neuroinflammation exacerbating neurodegeneration has similarities across multiple sclerosis and other neurological disorders, such as stroke and neurodegenerative diseases. Thus, lessons from successful disease-modifying therapies in multiple sclerosis may provide insights into strategies for modulating neuroinflammation and reducing neural injury in other neurological conditions. In this Review, we discuss these lessons and potential strategies for counteracting neuroinflammation, including taming the microglia-orchestrated brain immune responses that contribute to progressing neuropathology.
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Photoredox catalysis driven by visible light has improved chemical synthesis by enabling milder reaction conditions and unlocking distinct reaction mechanisms. Despite the transformative impact, visible-light photoredox catalysis remains constrained by the thermodynamic limits of photon energy and inefficiencies arising from unproductive back electron transfer, both of which become particularly pronounced in thermodynamically demanding reactions. In this work, we introduce an organic photoredox catalyst system that overcomes these obstacles to drive chemical transformations that require super-reducing capabilities. This advancement is accomplished by coupling the energy of two photons into a single chemical reduction, whereas inefficiencies from back electron transfer are mitigated through a distinct proton-coupled electron transfer mechanism embedded in the catalyst design. The super-reducing capabilities of this organic catalyst system are demonstrated through efficient application in a broad scope of challenging arene reductions.
The brain’s ability to prioritize sensory information is crucial for adaptive behavior, yet its mechanisms remain unclear. We investigated basal forebrain cholinergic neurons modulating olfactory bulb (OB) circuits in mice. The activity of cholinergic feedback axons in OB correlated with orofacial movements, with little responses to passively experienced odors. When mice engaged in an olfactory task, OB cholinergic axons rapidly shifted their response patterns from movement correlated to odor aligned. This response shift was absent in cholinergic axons projecting to the dorsal cortex during olfactory task engagement, and in OB, during an auditory task. Inactivation of OB-projecting cholinergic neurons impaired olfactory task performance and reduced odor responses in OB granule cells. Thus, the cholinergic system dynamically modulates sensory processing in a modality-specific and context-dependent manner.
The nature and spectrum of elementary excitations are defining features of a many-body system. Here, we use a Rydberg quantum simulator to demonstrate a form of spectroscopy, called quench spectroscopy, that probes these low-energy excitations. We illustrate the method on a two-dimensional simulation of the spin-1/2 dipolar XY model. Through microscopic measurements of the spatial spin correlation dynamics following a quench, we extract the dispersion relation of the elementary excitations for both ferro- and anti-ferromagnetic couplings. The ferromagnet exhibits elementary excitations behaving as linear spin waves, whereas in the anti-ferromagnet, spin waves appear to decay, suggesting the presence of strong nonlinearities. Our demonstration highlights the importance of power-law interactions on the excitation spectrum of a many-body system.
Lipid nanoparticles are designed to generate therapeutic T cells inside living animal models
The Sun’s corona is its tenuous outer atmosphere of hot plasma, which is difficult to observe. Most models of the corona extrapolate its magnetic field from that measured on the photosphere (the Sun’s optical surface) over a full 27-day solar rotational period, providing a time-stationary approximation. We present a model of the corona that evolves continuously in time, by assimilating photospheric magnetic field observations as they become available. This approach reproduces dynamical features that do not appear in time-stationary models. We used the model to predict coronal structure during the total solar eclipse of 8 April 2024 near the maximum of the solar activity cycle. There is better agreement between the model predictions and eclipse observations in coronal regions located above recently assimilated photospheric data.
As the world nears 1.5°C of global warming, near-term emissions reductions and adequate adaptation become ever more important to ensure a safe and livable planet for present and future generations
Collapsing international support for population data collection is compromising government planning all around the world
RFK Jr.’s purge of key advisory committee represents a major loss of expertise, as measured by scientific papers
The Vera C. Rubin Observatory is set to transform astronomy. Its wide and fast survey will discover billions of dynamic objects while building up a deep map of the universe
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Prokaryotic defense-associated reverse transcriptases (DRTs) were recently identified with antiviral functions; however, their functional mechanisms remain largely unexplored. Here we show that DRT9 forms a hexameric complex with its upstream noncoding RNA (ncRNA) to mediate antiphage defense by inducing cell growth arrest through abortive infection. Upon phage infection, the phage-encoded ribonucleotide reductase NrdAB complex increases intracellular deoxyadenosine triphosphate levels, activating DRT9 to synthesize long, polyadenylate [poly(A)]–rich single-stranded complementary DNA (cDNA), which likely sequesters the essential phage single-stranded DNA binding (SSB) protein and disrupts phage propagation. We further determined the cryo–electron microscopy structure of the DRT9-ncRNA hexamer complex, providing mechanistic insights into its cDNA synthesis. These findings highlight the diversity of RT-based antiviral defense mechanisms, expand our understanding of RT biological functions, and provide a structural basis for developing DRT9-based biotechnological tools.
Although the global greening associated with climate change is well documented on land, similar trends in the ocean have not been thoroughly identified. Using satellite observations of ocean chlorophylla(Chl) concentration, we show that the surface ocean experienced a poleward greening from 2003 to 2022. Contemporaneously, the subtropical regions of the Northern Hemisphere experienced a decrease in Chl. As such, the latitudinal disparity in Chl, as documented by an inequality index, has been increasing over the past two decades, particularly in the Northern Hemisphere. Rising water temperatures may primarily influence the Chl trends. The increasing Chl inequality—marked by “greener green and bluer blue” waters—has the potential to cascade to higher trophic levels, with implications for the fisheries and economies of coastal nations.
How birds retuned sour perception to eat fruits
Molecules are typically synthesized through stepwise processes involving chemical reactions between simple molecular precursors. Here, we report an advance in the synthesis of new organic molecules based on the approach of clip-off chemistry, in which molecules are excised from ordered, extended organic structures. We synthesized macrocycles by selectively cleaving them out of covalent organic frameworks. The synthesized macrocycles include eight macrocyclic polyamides with 114-, 138-, and 162-atom rings, and one 114-atom ring macrocyclic polyimide. This excision approach expands the scope of chemical organic synthesis to previously inaccessible macromolecules.
Already rocked by decades of political interference, corporate influence, mismanagement, and partisan efforts to undermine its authority, the expert bureaucracy, the “lifeblood” of the US administrative state, is now gasping for air. On 23 May, President Trump issued an executive order (EO)—Restoring Gold Standard Science—promising to fix these issues. Instead, the EO is poised to make them far worse: It officially empowers political appointees to override conclusions and interpretations of government scientists, threaten their professional autonomy, and undermine the scientific capacity of research and regulatory agencies.
Macroscale evaluations of chemical monitoring data require the integration of chemical, spatial, and temporal dimensions. Here, we linked 64 million US surface water monitoring records (1900 chemicals, date range 1958 to 2019, 310,000 sites) and 37 million analytical limits and in vivo and in silico toxicity thresholds. We found that the exposure data required for retrospective risk assessment were available for less than 1% of chemicals with potential environmental concern (n≈ 297,000). In contrast to the situation with persistent and often inorganic contaminants in the 1970s, current monitoring schemes lack control of a much larger number of organic chemicals and their degradates. Insufficient chemical and spatial coverage of monitoring, along with analytical limits being far too high to track some of the most toxic chemicals, biases risk perceptions for important chemicals.
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Translation termination is essential in all living organisms because it ensures that proteins have lengths strictly defined by their genes. This universal process is mediated by peptide release factors (RFs) that recognize stop codons and catalyze the hydrolysis of peptidyl transfer RNA (peptidyl-tRNA) on the ribosome, presumably by activating a water molecule. We report structures of the bacterial ribosome in complex with peptidyl-tRNA and RFs in the prepeptide release state. No hydrolytic water molecule was seen in the peptidyl transferase center. Instead, RFs induced rearrangements of the peptidyl-tRNA adenine 76 (A76) ribose pucker that orient the 2′-OH for the nucleophilic attack onto the neighboring carbonyl group. These findings suggest a catalytic mechanism of RF-mediated peptide release and provide a structural basis for the universal conservation of the catalytic domain in peptide RFs.
With DNA focused almost entirely on replication, newly discovered organism blurs the line between cells and viruses
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Plastic pollution threatens marine and freshwater ecosystems and the services they provide. Although plastic bag bans and taxes are increasingly implemented worldwide, their effectiveness in reducing plastic litter remains unknown. Leveraging the patchwork of bag policies across different geographic scales in the United States and citizen science data on 45,067 shoreline cleanups, we assess the impact of these policies on plastic bag litter. We find that plastic bag policies lead to a 25 to 47% decrease in plastic bags as a share of total items collected at cleanups relative to areas without policies, with taxes possibly further reducing shoreline litter. At a time when many jurisdictions are considering bag policies, while others are preemptively prohibiting them, our study provides evidence that they mitigate shoreline plastic pollution.
Denisovans are a hominin group primarily known through genomes or proteins, but the precise morphological features of Denisovans remain elusive due to the fragmentary nature of discovered fossils. Here we report ninety-five endogenous proteins retrieved from a nearly complete cranium from Harbin, China, dating to at least 146,000 years ago and previous assigned to a new species,Homo longi. This individual has three Denisovan derived amino acid variants and clusters with Denisova 3, suggesting the Harbin individual belongs to a Denisovan population. This study fills the gap between morphological and molecular evidence, enhancing our understanding of Denisovans’ spatiotemporal dispersal and evolutionary history.
A tiny sliver of NIH, the institute has provided evidence base for bedside care
Editors’ selections from the current scientific literature
Ivy League universities have dominated recent news headlines, having become popular targets for critics of higher education. But the threats they face—cuts to federal research funding, assaults on academic freedom, and bans on admitting international students—extend far beyond their campuses. Research universities across the country—large and small, public and private—are grappling with these same pressures. These institutions are behind the breakthroughs that shape daily lives. Undermining them doesn’t just jeopardize higher education, it threatens national and global strength. This means that economic, technological, and intellectual collapse is inevitable if US research institutions fall to federal and state disinvestment.
Technology could be a boon for science, but raises ethical concerns
Tailoring carrier density in atomically thin two-dimensional (2D) semiconductors is challenging because of the inherently limited physical space for incorporating charge dopants. Here, we report that interlayer charge-transfer doping in type III van der Waals heterostructures can be greatly modulated by an external gate to realize a hyperdoping effect. Systematic gated-Hall measurements revealed that the modulated carrier density is about five times that of the gate capacitive charge, achieving an ultrahigh 2D hole density of 1.49 × 1014per square centimeter, far exceeding the maximum possible electrostatic doping limit imposed by typical dielectric breakdown. The highly efficient hole-doping enables high-performance p-type 2D transistors with an ultralow contact resistance of ~0.041 kilohm micrometers and a record-high ON-state current density of ~2.30 milliamperes per micrometer.
Quantitatively mapping enzyme sequence-catalysis landscapes remains a critical challenge in understanding enzyme function, evolution, and design. In this study, we leveraged emerging microfluidic technology to measure catalytic constants—kcatandKM—for hundreds of diverse orthologs and mutants of adenylate kinase (ADK). We dissected this sequence-catalysis landscape’s topology, navigability, and mechanistic underpinnings, revealing catalytically heterogeneous neighborhoods organized by domain architecture. These results challenge long-standing hypotheses in enzyme adaptation, demonstrating that thermophilic enzymes are not universally slower than their mesophilic counterparts. Semisupervised models that combine our data with the rich sequence representations from large protein language models predict orthologous ADK-sequence catalytic parameters better than existing approaches. Our work demonstrates a promising strategy for dissecting sequence-catalysis landscapes across enzymatic evolution, opening previously unexplored avenues for enzyme engineering and functional prediction.
Biological nitrogen fixation is a key driver of global primary production and climate. Decades of effort have repeatedly updated nitrogen fixation estimates for terrestrial and open ocean systems, yet other aquatic systems in between have largely been ignored. Here we present an evaluation of nitrogen fixation for inland and coastal waters. We demonstrate that water column and sediment nitrogen fixation is ubiquitous across these diverse aquatic habitats, with rates ranging six orders of magnitude. We conservatively estimate that, despite accounting for less than 10% of the global surface area, inland and coastal aquatic systems fix 40 (30 to 54) teragrams of nitrogen per year, equivalent to 15% of the nitrogen fixed on land and in the open ocean. Inland systems contribute more than half of this biological nitrogen fixation.
Type III CRISPR-Cas systems defend against viral infection in prokaryotes by using an RNA-guided complex that recognizes foreign transcripts and synthesizes cyclic oligoadenylate (cOA) messengers to activate CRISPR-associated Rossmann-fold (CARF) immune effectors. In this study, we investigated a protein containing a CARF domain–fused Toll/interleukin-1 receptor (TIR) domain, Cat1. We found that Cat1 provides immunity by cleaving and depleting oxidized nicotinamide adenine dinucleotide (NAD+) molecules from the infected host, inducing a growth arrest that prevents viral propagation. Cat1 forms dimers that stack upon each other to generate long filaments that are maintained by bound cOA ligands, with stacked TIR domains forming the NAD+cleavage catalytic sites. Furthermore, Cat1 filaments assemble into distinct trigonal and pentagonal networks that enhance NAD+degradation. Cat1 presents an unprecedented chemistry and higher-order protein assembly for the CRISPR-Cas response.
Predicting plant responses to rising temperatures, including acute heat waves and hot droughts of varying intensity and duration, is central to addressing the climate and biodiversity crises. However, plant responses to heat are scale-dependent, complicating cross-scale prediction. We highlight recent progress revealing how and why plant responses to heat change across scales, including scales of biological organization and space versus time. We give examples of scaling up from molecular- and leaf-scale data and processes, which are modified by homeostatic and buffering mechanisms at whole plant and ecosystem scales. We show that scaling down—predicting plant responses to warming from broad-scale spatial patterns—can also be misleading, even in direction. Addressing such scale dependencies is essential to improving the prediction of plant responses to heat.
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Highlights from theSciencefamily of journals
Continuous geodetic measurements near volcanic systems can image magma transport dynamics, yet resolving dike intrusions with high spatiotemporal resolution remains challenging. We introduce fiber-optic geodesy, leveraging low-frequency distributed acoustic sensing (LFDAS) recordings along a telecommunication fiber-optic cable, to track dike intrusions near Grindavík, Iceland, on a minute timescale. LFDAS revealed distinct strain responses from nine intrusive events, six resulting in fissure eruptions. Geodetic inversion of LFDAS strain reveals detailed magmatic intrusions, with inferred dike volume rate peaking systematically 15 to 22 min before the onset of each eruption. Our results demonstrate DAS’s potential for a dense strainmeter array, enabling high-resolution, nearly real-time imaging of subsurface quasistatic deformations. In active volcanic regions, LFDAS recordings can offer critical insights into magmatic evolution, eruption forecasting, and hazard assessment.
Chromosomal inversions can contribute to adaptive speciation by linking coadapted alleles. By querying 1375 genomes of the species-rich Malawi cichlid fish radiation, we discovered five large inversions segregating in the benthic subradiation that each suppress recombination over more than half a chromosome. Two inversions were transferred from deepwater pelagicDiplotaxodonthrough admixture, whereas the others established early in the deep benthic clade. Introgression of haplotypes from lineages inside and outside the Malawi radiation coincided with bursts of species diversification. Inversions show evidence for transient sex linkage, and a notable excess of protein changing substitutions points toward selection on neurosensory, physiological, and reproductive genes. These results indicate that repeated interplay between depth adaptation and sex-specific selection on large inversions has been central to the evolution of this iconic system.
In natural habitats, nutrient availability limits bacterial growth. We discovered that bacteria can overcome this limitation by acquiring nutrients by lysing neighboring cells through contact-dependent antagonism. Using single-cell live imaging and isotopic markers, we found that during starvation, the type VI secretion system (T6SS) lysed neighboring cells and thus provided nutrients from lysing cells for growth. Genomic adaptations in antagonists, characterized by a reduced metabolic gene repertoire, and the previously unexplored distribution of the T6SS across bacterial taxa in natural environments suggest that bacterial antagonism may contribute to nutrient transfer within microbial communities in many ecosystems.
Reactive oxygen species function as key signals in plant adaptation to environmental stresses like drought. Roots respond to transient water unavailability by temporarily ceasing branching through the acclimative response xerobranching. In this study, we report how a xerobranching stimulus triggers rapid changes of ROS levels in root nuclei, triggering redox-dependent multimerization of the auxin repressor protein IAA3. Mutations in specific cysteine residues of IAA3 disrupt redox-mediated multimerization and interaction with co-repressor TPL, thereby attenuating IAA3 mediated target gene repression. Other AUX/IAA proteins also vary in their redox mediated multimerization, revealing a regulatory mechanism that connects dynamic changes in cellular redox status to auxin signaling. Our study reveals how ROS, auxin and water availability intersect and shape root adaptive responses, thereby maintaining phenotypic plasticity in plants.
Bottom sediments are important for nitrogen production in inland and coastal waters
Plants are highly sensitive to temperature, and climate change is predicted to have negative impacts on agricultural productivity. Warming temperatures, coupled with a growing population, present a substantial challenge for food security and motivate research to understand how plants sense and respond to changes in temperature. Here, we synthesize our current understanding of temperature sensing and response in plants. We outline how temperature cues are integrated into preexisting signaling cascades using inherently temperature-sensitive proteins or processes. This dispersed nature of thermo-sensitive proteins and processes makes distinct signaling cascades sensitive to temperature. This model integrates current knowledge and distinguishes thermosensing from other conventional sensing and signaling mechanisms in plants.
Recent case law can shape how innovation unfolds
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The region’s grasslands—vital ecosystems and carbon sinks—have been farmed and ranched beyond recognition
Wild plant species harbor a vast but largely unknown diversity of temperature stress solutions
In the world’s hottest forests, scientists are probing how plants cope with rising temperatures
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Rising temperatures change the structure and function of plant microbial communities
A no-fault compensation scheme may help balance innovation and patient protection
Bacteria leverage a secretion system to kill and scavenge nutrients from nearby competitors
Driven largely by open access, the trend puts society programming at risk
Our ability to produce human-scale biomanufactured organs is limited by inadequate vascularization and perfusion. For arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion poses a major hurdle. We introduce a model-driven design platform that demonstrates rapid synthetic vascular model generation alongside multifidelity computational fluid dynamics simulations and three-dimensional bioprinting. Key algorithmic advances accelerate vascular generation 230-fold and enable application to arbitrarily complex shapes. We demonstrate that organ-scale vascular network models can be generated and used to computationally vascularize >200 engineered and anatomic models. Synthetic vascular perfusion improves cell viability in fabricated living-tissue constructs. This platform enables the rapid, scalable vascular model generation and fluid physics analysis for biomanufactured tissues that are necessary for future scale-up and production.
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Jaundice is a common presentation ofPlasmodiumfalciparummalaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response toPlasmodiumspp. infection. We found that asymptomaticP. falciparuminfection in humans was associated with a higher ratio of unconjugated over conjugated bilirubin and parasite burden compared with symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, through genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was protective against malaria in mice. Unconjugated bilirubin inhibitedP. falciparumproliferation in red blood cells by a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin crystallization and compromised the parasite’s food vacuole. Hence, jaundice appears to represent a metabolic response toPlasmodiumspp. infection that limits malaria severity.
Retrons are antiphage defense systems that produce multicopy single-stranded DNA (msDNA) and hold promises for genome engineering. However, the mechanisms of defense remain unclear. The Retron-Septu system uniquely integrates retron and Septu antiphage defenses. Cryo-electron microscopy structures reveal asymmetric nucleoprotein complexes comprising a reverse transcriptase (RT), msDNA (a hybrid of msdDNA and msrRNA), and two PtuAB copies. msdDNA and msrRNA are essential for assembling this complex, with msrRNA adopting a conserved lariat-like structure that regulates reverse transcription. Notably, the assembled Retron-Septu complex is inactive, with msdDNA occupying the PtuA DNA-binding site. Activation occurs upon disassembly, releasing PtuAB, which degrades single-stranded DNA to restrict phage replication. This “arrest-and-release” mechanism underscores the dynamic regulatory roles of msDNA, advancing our understanding of antiphage defense strategies.
Defining viral proteomes is crucial to understanding viral life cycles and immune recognition but the landscape of translated regions remains unknown for most viruses. We have developed massively parallel ribosome profiling (MPRP) to determine open reading frames (ORFs) across tens of thousands of designed oligonucleotides. MPRP identified 4208 unannotated ORFs in 679 human-associated viral genomes. We found viral peptides originating from detected noncanonical ORFs presented on class-I human leukocyte antigen in infected cells and hundreds of upstream ORFs that likely modulate translation initiation of viral proteins. The discovery of viral ORFs across a wide range of viral families—including highly pathogenic viruses—expands the repertoire of vaccine targets and reveals potential cis-regulatory sequences.
Climate forcings by greenhouse gases and aerosols cause an imbalance at the top of the atmosphere between the net incoming solar radiation and outgoing longwave radiation from Earth. This Earth energy imbalance has strengthened over the period 2001 to 2023 with satellite data. Here, we show that low climate sensitivity models fail to reproduce the trend in Earth energy imbalance, particularly in the individual longwave and shortwave contributions to the imbalance trend. The inability to produce a strong positive shortwave and strong negative longwave Earth energy imbalance trend is found to be a robust feature in the low climate sensitivity models, especially for models with a climate sensitivity below 2.5 kelvin. The negative longwave contribution to Earth energy imbalance is driven by surface temperature increases and is therefore most pronounced in high climate sensitivity models, whereas the shortwave contribution is generally positive and amplified by greater surface warming.
BBO-10203 is an orally available drug that covalently and specifically binds to the RAS-binding domain of phosphoinositide 3-kinase α (PI3Kα), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3Kα activation in tumors with oncogenic mutations inKRASorPIK3CA, and in tumors with human epidermal growth factor receptor 2 (HER2) amplification or overexpression. In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2 and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and Serine/Threonine Kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, as insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake.
Reform movement should have seen call for “gold standard science” coming, critics say
A computational algorithm can render a complex artificial vascular structure in minutes
“You’re killing a newborn baby,” says one astrophysicist
Crystalline solids are governed by universal structure-property relationships derived from their crystal symmetry, leading to paradigmatic rules on what properties they can and cannot exhibit. A long-held structure-property relationship is that centrosymmetric crystals cannot differentially absorb circularly polarized light. In this study, we demonstrate the design, synthesis, and characterization of the centrosymmetric material Li2Co3(SeO3)4, which violates this relationship not by defying symmetry-imposed selection rules but by invoking a photophysical process not previously characterized for crystalline solids. This process originates from an interference between linear dichroism and linear birefringence, referred to as LD-LB, and involves strong chiroptical signals that invert upon sample flipping. In addition to enabling a chiroptical response under centrosymmetry, this process opens up photonic engineering opportunities based on crystalline solids.
A new film celebrates the subterranean
(Bi)carbonate salt formation has been widely recognized as a primary factor in poor operational stability of the electrochemical carbon dioxide reduction reaction (CO2RR). We demonstrate that flowing CO2gas into an acid bubbler—which carries trace amounts of acid vapor into a gas diffusion electrode for silver-catalyzed CO2RR to carbon monoxide (CO)—can prevent salt accumulation. In a 100-square-centimeter, scaled-up CO2RR membrane electrode assembly electrolyzer with single serpentine flow channels, the acid humidification method achieved the 4500 hours of stability milestone at 100 mA cm−2without compromising the CO faradaic efficiency, whereas a conventional water-humidified CO2feed only operated stably for ~80 hours. The acid-humidified CO2approach was extended to bismuth, copper, and zinc catalysts.
Scientists say India-Pakistan treaty needs to be rethought for a changing world
G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ–mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival.
For decades, empirical evidence has pointed to the unsustainable trajectory of global food systems, linking industrialized production tosoil degradation,water stress, andnutrition deficitsacross vulnerable populations and underscoring the urgent need for science-based policy interventions. But despite robust, peer‐reviewed evidence outlining both the magnitude of food‐system threats and an extensive array of potential science-backed interventions, structural obstacles such as institutional inertia, competing policy agendas, and chronic resource constraints have consistently prevented the uptake of scientific recommendations into effective policy frameworks.
Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we found that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions developed from a few highly mutated clones that dominate most of the bronchial tree. Multisite sequencing in human patients confirmed the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung.
A buildup of unconjugated bilirubin may be a protective response to malaria
Continued greenhouse gas emissions will accelerate global warming and intensity of heat waves, which already harm crop productivity. From the stability of key enzymes to canopy processes, photosynthesis is affected by temperature. All crops suffer declines in photosynthetic rate when temperatures cross critical thresholds, with irreversible losses typically occurring above 40° to 45°C. Protective measures within plants can be induced by growth at elevated temperatures but not from the sudden temperature elevation of heat waves. Strategies to improve the heat resilience of photosynthesis include modifying surface energy balance, optimizing canopy architecture, improving enzymatic heat tolerance, and (re)engineering key metabolic pathways for greater efficiency or to remove bottlenecks. This Review summarizes present knowledge on the major mechanisms that underlie high-temperature inhibition of photosynthesis and explores opportunities for breeding and biotechnological interventions to overcome them.
The phrase “Sputnik moment” is often used to describe a moment when a country—usually the United States—needs to respond to some technological leap made by another nation. The wake-up call is meant to provoke more investment in research, development, and education. Today, the United States faces another Sputnik moment, but this time, the threat isn’t coming from abroad—it’s coming from within.
Editors’ selections from the current scientific literature
The renowned American management consultant and author Peter Drucker is often credited as saying that “the best way to predict the future is to create it”—a view that applies to science as much as to the business world. It implies that gaining insights and ideas that lead to new discoveries and technologies allows victory in the marketplace, ahead of the competition. As the Trump administration continues to drastically defund and dismantle basic science in America, the United States is presenting other countries with opportunities to take the lead in seeing farther ahead, anticipate where scientific and technological prowess is going, and create the future, while the United States stands on the sidelines. This is a matter not only of scientific prestige but also of economic vitality. The country will no longer be at the forefront of commercializing breakthroughs and leveraging them for maximum economic and societal benefit. Moreover, this will trigger a massive transition for the global scientific community and alter the framework that shapes how the world’s economies connect and grow.
Innovative techniques yielded corn, beans, and squash for 600 years before European contact
A biologist pushes back against attacks on curiosity-driven research
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Trump request favors one giant telescope and kills a gravitational wave detector
Integrating radiative and evaporative cooling shows promise for enhancing passive cooling, but durable self-curing integrated cooling paints remain underdeveloped. We designed a modified cementitious structure with advanced thermal-optical and mass transfer properties, boosting cooling power while ensuring durability, mechanical strength, and broad adhesion. The paint achieves 88 to 92% solar reflectance (depending on wetting), 95% atmospheric window emittance, ~30% water retention, and self-replenishing properties, maintaining stable optical performance even when wet. Field tests in tropical Singapore demonstrated superior cooling performance compared with commercial white paints. Pilot-scale demonstrations highlighted consistent electricity savings under varying weather conditions, supported by theoretical modeling. By leveraging sustainable water evaporation and thermal radiation, this paint offers a practical and long-term solution for mitigating the urban heat island effect.
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“Knowledge is power”—or at least it was whenSir Francis Bacon coined this phrasein the 16th century. In today’s world, we frequently encounter a different variant of this philosophy, perhaps best described as “power dismisses knowledge.” We need look no further than the recent US measles outbreak to see how this modern framework wreaks havoc when applied to public health.
Present vision restoration technologies have substantial constraints that limit their application in the clinical setting. In this work, we fabricated a subretinal nanoprosthesis using tellurium nanowire networks (TeNWNs) that converts light of both the visible and near-infrared–II spectra into electrical signals. The broad-spectrum coverage is made possible by a combination of narrow bandgaps, strong absorption, and engineered asymmetries. Implanted into blind mice, the TeNWNs restored pupillary reflexes and enabled visually cued learning under visible and near-infrared 1550-nanometer light. In nonhuman primates, TeNWNs elicited robust retina-derived neural responses, confirming biocompatibility and feasibility. By restoring lost photosensitivity and extending vision to near-infrared, this nanoprosthesis offers a promising approach for restoring vision.
Projecting the local impacts of global warming is a stubborn challenge. But cities need answers fast
Halt to foreign “subawards” disrupts studies and compromises ethical obligations to trial volunteers
Long-running experiment concludes muon is no more magnetic than theory predicts
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A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
The quantum metric tensor is a central geometric quantity in modern physics that is defined as the distance between nearby quantum states. Despite numerous studies highlighting its relevance to fundamental physical phenomena in solids, measuring the complete quantum metric tensors in real solid-state materials is challenging. In this work, we report a direct measurement of the full quantum metric tensors of Bloch electrons in solids using black phosphorus as a representative material. We extracted the momentum space distribution of the pseudospin texture of the valence band from the polarization dependence of angle-resolved photoemission spectroscopy measurement. Our approach is poised to advance our understanding of quantum geometric responses in a wide class of crystalline systems.
Dopamine (DA) plays a crucial role in a variety of brain functions through intricate interactions with other neuromodulators and intracellular signaling pathways. However, studying these complex networks has been hindered by the challenge of detecting multiple neurochemicals in vivo simultaneously. To overcome this limitation, we developed a single-protein chemigenetic DA sensor, HaloDA1.0, which combines a cpHaloTag–chemical dye approach with the G protein–coupled receptor activation–based (GRAB) strategy, providing high sensitivity for DA, subsecond response kinetics, and a far-red to near-infrared spectral range. When used together with existing green and red fluorescent neuromodulator sensors, calcium indicators, cyclic adenosine 5′-monophosphate sensors, and optogenetic tools, HaloDA1.0 showed high versatility for multiplex imaging in cultured neurons, brain slices, and behaving animals, facilitating in-depth studies of dynamic neurochemical networks.
Chromatin remodelers utilize the energy of adenosine triphosphate (ATP) hydrolysis to slide nucleosomes, regulating chromatin structure and gene activity in cells. In this work, we report structures of imitation switch (ISWI) bound to the nucleosome during active ATP hydrolysis and remodeling, revealing conformational transitions of the remodeling motor across the adenosine triphosphatase (ATPase) cycle. The DNA strands were distorted accordingly, showing one full base-pair bulge and a loss of histone contact at the site of motor binding in the adenosine diphosphate* (ADP*) and apo* (unbound) states. We also identified several important elements for regulation of the remodeling activity. Notably, an enzyme conformation exiting the remodeling cycle reveals a linker DNA–sensing brake mechanism. Together, our findings elucidate a multistate model of ISWI action, providing a comprehensive mechanism of DNA translocation and regulation underpinning chromatin remodeling.
Variants in a ciliary receptor are associated with obesity
The recent Kunming-Montreal Global Biodiversity Framework (GBF) sets ambitious goals but no clear pathway for how zero loss of important biodiversity areas and halting human-induced extinction of threatened species will be achieved. We assembled a multi-taxa tracking dataset (11 million geopositions from 15,845 tracked individuals across 121 species) to provide a global assessment of space use of highly mobile marine megafauna, showing that 63% of the area that they cover is used 80% of the time as important migratory corridors or residence areas. The GBF 30% threshold (Target 3) will be insufficient for marine megafauna’s effective conservation, leaving important areas exposed to major anthropogenic threats. Coupling area protection with mitigation strategies (e.g., fishing regulation, wildlife-traffic separation) will be essential to reach international goals and conserve biodiversity.
Many functional molecules and materials have been produced with organic chemistry or with in vitro enzymatic approaches. Individual organisms, such as insects, have the potential to serve as natural reaction platforms in which high densities of multiple enzymes can perform new and complex reactions. We report an “in-insect” unnatural product synthesis that takes advantage of their xenobiotic metabolism. We selectively transform belt- and ring-shaped molecular nanocarbons into otherwise difficult-to-prepare derivatives in which oxygen atoms are inserted into aromatic rings. Cytochrome P450 variants are most likely the enzymes responsible for this reaction. Molecular dynamics simulations and quantum chemical calculations indicated a possible mode of substrate incorporation into the enzyme and an unconventional mechanism of direct oxygen insertion into carbon–carbon bonds.
The complex morphological evolution of lithium metal at the solid-state electrolyte interface limits performance of solid-state batteries, leading to inhomogeneous reactions and contact loss. Inspired by biological morphogenesis, we developed an interfacial self-regulation concept in which a deformable secondary phase dynamically aggregates at the interface in response to local electro-chemo-mechanical stimuli, enhancing contact. The stripping of a lithium electrode that contains 5 to 20 mole % electrochemically inactive sodium domains causes spontaneous sodium accumulation across the interface, with the sodium deforming to attain intimate electrical contact without blocking lithium transport. This process, characterized with operando x-ray tomography and electron microscopy, mitigates voiding and improves cycling at low stack pressures. The counterintuitive strategy of adding electrochemically inactive alkali metal to improve performance demonstrates the utility of interfacial self-regulation for solid-state batteries.
Anaerobic metabolisms are thought to dominate nitrogen cycling in anoxic marine zones (AMZs). However, thriving populations of aerobic nitrite-oxidizing bacteria (NOB) in AMZs challenge this assumption and remain unexplained. Using theory and modeling, we show how periodic oxygen intrusions sustain aerobic NOB in AMZs alongside more competitive aerobic heterotrophs. Ecological theory, supported by numerical simulations and genomics, frames NOB as opportunists exploiting a fleeting supply of oxygen. Consistent with in situ observations, simulated NOB contribute substantially to total oxygen consumption at AMZ boundaries, which implies that NOB may provide a major stabilizing feedback to AMZs. Fine-scale ocean currents increase the metabolic diversity in AMZs, which could stabilize AMZ volume under climate change.
Venerable advisory organization hit by Trump’s contract cancellations
Carbon and nitrogen are central elements in global biogeochemical cycles. To effectively manage carbon and nitrogen in China, we developed a comprehensive model for quantifying their fluxes, investigating their interplay across 16 human and natural subsystems. Between 1980 and 2020, nitrogen losses in China increased 2.3-fold and carbon emissions surged 6.5-fold. Integrated carbon and nitrogen management holds the potential for a 74% reduction in nitrogen losses to air and water and a 91% decrease in carbon emissions to the atmosphere by 2060. Compared with separate control of carbon or nitrogen, integrated management delivers an additional reduction of 1.8 million tons of nitrogen and 26.5 million tons of carbon by 2060, bringing out a 37% decrease in unit abatement cost and a net societal benefit of 1384 billion USD.
Across 11 southern African reserves protecting the world’s largest rhino population, we documented the poaching of 1985 rhinos (2017–2023, ~6.5% of the population annually) despite approximately USD 74 million spent on antipoaching. Most investment focused on reactive law enforcement—rangers, tracking dogs, access controls, and detection cameras—which helped achieve >700 poacher arrests. Yet we found no statistical evidence that these interventions reduced poaching (horn demand, wealth inequality, embedded criminal syndicates, and corruption likely combine to drive even high-risk poaching). By contrast, reducing poacher reward through dehorning (2284 rhinos across eight reserves) achieved large (~78%) and abrupt reductions in poaching using 1.2% of the budget. Some poaching of dehorned rhinos continued because poachers targeted horn stumps and regrowth, signaling the need for regular dehorning alongside judicious use of law enforcement.
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The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations inMC4RandADCY3as well as ciliary dysfunction lead to obesity, but how melanocortin signaling works in cilia remains unclear. Using mouse random germline mutagenesis, we identified two missense mutations inG protein–coupled receptor 45 (Gpr45)that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gαsto increase ciliary cyclic adenosine monophosphate (cAMP) via ADCY3. GPR45 colocalized with MC4R in PVH cilia and promoted ciliary MC4R activation. Loss of GPR45 in the PVH or MC4R+neurons caused obesity. These findings establish GPR45 as a key regulator of the ciliary melanocortin system, bridging MC4R and ADCY3.
The field ignores moral plurality at its peril
Area-based conservation is not sufficient to protect the ocean’s most highly mobile species
Sodium in the lithium anode promotes fast discharge in a solid-state battery
Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographically distinct human cohorts as well as in nonhuman primates and mice when measured longitudinally (repeatedly in the same population) or cross-sectionally (sampling distinct populations at various ages). Moreover, considerable variability was observed in associations between taurine and age-related changes in health outcomes pertaining to gross motor function and energy homeostasis. Our results suggest that changes in circulating taurine are not a universal feature of aging and that its pleiotropic effects may be dependent on the temporal and physiological context of each individual.
Tellurium nanowire networks could open up new avenues for artificial vision
Critical mineral supply and demand require global coordination to reduce market volatility and conflict risk
Proposal comes as White House pulls its nominee to lead NASA
We describe archaeological evidence of intensive ancestral Native American agriculture in the now heavily forested Upper Peninsula of Michigan. Recent LIDAR (light detection and ranging) and excavation data have uncovered densely clustered ancient agricultural raised garden bed ridges covering an expanse far greater than previously realized. These raised agricultural fields are deeply enmeshed in the broader cultural landscape, as ceremonial and other features were also found. Our results demonstrate a rich anthropogenic landscape created by small-scale ancestral Menominee communities, located near the northern limits of maize agriculture. The excellent preservation of this site is exceptional in eastern North America and suggests that the precolonial landscape was more anthropogenically influenced than currently recognized.
Although model organisms have provided insight into the earliest stages of cardiac and hepatic vascularization, we know very little about this process in humans because of ethical restrictions and the technical difficulty of obtaining embryos during very early development. In this study, we demonstrate that micropatterned human pluripotent stem cell–derived gastruloids enable in vitro modeling of the earliest stages of vascularization. We identify a combination of vascular-inducing factors that give rise to cardiac vascularized organoids with a spatially organized and branched vascular network. To show the broader utility of our vascularization strategy, we use the same vascular-inducing factors to produce hepatic vascularized organoids. Our results suggest that a conserved developmental program generates the vasculature within different types of organs.
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AbstractA critical challenge in mass spectrometry proteomics is accurately assessing error control, especially given that software tools employ distinct methods for reporting errors. Many tools are closed-source and poorly documented, leading to inconsistent validation strategies. Here we identify three prevalent methods for validating false discovery rate (FDR) control: one invalid, one providing only a lower bound, and one valid but under-powered. The result is that the proteomics community has limited insight into actual FDR control effectiveness, especially for data-independent acquisition (DIA) analyses. We propose a theoretical framework for entrapment experiments, allowing us to rigorously characterize different approaches. Moreover, we introduce a more powerful evaluation method and apply it alongside existing techniques to assess existing tools. We first validate our analysis in the better-understood data-dependent acquisition setup, and then, we analyze DIA data, where we find that no DIA search tool consistently controls the FDR, with particularly poor performance on single-cell datasets.
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AbstractThe networked architecture of the brain promotes synchrony among neuronal populations. These communication patterns can be mapped using functional imaging, yielding functional connectivity (FC) networks. While most studies use Pearson’s correlations by default, numerous pairwise interaction statistics exist in the scientific literature. How does the organization of the FC matrix vary with the choice of pairwise statistic? Here we use a library of 239 pairwise statistics to benchmark canonical features of FC networks, including hub mapping, weight–distance trade-offs, structure–function coupling, correspondence with other neurophysiological networks, individual fingerprinting and brain–behavior prediction. We find substantial quantitative and qualitative variation across FC methods. Measures such as covariance, precision and distance display multiple desirable properties, including correspondence with structural connectivity and the capacity to differentiate individuals and predict individual differences in behavior. Our report highlights how FC mapping can be optimized by tailoring pairwise statistics to specific neurophysiological mechanisms and research questions.
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AbstractBrain connectivity can be estimated in many ways, depending on modality and processing strategy. Here, we present the Krakencoder, a joint connectome mapping tool that simultaneously bidirectionally translates between structural and functional connectivity, and between different atlases and processing choices via a common latent representation. These mappings demonstrate exceptional accuracy and individual-level identifiability; the mapping between structural and functional connectivity has identifiability 42–54% higher than existing models. The Krakencoder combines all connectome flavors via a shared low-dimensional latent space. This fusion representation better reflects familial relatedness, preserves age- and sex-relevant information, and enhances cognition-relevant information. The Krakencoder can be applied, without retraining, to new out-of-distribution data while still preserving inter-individual differences in the connectome predictions and familial relationships in the latent representations. The Krakencoder is a notable leap forward in capturing the relationship between multimodal brain connectomes in an individualized, behaviorally and demographically relevant way.
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AbstractHigh-density silicon probes have transformed neuroscience by enabling large-scale neural recordings at single-cell resolution. However, existing technologies have provided limited functionality in nonhuman primates (NHPs) such as macaques. In the present report, we describe the design, fabrication and performance of Neuropixels 1.0 NHP, a high-channel electrode array designed to enable large-scale acute recording throughout large animal brains. The probe features 4,416 recording sites distributed along a 45-mm shank. Experimenters can programmably select 384 recording channels, enabling simultaneous multi-area recording from thousands of neurons with single or multiple probes. This technology substantially increases scalability and recording access relative to existing technologies and enables new classes of experiments that involve electrophysiological mapping of brain areas at single-neuron and single-spike resolution, measurement of spike–spike correlations between cells and simultaneous brain-wide recordings at scale.
AbstractInterictal epileptiform discharges (IEDs) are expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes, as most therapeutic approaches target seizures. We show, in a kindling model of progressive focal epilepsy, that IEDs produce pathological oscillatory coupling associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expand the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human participants with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing the spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation.
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AbstractTo reinforce rewarding behaviors, events leading up to and following rewards must be remembered. Hippocampal place cell activity spans spatial and non-spatial episodes, but whether hippocampal activity encodes entire sequences of events relative to reward is unknown. Here, to test this possibility, we performed two-photon imaging of hippocampal CA1 as mice navigated virtual environments with changing hidden reward locations. We found that when the reward moved, a subpopulation of neurons updated their firing fields to the same relative position with respect to reward, constructing behavioral timescale sequences spanning the entire task. Over learning, this reward-relative representation became more robust as additional neurons were recruited, and changes in reward-relative firing often preceded behavioral adaptations following reward relocation. Concurrently, the spatial environment code was maintained through a parallel, dynamic subpopulation rather than through dedicated cell classes. These findings reveal how hippocampal ensembles flexibly encode multiple aspects of experience while amplifying behaviorally relevant information.
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AbstractCortical function, including sensory processing, is surprisingly resilient to neuron loss during aging and neurodegeneration. In this Article, we used the mouse auditory cortex to investigate how homeostatic mechanisms protect the representational map of sounds after neuron loss. We combined two-photon calcium imaging with targeted microablation of 30–40 sound-responsive neurons in layer 2/3. Microablation led to a temporary disturbance of the representational map, but it recovered in the following days. Recovery was primarily driven by neurons that were initially unresponsive to sounds but gained responsiveness and strengthened the network’s correlation structure. By contrast, selective microablation of inhibitory neurons caused prolonged disturbance, characterized by destabilized sound responses. Our results link individual neuron tuning and plasticity to the stability of the population-level representational map, highlighting homeostatic mechanisms that safeguard sensory processing in the neocortex.
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AbstractFrom visual perception to language, sensory stimuli change their meaning depending on previous experience. Recurrent neural dynamics can interpret stimuli based on externally cued context, but it is unknown whether they can compute and employ internal hypotheses to resolve ambiguities. Here we show that mouse retrosplenial cortex (RSC) can form several hypotheses over time and perform spatial reasoning through recurrent dynamics. In our task, mice navigated using ambiguous landmarks that are identified through their mutual spatial relationship, requiring sequential refinement of hypotheses. Neurons in RSC and in artificial neural networks encoded mixtures of hypotheses, location and sensory information, and were constrained by robust low-dimensional dynamics. RSC encoded hypotheses as locations in activity space with divergent trajectories for identical sensory inputs, enabling their correct interpretation. Our results indicate that interactions between internal hypotheses and external sensory data in recurrent circuits can provide a substrate for complex sequential cognitive reasoning.
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AbstractAging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins—like the dementia- and ALS-associated protein TDP-43—mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.
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AbstractLipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)–PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.
AbstractIn plants, the maintenance of DNA methylation is controlled by several self-reinforcing loops involving histone methylation and non-coding RNAs. However, how methylation is initially patterned at specific genomic loci is largely unknown. Here we describe fourArabidopsisREM transcription factors, VDD, VAL, REM12 and REM13, that recognize specific sequence regions and, together with the protein GENETICS DETERMINES EPIGENETICS1 (GDE1), recruit RNA polymerase IV transcription complexes. This targeted recruitment leads to the production of 24-nucleotide small interfering RNAs that guide DNA methylation to specific genomic sites in plant female reproductive tissues. In the absence ofGDE1, polymerase IV transcription complexes are directed to loci bound by an alternative transcription factor, REM8, highlighting the role of REM transcription factors and GDE1 proteins as positional cues for epigenetic modulation. These findings establish a direct connection between sequence-specific transcription factors and the spatial regulation of siRNA production and DNA methylation, offering new insights into the genetic control of epigenetic patterning.
AbstractLysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example,vha-6), which are essential for intestinal lumen acidification inCaenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.
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AbstractMitotic spindles are dynamically intertwined with the cytoplasm they assemble in. How the physicochemical properties of the cytoplasm affect spindle architecture and size remains largely unknown. Using quantitative biochemistry in combination with adaptive feedback microscopy, we investigated mitotic cell and spindle morphology during neural differentiation of embryonic stem cells. While tubulin biochemistry and microtubule dynamics remained unchanged, spindles changed their scaling behaviour; in differentiating cells, spindles were considerably smaller than those in equally sized undifferentiated stem cells. Integrating quantitative phase imaging, biophysical perturbations and theory, we found that as cells differentiated, their cytoplasm became more dilute. The concomitant decrease in free tubulin activated CPAP (centrosomal P4.1-associated protein) to enhance the centrosomal nucleation capacity. As a consequence, in differentiating cells, microtubule mass shifted towards spindle poles at the expense of the spindle bulk, explaining the differentiation-associated switch in spindle architecture. This study shows that cell state-specific cytoplasmic density tunes mitotic spindle architecture. Thus, we reveal physical properties of the cytoplasm as a major determinant in organelle size control.
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AbstractHepatitis B virus (HBV) infection is associated with hepatitis and hepatocellular carcinoma (HCC). Considering that most HBV-infected individuals remain asymptomatic, the mechanism linking HBV to hepatitis and HCC remains uncertain. Herein, we demonstrate that HBV alone does not cause liver inflammation or cancer. Instead, HBV alters the chronic inflammation induced by chemical carcinogens to promote liver carcinogenesis. Long-term HBV genome expression in mouse liver increases liver inflammation and cancer propensity caused by a carcinogen, diethylnitrosamine (DEN). HBV plus DEN-activated interleukin-33 (IL-33)/regulatory T cell axis is required for liver carcinogenesis. Pitavastatin, an IL-33 inhibitor, suppresses HBV plus DEN-induced liver cancer. IL-33 is markedly elevated in HBV+hepatitis patients, and pitavastatin use significantly correlates with reduced risk of hepatitis and its associated HCC in patients. Collectively, our findings reveal that environmental carcinogens are the link between HBV and HCC risk, creating a window of opportunity for cancer prevention in HBV carriers.
AbstractT-ALL relapses are characterized by chemotherapy resistance, cellular diversity and dismal outcome. To gain a deeper understanding of the mechanisms underlying relapses, we conduct single-cell RNA sequencing on 13 matched pediatric T-ALL patient-derived samples at diagnosis and relapse, along with samples derived from 5 non-relapsing patients collected at diagnosis. This comprehensive longitudinal single-cell study in T-ALL reveals significant transcriptomic diversity. Notably, 11 out of 18 samples exhibit a subpopulation of T-ALL cells with stem-like features characterized by a common set of active regulons, expression patterns and splice isoforms. This subpopulation, accounting for a small proportion of leukemia cells at diagnosis, expands substantially at relapse, indicating resistance to therapy. Strikingly, increased stemness at diagnosis is associated with higher risk of treatment induction failure. Chemotherapy resistance is validated through in-vitro and in-vivo drug testing. Thus, we report the discovery of treatment-resistant stem-like cells in T-ALL, underscoring the potential for devising future therapeutic strategies targeting stemness-related pathways.
AbstractMelanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combiningBrafactivation with heterozygous loss ofPten. Here we show that similar tumors can arise in albino mice bearing only aBrafmutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only aBrafmutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify a cell type resembling “neural crest-like” cells in human and mouse melanomas. These exist in normal mouse skin, expand uponBrafactivation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that may provide a diagnostically and therapeutically important source of cellular heterogeneity.
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AbstractSpinal cord injury (SCI) can cause permanent loss of sensory, motor, and autonomic functions, with limited therapeutic options available. Low-frequency electric fields with changing polarity have shown promise in promoting axon regeneration and improving outcomes. However, the metal electrodes used previously were prone to corrosion, and their epidural placement limited the penetration of the electric field into the spinal cord. Here, we demonstrate that a thin-film implant with supercapacitive electrodes placed under the dura mater can safely and effectively deliver electric field treatment in rats with thoracic SCI. Subdural stimulation enhanced hind limb function and touch sensitivity compared to controls, without inducing a neuroinflammatory response in the spinal cord. While axon density around the lesion site remained unchanged after 12 weeks, in vivo monitoring and electrochemical testing of electrodes indicated that treatment was administered throughout the study. These results highlight the promise of electric field treatment as a viable therapeutic strategy for achieving long-term functional recovery in SCI.
AbstractHepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we develop a high content RNA-FISH-based imaging assay that allows for the investigation of the entry pathways of both naked and quasi-enveloped HEV particles. Surprisingly, we find that integrin α3, previously implicated in nHEV cell entry, is not expressed in the cell types that are most permissive for HEV infection. Instead, we identify integrin β1 (ITGB1) pairing with different α-integrins as the key player mediating nHEV cell entry. Our results indicate that the interaction of nHEV with ITGB1 facilitates entry through Rab11-positive recycling endosomes. In contrast, eHEV particles do not interact with ITGB1 and enter cells using a classical endocytic route via Rab5a-positive early endosomes. The entry of both types of HEV particles requires endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm.
AbstractFrameshifts can be caused by specific combinations of tRNA and mRNA. The wildtype AGC-decodingE. colitRNASer3GCUhas been shown to induce −1 ribosomal frameshifting on GCA alanine codons, and proposed to read a two-base codon instead of a canonical triplet. However, it has remained unclear whether this type of non-cognate decoding can be accommodated by the ribosome. Here, we perform single-particle cryo-EM reconstructions onE. coli70S ribosomes with the frameshift-inducing tRNASer3bound to the non-cognate GCA codon or the cognate AGC codon in the ribosomal A site. The structures demonstrate that doublet decoding is made possible when A1493, the conserved monitoring base in 16S rRNA, mimics a first codon base, forming a Hoogsteen base pair with U36 from the anticodon and stacking with the mRNA. This interaction pushes the first two bases of the A-site codon in position for base pairing with C35 and G34 of the anticodon.
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AbstractHIV-1 infection establishes a reservoir of long-lived cells with integrated proviral DNA that can persist despite antiretroviral therapy (ART). Certain reservoir cells can be reactivated to reinitiate infection. The mechanisms governing proviral latency and transcriptional regulation of the provirus are complex. Here, we identify a role for histone H3 citrullination, a post-translational modification catalyzed by protein-arginine deiminase type-4 (PADI4), in HIV-1 transcription and latency. PADI4 inhibition by the small molecule inhibitor GSK484 reduces HIV-1 transcription after T cell activation in ex vivo cultures of CD4+T cells from people living with HIV-1 in a cross-sectional study. The effect is more pronounced in individuals with active viremia compared to individuals under effective ART. Cell models of HIV-1 latency show that citrullination of histone H3 occurs at the HIV-1 promoter upon T cell stimulation, which facilitates proviral transcription. HIV-1 integrates into genomic regions marked by H3 citrullination and these proviruses are less prone to latency compared to those in non-citrullinated chromatin. Inhibiting PADI4 leads to compaction of the HIV-1 promoter chromatin and an increase of heterochromatin protein 1α (HP1α)-covered heterochromatin, in a mechanism partly dependent on the HUSH complex. Our data reveal a novel mechanism to explain HIV-1 latency and transcriptional regulation.
AbstractObesity-driven pathological expansion of white adipose tissue (WAT) is a key driver of endothelial dysfunction. However, early vascular alterations associated with over-nutrition also serve to exacerbate WAT dysfunction. Here, we conduct a single-cell transcriptomic analysis of WAT endothelium to delineate endothelial heterogeneity and elucidate vascular alterations and its consequence in a male murine model of obesity. We demarcate depot-specific differences in subcutaneous (sWAT) and visceral WAT (vWAT) endothelium through in sillico analysis and further corroboration of our findings. Moreover, we identify a sWAT-specific fenestrated endothelial cell (EC) subtype, which declines in obese conditions. Utilizing systemic anti-VEGFA blockade and geneticVegfamanipulation, we demonstrate that VEGFA is necessary for maintaining fenestration in sWAT. Additionally, we detect this fenestrated EC subtype in male human WAT, which undergoes reduction in individuals with obesity. Collectively, this atlas serves as a valuable tool for future studies to decipher the functional significance of different WAT EC subtypes.
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AbstractRecent studies emphasize that incorporating lithium metal electrodes can increase the energy density of next generation batteries. However, the production of lithium metal with high purity requires multi-stage purification steps due to its high reactivity. Furthermore, subsequent handling under inert conditions is required to prevent degradation. To circumvent handling of lithium metal and further improve energy density, researchers are exploring reservoir-free cells often referred to as “anode-free” cells. Reservoir-free cells are assembled without using lithium metal. Instead, lithium is electrodeposited at the interface between a current collector and a solid electrolyte from positive electrode materials during the first charge. Despite the potential of reservoir-free cells, there is limited understanding of the purity of electrodeposited lithium metal and how impurities might affect the electrochemical kinetics. This study examines first the purity of electrodeposited lithium at the steel|Li6PS5Cl interface. Then, it shows how impurities in lithium electrodes affect stripping capacity when using commercial lithium metal foils with both Li6PS5Cl and Li6.25Al0.25La3Zr2O12as solid electrolytes. By using time-of-flight secondary mass spectrometry and X-ray photoelectron spectrometry, we reveal that a lithium layer with high purity is electrodeposited at the negative electrode in reservoir-free cells and that common impurities in lithium metal (reservoir-type) electrodes like e.g. sodium negatively influence the accessible lithium capacity during discharge.
AbstractRapid learning in complex and changing environments is a hallmark of intelligent behavior. Humans achieve this in part through abstract concepts applicable to multiple, related situations. It is unclear, however, whether the computational mechanisms underlying rapid learning are unique to humans or also exist in other species. We combined behavioral, computational and electrophysiological analyses of a multidimensional rule-learning paradigm in male rats and in humans. We report that both species infer task rules by sequentially testing different hypotheses, rather than learning the correct action for all possible cue combinations. Neural substrates of hypothetical rules were detected in prefrontal network activity of both species. This species-conserved mechanism reduces task dimensionality and explains key experimental observations: sudden behavioral transitions and facilitated learning after prior experience. Our findings help to narrow the explanatory gap between human macroscopic and rodent microcircuit levels and provide a foundation for the translational investigation of impaired cognitive flexibility.
AbstractLymphostatin is a key virulence factor of enteropathogenic and enterohaemorrhagicEscherichia coli, playing roles in bacterial colonisation of the gut and in the inhibition of lymphocyte proliferation and proinflammatory responses. The protein’s glycosyltransferase and cysteine protease motifs are required for activity against lymphocytes, but high-resolution structural information has proven elusive. Here, we describe the structure of lymphostatin from enteropathogenicE. coli O127:H6, determined by electron cryo-microscopy at different pH values. We observe three conformations of a highly complex molecule with two glycosyltransferase domains, one PaToxP-like protease domain, an ADP-ribosyltransferase domain, a vertex domain and a delivery domain. Long linkers hold these domains together and occlude the catalytic sites of the N-terminal glycosyltransferase and protease domains. Lymphostatin binds to bovine T-lymphocytes and HEK-293T cells, forming clusters at the plasma membrane that are internalized. With six distinct domains, lymphostatin can be regarded as a multitool of pathogenicEscherichia coli, enabling complex interactions with host cells.
AbstractDespite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P.1 vaccines and WA-1 or P.1 infection are immunized with a bivalent WA-1/Omicron BA.5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA.5-specific responses. Reinfection with heterologous Omicron XBB.1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-naïve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69+CD103+lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.
AbstractTo select appropriate behaviour, individuals must rely on encoding of relevant features within their environment in the context of current and past experiences. This function has been linked to goal-associated activity patterns of hippocampal principal cells. Using single-unit recordings from optogenetically identified somatostatin-expressing interneurons (SOMIs) in the dentate gyrus of head-fixed mice trained in a spatial goal-oriented reward-learning task in virtual realities, we show that SOMI activity temporally precedes reward-locations in expert mice characterized by goal-anticipatory behaviour. Predictive goal-encoding by SOMIs is lost after translocation of learned goals to novel previously unrewarded sites leading to rapid reductions in anticipatory behaviour and fast reconfiguration of SOMI activity to times after reward onset in association with reward consumption at novel goal-sites. Chemogenetic silencing of SOMIs caused a loss of memory that trained goal-sites were no longer available. Thus, our data reveal the ability of SOMIs to flexibly encode goal-locations depending on current and past experiences to bias behavioral outcomes.
AbstractPrions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPCcreates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPCand infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPCinitially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.
AbstractIκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ’s function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppressesCxcl9,Cxcl10, andCcl5expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8+T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.
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AbstractThe flow-induced activation of mechanophores embedded in linear polymers by ultrasound (US) suffers from slow mechanochemical conversions at the commonly used frequency of 20 kHz and in many cases remains ineffective with higher MHz frequencies. Here, we present polymeric microbubbles (PMBs) as a platform that accelerates the mechanochemical activation of several mechanophores under both 20 kHz and MHz irradiation. MHz irradiation generated by biocompatible high-intensity focused US (HIFU). Through their pressure-sensitive gas core, PMBs act as acousto-mechanical transducers for the transformation of sound energy into stretching and compression forces as well as fracturing the polymer shell by the volume oscillation of PMB. We investigate three different mechanophores among which one flex-activation derivative was unexpectedly activated by US. Through a combination of experiments and computation, we find that PMBs likely exert compressive force onto the copolymerized mechanophores rather than the typical elongational forces solvated chain fragments experience in flow. We thereby underscore the mechanochemical properties of the PMB platform and its versatility for accelerated mechanochemical transformations with a perspective on biomedical applications.
AbstractDevelopmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation—TTLL glutamylases vs. CCP deglutamylases—accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.
AbstractEmbryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ+pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.
AbstractMycetoma is a chronic granulomatous infection of the subcutaneous tissue, most often caused by the fungal pathogenMadurella mycetomatis. Characteristic of the infection is the formation of grains. However, knowledge of the function and formation of the grain is limited. Here, we use aGalleria mellonellalarvae infection model and transcriptomic profiling to identify processes associated withM. mycetomatisgrain formation. Larvae were infected withM. mycetomatisand, after 4, 24, 72 and 168 h post-inoculation, RNA was extracted from larval content and sequenced. We found that 3498G. mellonellaand 136M. mycetomatisgenes were differentially expressed during infection. In particular, genes encoding proteins related to iron transport were highly expressed by bothG. mellonella(transferrin and ferritin) andM. mycetomatis(SidA, SidD and SidI). LC-MS/MS analysis ofM. mycetomatiscultured under iron-limiting conditions revealed the presence of SidA and SidD orthologs, and concurrent RP-HPLC and LC-MS identified a singly charged, putative siderophore in culture supernatant. Furthermore, we show thatM. mycetomatiscan obtain iron from holoferritin. Thus, our results highlight the importance of iron acquisition pathways during grain formation, suggesting potential avenues for development of new diagnostic and therapeutic strategies for mycetoma.
AbstractS-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
AbstractCognitive processing relies on the brain’s ability to balance flexibility for encoding new information with stability for maintaining it. We examined these dynamics in three magnetoencephalography (MEG) datasets of visuospatial working memory (vsWM) tasks. Across all tasks, we identified four distinct networks in the theta and alpha bands, which were used to define functional states. Optimal transitioning rate between states was associated with better cognitive performance. Further, two of the states were linked to flexibility and stability, respectively: an encoding state dominated by a posterior theta and a maintenance state dominated by a dorsal alpha. We simulated the states in an in-silico model with biologically realistic cortical connectivity. The model, featuring spiking and oscillatory cortical layers interacting via phase-amplitude coupling, demonstrated how frequency and spatial region could modulate information flow. Our findings suggest a cognitive control mechanism, where selective transitions between large-scale networks optimize information flow, enabling both stable and flexible visual representations.
AbstractDeep tissue imaging with high contrast close to or even below the optical resolution limit is still challenging due to optical aberrations and scattering introduced by dense biological samples. This results in high complexity and cost of microscopes that can facilitate such challenges. Here, we demonstrate a cost-effective and simple to implement method to turn most two-photon laser-scanning microscopes into a super-resolution microscope for deep tissue imaging. We realize this by adding inexpensive optical devices, namely a cylindrical lens, a field rotator, and a sCMOS camera to these systems. By combining two-photon excitation with patterned line-scanning and subsequent image reconstruction, we achieve imaging of sub-cellular structures inPinus radiata, mouse heart muscle and zebrafish. In addition, the penetration depth of super-resolved imaging in highly scattering tissue is considerably extended by using the camera’s lightsheet shutter mode. The flexibility of our method allows the examination of a variety of thick samples with a variety of fluorescent markers and microscope objective lenses. Thus, with a cost-efficient modification of a multi-photon microscope, an up to twofold resolution enhancement is demonstrated down to at least 70μm deep in tissue.
AbstractDecision-makers often process new evidence selectively, depending on their current beliefs about the world. We asked whether such confirmation biases result from biases in the encoding of sensory evidence in the brain, or alternatively in the utilization of encoded evidence for behavior. Human participants estimated the source of a sequence of visual-spatial evidence samples while we measured cortical population activity with magnetoencephalography. Halfway through the sequence, participants were prompted to judge the more likely source category. We find that processing of subsequent evidence depends on its consistency with the previously chosen category. Evidence encoded in parietal cortex contributes more to the estimation report when that evidence is consistent with the previous choice compared to when it contradicts that choice. Our results indicate that information contradicting pre-existing beliefs has little impact on subsequent behavior, despite being precisely encoded in the brain. This provides room for deliberative control to counteract confirmation biases.
AbstractDysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase inDrosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan by catalase upregulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.
AbstractSpontaneous parametric down-conversion (PDC) of photons is a gateway into the quantum realm – thoroughly studied in nonlinear optics and ubiquitously used to generate non-classical states of light. Extending PDC from the visible regime towards shorter wavelengths further enables microscopic resolution of electronic structure and quantum-enhanced X-ray detection, but remained challenging due to the process’ inherently low conversion rate. Here, we resolve the full signal cone of non-degenerate down-conversion at X-ray wavelengths and identify imprints of a polariton in the extreme ultraviolet (EUV) regime. We confirm our finding of the EUV-polariton with theoretical simulations and establish that our approach directly images the characteristic anti-crossing of polaritonic dispersion branches. This insight could open a pathway to explore strong-coupling phenomena of EUV-light-matter interaction.
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AbstractLittle is known about the genetic connection system and community organization of Late Neolithic and Early Copper Age populations of the Carpathian Basin. Here, we present a comprehensive genetic investigation of these populations, leveraging whole genome data from 125 individuals. Using population genetics, kinship analyses and the study of networks of identity-by-descent haplotype segment sharing, we elucidate the social and genetic dynamics of these communities between 4800−3900 calibrated years BCE. Despite changes in settlement patterns, burial practices, and material culture, we document a high degree of genetic continuity. While one set of individuals from a large community cemetery is genetically diverse, another site is more homogenous and closed, with numerous consanguineous relationships and evidence of patrilineality and patrilocality. In this work, we document important differences in kinship systems in contemporaneous Early Copper Age communities using similar material culture and living only about 100 km apart.
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AbstractThe development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primateMicrocebus murinus(the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque (Macaca fascicularis) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.
AbstractTissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report that apical size reduction via macropinocytosis serves as a malleable and less destructive form of tissue remodeling that can alleviate the need for cell loss. We find that macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane. This drives a reduction in apical surface which alleviates crowding. We report that this mechanism regulates the long-term organization of the developing epithelium and controls the timing of proliferation-induced cell extrusion. Additionally, we observe a wave of macropinocytosis in response to acute external compression. In both scenarios, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to both developmental and external compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.
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AbstractBrain waste is cleared via a cerebrospinal fluid (CSF) pathway, the glymphatic system, whose dysfunction may underlie many brain conditions. Previous studies show coherent vascular oscillation, measured by blood oxygenation level-dependent (BOLD) fMRI, couples with CSF inflow to drive fluid flux. Yet, how this coupling is regulated, whether it mediates waste clearance, and why it is impaired remain unclear. Here we demonstrate that cholinergic neurons modulate BOLD-CSF coupling and glymphatic function. We find BOLD-CSF coupling correlates cortical cholinergic activity in aged humans. Lesioning basal forebrain cholinergic neurons in female mice impairs glymphatic efflux and associated changes in BOLD-CSF coupling, arterial pulsation and glymphatic influx. An acetylcholinesterase inhibitor alters these dynamics, primarily through peripheral mechanisms. Our results suggest cholinergic loss impairs glymphatic function by a neurovascular mechanism, potentially contributing to pathological waste accumulation. This may provide a basis for developing diagnostics and treatments for glymphatic dysfunction.
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AbstractPhytochromes are biliprotein photoreceptors widespread amongst microorganisms and ubiquitous in plants where they control developmental processes as diverse as germination, stem elongation and floral induction through the photoconversion of inactive Pr to the Pfr signalling state. Here we report crystal structures of the chromophore-binding module of soybean phytochrome A, including ~2.2 Å XFEL structures of Pr and Pfr at ambient temperature and high resolution cryogenic structures of Pr. In the Pfr structure, the chromophore is exposed to the medium, the D-ring remaining α-facial following the likely clockwise photoflip. The chromophore shifts within its pocket, while its propionate side chains, their partners as well as three neighbouring tyrosines shift radically. Helices near the chromophore show substantial shifts that might represent components of the light signal. These changes reflect those in bacteriophytochromes despite their quite different signalling mechanisms, implying that fundamental aspects of phytochrome photoactivation have been repurposed for photoregulation in the eukaryotic plant.
AbstractIron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
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AbstractWeak transitions between quantum states are of fundamental importance for a broad range of phenomena from analytical biochemistry to precision physics, but generally challenge experimental detection. Due to their small cross sections scaling with the absolute square of their transition matrix elements, spectroscopic measurements often fail in particular in the presence of competing background processes. Here we introduce a general concept to break this scaling law and enhance the transition probability by exploiting a stronger laser-coupled pathway to the same excited state. We demonstrate the concept experimentally by attosecond transient absorption spectroscopy in helium atoms. The quasi-forbidden transitions from the ground state 1s2to the weakly coupled doubly excited 2p3dandsp2,4−states are boosted by an order of magnitude. Enhancing single-photon-suppressed transitions can find widespread applicability, from spectral diagnostics of complex molecules in life and chemical sciences to precision spectroscopy of weak transitions in metastable atomic nuclei in the search for new physics.
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AbstractMany countries worldwide are transitioning from fossil fuel-dependent economies to carbon neutrality, driven by the 2030 agenda for sustainable development and the Paris Agreement. However, without considering the regional distribution of essential services like water and energy, this transition could inadvertently maintain or increase inequities, threatening sustainable development. Here, we argue that spatial equity of benefits should be considered in planning low-carbon energy transitions, especially in developing countries with multisector interdependencies and high service disparities between regions. We propose an analytical framework that can help analysts and policymakers plan for regionally equitable climate-compatible futures. The multisector design framework combines integrated river basin-power system simulation with artificial intelligence design tools. The utility of the framework is demonstrated for Ghana by identifying the most efficient infrastructure intervention portfolios and their implied trade-offs between spatial equity in water and energy service provision, carbon emissions, food production, and river ecosystem performance. Case-study results show that an equitable low-carbon energy transition will require increased investments in renewable energy and transmission alongside more informed infrastructure system planning. With low renewable investments, equity can be improved, but at the cost of higher emissions and electricity supply curtailments.
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AbstractAlthough aluminum-containing cements have gained attention as environmentally friendly construction materials, the nanocrystalline structure and mechanical behavior of their primary hydration product, calcium aluminate silicate hydrate (C-A-S-H), remain poorly understood due to its complex chemical composition and structural disorder. Here, we present a high-throughput atomistic modeling framework to systematically investigate the structural and mechanical properties of C-A-S-H across a broad range of Ca/Si (1.3–1.9) and Al/Si (0–0.15) ratios. The compositional, structural, and mechanical features of C-A-S-H are accurately captured by molecular dynamics simulations of 1600 distinct C-A-S-H structures constructed using our in-house automatic structure generation program, CASHgen. Our findings highlight the influence of Ca/Si and Al/Si ratios on key C-A-S-H characteristics, including the mean chain length (MCL), interlayer spacing, coordination number and elastic moduli. Specifically, C-A-S-H exhibits optimal mechanical performance at a Ca/Si ratio of approximately 1.5, while further increases in Ca/Si introduce disorder and reduce stiffness. In contrast, increasing the Al/Si ratio promotes chain polymerization, leading to longer MCLs and improved mechanical performance. These results provide atomic-scale insights into the structure-property relationships in C-A-S-H and offer design guidelines for high-performance, low-carbon cementitious materials.
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AbstractAfter acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.
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AbstractOver the past 50 years, Arctic sea ice has declined in all seasons, with particularly pronounced winter reductions in the Barents Sea. While temperature changes in the Atlantic Water inflow and atmospheric-driven melt have been identified as key drivers of this decline, the role of the return-flow of Atlantic Water in the northern Barents Sea Opening, linked to its recirculation back into the Nordic Seas, has remained largely unrecognized. Using a global ocean and sea ice model, we find that the volume transport of the Atlantic Water return-flow is strongly correlated with the sea ice area in the Barents Sea. In addition, we find that, over the past 40 years, the return-flow has steadily weakened without a corresponding change in inflow. Here, we show that reduced Atlantic Water removal by a weakened return-flow contributes to both interannual variability and the sustained loss of Barents Sea sea ice.
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AbstractBio-instructive materials that intrinsically inhibit biofilm formation have significant anti-biofouling potential in industrial and healthcare settings. Since bacterial surface attachment is sensitive to surface topography, we experimentally surveyed 2176 combinatorially generated shapes embossed into polymers using an unbiased screen. This identified microtopographies that, in vitro, reduce colonization by pathogens associated with medical device-related infections by up to 15-fold compared to a flat polymer surface. Machine learning provided design rules, based on generalisable descriptors, for predicting biofilm-resistant microtopographies. On tracking single bacterial cells we observed that the motile behaviour ofPseudomonas aeruginosais markedly different on anti-attachment microtopographies compared with pro-attachment or flat surfaces. Inactivation of Rhl-dependent quorum sensing inP. aeruginosathrough deletion ofrhlIorrhlRrestored biofilm formation on the anti-attachment topographies due to the loss of rhamnolipid biosurfactant production. Exogenous provision ofN-butanoyl-homoserine lactone to therhlImutant inhibited biofilm formation, as did genetic complementation of therhlI,rhlRorrhlAmutants. These data are consistent with confinement-induced anti-adhesive rhamnolipid biosurfactant ‘autolubrication’. In a murine foreign body infection model, anti-attachment topographies are refractory toP. aeruginosacolonization. Our findings highlight the potential of simple topographical patterning of implanted medical devices for preventing biofilm associated infections.
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AbstractCombinatorial control by transcription factors (TFs) is central to eukaryotic gene regulation, yet its mechanism, evolution, and regulatory impact are not well understood. Here we use natural variation in the yeast phosphate starvation (PHO) response to examine the genetic basis and species variation in TF interdependence. InSaccharomyces cerevisiae, the main TF Pho4 relies on the co-TF Pho2 to regulate ~28 genes, whereas in the related pathogenCandida glabrata, Pho4 has reduced Pho2 dependence and regulates ~70 genes. We foundC. glabrataPho4 (CgPho4) binds the same motif with 3–4 fold higher affinity. Machine learning and yeast one-hybrid assay identify two intrinsically disordered regions (IDRs) in CgPho4 that boost its activation domain’s activity. In ScPho4, an IDR next to the DNA binding domain both allows for enhanced activity with Pho2 and inhibits activity without Pho2. This study reveals how IDR divergence drives TF interdependence evolution by influencing activation potential and autoinhibition.
AbstractEquitable coverage and reliable operation of electric vehicle charging stations (EVCSs) are crucial for a just transition to a carbon-free future. Yet, a comprehensive national analysis of public EVCSs across different communities is lacking in the United States. Here, we utilize real-world reviews (n= 470,142) from a user-generated content platform to analyze public EVCSs at the census tract level. We find that disadvantaged communities (DACs) have 64% fewer public EVCSs per capita than non-DACs. This disparity rises to 73% when considering renters in multi-dwelling units. Additionally, EVCS users in DACs and urban areas experience significantly more reliability issues compared to those in non-DACs and rural areas, primarily related to hardware and technical failures. Given the limited access to home charging in DACs and their underserved public infrastructure, these findings highlight critical equity concerns and call for targeted investment in EVCS infrastructure and reliability improvements, particularly in DACs.
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AbstractCellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthesis, induces a long-term yet reversible proliferative arrest in human cells. Severely compromised biogenesis of rRNAs along with acute transcriptional reprogramming precede a gradual decline of the critical cellular functions. Unexpectedly, many arresting cells show increased levels of histone mRNAs, which accumulate locally in the cytoplasm, and S-phase DNA amount. The ensuing proliferative arrest is entered from multiple stages of the cell cycle and can last for several weeks with uncompromised cell viability. Strikingly, restoring expression of RNase MRP leads to a complete reversal of the arrested state with resumed cell proliferation at the speed of control cells. We suggest that targeting rRNA biogenesis may provide a general strategy for rapid induction of a reversible proliferative arrest, with implications for understanding and manipulating cellular quiescence.
AbstractThe eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity ofUSP37knockout cells to topoisomerase inhibitors. InXenopusegg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37’s response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.
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AbstractDue to low availability of CO2in aquatic environment, microalgae have evolved a CO2concentrating mechanism (CCM). It has long been thought that operation of CCM would suppress photorespiration by increasing the CO2concentration at the Rubisco active site, but experimental evidence is scarce. To better explore the function of photorespiration in algae, we first characterized aChlamydomonas reinhardtiimutant defected in low-CO2inducible 20 (LCI20) and show that LCI20 is a chloroplast-envelope glutamate/malate transporter playing a role in photorespiration. By monitoring growth and glycolate excretion in mutants deficient in either CCM or photorespiration, we conclude that: (i.) CCM induction does not depend on photorespiration, (ii.) glycolate excretion together with glycolate dehydrogenase down-regulation prevents the toxic accumulation of non-metabolized photorespiratory metabolites, and (iii.) photorespiration is active at low CO2when the CCM is operational. This work provides a foundation for a better understanding of the carbon cycle in the ocean where significant glycolate concentrations have been found.
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AbstractAnti-NMDA receptor (NMDAR) encephalitis is a devastating disease with severe psychiatric and neurological symptoms believed to be caused by pathogenic autoantibodies that bind to the N-terminal domain (NTD) of the NMDAR GluN1 subunit (GluN1-NTD) crosslinking adjacent NMDARs and driving their internalization. Here we describe ART5803, a humanized monovalent antibody, as a potential therapy for anti-NMDAR encephalitis. ART5803 binds with a high affinity (KD= 0.69 nM) to GluN1-NTD without affecting NMDAR activity or inducing internalization. ART5803 blocks NMDAR internalization induced by patients’ pathogenic autoantibodies, and restores NMDAR function. A marmoset animal model was developed using sustained intracerebroventricular (ICV) administration of a human pathogenic autoantibody to evoke behavioral and motor abnormalities. ART5803 ICV infusion or peripheral injections rapidly reversed these abnormalities. These data, together with the pharmacokinetic profile in cynomolgus monkeys, indicate a therapeutic potential for intravenous (IV)-administered ART5803 as a fast-acting and efficacious option for anti-NMDAR encephalitis.
AbstractAneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
AbstractIncidence of type 1 diabetes is increasing globally, which is hypothesized to be due to environmental influences. We leverage Swedish nationwide registers linked to all children (n= 2,928,704) born in 1982–2010 to investigate if the heritability of childhood-onset type 1 diabetes has changed over time and how alterations in environmental factors have contributed to the rising type 1 diabetes incidence. The heritability is estimated at 0.83 (95% confidence interval: 0.79, 0.86) and stable over the observation period (0.80 [0.71, 0.86] in 1982, 0.83 [0.79, 0.86] in 2000, and 0·83 [0.79, 0.86] in 2010, respectively). Environmental factors including maternal smoking during pregnancy and childhood adiposity explain <10% of the increasing type 1 diabetes incidence. In this work, the heritability of childhood-onset type 1 diabetes has remained high and stable over the last 30 years. Our findings indicate that the available environmental factors are not the major contributors to the rise in type 1 diabetes in Sweden.
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AbstractHistologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression ofMUC16(CA125),MUC4, andKRT24. This cell state is enriched in metastases, predicted to be highly resistant to chemotherapy, and linked with poor survival. We also find enriched expression ofTM4SF1, a transmembrane protein, in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in aTM4SF1expression-dependent manner, highlighting its potential as a therapeutic target.
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AbstractPost-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and functionally important regulatory regions. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and intervention.
AbstractMicrotubules and nuclear transmembrane SUN1/2 proteins promote the mobility of DNA Double Strand Breaks (DSBs) induced by ionizing radiation and the misrepair of one-ended DSBs induced in BRCA1-deficient cells by Poly(ADP-ribose) polymerase inhibitors (PARPi). However, whether microtubules promote aberrant DSBs repair by altering the nuclear structure and whether the nuclear structure itself plays a role in these processes is still unclear. Here we show that microtubule-dependent DSBs mobility in BRCA1-deficient cells after PARPi treatment is associated with nuclear envelope (NE) invaginations. Furthermore, increasing NE invaginations byLmnadeletion or inhibition of sphingolipid synthesis increases DSBs mobility, chromosomal aberrations, and PARPi cytotoxicity in BRCA1-deficient cells. These findings reveal a functional connection between the NE and DSB repair and suggest that drugs increasing NE deformability will enhance PARPi therapy efficacy in BRCA1-deficient cancers.
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AbstractSpatial multi-slice multi-omics (SMSMO) integration has transformed our understanding of cellular niches, particularly in tumors. However, challenges like data scale and diversity, disease heterogeneity, and limited sample population size, impede the derivation of clinical insights. Here, we propose stClinic, a dynamic graph model that integrates SMSMO and phenotype data to uncover clinically relevant niches. stClinic aggregates information from evolving neighboring nodes with similar-profiles across slices, aided by a Mixture-of-Gaussians prior on latent features. Furthermore, stClinic directly links niches to clinical manifestations by characterizing each slice with attention-based geometric statistical measures, relative to the population. In cancer studies, stClinic uses survival time to assess niche malignancy, identifying aggressive niches enriched with tumor-associated macrophages, alongside favorable prognostic niches abundant in B and plasma cells. Additionally, stClinic identifies a niche abundant inSPP1+MTRNR2L12+ myeloid cells and cancer-associated fibroblasts driving colorectal cancer cell adaptation and invasion in healthy liver tissue. These findings are supported by independent functional and clinical data. Notably, stClinic excels in label annotation through zero-shot learning and facilitates multi-omics integration by relying on other tools for latent feature initialization.
AbstractA major challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma types and the corresponding lack of suitable model systems. Here we describe the development of a genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by muscle electroporation (EPO) in wildtype mice. This EPO-GEMM (EPO-based genetically engineered mouse model) platform allows the generation of ten genetically distinct sarcomas on an isogenic background, including the first model ofETV6::NTRK3-driven sarcoma. Comprehensive histological and molecular profiling reveals that this mouse sarcoma cohort recapitulates a spectrum of molecularly diverse sarcomas with gene fusions acting as major determinants of sarcoma biology. Integrative cross-species analyses show faithful recapitulation of human sarcoma subtypes, including expression of relevant immunotherapy targets. Comparison of syngeneic allografting methods enables reliable preservation and scalability of sarcoma-EPO-GEMMs for preclinical treatment trials, such as NTRK inhibitor therapy in an immunocompetent background.
AbstractHigh ambient temperatures are associated with reduced sleep duration and quality, but effects on obstructive sleep apnea (OSA) severity are unknown. Here we quantify the effect of 24 h ambient temperature on nightly OSA severity in 116,620 users of a Food and Drug Administration-cleared nearable over 3.5 years. Wellbeing and productivity OSA burden for different levels of global warming were estimated. Globally, higher temperatures (99thvs. 25th; 27.3 vs. 6.4 °C) were associated with a 45% higher probability of having OSA on a given night (mean [95% confidence interval]; 1.45 [1.44, 1.47]). Warming-related increase in OSA prevalence in 2023 was estimated to be associated with a loss of 788,198 (489,226, 1,087,170) healthy life years (in 29 countries), and a workplace productivity loss of 30 (21 to 40) billion United States dollars. Scenarios with projected temperatures ≥1.8 °C above pre-industrial levels would incur a further 1.2 to 3-fold increase in OSA burden by 2100.
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AbstractCultural systems play an important role in shaping the interactions between humans and the environment, and are in turn shaped by these interactions. However, at present, cultural systems are poorly integrated into the models used by climate scientists to study the interaction of natural and anthropogenic processes (i.e. Earth systems models) due to pragmatic and conceptual barriers. In this Perspective, we demonstrate how the archaeology of climate change, an interdisciplinary field that uses the archaeological record to explore human-environment interactions, is uniquely placed to overcome these barriers. We use concepts drawn from climate science and evolutionary anthropology to show how complex systems modeling that focuses on the spatial structure of the environment and its impact on demographic variables, social networks and cultural evolution, can bridge the gap between large-scale climate processes and local-scale social processes. The result is a blueprint for the design of integrative models that produce testable hypotheses about the impact of climate change on human systems.
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AbstractOne of the key achievements of equilibrium polymer physics is the prediction of scaling laws governing the viscoelastic properties of entangled polymer systems, validated in both natural polymers, such as DNA, and synthetic polymers, including polyethylene, which form materials like plastics. Recently, focus has shifted to active polymers systems composed of motile units driven far from equilibrium, such as California blackworms, self-propelled biopolymers, and soft robotic grippers. Despite their growing importance, we do not yet understand their viscoelastic properties and universal scaling laws. Here, we use Brownian dynamics simulations to investigate the viscoelastic properties of highly-entangled, flexible self-propelled polymers. Our results demonstrate that activity enhances the elasticity by orders of magnitude due to the emergence of grip forces at entanglement points, leading to its scaling with polymer length ∼L. Furthermore, activity fluidizes the suspension, with the long-time viscosity scaling as ∼L2, compared to ∼L3in passive systems. These insights open new avenues for designing activity-responsive polymeric materials.
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AbstractExcitation energy transfer between photosynthetic light-harvesting complexes is vital for highly efficient primary photosynthesis. Controlling this process is the key for advancing the emerging artificial photosynthetic systems. Here, we experimentally demonstrate the enhanced excitation energy transfer between photosynthetic light-harvesting 2 complexes (LH2) mediated through the Fabry-Pérot optical microcavity. Using intensity-dependent pump-probe spectroscopy, we analyse the exciton-exciton annihilation (EEA) due to inter-LH2 energy transfer. Comparing EEA in LH2 within cavity samples and the bare LH2 films, we observe enhanced EEA in cavities indicating improved excitation energy transfer via coupling to a common cavity mode. Surprisingly, the effect remains even in the weak coupling regime. The enhancement is attributed to the additional connectivity between LH2s introduced by the resonant optical microcavity. Our results suggest that optical microcavities can be a strategic tool for modifying excitation energy transfer between molecular complexes, offering a promising approach towards efficient artificial light harvesting.
AbstractImporting renewable energy to Europe may offer many potential benefits, including reduced energy costs, lower pressure on infrastructure development, and less land use within Europe. However, open questions remain: on the achievable cost reductions, how much should be imported, whether the energy vector should be electricity, hydrogen, or derivatives like ammonia or steel, and their impact on Europe’s infrastructure needs. This study integrates a global energy supply chain model with a European energy system model to explore net-zero emission scenarios with varying import volumes, costs, and vectors. We find system cost reductions of 1-10%, within import cost variations of ± 20%, with diminishing returns for larger import volumes and a preference for methanol, steel and hydrogen imports. Keeping some domestic power-to-X production is beneficial for integrating variable renewables, leveraging local carbon sources and power-to-X waste heat. Our findings highlight the need for coordinating import strategies with infrastructure policy and reveal maneuvering space for incorporating non-cost decision factors.
AbstractPrognosis for thoracic aortic aneurysms is significantly worse for women than men, with a higher mortality rate observed among female patients. The increasing use of magnetic resonance breast imaging (MRI) offers a unique opportunity for simultaneous detection of both breast cancer and thoracic aortic aneurysms. We retrospectively validate a fully-automated artificial neural network (ANN) pipeline on 5057 breast MRI examinations from public (Duke University Hospital/EA1141 trial) and in-house (Erlangen University Hospital) data. The ANN, benchmarked against 3D-ground-truth segmentations, clinical reports, and a multireader panel, demonstrates high technical robustness (dice/clDice 0.88-0.91/0.97-0.99) across different vendors and field strengths. The ANN improves aneurysm detection rates by 3.5-fold compared with routine clinical readings, highlighting its potential to improve early diagnosis and patient outcomes. Notably, a higher odds ratio (OR = 2.29, CI: [0.55,9.61]) for thoracic aortic aneurysms is observed in women with breast cancer or breast cancer history, suggesting potential further benefits from integrated simultaneous assessment for cancer and aortic aneurysms.
AbstractSexual dysmorphism in the number and distribution of meiotic crossovers is seen across species but is poorly understood. Here, we disrupt multiple anti-crossover pathways in hermaphrodite Arabidopsis and analyze thousands of female and male progeny genomes. The greatest crossover increase is seen inzyp1 recq4mutants, with a 12-fold rise in females and 4.5-fold in males. Additional manipulation of crossover regulators does not further increase crossovers but shifts the balance between crossover pathways, suggesting competition for a shared, limited precursor pool. While wild-type crossover patterns differ between sexes, mutant crossover landscapes converge on a unique distinct profile, which we term Crossover Potential (COP). COPcan be accurately predicted using only sequence and chromatin features. We propose that COPreflects the density of eligible recombination precursors, which is determined by genomic features and is thus identical across sexes, with sexual dimorphism resulting solely from differential regulation of their maturation into crossovers.
AbstractConventional laboratory mice housed under specific pathogen-free (SPF) conditions are the standard model in biomedical research. However, in recent years, many rodent-based studies have been deemed irreproducible, raising questions about the suitability of mice as model organisms. Emerging evidence indicates that variability in SPF microbiota plays a significant role in data inconsistencies across laboratories. Although efforts have been made to standardize microbiota, existing microbial consortia lack the complexity and resilience necessary to replicate interactions in free-living mammals. We present a robust, feasible and standardizable approach for transplanting natural gut microbiota from wildlings into laboratory mice. Following engraftment, these TXwildlings adopt a structural and functional wildling-like microbiota and host physiology toward a more mature immune system, with characteristics similar to those of adult humans. We anticipate that adopting wild mouse-derived microbiota as standard for laboratory mouse models will improve the reproducibility and generalizability of basic and preclinical biomedical research.
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AbstractSalivary gland cancers are rare, diverse malignancies characterized by poor response to immunotherapy. The tumor immune environment in these cancers remains poorly understood. To address this, we perform an integrative analysis of the tumor immune microenvironment in a large cohort of advanced salivary gland cancer samples. Most tumors exhibit low immune activity with limited immune cell infiltration. Inflammation is linked to higher tumor mutational burden in non-adenoid cystic carcinoma histologies. Subtype specific expression of immune checkpoints is identified with prominent expression ofVTCN1in luminal-like cells within adenoid cystic carcinoma. Macrophages with immunosuppressive properties dominate the immune microenvironment across subtypes. Responses to immunotherapy are limited and associated with a higher ratio of T-cells relative to macrophages in individual cases, warranting further investigation. Here, we show an immunosuppressive environment in salivary gland cancers and identify subtype-specific immune vulnerabilities that could inform tailored therapeutic strategies.
AbstractWhile small carbocyclic rings have long been recognized as pivotal building blocks in chemistry, their all-boron counterparts have remained largely unexplored. In this work, we present a detailed account of the functionalization reactivity of our cyclic tetraborane B4(NCy2)4(Cy = cyclohexyl) encompassing both ring-expansion and ring-opening reactions. Specifically, diphenyl dichalcogenides effect ring expansion to five-membered B4E rings (E = S, Se, Te), while halogenating agents induce ring opening to generate linear tetraboranes with halide end groups. These transformations reveal reactivity patterns reminiscent of strained organic ring systems, thus highlighting the cyclic tetraborane’s potential as a versatile precursor for synthesizing intricate boron-rich architectures.
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AbstractNet-zero commitments have become the focal point for countries to communicate long-term climate targets. However, to this point it is not clear to what extent conventional emissions reductions and carbon dioxide removal (CDR) will contribute to net-zero. An integrated market for emissions and removals with a uniform carbon price delivers the economically efficient contribution of CDR to net-zero. Yet it might not fully internalise sustainability risks of CDR and hence could lead to its overuse. In this study, we explore the implications of separating targets for emissions and for removals delivered by novel CDR in global net-zero emissions pathways with the Integrated Assessment Model REMIND. We find that overall efficiency losses induced by such separation are moderate. Furthermore, limiting the CDR target comes with increasing emission prices but also significant benefits: lower cumulative emissions, a lower financial burden for public finance of CDR and limited reliance on geologic CO2storage but fails to lower the biomass demand. Proposed targets should also ensure sufficient CDR deployment to achieve net-negative emissions in the second half of the 21st century.
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AbstractMechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly understood due to its rarity. A subset of SNSCC is associated with human papillomavirus (HPV), but it is unclear whether HPV drives tumorigenesis or acts as a neutral bystander. Here, we show that HPV-associated SNSCC shares mutational patterns found in HPV-associated cervical and head and neck squamous cell carcinoma, including lack ofTP53mutations, hotspot mutations inPI3KandFGFR3, enrichment of APOBEC mutagenesis, viral integration at known hotspots, and frequent epigenetic regulator alterations. We identify HPV-associated SNSCC-specific recurrent mutations inKMT2C,UBXN11,AP3S1,MT-ND4, andMT-ND5, withKMT2DandFGFR3mutations correlating with reduced overall survival. We establish an HPV-associated SNSCC cell line, showing that combinatorial small-molecule inhibition of YAP/TAZ and PI3K synergistically suppresses clonogenicity. Combining YAP/TAZ blockade with vertical PI3K inhibition may benefit HPV-associated SNSCC, whereas targeting MYC and horizontal inhibition of RAS/PI3K may suit HPV-independent SNSCC.
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AbstractReforestation is a prominent climate change mitigation strategy, but available global maps of reforestation potential are widely criticized and highly variable, which limits their ability to provide robust estimates of both the locations and total area of opportunity. Here we develop global maps that address common critiques, build on a review of 89 reforestation maps created at multiple scales, and present eight reforestation scenarios with varying objectives, including providing ecosystem services, minimizing social conflicts, and delivering government policies. Across scenarios, we find up to 195 Mha (million hectares) are available (2225 TgCO2e (teragrams of carbon dioxide equivalent) per year total net mitigation potential), which is 71–92% smaller than previous estimates because of conservative modeling choices, incorporation of safeguards, and use of recent, high-resolution datasets. This area drops as low as 6 Mha (53 TgCO2e per year total net mitigation potential) if only statutorily protected areas are targeted. Few locations simultaneously achieve multiple objectives, suggesting that a mix of lands and restoration motivations will be needed to capitalize on the many potential benefits of reforestation.
AbstractIntrospection on memory states guides decision-making, but little is known about how it emerges in childhood. Toddlers’ behavioral responses to difficult memory decisions (e.g., information seeking) suggest early capacity to track uncertain situations, but it is unclear whether these behaviors relate to later emerging capacity to introspect on memory accuracy (i.e., metamemory monitoring). In a pre-registered longitudinal study, 176 25- to 34-month-olds encode images, then are asked to select the familiar image from arrays that also include a new image (Time 1). One year later (Time 2), 157 participants complete a similar memory task and report decision confidence. Higher gaze transitions between responses, indicative of evaluation processes, faster response latencies, and greater memory at Time 1 predict Time 2 metamemory monitoring (i.e., greater confidence for accurate than inaccurate decisions). At Time 2, gaze transitions are associated with lower overall confidence. Overall, this research reveals potential building blocks of emerging metamemory monitoring.
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AbstractBeyond conventional electrical modulation, flexoelectricity enables mechanical control of ferroelectric polarizations, offering a pathway for tactile-responsive ferroelectric systems. However, mechanical polarization switching typically requires substantial static threshold forces to overcome the significant energy barrier, resulting in material fatigue and slow response that compromises reliability and hinders practical applications. In this work, we address these challenges by introducing an imprint field through asymmetric electrostatic boundary design with distinct work functions. This built-in electric field stabilizes the energy landscape, effectively lowering the polarization switching barrier. Subsequently, nonvolatile polarization switching with a low threshold force of 12 nN·nm−1is achieved in CuInP2S6without material damage. Surpassing the limitations of slow static force controls, our work marks the first experimental demonstration of fast mechanical control of polarization switching with 4 millisecond-long low force pulses. To further highlight the potential of this rapid, low-force mechanical control, we propose a van der Waals heterostructured mechanically gated transistor with asymmetric electrostatic boundary, which exhibits gate force pulses-controlled multi-level, nonvolatile conductance states. Our findings establish a paradigm for next-generation ferroelectric electronics that integrate responsiveness to mechanical stimuli.
AbstractPost-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging.
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AbstractThe liver’s regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.
AbstractVisible-light-absorbing semiconductor nanocrystals have shown great promise as photocatalysts for promoting photoredox chemistry. However, their utilization in organic synthesis remains considerably limited compared to small molecule photosensitizers. Recently, the generation of hot electrons from quantum-confined systems has emerged as a powerful means of photoreduction, yet the efficiencies remain limited under mild conditions. In this study, we present an efficient hot-electron generation system facilitated by the spin-exchange Auger process in Mn2+-doped CdS/ZnS quantum dots. These hot electrons can be effectively utilized in a wide range of organic reactions, such as the Birch reduction and reductive cleavage of C-Cl, C-Br, C-I, C-O, C-C, and N-S bonds. Notably, these reactions accommodate substrate reduction potentials as low as −3.4 V versus the saturated calomel electrode. Through two-photon excitation, we achieve the generation of a “super” photoreductant using visible-light irradiation power that is only 1% of that previously reported for molecular and quantum dot systems. By modulating the intensity of light output, the spin-exchange Auger process enables the on/off generation of hot electrons, allowing for programmable assembly-point cross-coupling cascades. Our findings demonstrate the potential of quantum-confined semiconductors in facilitating challenging organic transformations that were unattainable with molecular photocatalysts.
AbstractHigh-resolution nanopore analysis technology relies on the design of novel transmembrane protein platforms. Traditional barrel-shaped protein channels are preferred for constructing nanopore sensors, which may miss protein candidates in non-barrel structures. Here, we demonstrate the globular ferritin displays excellent membrane-insertion capacity and stable transmembrane ionic current owing to its hydrophobic four-fold channels and hydrophilic three-fold channels. The ionic current rectification and voltage-gating characteristics are discovered in single-ferritin ionic current measurement. Notably, the ferritin is used as a nanopore sensor, by which we achieve the high resolution discrimination of L-cysteine, L-homocysteine, and cysteine-containing dipeptides with the assistance of equivalent Cu2+. The mechanistic studies by multiple controlled experiments and quantum mechanics/all-atom/coarse-grained multiscale MD simulations reveal that analytes are synergistically captured by His114, Cys126, and Glu130 within C3 channel, causing the current blockage signals. The promising ferritin nanopore sensor provides a guide to discovering new protein nanopores without shape restrictions.
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AbstractChemoselective dual functionalization of proteins has emerged as an invaluable tool to introduce two distinct payloads to proteins, thus greatly expanding their structural and functional repertoire for more advanced biomedical applications. Here, we introduceN-alkylpyridinium reagents as soft electrophiles for chemoselective dual modification of cysteine residues in peptides or proteins via a 1,6-addition reaction. TheN-alkylpyridinium derivatives can be synthesized in two reaction steps revealing good water solubility, high labelling efficiency and chemoselectivity towards cysteine over lysine/N-terminal amine residues, even when used in large excess. This reaction can be combined with strain-promoted azide-alkyne click (SPAAC) and inverse-electron-demand Diels−Alder (iEDDA) reactions to achieve dual functionalization of proteins in a sequential simple one-pot reaction. As a proof-of-concept, the Rho-inhibiting enzymeClostridium botulinumC3 is functionalized with a cancer cell-targeting peptide and a fluorescent dye for the inhibition of specific Rho-mediated intracellular pathways. The high stability, ease of synthesis, fast reaction kinetics, high water-solubility and chemoselectivity makeN-alkylpyridinium reagents unique for dual modification of peptides and proteins to increase their functional diversities for medical applications.
AbstractIn the era of big data, developing next-generation self-powered continuous energy harvesting systems is of great importance. Taking advantage of fallen leaves’ specific structural advantage gifted by nature, we propose a facile approach to convert fallen leaves into energy harvesters from ubiquitous moisture, based on surface treatments and asymmetric coating of hygroscopic iron hydrogels. Upon moisture absorption, a water gradient is established between areas with/without hydrogel coating, and maintained due to gel-like behaviors and leaf veins for water retention and diffusion restriction, thus forming electrical double layers over the leaf surface and showing capacitance-like behavior for energy charging and discharging. Besides, the specific leaf cell structures with small grooves enabled uniform carbon coatings instead of aggregations, and high electrical conductivity, resulting in 49 μA/cm2and 497 μW/cm3electrical output, achieving competitive performance with the state-of-art and potential for lower environmental impact compared to other types of energy harvesters.
AbstractWe develop a framework for understanding indirect assortative mating and provide updated definitions of key terms. We then develop family models that use partners of twins and siblings to freely estimate the degree of genetic and social homogamy, and account for it when investigating sources of parent-offspring similarity. We applied the models to educational attainment using 1,545,444 individuals in 212,070 extended families in the Norwegian population and Norwegian Twin Registry. Partner similarity in education was better explained by indirect assortment than direct assortment on observed educational attainment, with social homogamy being particularly important. The implied genotypic partner correlation (r= 0.34) was comparable to earlier studies, and higher than expected under direct assortment. About 38% of the parent-offspring correlation (r= 0.34) was attributable to various forms of environmental transmission. Alternative models that assumed direct assortment estimated environmental transmission to be lower, but these did not fit the data well.
AbstractMutations in theTANGO2gene cause an autosomal recessive disorder characterised by developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias along with severe metabolic crises. AlthoughTANGO2mutations result in a well characterised disease pathology, the function of TANGO2 is still unknown. To investigate the function of TANGO2, we knocked out theTANGO2gene in human cells and mice. We identify that loss of TANGO2 impairs intermediate filament structure, resulting in fragmented mitochondrial networks and formation of cup-like mitochondria. In male mice, loss of TANGO2 caused heart defects, reduced muscle function and glucose intolerance by remodelling of intermediate filaments, which altered the mitochondrial and cytoplasmic proteomes, N-glycosylation and nucleocytoplasmic O-GlcNAcylation. We identify that TANGO2 binds the small heat shock protein crystallin alpha B (CRYAB) to prevent the aggregation of the intermediate filament desmin and in the absence of TANGO2, mice develop desminopathy, which is consistent with features found in patients carrying mutations in either desmin or CRYAB.
AbstractThe self-powered photoelectrochemical components themselves featured advancements in operating independently without external supply. Ultimately, due to lack of assistance from the external bias, the photoelectrochemical response is commonly restricted by the deficient photo-quantum efficiency for the absence of carrier multiplication. This work demonstrates a self-powered photoelectrochemical photodetector based on CuOx/AlGaN nanowires with staggered band structure and enhanced built-in potential for efficient exciton extraction. The generated multiple excitons within reach-through CuOxlayer could be speedily separated before Auger recombination. This yields a 131.5% external quantum efficiency and 270.6 mA W−1responsivity at 255 nm. The work confirms the role of multiple exciton generation in photoelectrochemical systems, offering a solution on paving path of advance for self-powered optoelectronics and weak-light UV imaging applications.
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AbstractOptically generated microwaves exhibit unprecedented low noise, benefiting applications such as communications, radar, instrumentation, and metrology. To date, the purest microwave signals are produced using optical frequency division with femtosecond mode-locked lasers. However, their typical repetition rates of hundreds of MHz require multiplication methods to reach the microwave domain. Here, we introduce a miniaturized photonic integrated circuit-based interleaver, achieving a 64-fold multiplication of the repetition rate from 216 MHz to 14 GHz in Ku-Band. With the interleaver, the generated microwave power was improved by 35 dB, with a phase noise floor reduced by more than 10 folds by alleviating photodetector saturation. Based on a low-loss and high-density Si3N4waveguides, six cascaded stages of Mach-Zehnder interferometers with optical delay lines up to 33 centimeters long are fully integrated into a compact chip. Our result can significantly reduce the cost and footprint of mode-locked-laser-based microwave generation, enabling field deployment in aerospace and communication applications.
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AbstractIn materials exhibiting photoinduced phase transitions, and in which both charge transfer and spin transitions occur, there has long been a debate about which process drives the phase transition. Herein, we present experimental evidence supporting an optically charge-transfer-induced spin transition (CTIST) process, as demonstrated through femtosecond optical spectroscopy in two-dimensional cyanido-bridged cobalt-tungstate photomagnets. Optical and magnetic studies revealed that the photoexcitation of the ground low-temperature (LT) CoIIILS-WIVstate leads to a photoinduced phase transition towards the CoIIHS-WVstate, which is similar to the high temperature (HT) state. Ultrafast spectroscopy further indicates that this optical excitation of the intermetallic W-to-Co charge-transfer band produces a transient photoexcited (PE) CoIILS-WVstate, which decays within 130 fs through a spin transition towards the CoIIHS-WVstate. Here we show that the CTIST dynamics corresponds to the CoIIILS-WIV(LT) → CoIILS-WV(PE) → CoIIHS-WV(HT) sequence. The present work sheds a new light on understanding optical dynamics underlying the photoinduced phase transitions.
AbstractPeptide-specific PLZF+innate-like T (PILT) cells are a member of the innate-like T cell family utilizing a diverse set of T cell receptor (TCR) Vβ chains. Yet there are no present studies providing clues into the developmental features of PILT cells at a transcriptome level. Here, we performed single-cell transcriptomic analyses of PILT cells and compared them to other members of the innate-like T cell family. We show that PILT cells share similar transcriptional profiles and overlapping developmental trajectories with invariant Natural Killer T (iNKT) cells. However, in contrast to iNKT cells, PILT cells display a polyclonal TCR repertoire closely resembling the one of conventional CD8 T cells, inferring MHC I restriction and a broader range of antigen specificity. We further show that artificial thymic organoid cultures (ATOC) support selection and development of PILT cells in vitro exhibiting similar transcriptional profiles to their counterparts maturing in the thymus. Moreover, using an “on-time” TCR retrogenic ATOC system, we provide evidence for an instructive role of TCR specificity in PILT cell lineage commitment and functional differentiation. Altogether, our findings provide further insights into the PILT cells unique characteristics and molecular mechanisms governing their development.
AbstractStrong coupling between matter and vacuum electromagnetic fields in a cavity can induce novel quantum phases in thermal equilibrium via symmetry breaking. Particularly intriguing is the coupling with circularly polarized cavity fields, which can break time-reversal symmetry (TRS) and lead to topological bands. This has spurred significant interest in developing chiral cavities that feature broken TRS, especially in the terahertz (THz) frequency range, where various large-oscillator-strength resonances exist. Here, we present a design for high-quality-factor THz chiral photonic-crystal cavities (PCCs) that achieve broken TRS using a magnetoplasma in a lightly doped semiconductor. We incorporate ab initio density functional theory calculations into the derived microscopic model, allowing a realistic estimate of the vacuum-induced gap in graphene when coupled to our chiral cavity. Our calculations show an enhancement in the light–matter interaction due to Dirac nodes and predict an energy gap on the order of 1 meV. The THz chiral PCCs offer a promising platform for exploring cavity-dressed condensed matter with broken TRS.
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AbstractWe introduce universal diffractive waveguide designs that can match the performance of conventional dielectric waveguides and achieve various functionalities. Optimized using deep learning, diffractive waveguides can be cascaded to form any desired length and are comprised of transmissive diffractive surfaces that permit the propagation of desired modes with low loss and high mode purity. In addition to guiding the targeted modes through cascaded diffractive units, we also developed various waveguide components and introduced bent diffractive waveguides, rotating the direction of mode propagation, as well as spatial and spectral mode filtering and mode splitting diffractive waveguide designs, and mode-specific polarization control. This framework was experimentally validated in the terahertz spectrum to selectively pass certain spatial modes while rejecting others. Without the need for material dispersion engineering diffractive waveguides can be scaled to operate at different wavelengths, including visible and infrared spectrum, covering potential applications in, e.g., telecommunications, imaging, sensing and spectroscopy.
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AbstractThere is accumulating evidence that the human cerebellum is heavily implicated in adult social cognition. Yet, its involvement in the development of Theory of Mind (ToM), a hallmark of social cognition, remains elusive. Using openly available functional MRI data of children with emerging ToM abilities (N= 41, age range: 3-12 years) and adults (N= 78), we show that children who pass a false-belief assessment of ToM abilities activate cerebellar Crus I-II in response to ToM events during a movie-watching task, similar to adults. This activation is not statistically significant in children who do not pass the ToM assessment. Functional connectivity profiles between cerebellar and cerebral ToM regions differ as a function of children’s ToM abilities. Notably, task-driven connectivity shifts from upstream to downstream connections between cerebellar and cerebral ToM regions from childhood to adulthood. Greater dependence on connections emerging from the cerebellum early in life suggests an important role of the cerebellum in establishing the cognitive processes underlying ToM in childhood and thus for the undisrupted development of social cognition.
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AbstractmRNA localization to specific subcellular regions is common in mammalian cells but poorly understood in terms of its physiological roles. This study demonstrates the functional importance ofNet1mRNA, which we find prominently localized at the dermal-epidermal junction (DEJ) in stratified squamous epithelia.Net1mRNA accumulates at DEJ protrusion-like structures that interact with the basement membrane and connect to a mechanosensitive network of microfibrils. DisruptingNet1mRNA localization in mouse epithelium alters DEJ morphology and keratinocyte-matrix connections, affecting tissue homeostasis. mRNA localization dictates the cortical accumulation of the Net1 protein and its function as a RhoA GTPase exchange factor (GEF). Altered RhoA activity is in turn sufficient to alter the ultrastructure of the DEJ. This study provides a high-resolution in vivo view of mRNA targeting in a physiological context. It further demonstrates how the subcellular localization of a single mRNA can significantly influence mammalian epithelial tissue organization, thus revealing an unappreciated level of post-transcriptional regulation that controls tissue physiology.
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AbstractRelapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4cells did not clearly improve outcomes despite EBV-specific TTCR-C4cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.
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AbstractMetastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis.HLFdepletion enhances ccRCC cell migration and lung metastasis, whereasHLFoverexpression abrogates these effects. In ccRCC patients,HLFexpression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1.HLFlevels negatively correlate with migration potential in collagen. Mechanistically, HLF regulatesLPXNexpression, modulating the integration of collagen’s mechanical cues with the actin cytoskeleton through Paxillin, thereby suppressing cancer cell migration and lung metastasis. Overexpression ofHLFor pharmacological inhibition of BRG1 reduces cell invasion across multiple cancer types. Our findings suggest that targeting the BRG1-HLF axis offers a promising therapeutic strategy for combating metastatic cancers.
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AbstractSaccharomyces cerevisiaeprimarily generates energy through glycolysis and respiration. However, the manifestation of the Crabtree effect results in substantial carbon loss and energy inefficiency, which significantly diminishes product yield and escalates substrate costs in microbial cell factories. To address this challenge, we introduce the sucrose phosphorolysis pathway and delete the phosphoglucose isomerase genePGI1, effectively decoupling glycolysis from respiration and facilitating the metabolic transition of yeast to a Crabtree-negative state. Additionally, a synthetic energy system is engineered to regulate the NADH/NAD+ratio, ensuring sufficient ATP supply and maintaining redox balance for optimal growth. The reprogrammed yeast strain exhibits significantly higher yields of various non-ethanol compounds, with lactic acid and 3-hydroxypropionic acid production increasing by 8- to 11-fold comparing to the conventional Crabtree-positive strain. This study describes an approach for overcoming the Crabtree effect in yeast, substantially improving energy metabolism, carbon recovery, and product yields.
AbstractThe pathogenPseudomonas aeruginosaenhances its virulence and antibiotic resistance upon formation of durable biofilms. The exopolysaccharides Pel, Psl and alginate essentially contribute to the biofilm matrix, but their secretion mechanisms are barely understood. Here, we reveal the architecture of the outer membrane complex PelBC for Pel export, where the essential periplasmic ring of twelve lipoproteins PelC is mounted on top of the nanodisc-embedded β-barrel PelB. The PelC assembly is stabilized by electrostatic contacts with the periplasmic rim of PelB and via the membrane-anchored acyl chains. The negatively charged interior of the PelB β-barrel forms a route for the cationic Pel exopolysaccharide. The β-barrel is sealed at the extracellular side, but molecular dynamic simulations suggest that the short loop Plug-S is sufficiently flexible to open a tunnel for the exopolysaccharide transport. This gating model is corroborated by single-channel conductivity measurements, where a deletion of Plug-S renders a constitutively open β-barrel. Our structural and functional analysis offers a comprehensive view on this pathogenicity-relevant complex and suggests the route taken by the exopolysaccharide at the final secretion step.
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AbstractLactobacillusdisplacement from the vaginal microbiome associates with adverse health outcomes and is linked to increased risk of preterm birth. Glycans mediate bacterial adhesion events involved in colonisation and infection. Using customised glycan microarrays, we establish glycan interaction profiles of vaginal bacteria implicated in reproductive health. Glycan binding signatures of the opportunistic pathogensEscherichia coli,Fusobacterium nucleatumandStreptococcus agalactiaeto oligomannose N-glycans, galactose-terminating glycans and hyaluronic acid, respectively are highly distinct fromLactobacilluscommensals. Binding to sulphated glycosaminoglycans by vaginal bacteria is pH dependent, as is binding to neutral and sialic acid-terminating glycans byF. nucleatum. Adhesion ofLactobacillus crispatus,Lactobacillus iners,Gardnerella vaginalis,S. agalactiaeandF. nucleatumto vaginal epithelial cells is partially mediated by chondroitin sulphate.S. agalactiaebinding to chondroitin sulphate C oligosaccharides is inhibited byL. crispatus. This study highlights glycans as mediators of vaginal bacterial binding events involved in reproductive health and disease.
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AbstractThe fossil record provides direct evidence for the behavior of biological systems over millions of years, offering a vital source for studying how ecosystems evolved and responded to major environmental changes. Using network analysis on a dataset of over 3000 fossil species spanning the past 60 Myr, we find that ungulate continental assemblages exhibit prolonged ecological stability interrupted by irreversible reorganizations associated with abiotic events. During the early Cenozoic, continental assemblages are dominated by mid-sized browsers with low-crowned teeth, which show increasing functional diversity. Around 21 Ma, the formation of a land bridge between Eurasia and Africa triggers the first major global transition towards a new functional system featuring a prevalence of large browsers with mid- to high-crowned molars. Functional diversity continues to increase, peaking around 10 Ma. Shortly after, aridification and the spread of C4-dominated vegetation lead to a second tipping point towards a fauna characterized by grazers and browsers with high and low crowned teeth. A global decline in ungulate functional diversity begins 10 Ma ago and accelerates around 2.5 Ma, yet the functional structure of these faunas remains stable in the latest Cenozoic. Large mammal evolutionary history reflects two key transitions, aligning with major tectonic and climatic events.
AbstractLayered two-dimensional (2D) materials offer many promising avenues for advancing modern electronics, thanks to their tunable optical, electronic, and magnetic properties. Applying a strong electric field perpendicular to the layers, typically at the MV/cm level, is a highly effective way to control these properties. However, conventional methods to induce such fields employ electric circuit - based gating techniques, which are restricted to microwave response rates and face challenges in achieving device-compatible ultrafast, sub-picosecond control. Here, we demonstrate an ultrafast field effect in atomically thin MoS2embedded within a hybrid 3D-2D terahertz nanoantenna. This nanoantenna transforms an incoming terahertz electric field into a vertical ultrafast gating field in MoS2, simultaneously enhancing it to the MV/cm level. The terahertz field effect is observed as a coherent terahertz-induced Stark shift of exciton resonances in MoS2. Our results offer a promising strategy to tune and operate ultrafast optoelectronic devices based on 2D materials.
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AbstractThe design and control of atomic-scale spin structures constitute major challenges for spin-based quantum technology platforms, including quantum dots, color centers, and molecular spins. Here, we showcase a strategy for designing the quantum properties of molecular spin qubits by combining tip-assisted on-surface assembly with electron spin resonance scanning tunneling microscopy (ESR-STM): We fabricate magnetic dimer complexes that consist of an iron phthalocyanine (FePc) molecule and an organometallic half-sandwich complex formed by the FePc ligand and an attached iron atom, Fe(C6H6). The total complex forms a mixed-spin (1/2,1) quantum ferrimagnet with a well-separated correlated ground state doublet, which we utilize for coherent control. As a result of the correlation, the quantum ferrimagnet shows an improved spin lifetime ( > 1.5 μs) as it is partially protected against inelastic electron scattering. Lastly, the ferrimagnet units also enable intermolecular coupling, that can be used to realize both ferromagnetic or antiferromagnetic structures. Thus, quantum ferrimagnets provide a versatile platform to improve coherent control in general and to study complex magnetic interactions.
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AbstractThere has been a recent surge in transformer-based architectures for learning on graphs, mainly motivated by attention as an effective learning mechanism and the desire to supersede the hand-crafted operators characteristic of message passing schemes. However, concerns over their empirical effectiveness, scalability, and complexity of the pre-processing steps have been raised, especially in relation to much simpler graph neural networks that typically perform on par with them across a wide range of benchmarks. To address these shortcomings, we consider graphs as sets of edges and propose a purely attention-based approach consisting of an encoder and an attention pooling mechanism. The encoder vertically interleaves masked and vanilla self-attention modules to learn an effective representation of edges while allowing for tackling possible misspecifications in input graphs. Despite its simplicity, the approach outperforms fine-tuned message passing baselines and recently proposed transformer-based methods on more than 70 node and graph-level tasks, including challenging long-range benchmarks. Moreover, we demonstrate state-of-the-art performance across different tasks, ranging from molecular to vision graphs, and heterophilous node classification. The approach also outperforms graph neural networks and transformers in transfer learning settings and scales much better than alternatives with a similar performance level or expressive power.
AbstractThe exploitation of the strong light-matter coupling regime and exciton-polariton condensates has emerged as a compelling approach to introduce strong interactions and nonlinearities into numerous photonic applications. The use of colloidal semiconductor quantum dots with strong three-dimensional confinement as the active material in optical microcavities would be highly advantageous due to their versatile structural and compositional tunability and wet-chemical processability, as well as potentially enhanced, confinement-induced polaritonic interactions. Yet, to date, exciton-polariton condensation in a microcavity has neither been achieved with epitaxial nor with colloidal quantum dots. Here, we demonstrate room-temperature polariton condensation in a thin film of monodisperse, colloidal CsPbBr3quantum dots, placed in a tunable optical resonator with a Gaussian-shaped deformation serving as wavelength-scale potential well for polaritons. The onset of polariton condensation under pulsed optical excitation is manifested in emission by its characteristic superlinear intensity dependence, reduced linewidth, blueshift, and extended temporal coherence.
AbstractMultivalent proteins can form membraneless condensates in cells by liquid-liquid phase separation, and significant efforts have been made to study their biochemical properties. Here, we demonstrate the emergent mechanics of a functional multivalent condensate reconstituted with six postsynaptic density proteins, using atomic-force-microscopy-based mesoscale rheology and quantitative fluorescence measurements. The measured relaxation modulus and protein mobility reveal that the majority (80%) of the proteins in the condensate are mobile and diffuse through a dynamically cross-linked network made of the remaining (20%) non-mobile scaffold proteins. This percolating structure gives rise to a two-mode mechanical relaxation with an initial exponential decay followed by a long-time power-law decay, which differs significantly from simple Maxwell fluids. The power-law rheology with an exponentα≃ 0.5 is a hallmark of weak bonds’ binding/unbinding dynamics in the multivalent protein network. The concurrent molecular and mechanical profiling thus provides a reliable readout for characterizing the mechanical state of protein condensates and investigating their physiological functions and associations with diseases.
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AbstractOver three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMeBiobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores modify phenotypes amongst pathogenic carriers and that genetic background additionally alters the effects of pathogenic variants through interactions.
AbstractAmygdala hyperexcitability is a hallmark of stress-induced anxiety disorders. Stress-associated changes in both principal neurons and interneurons contribute to the increased excitability, but how exactly these mechanisms interact to regulate the function of behaviorally relevant circuits in the amygdala remains unclear. Here, we show that GluK1 subunit-containing kainate receptors in parvalbumin (PV) interneurons maintain high GABA release and control excitability of lateral amygdala (LA) principal neurons via tonic GABAB-receptor-mediated inhibition. Downregulation of GluK1 expression in PV interneurons after chronic restraint stress (CRS) releases the tonic inhibition and increases excitability of LA principal neurons. Stress-induced LA hyperexcitability was associated with increased glutamatergic transmission to central amygdala PKCδ-expressing neurons, implicated in fear generalization. Consistent with significance in anxiogenesis, absence of GluK1-GABABregulation confers resilience against CRS-induced LA hyperexcitability and anxiety-like behavior. Our data reveal a unique novel mechanism involving an interplay between glutamatergic and GABAergic systems in the regulation of amygdala excitability in response to chronic stress.
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AbstractEpigenetic responses to cannabis use could link cannabis use to health problems. We examined the DNA-methylation profiles of long-term cannabis users in midlife, re-evaluating a set of 246 cannabis-associated methylation markers that were previously identified in other studies. Data were from the Dunedin Study, a five-decade longitudinal study of a birth cohort (analyticn= 787). Peripheral whole blood was drawn when the cohort was age 45, and DNA methylation was assayed using the EPIC 850 K BeadChip. Analyses compared long-term cannabis users with non-users and, for a benchmark comparison, long-term tobacco users. Results showed that long-term cannabis use was associated with sixteen of the previously published 246 cannabis-related methylation markers. Methylation markers that were associated with long-term cannabis use were also associated with long-term tobacco use. However, after adjusting for long-term tobacco use and other covariates, long-term cannabis use was robustly associated with hypomethylation of nine markers: cg05575921, cg21566642, cg03636183, cg21161138, cg01940273, cg17739917, cg05086879, cg02978227, cg23079012. Cannabis-related hypomethylation was associated with higher gene expression in the Dunedin Cohort, suggesting meaningful biological associations. A comparison of long-term cannabis users with cannabis quitters revealed that quitters showed less extreme DNA hypomethylation. Long-term cannabis use could affect the epigenome similarly to tobacco use, possibly at least partly though smoke inhalation. Cannabis cessation, like tobacco cessation, may reverse altered DNA methylation.
AbstractTreatment-resistant depression (TRD), defined as major depressive disorder (MDD) with multiple failed responses to antidepressant treatments, has been suggested to be heritable, but identifying its genetic component is challenging. Using a restrictive TRD definition based on antidepressant medication followed by electroconvulsive therapy (ECT), which may represent a severe subset of TRD cases, we investigated both common variants and rare copy number variations (CNVs) associated with a) TRD risk (2 062 TRD vs. 441 037 healthy controls) and b) treatment resistance in MDD (2 062 TRD vs. 38 544 non-TRD) across three Nordic countries. We observed a significant SNP-based heritability for TRD risk at 26% (SE = 5%). Genome-wide association analysis identified one locus on chromosome 3 (intronic region ofSPATA16) for TRD risk and one suggestive locus for treatment resistance in MDD. TRD risk showed positive genetic correlations (rg) with other psychiatric disorders, with notablyrgwith bipolar disorder (0.86, SE = 0.20) and schizophrenia (0.57, SE = 0.13), as well as a negativergwith intelligence (−0.13, SE = 0.07). Analyses using PRS showed that TRD had higher common-variant burdens of various psychiatric disorders compared to non-TRD. Furthermore, TRD carried a higher CNV deletion burden in total and average lengths than healthy controls or non-TRD cases and was associated with a group of 54 known neuropsychiatric CNVs (ORs = 1.74–2.86). Given that our definition of TRD involves the use of ECT, our findings may reflect a severe form of treatment resistance. This work adds evidence on a genetic basis and provides insights into the genetic architecture of TRD, underscoring the need for further genomic research into this ‘difficult-to-treat’ condition.
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AbstractIndividuals with mood disorders present with cognitive impairment and functional disability, and small-scale studies underline aberrant cognitive control and default mode network activity as potential neuronal correlates underlying these deficiencies. The objectives of this large-scale, cross-sectional functional magnetic resonance imaging (fMRI) study were (I) to investigate the replicability of cognitive control network (CCN) hypo-activity and default mode network (DMN) hyper-activity in patients with mood disorders, and (II) to explore brain activity related to cognition and daily functioning across patients and controls. We pooled data from three studies conducted at the same study site, which resulted in a sample of 213 fully or partially remitted patients with mood disorders (189 with bipolar disorder, 24 with major depressive disorder) and 60 healthy controls (HC). All participants underwent fMRI, during which they performed a verbal working memory N-back task, as well as comprehensive neurocognitive testing and assessment of daily functioning. Patients showed task-related hypo-activity within the left dorsolateral prefrontal cortex as well as frontal and parietal nodes of the CCN, which correlated with poorer outside-scanner cognitive performance. Within the DMN, patients showed hyper-activity in the frontal medial cortex compared to HC. Cognitive performance was positively associated with task activity within the right middle frontal gyrus (p= 0.0005), located in the CCN, whereas daily functioning was negatively associated with activity within the cingulate gyrus, a key hub in the DMN (p= 0.007). In the largest study of its kind, we identified CCN and DMN abnormalities in mood disorders and associations with cognition and functioning. The findings highlight plausible neurocircuitry targets for enhancing cognitive and functional recovery in mood disorders.
AbstractFOXG1 (Forkhead Box G1) is a critical transcription factor for brain development, regulating progenitor cell proliferation, neuronal migration, and cortical circuit assembly. PathogenicFOXG1variants lead to FOXG1 syndrome, a neurodevelopmental disorder characterized by severe brain anomalies and cognitive impairments. Despite efforts to correlate genetic variants with clinical outcomes, the precise relationship remains elusive. Here, we analyzed clinical severity and brain anomalies in 14 individuals withFOXG1variants, investigating how these variants impact FOXG1’s properties and functions. We uncovered a strong correlation between the severity of brain anomalies in affected individuals and functional alterations of these variants. Variants with very low protein expression were associated with moderate-to-severe brain anomalies. A luciferase reporter assay was used to assess the ability of FOXG1 variants to repressCOUP-TFI(NR2F1) expression-a function of FOXG1 validated through single-cell RNA-sequencing (scRNA-seq). Variants losingCOUP-TFIrepression ability by binding toCOUP-TFI’s enhancer region consistently caused moderate-to-severe brain anomalies. Furthermore,in uteroelectroporation (IUE) in embryonic mouse brains was employed to study their impact on neuronal migration and differentiation. Electroporation of wild-typeFoxg1delayed neuronal migration and altered their cell fate. Remarkably, variants associated with moderate-to-severe brain anomalies impaired these functions, while those with mild brain anomalies caused partial impairment. Thus, by combining protein expression,COUP-TFIrepression, and neuronal migration assays, we developed a patient stratification paradigm for predicting the severity of FOXG1 syndrome. This workflow successfully differentiated 92.3% of cases, facilitating early diagnosis and guiding future therapeutic interventions.
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AbstractPeripartum depression can have severe impact on the mother’s and the infant’s health. Yet, its biological underpinnings are largely unknown. The present study sought to identify transcriptomic signatures of depressive symptoms during pregnancy and postpartum. Blood samples were collected during late pregnancy or early postpartum for mRNA isolation and sequencing, while depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Based on the timepoint when the samples were collected, differentially expressed genes (DEGs) were identified by (1) comparing mRNA levels between the depression symptom trajectory groups, and (2) correlating with EPDS scores. DEGs for samples collected during late pregnancy, but not postpartum, were associated with depressive symptoms occurring only during pregnancy or persisting postpartum, compared with controls. There were 16 upregulated and 109 downregulated DEGs significantly associated with EPDS score at week 32 among samples collected during late pregnancy. Gene Set Enrichment Analysis identified immune response and cell motility as processes linked to these DEGs. Hypothesis-based analysis on previously identified postpartum depressive symptoms-related DEGs replicated a positive association between expression of immune-related genesISG15andRSAD2with postpartum-onset depressive symptoms, both in samples taken during late pregnancy and postpartum. The present findings point to transcriptomic signatures associated with peripartum depressive symptoms, mostly related to immune system dysregulation.
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Conventional drug delivery methods for chronic disease often suffer from low potency and poor patient compliance, while current advanced devices face limitations because of bulkiness, frequent implantation needs, inflammation risk, and lack of precise control. To overcome these challenges, we developed the SUSTAIN—a smart, ultra-long-lasting, sequentially triggerable, and artfully implantable nozzle system. The SUSTAIN integrates an osmotic pressure–triggered module, an airflow-generated T-pipe (AGT), and a drug infusion pump (DIP) for controlled subcutaneous drug release. The AGT enables tunable dosing by varying NaHCO3/KH2PO4powder amounts, while shear thinning of the β-cyclodextrin/Pluronic F-127 hydrogel in the DIP ensures sustained drug infusion. In vivo studies show that the SUSTAIN delivers at least four doses of levothyroxine sodium over 10 days and three doses of semaglutide over 42 days, maintaining effective blood drug levels with minimal invasiveness. This system presents a highly promising solution for improving therapeutic outcomes and convenience in chronic disease management.
Cardiotoxicity, especially human ether-a-go-go–related gene (hERG)–related toxicity, is a leading cause of drug failure or market withdrawal. Reducing hERG binding to obviate potential cardiac toxicity is crucial. Nanotechnology has been applied to drug delivery for reducing drug toxicity and improving efficacy, but few studies have addressed hERG-related cardiotoxicity. We report the use of self-assembling dendrimer nanosystems for drug formulation and delivery, which effectively reduced hERG binding and associated toxicity while promoting therapeutic efficacy. Specifically, these dendrimer nanosystems efficiently encapsulated the antimalarial drug chloroquine, the anticancer agent doxorubicin, and the NUPR1 inhibitor ZZW115, all three having high affinity to hERG channels. These nanoformulations showed three- to eightfold reduced hERG binding affinity, which, in animal models, translated to abolished toxicity. These nanodrugs exhibited prolonged circulation, leading to enhanced accumulation at disease sites and improved treatment outcomes. This study highlights the potential of nanotechnology to reduce hERG binding and related toxicity while improving drug efficacy, offering valuable perspectives for drug development.
Skeletal harboring of hematopoietic stem cells (HSCs) is generally considered as vertebrate-specific innovation during water-to-land transition. However, this long-standing view has not been rigorously evaluated as hematopoietic sites remain poorly understood in most invertebrate groups. We report, to our knowledge, the first discovery of abundant HSCs in adult mollusk shells, an invertebrate hematopoietic niche resembling vertebrate bone marrow (BM). Cell-lineage analysis and functional assays reveal the developmental origin of HSCs during larval shell formation and their participation in hemocyte-mediated shell regeneration and soft-body blood supply. Widespread skeleton-related HSC-like cells are found in diverse invertebrate groups and bony fish group, suggesting skeletons as a universal niche for animal HSCs and HSC-skeleton association preceding vertebrate water-to-land transition. Comparison of invertebrate and vertebrate skeletal HSCs enables the macroevolutionary profiling of a core-set of animal HSC regulators. Our findings would boost fundamental paradigm shifts for hematopoiesis and stem cell research in invertebrates and provide the redefined understanding of vertebrate BM evolution and water-to-land transition.
Living organisms use intricate strategies to adapt and survive in response to potentially lethal environment changes. Inspired by cryptobiosis in nature, researchers have pioneered approaches to create cell-in-shell nanobiohybrids, aiming to endow cells with enhanced protection and exogenous functions. Yet, these methods still lack the biological autonomy intrinsic to natural cellular responses. Here, we present an innovative chemo-metabolically coupled strategy for the autonomous construction of cell-in-shell structures in cell growth medium. Our system harnesses ethanol fermentation bySaccharomyces cerevisiae, chemically coupled with an enzymatic cascade involving alcohol oxidase and horseradish peroxidase, to drive the nanoshell formation of polydopamine. The integration of autonomous shell formation with cellular proliferation produces anisotropic cell-in-shell structures, which can serve as enzyme-powered cell microrobots, upon conjugation with urease. Our autonomous system enables the creation of cell-in-shell nanobiohybrids with dynamic and adaptive environmental interactions, paving the way for transformative applications in synthetic biology, such as artificial cells, as well as advancements in cell-based therapies.
Identifying previously unknown targets for pathological cardiac hypertrophy and understanding its mechanisms are crucial. Here, we observed that the deubiquitinating enzyme YOD1 was moderately elevated in human hypertrophic myocardium and mouse models. Cardiomyocyte-specific knockout of YOD1 reduced Ang II– and TAC-induced cardiac hypertrophy. Subsequently, we used multiple proteomic analyses to identify and confirm STAT3 as a substrate protein for YOD1. Mechanistically, our findings revealed that the C155 site of YOD1 removes K48-linked ubiquitin chains from K97 on STAT3, stabilizing STAT3 levels and enhancing its nuclear translocation in cardiomyocytes under Ang II stimulation. Notably, inhibiting STAT3 reversed the antihypertrophic effects of YOD1 deficiency in Ang II–challenged mice. In addition, pharmacological inhibition of YOD1 mitigated Ang II–induced pathological ventricular remodeling in mice. This study clarifies the role of YOD1 and introduces a previously unidentified YOD1-STAT3 axis in regulating pathological cardiac hypertrophy, providing valuable insights for drug development targeting this condition.
CD4+T cells are crucial in shaping response and resistance to immunotherapy. To enhance our understanding of their multifaceted functions, we developed copper-64–radiolabeled nanobodies targeting the human CD4 receptor (64Cu-CD4-Nb1) for positron emission tomography (PET). In human CD4-receptor knock-in mice,64Cu-CD4-Nb1 specifically accumulated in different orthotopic tumors, correlating with histological CD4+cell densities. Based on intratumoral CD4+cell distribution patterns within the core and periphery, we distinguished responders to combined αPD-1/4-1BB antibodies early on-treatment. CD4-PET identified resistance to αPD-1 monotherapy, which was mitigated by adding regulatory T cell–depleting α4-1BB antibodies. Patients with early-stage non–small cell lung cancer who relapsed after neoadjuvant αPD-L1 therapy revealed low CD4+T cell densities in the tumor core. In human and mouse tumor tissues, regulatory T cells correlated with CD4+cell densities. Thus, visualizing the spatial distribution patterns of CD4+cells by PET offers mechanistic insights into CD4-mediated therapy efficacy, with great potential for guiding combinatorial immunotherapies in patients with cancer.
Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn2+release and inhibit pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP channel 1 (MTC1)–related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic reactive oxygen species, inhibiting macrophage pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing other inflammatory diseases.
Vesta, the only differentiated rocky protoplanet explored by a spacecraft, offers insight into early planetary formation. The Divalia Fossae, surface troughs comparable in size to the Grand Canyon, encircle two-thirds of the equator. Two giant impacts reshaped the southern hemisphere, where an older basin is partially superposed by the younger Rheasilvia basin. The origin of the Divalia Fossae is widely accepted as directly linked to the Rheasilvia impact, either by tectonics caused immediately by the impact, up-spinning, or secondary cratering. We present several geologic constraints that support a tectonic origin of the troughs due to the adjustment of Vesta’s spin axis to a geoid changed by both large impacts. The best fit to Vesta’s gravitational field corresponds to a spin axis reorientation of 3° that, when coupled with despinning, induces a stress state that predicts Divalia Fossae’s established location, fracture type, and orientation. These insights underline the importance of tectonic processes in the early evolution of protoplanets.
Porphyry copper deposits (PCDs) are the main source of copper globally, with the metals transported in and deposited from aqueous magmatic fluids. Processes that define the volume of magma and concentration of copper in the magma required to form PCDs, however, are not well understood. Here, we present the results of quantitative modeling of the behavior of Cu and Cl during magma evolution in the upper crust. We show that fractional crystallization is the most important process promoting efficient Cu extraction, and that high concentrations of Cu in the ore-forming hydrothermal fluids can be reached with moderate Cl concentrations. Unusually high concentrations of Cl and Cu in the magma and large magma volumes are not required. Arc magmas of modest volume (<103km3) and modest initial Cu and Cl concentrations can generate large PCDs, if a sufficient mass of magmatic fluid is exsolved at an advanced stage of crystallization.
Manipulation of polar functional groups to extend the druggability and developability space is an important approach in the current field of drug discovery. Here, we report an editing method that enables the direct insertion of anthranilyl units into inert amides to form versatile oligoamides and cyclic peptides under exceptionally mild reaction conditions. We showcase a diverse array of pharmaceuticals, natural products, and bioactive molecules involving the mentioned scaffold insertion. The synthesis of the secondary metabolites from marine-derived fungi, the expedited construction of bioactive molecules, and the assembly of functionalized peptide macrocycles through iterative insertions highlight the synthetic utility of this method. Computational tools and experimental measurements indicate that a hydrogen bond network formed by reacting and catalytic amide enables the insertion of the anthranilyl unit into a C─N bond.
Most baleen whales were severely overexploited during the past century, but many populations have received near-complete protection from exploitation for more than a half-century. Some of these populations have made remarkable recoveries and are now approaching pre-exploitation levels of abundance. Contrary to expectations of baleen whales making minor oscillations around equilibrium abundances, several populations that have made the strongest recoveries have experienced major mortality events. We review examples from the literature showing increasing demographic variability in recovering populations of baleen whales and present a simulation study on the expected response of recovered versus depleted whale population to environmental variability and climate impacts. We propose that baleen whales are more sensitive to environmental variability than previously recognized; that major demographic fluctuations will become the norm as baleen whales recover; and that climate-driven disruptions to whale population dynamics will be most dramatic in populations with the lowest rates of anthropogenic mortality.
Harmful algal blooms (HABs) of the toxigenic haptophyteChrysochromulinaare known to cause fish mortalities and collateral ecosystem damage. The ichthyotoxic mechanisms are poorly understood but likely dependent on toxigenesis by polyketide synthases (PKSs). We hypothesize that induction of PKS activity facilitates mixotrophic behavior during nutrient-depleted bloom conditions. To identify potential in situ stimuli for growth, toxigenicity, and bloom persistence, we compared environmental factors and biological processes identified by metaomics toChrysochromulina leadbeateriHABs between two fjords in northern Norway. We identified the polyketide ichthyotoxin leadbeaterin-1 from theC. leadbeateribloom and found potentially associated candidate PKS genes of which most were higher expressed at bloom stations. A relative depletion of inorganic nitrogen and phosphate during the bloom was correlated with higher expression of genes involved in endocytosis, autophagy, and lysosomal activity. Mixotrophy is evidently a compensatory nutritional strategy coupled to induction of toxigenesis and other metabolomic processes as biotic factors linked toChrysochromulinabloom dynamics.
Oriented electric currents in metals are routinely driven by applying an external electric potential. Although the response of electrons to the external electric fields occurs within attoseconds, conventional electronics do not use this speed potential. Ultrashort laser pulses with controlled shapes of electric fields that switch direction at petahertz frequencies open perspectives for driving currents in metals. Light field–driven currents were demonstrated in various media including dielectrics, semiconductors, and topological insulators. Now, our research question is whether we can drive and control orders of magnitude more charge carriers in metals enabling ultrafast switching with practically low-energy, picojoule-level pulses. Here, we demonstrate the interaction of light with nanometer-thick metallic layers, which leads to a generation of light field–controlled electric currents. We show that the implantation of metallic layers into a dielectric matrix leads to up to 40 times increase of the sensitivity in contrast to a bare dielectric, decreasing the intensity threshold for lightwave electronics.
Interleukin-4 (IL-4) plays a central role in type 2 immune responses. Despite its potential use for allergic and autoimmune diseases, its pleiotropic receptor binding complicates selective targeting of IL-4 signaling pathways. We developed a chemical synthesis of (i) IL-4 variants with atomically tailored side-chain modifications that deter specific receptor interactions and (ii) conditionally activatable IL-4 variants uncaged with 365-nanometer light. In primary cell studies, different variants elicited selective STAT5 or STAT6 phosphorylation in lymphocytes or neutrophils. In murine studies, photocaged IL-4 suppressed inflammation only upon UV irradiation, demonstrating precise on demand control. We accomplished the synthesis and folding of IL-4, a hydrophobic cytokine with three disulfide bonds, using the alpha-ketoacid–hydroxylamine (KAHA) ligation to assemble three segments. We introduced further conjugations, including PEGylation for half-life extension, through orthogonal ligations enabled by functionalized amino acid building blocks. This work highlights the flexibility of chemical protein synthesis to produce therapeutically valuable cytokines, including receptor-biased and spatiotemporally activatable IL-4 variants.
Human language is unique among communication systems since many elements are learned and transmitted across generations. Previous research suggests that this process is best predicted by infant-directed communication, i.e., a mode of communication directed by caregivers to children. Despite its importance for language, whether infant-directed communication is unique to humans or rooted more deeply in the primate lineage remains unclear. To assess this, we investigated directed and surrounding vocal communication in human infants and infants of wild nonhuman great apes. Our findings reveal that human infants receive dramatically more infant-directed communication than nonhuman great ape infants. These data suggest that the earliest hominins likely relied more on surrounding communication to become communicatively competent, while infant-directed vocal communication became considerably more prominent with human language.
Several inhibitory interneuron subtypes have been identified as critical in regulating sensory responses. However, the specific contribution of each interneuron subtype remains uncertain. In this work, we explore the contributions of cell type–specific activity and synaptic connections to the dynamics of a spatially organized spiking neuron network. We find that the firing rates of the somatostatin (SOM) interneurons align closely with the level of network synchrony irrespective of the target of modulatory input. Further analysis reveals that inhibition from SOM to parvalbumin interneurons must be limited to allow gradual transitions from asynchrony to synchrony and that the strength of recurrent excitation onto SOM neurons determines the level of synchrony achievable in the network. Our results are consistent with recent experimental findings on cell type–specific manipulations. Overall, our results highlight common dynamic regimes achieved across modulations of different cell populations and identify SOM cells as the main driver of network synchrony.
Climate change is altering marine ecosystems, driving shifts in sea turtle distributions and challenging conservation efforts. Our study examines how climate change affects the global sea distribution of all seven sea turtle species, intersecting with marine protected areas (MPAs) and shipping corridors. Using species distribution models and environmental data from 2000 to 2024, we project sea turtle habitats under current conditions and three future climate scenarios (SSP1-2.6, SSP2-4.5, and SSP5-8.5) for 2050 and 2100. Our results show substantial habitat redistributions, with poleward shifts and contractions, particularly under the SSP5-8.5 scenario. Over 50% of sea turtle hotspots may disappear by 2050, with many new habitats in high shipping intensity areas. Alarmingly, only 23% of current hotspots are within MPAs, highlighting the need for adaptive conservation strategies.
Methane is a major greenhouse gas and a key component of global biogeochemical cycles. Microbial methane often deviates from isotope and isotopolog equilibrium in surface environments but approaches equilibrium in deep subsurface sediments. The origin of this near-equilibrium isotopic signature in methane, whether directly produced by methanogens or achieved through anaerobic oxidation of methane (AOM), remains uncertain. Here, we show that, in the absence of AOM, microbial methane produced from deep-sea sediments exhibits isotopolog compositions approaching thermodynamic equilibrium due to energy limitation. In contrast, microbial methane from salt marsh and thermokarst lakes exhibits significant hydrogen and clumped isotopic disequilibrium due to high free-energy availability. We propose that clumped isotopologs of methane provide a proxy for characterizing the bioenergetics of environments for methane production. Together, these observations demonstrate methane clumped isotopes as a powerful tool to better understand the relation between methane metabolisms and the energy landscape in natural environments.
The maritime migration to the South Ryukyu Islands of southwestern Japan, which occurred approximately 30,000 years ago, was one of the most difficult sea crossings accomplished by the Late PleistoceneHomo sapiens. This study performs numerical simulations to investigate the conditions that were needed to cross between Taiwan and Yonaguni Island, where one of the world’s strongest ocean currents, the Kuroshio, remains active. We combined simulations based on three ocean models with data from an actual experimental voyage conducted in 2019. The results showed that travel across this sea would have been possible on both the modern and Late Pleistocene oceans if a dugout canoe was used with a suitable departure place and paddling strategy. Recognizing the Kuroshio, paddling to counteract this current, and using high-level navigation were crucial to success. This suggests that the Paleolithic maritime expansion in the Western Pacific involved both advanced technologies and strategic challenges.
Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
Achieving accurate locating of perforating arteries (PAs) has great clinical value in various biomedical applications, such as free flap transfer. However, the anatomical variability of these arteries presents a major challenge in PA locating, and existing methods have various disadvantages, limiting their applications. Here, we propose a reusable and flexible hydrogel biosensor array for noninvasive, precise, and efficient PA locating. Particularly, we develop electrically responsive hydrogels to establish rapidly detachable device/hydrogel interfaces, endowing the reusability of the biosensor array. Meanwhile, the adhesion of hydrogel/skin interfaces is also enhanced to facilitate high-fidelity signal acquisition. By analyzing the photoplethysmography (PPG) infrared (IR) signals, the biosensor array can accurately and responsively locate PAs across different types of free flaps in clinical cases, outperforming existing techniques. This biosensor array represents a promising platform for PA locating. The strategy of hydrogel interface design paves the way for the development of reusable flexible electronics in biomedical applications to avoid cross-infection and reduce device costs.
Archeological evidence indicates that full-scale expansion ofHomo sapiensacross the oceans began about 50,000 years ago in the Western Pacific, yet how this was achieved remains unclear. The Ryukyu Islands in southwestern Japan, where archaeological sites suddenly appeared 35,000 to 30,000 years ago, are of particular interest in this regard because of the apparent difficulty in crossing the surrounding waters. In this study, we test if a non-sailing dugout canoe can be produced with Upper Paleolithic tools, and if it can cross the 110-kilometer-wide strait at the western entrance of the Ryukyus, where one of the world’s strongest ocean currents intervenes. Our 7.5-meter-long dugout, manufactured with edge-ground stone axes, was speedy and durable enough to cross this strait. This supports the early development of functional boats, such as dugouts, while our experiment also highlighted that this type of sea travel was possible only for experienced paddlers with advanced navigational skills.
Robot collectives offer a promising solution for complex assignments that are nearly impossible for individual robots to execute. In microscopic scenarios, organizing microrobot collectives is now governed by agent-agent physical interactions. However, the existing methods are insufficient to produce robust connections and fail to tolerate harsh environments. We propose a strategy to efficiently program microrobots into reconfigurable robust collectives to operate in various dynamic environments. Magnetic collectives are produced to achieve reconfigurable pattern transformation with considerable structural enhancement via well-designed gradient magnetic fields. The strong gradient magnetic field–induced connections among individual microrobots enable a record-breaking 700-fold output force enhancement, and 0.2-gram microrobot collectives generate Newton-level output forces. The proposed reconfigurable microrobot collectives provide a stable and promising approach to executing droplet, fluid, and solid manipulations via powerful output forces. These results may have implications for further understanding of self-assembly, particle systems, microrobot collectives, smart dust, and related microscopic multiagent behaviors.
The spontaneous emergence of tissue patterns is often attributed to biochemical reaction-diffusion systems. InHydratissue regeneration, the formation of a Wnt signaling center exemplifies this process. However, a strictly biochemical mechanism for self-organization inHydraremains elusive. In this study, we investigated mechanical stimuli and identified a positive feedback loop between Wnt signaling and tissue stretching. We developed a mathematical model of mechanochemical pattern formation in a closed elastic shell, representing regeneratingHydraepithelial spheroids. Our model explains how mechanical forces drive axis formation and predict the organizer’s location under various perturbations. Validation by partially confining regenerating tissues showed that the organizer forms in regions with the greatest stretching potential. This work highlights a versatile mechanochemical mechanism for luminal epithelium patterning, which is relevant across various biological systems.
Overfishing is one human-driven perturbation driving major evolutionary pressure on marine populations. Fishing is often highly selective for particular traits and elicits marked phenotypic changes, while the evolutionary basis of such trait change remains unresolved. Here, we used a unique time series of the overexploited Eastern Baltic cod (Gadus morhua) to investigate growth trends during 25 years of heavy fishing along with hypothesized genetic changes at the full genome level. A growth analysis demonstrated a 48% decrease in asymptotic body length from 1996 to 2019 while a genome-wide association analysis revealed outlier loci and gene candidates linked to growth performance. The contributing loci showed signals of directional selection with high autocovariance of allele frequency change and significant overlap with regions of high genetic differentiation. Our findings suggest a genomic basis of fisheries-driven growth impairment and underscore implications for conservation policy regarding the adaptive potential of marine populations.
Detecting photon echoes from superconducting Higgs modes is challenging due to the necessity of preserving and retrieving phase coherence encoded in multiple Higgs and quasiparticle (QP) excitations. Here, we demonstrate the emergence of a Higgs echo in niobium superconductors. This approach disentangles unique quantum pathways involving the Higgs mode and QP excitations. Using Higgs echo spectroscopy, we also uncover unconventional echo formation caused by inhomogeneous broadening and “soft” QP bands, which dynamically evolve under terahertz (THz) driving. Specifically, THz pulse pairs modulate the superconducting gap, imprinting coherence and forming a temporal “Higgs grating.” This grating produces echoes with distinctive characteristics: (i) echo rephasing spectral peaks at superconducting gap frequencies, (ii) asymmetric echo formation delays unlike those observed in atoms or semiconductors, and (iii) negative-time echo signals stemming from Higgs-QP anharmonic interactions. Combined with advanced time-frequency analysis, these findings distinguish Higgs from QP responses and clarify their intricate interactions in THz-driven superconductivity.
Endothermy has independently evolved in several vertebrate lineages but remains rare among fishes. Using an integrated approach combining phylogenomic and ecomorphological data for 1051 ray-finned fishes, a time-dependent evolutionary model, and comparative genomic analyses of 205 marine vertebrates, we show that ecological interactions with modern cetaceans coincided with the evolution of endothermy in ray-finned fishes during the Eocene-Miocene. This result is supported by evidence of temporal and geographical overlap between cetaceans and endothermic fish lineages in the fossil record, as well as correlations between cetacean diversification and the origin of endothermy in fishes. Phylogenetic comparative analyses identified correlations between endothermy, large body sizes, and specialized swimming modes while challenging diet specialization and depth range expansion hypotheses. Comparative genomic analyses identified several genes under selection in endothermic lineages, includingcarnmt1(involved in fatty acid metabolism) anddcaf6(associated with development). Our findings advance the understanding of how ecological interactions and genomic factors shape key adaptations.
Adapting to change is a fundamental feature of human learning, yet its developmental origins remain elusive. We developed an experimental and computational approach to track infants’ adaptive learning processes via pupil size, an indicator of tonic and phasic noradrenergic activity. We found that 8-month-old infants’ tonic pupil size mirrored trial-by-trial fluctuations in environmental volatility, while phasic pupil responses revealed that infants used this information to dynamically optimize their learning. This adaptive strategy resulted in successful task performance, as evidenced by anticipatory looking toward correct target locations. The ability to estimate volatility varied significantly across infants, and these individual differences were related to infant temperament, indicating early links between cognitive adaptation and emotional responsivity. These findings demonstrate that infants actively adapt to environmental change, and that early differences in this capacity may have profound implications for long-term cognitive and psychosocial development.
Rice was a staple crop in the ancestral Austronesian regions of Taiwan and Island Southeast Asia, but it was unknown in any of the Pacific Islands at the time of European encounters, with the exception of the unique case of Guam and the Mariana Islands. Through multiple methodologies, including phytolith analysis, micro–computed tomography scanning, and thin-section petrography, this recent research confirms the presence of abundant rice husk and leaf phytoliths adhering to red-slipped pottery (“Marianas Red”) at the Ritidian Site Complex in Guam, dated by radiocarbon to 3500 to 3100 years ago. This study addresses the long-standing question of whether the first Pacific Islanders transported rice with them from the Philippines across 2300 kilometers of open sea, representing the longest known ocean voyage of the time. During this early period, rice was restricted to special ritual events in the Marianas. The early voyage apparently was planned with provisions of rice at 3500 years ago.
In every menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an inflammatory decidual reaction, rendering it poised for embryo implantation and transformation into the decidua of pregnancy. Here, we show that the sequential functions of the decidual reaction—implantation and decidualization—pivot on the time-sensitive loss of progesterone-resistantDIO2+stromal cells that form a specialized implantation niche and reciprocal expansion of progesterone-dependentPLA2G2A+predecidual cells. Simultaneously, uterine natural killer (uNK) cell proliferation results in the accumulation of immunotolerant subsets. Examination of endometrial biopsies from 924 women revealed that the recurrence risk of miscarriage closely aligns with the incidence of a weakened or stalled decidual reaction, more so than poor uNK cell expansion. Analysis of paired biopsies obtained in different cycles and modeling in assembloids intimated that prior miscarriages disrupt intercycle endometrial homeostasis and calibration of the decidual reaction. Our findings show that erosion of the decidual reaction following a miscarriage drives the recurrence risk irrespective of maternal age.
Sea level change is an important forcing on lowland fluvial systems. Although its impact is suggested to extend up to hundreds of kilometers inland, this impact is often considered confined to deltaic regions. We present luminescence dating of cores from the Jianghan Plain in the middle Yangtze River that demonstrates the influence of the last glacially driven sea level fall extended over 1000-kilometers inland. Luminescence ages reveal a common sedimentary hiatus from ~26 to ~17 thousand years ago (ka), reflecting fluvial incision of >35 meters triggered by sea level fall. Subsequent rapid aggradation occurred within these incised valleys during deglaciation between ~17 and ~9 ka and then slowed down afterward. A further synthesis on global continental rivers shows that sea level change affects large, low-gradient lowland fluvial systems farther upstream than generally recognized, with postperturbation geomorphologic equilibrium reachable in timescales comparable to the length of Quaternary glacial cycles.
The dorsal raphe nucleus (DRN) is an important source of serotonin in the brain, but fundamental aspects of its function remain elusive. Here, we present a combination of minimally invasive recording and disruption studies to show that DRN brings about changes in motivation states. We use recently developed methods for identifying temporal patterns in behavior to show that monkeys change their motivation depending on the availability of rewards in the environment. Distinctive patterns of DRN activity occur when monkeys transition between a high-motivation state occupied when rewards are abundant, to a low-motivation state engendered by reward scarcity. Disrupting DRN diminishes sensitivity to the reward environment and perturbs transitions in motivational states.
Movement of pedestrian crowds is ubiquitous in human society. However, it is unclear what dynamical regimes pedestrian crowds can exhibit at different crowd densities, how pedestrians move in these different dynamical regimes, and in which dynamical regime the movement synchronization of pedestrians is most likely to occur. Here, we conducted a unidirectional crowd movement experiment, in which we tracked the movement of pedestrian crowds through foot tracking. We find experimentally that pedestrian crowds can exhibit three distinct dynamical regimes (free regime, slow-moving regime, and jammed regime) depending on the crowd density. In the free regime, pedestrians’ movement is not constrained; in the slow-moving regime, pedestrians’ speed is constrained, but pedestrians’ movement direction in each step is not influenced; and in the jammed regime, both pedestrians’ speed and movement direction in each step are constrained. We also demonstrate that pedestrians are most likely to synchronize their movements spontaneously at the onset of jamming. Our findings provide important insights into crowd dynamics.
Cerebrospinal fluid (CSF) contains inflammatory cues that enable peripheral immune surveillance of the central nervous system (CNS). While some cranial nerves allow for CSF efflux, the immune environment around CSF-interfacing cranial nerves during neuroinflammation is still poorly understood. Using a mouse model of multiple sclerosis [experimental autoimmune encephalomyelitis (EAE)] and CNSMycobacterium tuberculosisinfection (CNS-Mtb), we examined immune responses around olfactory nerve bundles near the cribriform plate, a key CSF efflux route. During neuroinflammation, we found increased perineural immune cells that had access to intracranial injected beads, dye, and bacteria. Additionally, we identified osseous channels connecting the environment surrounding olfactory nerves to bone marrow in the cribriform plate (cpBM). Notably, the cpBM undergoes myelopoiesis during EAE, has access to components of intracranial drainage, and is vulnerable to Mtb bacteria invasion during CNS-Mtb infection. Our findings improve the understanding of how the environments of CSF-interfacing cranial nerves and bone marrow are altered within the skull during neuroinflammatory disease.
Emerging artificial intelligence for science (AI-for-Science) algorithms, such as the Fourier neural operator (FNO), enabled fast and efficient scientific simulation. However, extensive data transfers and intensive high-precision computing are necessary for network training, which challenges conventional digital computing platforms. Here, we demonstrated the potential of a heterogeneous computing-in-memristor (CIM) system to accelerate the FNO for scientific modeling tasks. Our system contains eight four-kilobit memristor chips with embedded floating-point computing workflows and a heterogeneous training scheme, representing a heterogeneous CIM platform that leverages precision-limited analog devices to accelerate floating-point neural network training. We demonstrate the capabilities of this system by solving the one-dimensional Burgers’ equation and modeling the three-dimensional thermal conduction phenomenon. An expected nearly 116 times to 21 times increase in computational energy efficiency was achieved, with solution precision comparable to those of digital processors. Our results extend in-memristor computing applicability beyond edge neural networks and facilitate construction of future AI-for-Science computing platforms.
Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca2+channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human CaV1.3A749Gmutation that causes low-voltage Ca2+channel activation. We demonstrate activation of Ca2+influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of CaV1.3A749G/A749Gmice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca2+channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of CaV1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.
Electrochemical carbon dioxide (CO2) capture and utilization, powered by renewable energy, are essential to achieving net-zero emissions and CO2valorization. While remarkable progress has been made in catalysts, solution design, and system engineering, recent breakthroughs reveal that nitrogen-containing molecules—specifically sp2-hybridized structures (e.g., pyridine) and sp3-hybridized moieties (e.g., ethanolamine) —hold untapped potential to revolutionize both CO2capture and conversion. These structures have been demonstrated as the Holy Grail in facilitating CO2activation, stabilizing key intermediates, and streamlining reaction pathways—capabilities rarely achievable with conventional strategies. However, limited mechanistic understanding of their physicochemical properties and interactions with CO2hampers broader application. This review highlights recent advances in leveraging sp2/sp3-hybridized nitrogen structures, unpacks their molecular roles in electrochemical CO2management, and offers a unifying framework for their dual-functionality across capture and conversion. By illuminating these nitrogen-based motifs, we uncover practical design principles and open avenues for integrating expanded N-containing compounds into energy technologies—paving the way for next-generation carbon management strategies.
Northern African climate is characterized by strongly contrasting wet summers and dry winters. Dust exported by the northeasterly trade (Harmattan) winds creates marine sedimentary records that have been long interpreted to show that northern African climate became drier and more variable across the Pliocene-Pleistocene boundary [2.58 million years ago (Ma)], when global climate cooled and high-latitude glacial-interglacial cycles intensified. However, questions about the impact of summer rainfall on winter dust fluxes and thus the history of the African summer monsoons remain. We present a leaf wax hydrogen isotope record from offshore northwestern Africa that demonstrates that rainfall regimes remained stable and varied solely in response to 21,000-year cycles in summer insolation from 3.5 to 2.5 Ma. We infer that the summer rains and winter winds respond to different climate forcings, with summer rainfall driven by solar radiation over the northern African landmass and the winter trades affected by high-latitude climate and meridional temperature gradients.
Sustaining the growth of the data volume generated by artificial intelligence and the internet of things demands to develop schemes for data storage and processing operating at terahertz frequencies, unrestrained by thermal throttling. The optical drive of coherent magnetic collective excitations, namely magnons, represents a promising route. The ability to arbitrarily and nonthermally increase the magnon frequencies with laser pulses could enable this progress. However, this effect has not been reported to date. To achieve it, here, we explore the optical resonant excitation of high-momentum magnons, which experimentally are observed to couple to low-momentum magnons, modifying the frequencies and amplitudes thereof. This evidence, not caused by laser heating, is explained with a resonant light-scattering mechanism coupling high- and low-momentum eigenmodes across momentum space. Our results disclose routes to inducing instabilities and phase transitions via mode softening and potentially even light-driven Bose-Einstein condensation of magnons and superconductivity mediated by high-momentum spin-fluctuations.
Hexagonal boron nitride (h-BN) has emerged as a promising platform for generating room temperature single photons exhibiting high brightness and spin-photon entanglement. However, improving emitter purity, stability, and scalability remains a challenge for quantum technologies. Here, we demonstrate highly pure and stable single-photon emitters (SPEs) in h-BN by directly growing carbon-doped, centimeter-scale h-BN thin films using the pulsed laser deposition (PLD) method. These SPEs exhibit room temperature operation with polarized emission, achieving ag(2)(0) value of 0.015, which is among the lowest reported for room temperature SPEs and the lowest achieved for h-BN SPEs. It also exhibits high brightness (~0.5 million counts per second), remarkable stability during continuous operation (>15 min), and a Debye-Waller factor of 45%. First-principles calculations reveal unique carbon defects responsible for these properties, enabled by PLD’s low-temperature synthesis and in situ doping. Our results demonstrate an effective method for large-scale production of high-purity, stable SPEs in h-BN, enabling robust quantum optical sources for various quantum applications.
Phytophagous mites, includingTetranychus cinnabarinus, are arthropods known for their wide infestation of host plants and pesticide resistance. We found that fenpropathrin-resistant female mites (YN-FeR, with target resistance: F1538Ikdrmutation) exhibited significantly enhanced adaptability to various stress conditions, including exposure to different acaricides and high-temperature (34°C) and low-humidity environments (40% relative humidity). This evolution was attributed to cuticle thickening in resistant female mites. Cuticle proteinCPR25was identified as a critical gene mediating cuticle thickening.CPR25regulated its own overexpression by producing a circular RNA, namedcircCPR25, which acted as a decoy to selectively sequester and bind to the miR-34~317 cluster. This study revealed a distinctive mechanism underlying the evolution of stress resistance in spider mites. Specifically, a cuticle protein in spider mites regulates its own overexpression by producing a decoy circRNA, thereby promoting cuticle thickening and facilitating rapid adaptation to adverse conditions.
The health sciences largely focus on disease. However, the interconnected determinants of diseases suggest that we need a science of health, a framework to examine the biology of homeodynamics in a changing environment and how this affects the health we value. We build on first principles and recent discoveries on biological system dynamics to develop the concept of intrinsic health, a field-like state emerging from the dynamic interplay of energy, communication, and structure within the organism, giving rise to robustness/resilience, plasticity, performance, and sustainability. Intrinsic health is a quantifiable property of individuals that declines with age and interacts with context. We propose a measurement framework and describe how it will contribute to achieving the shared goals of medicine and public health.
Calcium carbonate dissolution is the dominant negative feedback in the ocean for neutralizing the acidity from rising atmospheric carbon dioxide. Mimicking this natural process, the accelerated weathering of limestone (AWL) can store carbon as bicarbonate in the ocean for tens of thousands of years. Here, we evaluate the potential of AWL on ships as a carbon sequestration approach. We show a successful prediction of laboratory measurements using a model that includes the most recent calcite dissolution kinetics in seawater. When simulated along a Pacific shipping lane in the Estimating the Circulation and Climate of the Ocean–Darwin ocean–general circulation model, surface alkalinity and dissolved inorganic carbon increase by <1.4% after 10 years of continuous operation, leaving a small pH and partial pressure of carbon dioxide impact to the ocean while reducing 50% carbon dioxide emission in maritime transportation.
We present a strategy to achieve absolute asymmetric catalysis that is effectively controlled by an external magnetic field via a spin-exchange reaction leveraging the chirality-induced spin selectivity effect. Using an external magnetic field to achieve asymmetric synthesis has long been desired. Here, we demonstrate 90% enantiomeric excess (ee) in [3 + 2] cycloadditions and 89% ee in aldol reactions, where the handedness of the product is determined by the ~±150 mT external magnetic polarization of a ferromagnet (FM). Our approach uses an enantioselective crystallization of racemic catalysts on a FM surface, using a small-scale crystallization vial connected to a bulk racemic solution. Racemic catalysts controllably crystallize into their respective enantiopure forms and are directly used in asymmetric reactions. Thus, we demonstrate that an external magnetic field can serve as a versatile symmetry-breaking tool to achieve highly enantioselective organic synthesis eliminating the need of any enantioenriched reagents.
Diaplectic glass and maskelynite in shocked plagioclase serve as key diagnostic features for high level of shock metamorphism in impact craters and meteorites. However, their formation mechanisms remain unclear and have long been argued, mainly due to the lack of phase diagram for plagioclase with extended pressure-temperature conditions. We report the stabilities of labradorite and anorthite at pressure up to 65 gigapascals and temperature up to 4000 kelvin. Our experimental results reveal the pressure-temperature conditions for amorphization, decomposition, and melting of labradorite and anorthite. The boundary between amorphous plagioclase and crystalline high-pressure phases in our phase diagram indicate diaplectic glass can form at 1300 to 1500 kelvin, and the melting line suggests that maskelynite can be generated above 3000 kelvin at high pressures. Formation conditions of diaplectic glass and maskelynite in plagioclase-bearing rocks are also suggested by the combination of phase diagram and shock Hugoniot data. These findings will advance our understanding of the bombardment history on rocky planetary surfaces.
Protein and peptide aggregation poses substantial challenges in disease pathology and therapeutic development. While natural glycosylation may mitigate aggregation, its efficacy and underlying mechanisms remain poorly understood due to limited access to homogeneous samples with complex glycans. This study addresses these knowledge gaps by investigating the natural glycosylation of islet amyloid polypeptide (IAPP), a peptide with therapeutic potential for type 2 diabetes but problematic aggregation. An optimized chemical synthesis enabled preparation of diverse IAPP glycoforms with complex glycan structures, allowing systematic evaluation of their effects on aggregation, cytotoxicity, and solubility. Sialylated glycans at Thr30completely inhibited IAPP aggregation, eliminated cytotoxicity toward pancreatic β cells, and enhanced solubility by up to 280-fold. Replica exchange molecular dynamics simulations revealed that glycosylation impedes adoption of a four-stranded β-sheet conformation in IAPP dimers. These findings advance the understanding of the role of natural glycosylation in aggregation and highlight its potential as an evolutionarily inspired strategy to enhance the therapeutic utility of IAPP.
Valley Hall photonic crystals (VPCs) offer the potential for creating topological waveguides capable of guiding light through sharp bends on a chip, enabling seamless integration with functional components in compact spaces, making them a promising technology for terahertz topological photonic integrated circuits. However, a key limitation for terahertz-scale integrated VPC-based devices has been the absence of arbitrary bend interconnects, as traditional VPC-designs restricted to principal lattice axes (i.e., only 0°, 60°, or 120°) due to crystalline symmetry. Here, we present an on-chip, all-silicon implementation of deformed VPCs that enable robust transmission along arbitrary shapes and bends. Although the lattice is amorphous and lacks long-range periodicity, the topological protection is sustained by short-range order. Furthermore, we show an amorphous lattice functioning as a frequency-dependent router, splitting input signals into two perpendicular output ports. We also demonstrate on-chip terahertz communication, achieving data rates of up to 72 Gbps. Our findings show that amorphous topological photonic crystals enhance interconnect adaptability while preserving performance.
Colletotrichumfungi cause destructive diseases among a wide range of hosts worldwide. We found that effector CfEC92 fromC. fructicolaspecifically binds ATP through an unidentified ATP-binding domain, leading to changes in the protein secondary structure. The residues Cys26, Asn38, and Cys39were critical for ATP binding with CfEC92, and mutations at these sites impaired the ability to suppress host immunity. CfEC92 interacted with MdNDPK2, a negative immune regulator in apple. The CfEC92-ATP complex altered the conformation of MdNDPK2, enhancing its affinity for ATP, and further increasing its autophosphorylation and kinase activity. The activated MdNDPK2 phosphorylated MdMPK3 to suppress host immunity. Homology and functional tests showed that the Cx11NC motif was highly conserved amongColletotrichumspecies, suggesting that CNC effectors represent a class of broad-spectrum virulence factors. Our findings revealed a mechanism by whichColletotrichumeffectors cooperate with helper ATP to promote target protein phosphorylation and suppress host immunity.
Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments.
Protein sequence similarity search is fundamental to biology research, but current methods are typically not able to consider crucial genomic context information indicative of protein function, especially in microbial systems. Here, we present Gaia (Genomic AI Annotator), a sequence annotation platform that enables rapid, context-aware protein sequence search across genomic datasets. Gaia leverages gLM2, a mixed-modality genomic language model trained on both amino acid sequences and their genomic neighborhoods to generate embeddings that integrate sequence-structure-context information. This approach allows for the identification of functionally and/or evolutionarily related genes that are found in conserved genomic contexts, which may be missed by traditional sequence- or structure-based search alone. Gaia enables real-time search of a curated database comprising more than 85 million protein clusters from 131,744 microbial genomes. We compare the homolog retrieval performance of Gaia search against other embedding and alignment-based approaches. We provide Gaia as a web-based, freely available tool.
Microbes use signaling molecules to regulate multiple physiological processes and mediate chemical interactions. Decoding these chemical languages is instrumental in comprehending microbial regulatory mechanisms within complex microbiota. Here, we discover previously unidentified autoinducing peptides (AIPs) derived from the plant probiotic bacteriumPaenibacillus polymyxa, identified as Pp-AIPs. Omics analyses coupled with genetic manipulations revealed that Pp-AIP1 could effectively modulate the production of multiple antimicrobial secondary metabolites at nanomolar concentration, expanding known AIP functions. Furthermore, through inoculatingP. polymyxain the natural rhizosphere microbiome and analyzing its antagonistic interactions against root microbes, we suggest that Pp-AIPs may influence the microbial community composition through modulating the antimicrobial spectrum. Global analysis of biosynthetic gene clusters (BGCs) reveal widespread co-occurrence of uncharacterized AIPs with secondary metabolite BGCs. This study underscores the unreported roles of AIPs in antibiotic regulation and the microbiome interactions, advancing knowledge of quorum-sensing mechanisms in microbial ecosystems.
We propose a general principle for the formation of topological structures in ferroelectrics, demonstrating that the fundamental formation mechanism of ferroelectric vortex is the superposition of two orthogonal dipole waves, which has also been validated by the mathematical deduction, phase-field simulations, and angle-resolved piezoelectric force microscopy. Moreover, it is demonstrated that this principle can also be extended to a range of nontrivial topological structures, including Ising, Néel, and Bloch domain walls, merons, skyrmions, Hopf rings, Solomon rings, and others. These findings not only improve our understanding of the fundamental formation mechanism of existing topological structures but also enable the prediction of topological structures, such as Star of David rings, in ferroelectric/ferromagnetic materials, liquid crystals, and Bose-Einstein condensate states (superconductors and superfluids).
Cell behavior emerges from the intracellular distribution of properties such as protrusion, contractility, and adhesion. Thus, characteristic emergent rules of collective migration can arise from cell-cell contacts locally tweaking architecture, orchestrating self-regulation during development, wound healing, and cancer progression. TheDrosophilatestis-nascent-myotube system allows dissection of contact-dependent migration in vivo at high resolution. Here, we describe a role for the axon guidance factor Plexin A in collective cell migration: maintaining cell-cell interfaces at a precise point on the mesenchymal-to-epithelial continuum. This is crucial for testis myotubes to migrate as a continuous sheet, allowing normal sculpting-morphogenesis. Cells must maintain filopodial N-cadherin–based junctions and remain ECM-tethered near cell-cell contacts to spread while collectively moving. Our data further suggest Semaphorin 1b is a Plexin A antagonist, fine-tuning activation. This reveals a contact-dependent mechanism to maintain sheet integrity during migration, driving organ morphogenesis. This is relevant for mesenchymal organ sculpting in other migratory contexts such as angiogenesis.
Linkage drag can hinder the integration of resistance genes from wild crop relatives into breeding programs. We used a chromosome-scaleNicotiana alatagenome assembly and a segregating population exceeding 160,000 plants to dissect the complex genetic architecture and overcome the tight linkage between resistance and deleterious loci to produce plants free from linkage drag. We clonedN. alata RTSW, encoding an immune receptor that confers broad-spectrum resistance to orthotospoviruses through the interaction of its carboxyl-terminal domain with an orthotospovirus-encoded protein. Notably, despite recognizing the same avirulence factor,RTSWgenes fromN. alataandSw-5bfromSolanum peruvianumhave evolved independently of adjacent nonorthologous ancestral loci. Our work illustrates the potential of wild relative genomes as resources from which to precisely introduce disease resistance into cultivated crops.
Intracellular parasites, includingBabesiaandPlasmodium, the agents of human babesiosis and malaria, depend on the salvage or de novo synthesis of critical nutrients for survival within human erythrocytes. Among these, polyamines play a pivotal role, but their specific requirements and molecular functions in intraerythrocytic parasites remain poorly understood. We identify spermidine as a key polyamine forBabesia duncaniandPlasmodium falciparumfor intraerythrocytic development. We demonstrate that spermidine is indispensable for regulating protein translation through hypusination of the eukaryotic translation initiation factor eIF5A, and its depletion leads to increased production of reactive oxygen species. Disruption of spermidine biosynthesis or its conversion from spermine results in parasite death. We also show thatB. duncaniand otherBabesiaspecies use an ancestral spermidine synthase–like enzyme, highlighting a distinct evolutionary adaptation fromP. falciparum. Our results reveal the spermidine’s dual role in oxidative stress defense and translation regulation, positioning spermidine biosynthesis as a critical vulnerability and a promising therapeutic target.
The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson’s disease (PD), contributes to dopaminergic cell death. Injection of PD patient–derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable α-syn pathology. We demonstrate that distinct assemblies of α-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.
Emulating complex neural computations like solving linearly inseparable tasks within single artificial neurons has remained an elusive goal in neuromorphic engineering. Here, we report a dendritic organic electrochemical neuron (d-OECN) capable of achieving anticoincidence detection by classifying the exclusive-OR (XOR) problem—a quintessential linearly inseparable task—within an individual neuron. Inspired by human cortical neurons that perform XOR through dendritic calcium spikes, the d-OECN leverages ion-tunable antiambipolarity in mixed ionic-electronic conducting polymers to mimic voltage-gated dendritic calcium dynamics. By integrating this dendritic component with a tunable spiking circuit representing the soma, the d-OECN achieves XOR classification through its inherent nonlinear activation profile, with decision boundaries that are both ionically and electrically tunable. Moreover, we demonstrate the d-OECN’s ability to perform edge detection using XOR in a tactile sensing system, showcasing its potential for event-based sensing and processing. The d-OECNs, replicating key aspects of biological intelligence, pave the way for next-generation bioelectronics and robotics requiring complex neural computation.
A universal quantum computer can simulate diverse quantum systems, with electronic structure for chemistry offering challenging problems for practical use cases around the hundred-qubit mark. Although current quantum processors have reached this size, deep circuits and a large number of measurements lead to prohibitive runtimes for quantum computers in isolation. Here, we demonstrate the use of classical distributed computing to offload all but an intrinsically quantum component of a workflow for electronic structure simulations. Using a Heron superconducting processor and the supercomputer Fugaku, we simulate the ground-state dissociation of N2and the ground state properties of [2Fe-2S] and [4Fe-4S] clusters, with circuits up to 77 qubits and 10,570 gates. The proposed algorithm processes quantum samples to produce upper bounds for the ground-state energy and sparse approximations to the ground-state wave functions. Our results suggest that, for current error rates, a quantum-centric supercomputing architecture can tackle challenging chemistry problems beyond sizes amenable to exact diagonalization.
Imagine being able to study the human brain in real-world scenarios while the subject displays natural behaviors such as locomotion, social interaction, or spatial navigation. The advent of ultrafast ultrasound imaging brings us closer to this goal with functional ultrasound imaging (fUSi), a mobile neuroimaging technique. Here, we present real-time fUSi monitoring of brain activity during walking in a subject with a clinically approved sonolucent skull implant. Our approach uses personalized 3D-printed fUSi helmets for stability, optical tracking for cross-modal validation with functional magnetic resonance imaging, advanced signal processing to estimate hemodynamic responses, and facial tracking of a lick licking paradigm. These combined efforts allowed us to show consistent fUSi signals over 20 months, even during high motion activities such as walking. These results demonstrate the feasibility of fUSi for monitoring brain activity in real-world contexts, marking an important milestone for fUSi-based insights in clinical and neuroscientific research.
We report evidence that organic aerosols containing carboxylic acids can be spontaneously oxidized in the dark under normal atmospheric conditions due to interfacial hydroxyl radical production. Product formation is negligible under dry conditions and increases with increasing relative humidity. In a dioxygen-free environment, the oxidation efficiency is substantially decreased. Size-resolved measurements show an increase in the reactivity and product formation yields for smaller particles, correlated with their surface-to-volume ratio. Our findings suggest that spontaneous hydroxyl radical production at the air-water interface of organic nanodroplets may be an important pathway in their oxidation, especially during nighttime.
Endovascular interventions require fast access to affected regions, followed by effective treatment. Catheterizations are effective approaches for treating vascular diseases; however, they face challenges in accessibility, efficiency, and invasiveness in narrow, tortuous vascular systems. This study presents a submillimeter magnetically actuated soft rotatable-tipped microcatheter (MSRM) designed to access small blood vessels and provide efficient, minimally invasive therapeutic interventions for blood clot treatment. The MSRM’s rotatable tip design enhances accessibility and navigation speed through a rotation-assisted active steering strategy. Improved blood clot treatment efficiency is achieved through the MSRM’s multifunctionality: It can accelerate drug-blood clot interactions, mechanically break down blood clots, and retrieve clot debris. The low invasiveness is attributed to the soft material design and conservative actuation strategy. The performance of the MSRM is validated in both in vitro phantom studies and in vivo rabbit models, and the invasiveness is evaluated using a human placenta model.
The increasing clinical trials of single-stranded mRNA (ss-mRNA) therapeutics highlight the urgent need to develop efficient, scalable, and economic purification methods. Current diffusion-driven, resin-based purification techniques constrain productivity and rely on expensive oligo(dT) ligands for target ss-mRNA poly(A) tail hybridization. To overcome these challenges, we use interfacial molecular forces, such as charge and hydrogen bonds, between nucleic acid variants and a positively charged synthetic microporous membrane to purify ss-mRNA, a desirable therapeutic, from an undesirable impurity, immunogenic double-stranded RNA (dsRNA). Membranes achieved high binding capacities (1.28 mg/m2) and up to 100% ss-mRNA recovery at ~pH 9.0, with optimized surface density (4000 to 10,000 nmol/m2). Purification was operated at rapid flow rates (1.5 ml/min,1000 MV/min) with reusability (>10 trials) and negligible ligand leaching. The key discovery of this cost-effective ligand-less multimodal surface-modified approach is that the addition of the polyamine spermine, which selectively neutralizes dsRNA charge at amine-to-phosphate ratios >450, enhanced separation efficiency.
As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the health care system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenicEscherichia coli(UPEC), whereasKlebsiella pneumoniaecauses a large portion of non-UPEC UTIs. Both bacteria express type 1 pili tipped with the mannose-binding FimH adhesin critical for UTI pathogenesis. We generated and biochemically characterized 33 murine monoclonal antibodies (mAbs) to FimH. Three mAbs protected mice fromE. coliUTI. Mechanistically, we show that this protection is Fc independent and mediated by the ability of these mAbs to sterically block FimH function by recognizing a high-affinity FimH conformation. Our data reveal that FimH mAbs hold promise as an antibiotic-sparing treatment strategy.
Materials with circumferentially aligned fibers, such as intervertebral discs and arteries, are abundant in nature but challenging to replicate artificially, despite their mechanical advantages. Although ice-templating can create bioinspired materials, the achievable structures remain limited to simple forms, such as honeycomb, lamellar, and radial structures. Here, we developed a unique ice-templating technique that constructs circumferential fibrous structures in hydrogels through slow freezing. Enhanced with rotary compression annealing, these hydrogels exhibit record-breaking features that cannot concurrently be achieved in conventional ice-templated and top-performing tough hydrogels, including high tensile properties, isotropic fatigue threshold of 2320 joules per square meter, ultracompressibility (8% strain after 500 cycles), and extraordinary burst pressure of 1.6 bar while maintaining 85 weight % water content. These properties enable opportunities in robotics, including hydrogel pneumatic grippers and an untethered bioinspired robotic fish that exhibits high-force actuation and long-term robustness. Our approach enriches the diversity of bioinspired structures in artificial materials, establishing exceptional mechanical properties through cross-length scale structural design.
Pain hypersensitivity is associated with increased activity of peripheral and central neurons along the pain neuroaxis. We show that at the peak of acute inflammatory pain, superficial medullary dorsal horn projection neurons (PNs) that relay nociceptive information to the parabrachial nucleus reduce their intrinsic excitability and, consequently, action potential firing. When pain resolves, the excitability of these neurons returns to baseline. Using electrophysiological and computational approaches, we found that an increase in potassium A-current (IA) underlies the decrease in the excitability of medullary dorsal horn PNs in acute pain conditions. In chronic pain conditions, no changes ofIAwere observed, and medullary dorsal horn PNs exhibit increased intrinsic excitability and firing. Our results reveal a differential modulation of the excitability of medullary dorsal horn projection neurons in acute and chronic pain conditions, suggesting a regulatory mechanism that, in acute pain conditions, tunes the output of the dorsal horn and, if lacking, could facilitate pain chronification.
Discovery of human footprints in alluvium dated to the Last Glacial Maximum (LGM) at White Sands, New Mexico, was a notable step in understanding the initial peopling of the Americas, but that work was met with criticism focused on the reliability of the materials used in the radiocarbon dating (seeds ofRuppiaand pollen). This paper reports on an independent study of the chronology of a previously unrecognized stratigraphic record of paleolake Otero that is directly traceable into the track-bearing alluvium. The stratigraphic data along with 26 additional radiocarbon dates on palustrine mud determined by two labs independent of the original investigations document an aggrading lake/wetland/stream record that includes the tracks and spans >23.6 thousand years to ~17.0 thousand calibrated years before present, providing another line of evidence further supporting the validity of an LGM age for the tracks.
Single-walled carbon nanotubes, as prototypical one-dimensional systems, have been extensively studied for their extreme confinement effects and the formation of strongly bound excitons. However, their high surface-to-volume ratio renders their dynamics highly susceptible to variations in the surrounding environment. Yet, visualizing photoinduced dynamics within individual nanotubes has remained a major challenge because of the lack of methods combining sufficient spatial and temporal resolution with sensitivity to an exceedingly small number of electron-hole pairs. Here, we apply ultrafast infrared nanospectroscopic imaging to probe local electron-hole dynamics in both isolated and bundled carbon nanotubes grown by chemical vapor deposition. This approach unravels heterogeneity in electron-hole pair creation and annihilation, arising from disordered stress within a tube and/or interactions with neighboring tubes. The capability to visualize local electron-hole dynamics in real time and space is essential for advancing carbon nanotubes as fundamental building blocks in nanophotonic and optoelectronic devices.
Predation is a major evolutionary driver of life history and morphology. However, whether these traits evolve directly via predation or indirect effects is largely unresolved. We used artificial selection to experimentally test the impact of adult predation on the evolution of life history and morphology in guppies (Poecilia reticulata). We found that, compared to control fish, predation-selected fish produced larger offspring and larger broods early in life. However, other life history parameters, such as interbrood interval and total number of offspring, showed no response. We also found that predation selected for smaller and lighter females and for shorter tails and gonopodia in males, with no effect on body coloration. Our results show that while several traits evolve fast under selection on adult predation, several “classic” predation-dependent traits seem unaffected by predation selection. By comparing our experimental results to those from natural populations, we can disentangle the contribution of direct and indirect effects on trait evolution under predation pressure.
Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations inStk11(which encodes LKB1) display signatures of pathogenic IL-17–producing CD4+T helper 17 (TH17) cells. LKB1 constrains T cell inflammatory potential, asStk11/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17–producing T cell lineages (CD4+TH17 and CD8+Tc17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)–dependent signaling drives pathogenic TH17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17–dependent) T cell responses and identify a CRTC2–IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.
Glutamine reprogramming plays a crucial role in the growth and survival of clear cell renal cell carcinoma (ccRCC), although the mechanisms governing its regulation are still not fully understood. We demonstrate that the RNA demethylase fat mass and obesity-associated gene (FTO) drives glutamine reprogramming to support ccRCC growth and survival. Genetic and pharmacologic inhibition of FTO in ccRCC cells impaired glutamine-derived reductive carboxylation, depleted pyrimidines, and increased reactive oxygen species. This led to increased DNA damage and reduced survival, which could be rescued by pyrimidine nucleobases or the antioxidantN-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter solute carrier family 1 member 5 (SLC1A5) messenger RNA to promote its expression. Restoration of SLC1A5 expression in FTO-knockdown cells rescued metabolic and survival defects. FTO inhibition reduced ccRCC tumor xenograft and PDX growth under the renal capsule. Our findings indicate that FTO is an epitranscriptomic regulator of ccRCC glutamine reprogramming and highlight the therapeutic potential of targeting FTO for the treatment of ccRCC.
HIV-1 uses the microtubule cytoskeleton to reach the host cell nucleus during replication, yet the molecular basis for microtubule-dependent HIV-1 motility is poorly understood. Using in vitro reconstitution biochemistry and single-molecule imaging, we found that HIV-1 binds to the retrograde microtubule-associated motor, dynein, directly and not via a cargo adaptor, as has been previously suggested. The HIV-1 capsid lattice binds to accessory chains on dynein’s tail domain. Further, we demonstrate that multiple dynein motors tethered to rigid cargoes, such as HIV-1 capsids, display reduced motility, distinct from the behavior of multiple motors on membranous cargoes. Our results provide an updated model of HIV-1 trafficking wherein HIV-1 binds to dynein directly to “hijack” the dynein transport machinery for microtubule motility.
Paxillin (PXN) and focal adhesion kinase (FAK) are two major components of the focal adhesion complex, a multiprotein structure linking the intracellular cytoskeleton to the cell exterior. The interaction between the disordered amino-terminal domain of PXN and the carboxyl-terminal targeting domain of FAK (FAT) is necessary and sufficient for localizing FAK to focal adhesions. Furthermore, PXN serves as a platform for recruiting other proteins that together control the dynamic changes needed for cell migration and survival. Here, we show that the PXN N-domain undergoes significant compaction upon FAT binding, forming a 48-kilodalton multimodal complex with four major interconverting states. Although the complex is flexible, each state has unique sets of contacts involving disordered regions that are both highly represented in ensembles and conserved. PXN being a hub protein, the results provide a structural basis for understanding how shifts in the multistate equilibrium (e.g., through ligand binding and phosphorylation) may rewire cellular networks leading to phenotypic changes.
Nonhomologous end joining (NHEJ) is required for repairing DNA double strand breaks (DSBs) generated by the RAG endonuclease during lymphocyte antigen receptor gene assembly by V(D)J recombination. The ataxia telangiectasia–mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) kinases regulate functionally redundant pathways required for NHEJ. Here, we report that loss of the senataxin helicase leads to a strong defect in RAG DSB repair upon inactivation of DNA-PKcs. The NHEJ function of senataxin is redundant with the RECQL5 helicase and the HLTF translocase and is epistatic with ATM. Co-inactivation of ATM, RECQL5, and HLTF results in an NHEJ defect similar to that from the combined deficiency of DNA-PKcs and senataxin or losing senataxin, RECQL5, and HLTF. These data suggest that ATM and DNA-PKcs regulate the functions of senataxin and RECQL5/HLTF, respectively, to provide redundant support for NHEJ.
Bovine pericardium is the tissue of choice for replacing heart valves of human patients in minimally invasive surgery. The tissue has an extraordinarily high toughness of ~100 kilojoules per square meter. Here, we investigate the origin of the toughness through mechanical tests and microscopic observations. In the tissue, crimped, long, strong collagen fibers are embedded in a soft matrix. As a crack grows in the matrix, the fibers decrimp, reorient, slip, and bridge the crack. These microscopic processes enable the fibers to transmit high tension over a long distance. Using two types of experiments, we measure the bridging traction as a function of crack separation, σ(δ). The peak traction is σ0~ 60 megapascals. The maximum separation is δ0~ 6 millimeters, two to four orders of magnitude higher than that of hard tissues. Both the high traction and large separation of the bovine pericardium contribute to its high toughness.
DNA-based storage offers a compelling alternative to traditional optical and magnetic devices. However, random data access usually requires additional noncoding primer DNA as indexes, which substantially reduce the physical data density. Here, we propose an alternative strategy to overcome this barrier by loading different data-encoding DNA files into porous microspheres, each distinguished by unique photonic bandgaps and diameters, allowing for 105types of indexing. With the two features as the addressing indexes, the physical separation of subsets from a diverse pool of DNA files is achieved, thereby facilitating the selective retrieval of stored data. The interconnected nanopore arrays and uniformly distributed positive charges within the microspheres enhance DNA enrichment, achieving a storage density of up to 22.6 exabytes per gram, far exceeding that of previous random access storage methods. This work outlines a simple and scalable method for creating nonfading photonic indexes, enabling long-term random access while maintaining high storage capacity.
The circadian system provides a temporal framework for animals to anticipate environmental events, including threats. However, the effects of stressors on the circadian system remain poorly understood. Here, we demonstrate that, in mice, stressors shift the phase of the central pacemaker, housed in the suprachiasmatic nucleus (SCN), through glutamatergic inputs from the anterior paraventricular nucleus of the thalamus (aPVT). Unlike light, which can phase delay or advance the central pacemaker, stressors consistently induce delays, effects attenuated by inhibiting aPVT neurons. Stressors robustly activate AVP-expressing neurons within the SCN and are associated with inhibition of VIP-expressing neurons, whereas light strongly activates VIP-expressing neurons with minimal effects on AVP-expressing neurons. Pairing stressors with light reveals distinct time-dependent interactions, enhancing phase delays at early night but abolishing phase advances at late night. Our findings uncover distinct SCN microcircuits that differentially encode light and stressors, providing insights into how environmental cues modulate circadian timing.
The fossil record provides the only direct evidence of changes in biodiversity over time. Patterns in more inclusive taxonomic levels (e.g., families and orders) often become more complex because of interactions between biological traits and environmental conditions across different evolutionary lineages. Using supercomputing and artificial intelligence algorithms, we analyzed a high-resolution global dataset of fusuline foraminifera—the most diverse marine fossil group from the Carboniferous to the Permian (~340 to 252 million years ago)—at an unprecedented temporal resolution of <45 thousand years. Our unbinned diversity reconstruction reveals unexpectedly simple diversity dynamics in this exceptionally well-preserved clade. We identify two (and likely a third) truncated exponential diversifications and four major diversity declines. During this interval, long-term cooling consistently promoted biodiversification, whereas warming events were closely linked to extinctions. These findings imply that the current rapid global warming, driven by anthropogenic CO2emissions, represents a critical threat to modern ecosystems.
While occupying an influential position within one’s social network brings many advantages, it is unknown how certain individuals rise in social prominence. Leveraging a longitudinal dataset that tracks an entirely new network of college freshmen (N= 187), we test whether “climbing the social ladder” depends on knowing how other people are connected to each other. Those who ultimately come to occupy the most influential positions exhibit early and accurate representations of their network’s general, abstract structure (i.e., who belongs to which communities and cliques). In contrast, detailed, granular representations of specific friendships do not translate into gains in social influence over time. Only once the network stabilizes do the most influential individuals exhibit the most accurate representations of specific friendships. These findings reveal that those who climb the social ladder first detect their emerging network’s general structure and then fine-tune their knowledge about individual relationships between their peers as network dynamics settle.
A nematic phase lacks translation order but has orientational order. Nematic phases have been discovered in a variety of systems, including liquid crystals, correlated materials, and superconductors. Here, we report on a magnetic nematic phase, where the basis components are composed of magnetic helices. We directly probed the order parameters associated with the magnetic helices using resonant soft x-ray scattering and find two distinct nematic phases with complex spatiotemporal signatures. Using x-ray correlation spectroscopy, we find that near the phase boundary between the two nematic phases, fluctuations coexist on multiple disparate timescales. Our micromagnetic simulations and density functional theory calculations show that the fluctuations occur concomitantly with a reorientation of the magnetic helices, indicating spontaneous symmetry breaking and the emergence of additional degrees of freedom. Our results provide a framework for characterizing exotic phases that can be extended to a broad class of physical systems.
Ocean waves have long been a hazard to marine operations, making water wave isolation critical in ocean engineering. Traditional methods suffer from large area requirements, high costs, and incomplete isolation. We design a water wave isolation device using periodic gear arrays (PGAs), which overcomes these drawbacks and achieves perfect water wave isolation across a wide frequency band. Water wave isolation occurs by effectively creating a negative water depth, which fills a major gap in the field of manipulating water waves using metamaterial concept. We demonstrate the water wave isolation of PGAs through analytical methods, simulations, and experiments, proving that effective negative water depth is key to achieving the isolation of water waves. The PGAs perform well across a wide frequency band, with potential applications in port and ocean wave isolation. This discovery enriches water wave manipulation techniques and advances the development of water wave metamaterials.
Bioinspired piezoelectricity is extensively explored for diverse bio-machine interface and biomedical engineering applications. Nevertheless, state-of-the-art bio-piezoelectricity mainly focuses on crystallization. Yet, crystalized structures exhibit several shortcomings, including limited biocompatibility or biodegradability along with intrinsic non-stretchability. Herein, peptides fibrillization is reported to present inherent bio-piezoelectricity. Upon forming double-network framework with silk fibroin, fibrous peptide piezogels of innate biocompatibility and biodegradability are achieved, showing a programmable piezoelectricity. In particular, the bioinspired supramolecular piezogel can linearly respond to external compression and stretching in large force regions, extensively expanding the application potential bio-piezoelectricity. Upon designing a “W”-shaped structural conformation, a peptide fibrous piezogel–based piezoelectric sensor is shown to be used for detection of limb movements and subcutaneous implantation of the bioinspired piezoelectric electronics, realizing in situ and real-time monitoring of stimuli responses. The findings suggest the promising potential of peptide fibrillization–based bio-piezoelectricity for diverse bio-machine interface and biomedical engineering applications.
The advancement of molecular junction transistors relies heavily on precise modulation of molecular orbitals, yet this is hindered by a limited transmission window and reduced bias stability, which typically restricts the range of active channel molecules adopted to those with orbital levels near Fermi level of the contacts. In this study, we demonstrate an effective orbital gating of prototypical alkanethiol–based molecules with deeper orbital levels in vertical large-area mixed self-assembled monolayers (SAMs) configuration that offers enhanced electrical bias stability and gating efficiency. By using ion gel gating in Au-molecule-graphene junction, the channel conductance could be modulated notably according to a clear transition from direct tunneling to Fowler-Nordheim tunneling regime. The mixed SAM molecular transistors also showed a superior gating efficiency due to the suppressed field screening effect by the net molecular dipole. This work is expected to contribute toward developing reliable three-terminal molecular device platform extended to molecules with deep orbital levels.
The cellular networks that maintain genome stability encompass numerous pathways involved in all aspects of nucleic acid metabolism. Through bioinformatic analysis, we identified the Zinc Finger CCCH-Type Containing 4 protein (ZC3H4), a suppressor of noncoding RNA (ncRNA) production, as a pivotal player in this system. Experimentally, ZC3H4 deficiency led to increased DNA damage, abnormal mitosis, and cellular senescence. Biochemical analysis and super-resolution microscopy revealed that the loss of ZC3H4 increased replication stress (RS)—a major driver of genome instability—by inducing a hypertranscription state that promoted R loop formation and transcription-replication conflicts (TRCs), both of which drive RS. Further bioinformatic analysis demonstrated that ZC3H4 preferentially binds to genomic regions prone to TRCs and R loops, where it suppresses ncRNA bursts, functioning as part of the Restrictor complex. Our findings identify ZC3H4 as a crucial factor in maintaining genome integrity, strategically positioned at the critical intersection of DNA and RNA synthesis.
R2 retrotransposons are site-specific eukaryotic non–long terminal repeat retrotransposons that copy and paste into gene loci encoding ribosomal RNAs. Recently, we demonstrated that avian A-clade R2 proteins achieve efficient and precise insertion of transgenes into their native safe-harbor loci in human cells. The features of A-clade R2 proteins that support gene insertion are not well characterized. Here, we report high-resolution cryo–electron microscopy structures of two vertebrate A-clade R2 proteins at the initiation of target-primed reverse transcription and after cDNA synthesis and second-strand nicking. Using biochemical and cellular assays, we illuminate the basis for high selectivity of template use and unique roles for each of the three zinc-finger domains in nucleic acid recognition. Reverse transcriptase active site architecture is reinforced by an unanticipated insertion motif specific to vertebrate A-clade R2 proteins. Our work provides the first insights into A-clade R2 protein structure during gene insertion and may enable future improvement and adaptation of R2-based systems for precise transgene insertion.
In living tissues, collagen networks rarely exist alone because they are embedded within other biological matrices. When combined, collagen networks rigidify via synergistic mechanical interactions and stiffen only with higher mechanical loads. However, how cells respond to the nonlinear elasticity of collagen in hybrid networks remains largely unknown. Here, we demonstrate that when collagen rigidifies by the interpenetration of a second polymer, the amount of force that initially stiffens the network (onset of stiffening, σc) increases and is sufficient to stimulate an increase in intracellular tension. We investigated this effect by precisely controlling the nonlinear elasticity of collagen with the synthetic semiflexible polymer, polyisocyanopeptides. We find that small increases in σcinduce a biphasic response in cell-matrix interactions, influencing how cells migrate, proliferate, and generate contractile force. Our results suggest that cells adaptively respond to changes in the nonlinear mechanics of collagen, which may be a mechanistic behavior used during tissue homeostasis or when collagen rigidifies during pathological conditions.
Despite their large environmental impact and multiple independent emergences, the processes leading to the evolution of anaerobic methanotrophic archaea (ANME) remain unclear. This work uses comparative metagenomics of a recently evolved but understudied ANME group, “CandidatusMethanovorans” (ANME-3), to identify evolutionary processes and innovations at work in ANME, which may be obscured in earlier evolved lineages. We identified horizontal transfer ofhdrAhomologs and convergent evolution in carbon and energy metabolic genes as potential early steps inMethanovoransevolution. We also identified the erosion of genes required for methylotrophic methanogenesis along with horizontal acquisition of multiheme cytochromes and other loci uniquely associated with ANME. The assembly and comparative analysis of multipleMethanovoransgenomes offers important functional context for understanding the niche-defining metabolic differences between methane-oxidizing ANME and their methanogen relatives. Furthermore, this work illustrates the multiple evolutionary modes at play in the transition to a globally important metabolic niche.
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Elevated levels of asparagine, catalyzed by asparagine synthetase (ASNS), have been identified as a prerequisite for lung metastasis in breast cancer. However, the roles and regulatory mechanisms of ASNS in breast cancer brain metastasis (BCBM) are not well understood. Our study revealed that the family with sequence similarity 50 member A (FAM50A) gene substantially modulates the brain metastatic potential of breast cancer by up-regulating ASNS and promoting asparagine biosynthesis. We demonstrated that FAM50A forms a complex with chromosome 9 open reading frame 78 (C9ORF78), specifically at the S121 residue, to enhance ASNS transcription. This interaction accelerates the rate of ASNS-mediated asparagine synthesis, which is essential in facilitating metastatic cascades to the brain. From a therapeutic perspective, both the genetic suppression of FAM50A and pharmacological inhibition of asparagine synthesis effectively counteract BCBM. Our results highlight the importance of the FAM50A-ASNS signaling pathway in BCBM therapy.
Expanded polytetrafluoroethylene (e-PTFE) is extensively used in medical implants for its excellent bioinertness. Existing methods to fix e-PTFE implants on host tissues mainly use invasive anchorage such as sutures, spiral tacks, or metal skeletons, which has limitations such as being time-consuming and causing leakage and tissue damage. To overcome these limitations, we introduce a bioadhesive interface to realize the adhering fixation of e-PTFE implants. We integrate a hydrophilic and bioadhesive hydrogel layer on the hydrophobic and bioinert e-PTFE by designing a facile approach of freezing-induced micromechanical interlocking. The integration is robust enough as pulling hydrogel out of the interlocked pores on e-PTFE requires large energy dissipation. This bioadhesive interface enables instant (operating time < 10 seconds) and secure (adhesion energy >200 joules per square meter) adhering fixation of e-PTFE implants to wet tissue. The advantages for reducing inflammatory response, fibrogenesis, and the resultant postoperative adhesion are further demonstrated in a reconstructive surgery of an abdominal wall defect in rabbits.
The ecological and evolutionary success of multicellular lineages stems substantially from their increased size relative to unicellular ancestors. However, large size poses biophysical challenges, especially regarding nutrient transport: These constraints are typically overcome through multicellular innovations. Here, we show that an emergent biophysical mechanism—spontaneous fluid flows arising from metabolically generated density gradients—can alleviate constraints on nutrient transport, enabling exponential growth in nascent multicellular clusters of yeast lacking any multicellular adaptations for nutrient transport or fluid flow. Beyond a threshold size, the metabolic activity of experimentally evolved snowflake yeast clusters drives large-scale fluid flows that transport nutrients throughout the cluster at speeds comparable to those generated by ciliary actuation in extant multicellular organisms. These flows support exponential growth at macroscopic sizes that theory predicts should be diffusion limited. This demonstrates how simple physical mechanisms can act as a “biophysical scaffold” to support the evolution of multicellularity by opening up phenotypic possibilities before genetically encoded innovations.
Roadbed tribological energy (RTE) is a promising recoverable resource with an estimated potential on the terawatt scale, generated annually by the interaction between tires and road surfaces. However, RTE remains underutilized due to the lack of effective energy harvesting technologies that can address its high-entropy characteristics. Here, we present a revolutionary harvester formed by a freestanding layer triboelectric nanogenerator array embedded in the road. The harvester effectively converts low-grade vibratory RTE into electrical energy. It demonstrates the potential to achieve a peak power of 16.409 milliwatts and an average power of 2.2 milliwatts from a compact 78–square centimeter road area under a single tire impact, with a triboelectric conversion efficiency of 11.723%. In addition, we developed a self-powered intelligent and connected transportation system (SP-ICTS), integrating a five-in-one harvesting array. Experimental findings show that the system can meet the SP-ICTS’s electricity requirements along a 1-kilometer segment with a 50-meter harvester.
Competition among news sources over public opinion can incentivize them to resort to misinformation. Sharing misinformation may lead to a short-term gain in audience engagement but ultimately damages the credibility of the source, resulting in a loss of audience. To understand the rationale behind news sources sharing misinformation, we model the competition between sources as a zero-sum sequential game, where news sources decide whether to share factual information or misinformation. Each source influences individuals based on their credibility, the veracity of the article, and the individual’s characteristics. We analyze this game through the concept of quantal response equilibrium, which accounts for the bounded rationality of human decision-making. The analysis shows that the resulting equilibria reproduce the credibility-opinion distribution of real-world news sources, with hyperpartisan sources spreading the majority of misinformation. Our findings provide insights for policymakers to mitigate the spread of misinformation and promote a more factual information landscape.
Plexiform neurofibromas (PNFs) are benign tumors of the peripheral nervous system that represent a major source of morbidity in neurofibromatosis type 1 (NF1). A substantial proportion of patients do not respond to current therapies or experience intolerable side effects. Transcriptomic characterization of murine and human PNF at bulk and single-cell resolution identified transforming growth factor–β (TGFβ) signaling as a key upstream regulator, driving aberrant basement membrane (BM) protein production by neoplastic Schwann cells and Fbs. Conditional TGFβ1 overexpression inNf1-deficient Schwann cells driven byHoxb7-Cre promoted PNF growth and malignant transformation in vivo. Conversely, pharmacologic inhibition of the type I TGFβ receptor (TGFβRI) reduced PNF tumor burden inNf1mutant mice. Proteomic characterization of the extracellular matrix (ECM) showed reduced BM proteins upon TGFβRI inhibition. These findings implicate TGFβ as a potential therapeutic target in PNF and provide insights into the role of TGFβ signaling in orchestrating ECM dynamics in the PNF microenvironment.
The heterotrimeric G protein–coupled serotonin receptor 5-HT1Areceptor (5-HT1AR) mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, we evolved ST171, a bitopic 5-HT1AR agonist that revealed highly potent and functionally selective Gi/osignaling without Gsactivation and marginal β-arrestin recruitment. ST171 is effective in acute and chronic pain models. Cryo–electron microscopy structures of ST171 bound to 5-HT1AR in complex with the Giprotein compared to the canonical agonist befiradol bound to complexes of 5-HT1AR with Gior Gsrevealed that the ligands occupy different exo-sites. The individual binding poses are associated with ligand-specific receptor conformations that were further studied by molecular dynamics simulations, allowing us to better understand ligand bias, a phenomenon that may be crucial to the discovery of more effective and safe G protein–coupled receptor drugs.
The Argonaute CSR-1 is essential for germline development inC. elegans. Loss of CSR-1 leads to the down-regulation of thousands of germline-expressed genes, supporting a model in which CSR-1 “licenses” gene expression via a poorly understood mechanism. In contrast, a small subset of genes is up-regulated incsr-1mutants, includingmorc-1, which encodes a conserved GHKL-type ATPase. We show thatmorc-1is overexpressed incsr-1mutants and accumulates over CSR-1 licensed targets, coinciding with aberrant gain of H3K9me3, reduced H3K36me3, and transcriptional repression. Notably, loss ofmorc-1fully rescues these chromatin defects and partially restores gene expression and fertility incsr-1mutants. Conversely, ectopic overexpression of MORC-1 in the wild-type germ line is sufficient to repress CSR-1 licensed targets and severely compromise fertility. These findings support a model in which CSR-1 prevents MORC-1 overexpression and consequent misregulation of CSR-1 licensed genes.
Evolution of Archean continental crust involved partial melting of mafic crust to form the tonalite-trondhjemite-granodiorite (TTG) series. However, crustal generation remains enigmatic with both plate tectonic and non-plate tectonic modes proposed. In this study, we show that zircons from the ~2.5–billion years ago TTGs in the Eastern Block (EB) of the North China Craton have low water contents (median of 263 parts per million) and high δ18O values (median of 6.22‰) and a negative correlation between them, which suggest a thick hybridized and hydrated mafic source. By contrast, zircon water contents of the adjoining coeval TTGs in the Trans-North China Orogen, formed in a supra-subduction zone setting, are notably higher. These results support a two-stage mantle plume-sagduction process for TTG formation. Our study suggests that Archean continental crust, such as that in the EB, most likely originated from plume-related oceanic plateaus, rather than subduction-related island arc magmatism under a plate tectonic regime.
Capturing the intricate dynamics of neural activity in freely behaving animals is essential for understanding the neural mechanisms underpinning specific behaviors. Miniaturized microscopy enables investigators to track population activity at the cellular level, but the field of view (FOV) of these microscopes has often been limited and do not support multi-brain region imaging. To fill this technological gap, we have developed the eXtra Large FOV Miniscope (MiniXL) for mice, a 3.5-gram miniaturized microscope with an FOV measuring 3.5 mm in diameter. We demonstrate the capabilities of the MiniXL through large-scale neuronal population records in hippocampal dorsal CA1. We also demonstrate simultaneous multi-brain region imaging across bilateral medial prefrontal cortex (mPFC) and mPFC and nucleus accumbens (NAc) during complex social behavior and stably track cells across multiple days. As with all microscopes in the UCLA Miniscope ecosystem, the MiniXL is fully open-source and designed to be shared with the neuroscience community to lower the barriers for adoption of this technology.
Ferroelectric domain walls (FDWs) exhibit exotic structural and electronic properties, positioning them as a promising functional element for next-generation nanoelectronics. However, achieving the deterministic creation of FDWs with nanoscale precision and controlled polarization of domains remains a substantial challenge for the scalable FDW-device fabrication and circuit design. Here, we demonstrate a strategy for FDW engineering by tailoring the interfacial electrostatic profile. Using SrRuO3islands as “nano-masks,” we spatially modulate the interfacial atomic termination to generate alternating positive and negative built-in electric fields. The boundaries where the electric field switches polarity drive the formation of 180° FDWs in BiFeO3thin films. This mechanism is validated through theoretical calculations and direct experimental observations. Furthermore, atomic-scale analysis reveals localized lattice distortions, structural chirality of the FDWs, as well as the edge effect of SrRuO3islands on the position precision of FDW nucleation. Our findings pave the way toward a scalable and controllable bottom-up FDW-growth technique for future FDW nanoelectronics.
To gain insight into the root causes of metabolic dysfunction, it is essential to understand how tissues communicate and coordinate their metabolic functions. Here, we sought to address this in the context of cold exposure, a well-studied metabolic perturbation. We performed proteomics across six metabolic tissues and plasma, quantifying 11,394 proteins. Beginning our investigation in brown adipose tissue (BAT), we identified a mechanism to explain enhanced glucose utilization in cold-adapted BAT. This was characterized by select remodeling of upper glycolysis and pentose cycling to increase oxygen consumption, likely by increasing uncoupling protein 1 activity through the production of reactive oxygen species. Cold-induced remodeling of the plasma proteome appeared to underpin the ability of BAT to modify its fuel preference, stimulating lipolysis in white adipose tissue and glucose production in the liver. These findings emphasize the importance of considering metabolic adaptations in the context of the whole body and suggest overlap between the mechanisms of cold adaptation and obesity.
Rapid, millennial-scale changes in sea level have been proposed for the beginning, middle, and/or end of the Last Interglacial (LIG) [~129 to 116 thousand years ago (ka)]. Each of these scenarios has different implications for polar ice sheet behavior in a warming world. Here, we present a suite of230Th ages for fossil corals in the Seychelles within a detailed sedimentary and stratigraphic context to evaluate the evolution of sea level during this past warm period. The rise to peak sea level at ~122 to 123 ka was punctuated by two abrupt stratigraphic discontinuities, defining three distinct generations of reef growth. We attribute the evidence of episodic reef growth and ephemeral sea-level fall to the competing influence of Northern Hemisphere ice melt and Antarctic ice regrowth. Asynchronous ice sheet contributions would mask the full extent of retreat for individual ice sheets during the LIG and imply greater temperature sensitivity of ice sheets than previously inferred.
Prediction of peptide secondary structure is challenging because of complex molecular interactions, sequence-specific behavior, and environmental factors. Traditional design strategies, based on hydrophobicity and structural propensity, can be biased and could indeed prevent discovery of interesting, diverse, and unconventional peptides with desired nanostructure assembly. Using β sheet formation in pentapeptides as a case study, we used an integrated high-throughput experimental workflow and an artificial intelligence–driven active learning framework to improve prediction accuracy of self-assembly. By focusing on sequences where machine learning (ML) predictions deviate from conventional design strategies, we synthesized and tested 268 pentapeptides, successfully finding 96 forming β sheet assemblies, including unconventional sequences (e.g., ILFSM, LMISI, MITIY, MISIW, and WKIYI) not predicted by traditional methods. Our ML models outperformed conventional β sheet propensity tables, revealing useful chemical design rules. A web interface is provided to facilitate community access to these models. This work highlights the value of ML-driven approaches in overcoming the limitations of current peptide design strategies.
T cells targeting epitopes in infectious diseases or cancer play a central role in spontaneous and therapy-induced immune responses. Epitope recognition is mediated by the binding of the T cell receptor (TCR), and TCRs recognizing clinically relevant epitopes are promising for T cell–based therapies. Starting from a TCR targeting the cancer-testis antigen NY-ESO-1157–165epitope, we built large phage display libraries of TCRs with randomized complementary determining region 3 of the β chain. The TCR libraries were panned against NY-ESO-1, which enabled us to collect thousands of epitope-specific TCR sequences. Leveraging these data, we trained a machine learning TCR-epitope interaction predictor and identified several epitope-specific TCRs from TCR repertoires. Cellular assays revealed that the predicted TCRs displayed activity toward NY-ESO-1 and no detectable cross-reactivity. Our work demonstrates how display technologies combined with TCR-epitope interaction predictors can effectively leverage large TCR repertoires for TCR discovery.
Prostate cancer risk is influenced by various factors, including exposure to heavy metals like cadmium (Cd). The study reveals that the autophagy-regulating gene PLAC8 (placenta-specific 8) is significantly involved in Cd-induced prostate carcinogenesis, and NF-κB acts as the upstream transcriptional activator of PLAC8, which then selectively up-regulates BCL-xL, providing a survival advantage to Cd-transformed cells. NF-κB activation stabilizes PLAC8 in the cytosol, disrupting autophagy by allowing PLAC8 to colocalize with LC3B instead of LAMP1. Silencing NF-κB down-regulates PLAC8 and its survival function while inhibiting NF-κB or PLAC8, which restores autophagy and decreases tumor growth in xenograft models. In addition, targeting BCL-xL confirmed this signaling pathway. The findings suggest that sustained NF-κB activation regulates PLAC8 and highlights the NF-κB–PLAC8–BCL-xL axis as a potential target for early detection and therapies in metal-induced prostate cancer.
Unique electrical properties emerging at nanoscale ferroelectric interfaces originate from the polarization induced charges. However, real-space characterization of polarization induced charges at nanoscale ferroelectric interfaces has been extremely challenging. Here, directly observing the nanoscale electric field by tilt-scan averaged differential phase contrast scanning transmission electron microscopy enables us to measure the spatially varying total charge density profiles across both head-to-head and tail-to-tail domain walls in a ferroelectric crystal. Combined with atomic column displacement measurements, the spatial distribution of polarization bound charges and screening charges across the domain walls can be disentangled. Our results reveal the true charge states of the nanoscale ferroelectric interfaces, providing an opportunity for experimentally exploring the interplay between atomic-scale local polarization structures and their charge states in ferroelectric interfaces.
The integration of high strength, super toughness, damage resistance, body-temperature shape memory, and biosafety into a single skin-mimic material system has been a notable challenge in the realm of material science and biomedical applications. In this study, “Lego-like” polyurethane (PU) was selected to amalgamate multiple properties through the design of multilevel structures. By comprehensively designing the chemical and sequence structures of blocks, coordinating weak/strong hydrogen bonds, and achieving rational microphase separation and crystallization, an elastomer was obtained with an exceptional true tensile strength of 1.42 gigapascal, a high fracture energy of 384.7 ± 18.9 kJ/m2, and a skin-like nonlinear mechanoresponse. The coordination of crystallization and physical cross-linking also guaranteed excellent body-temperature shape memory properties, which are applicable in 4D printing. Moreover, the obtained elastomer is biosafe and has the potential to promote cell proliferation and DNA repair, which will find wide applications in the biomedical field including minimally invasive surgery.
Brain geometry affects brain function. A quantitative encoding of form is provided by the Laplace-Beltrami operator’s spectrum of eigenvalues (LBS). We examined LBS genetics of 22 subcortical brain structures and cerebellum in 19,862 healthy White-British UK Biobank participants by multivariate genome-wide association study on the first 49 eigenvalues each. Controlling for surface and volume, we identified 80 unique variants influencing the shapes of one or several structures, with the highest yield (37 variants) for brain stem. The previously known influence of several of these loci on basic morphology, such as volume, is thus shown to also influence complex shape. Known associations of observed loci with blood pressure, neurodegeneration, alcohol consumption, and mental disorders hint at preclinical stages of these conditions potentially mediating the genetic effect on brain morphology. Significant correlations between LBS of several brain structures and the polygenic risks of hypertension, ischemic stroke, and schizophrenia evince brain shapes as early biomarkers.
Exciton dissociation in organic solar cells (OSCs) is primarily achieved through interfacial charge-transfer (CT) states, leading to a trade-off between open-circuit voltage (VOC) and short-circuit current (JSC). Spatially dispersed delocalized singlet excitons (DSEs) in nonfullerene acceptors (NFAs) provide an alternative channel to promote charge generation without interfacial CT state. Here, we manipulate intermolecular interactions, carrier dynamics, and photovoltaic properties through selective asymmetric fluorination. Two asymmetric molecules, Z12 and Z13, were synthesized by substituting the terminal group with different fluorine atoms compared with the symmetrical molecule, Z11. Z12 showed enhanced molecular interactions, promoting to more compact and ordered stacking, which in turn promotes the DSE formation, benefiting the synergistic enhancement ofVOCandJSC. The D18:Z12-based device achieved a remarkable power conversion efficiency of 19.5%, notably outperforming the other two devices. Our study indicates that controlling the molecular configuration by selective fluorination to enhance the DSE formation in NFAs is an effective strategy to achieve efficient OSCs.
Widespread application of bacterial-based cancer therapy is limited because of the need to increase therapeutic bacteria specificity to the tumor to improve treatment safety and efficacy. Here, we harness the altered tumor metabolism and specifically elevated kynurenine accumulation to target engineered bacteria to the cancer site. We cloned and leveraged kynurenine-responsive transcriptional regulator (KynR) with its cognate promoter inEscherichia coli. Optimizing KynR expression coupled with overexpressing kynurenine transporter and amplifying the response through plasmid copy number–based signal amplification enabled the response to kynurenine at the low micromolar levels. Knocking out genes essential for cell wall synthesis and supplying these genes via kynurenine-controlled circuits allowed tuningSalmonella entericagrowth in response to kynurenine. Our kynurenine-controlledS. enterica(hereafter named AD95+) showed superior tumor specificity in breast and ovarian cancer murine models compared toS. entericaVNP20009, one of the best characterized tumor-specific strains. Last, AD95+ showed anticancer properties compared to vehicle controls, demonstrating the potential as an anticancer therapeutic.
Sound is a crucial sensing element for many organisms in nature, with various species evolving organic structures that produce complex acoustic scattering and dispersion phenomena to emit and perceive sound clearly. To date, designing artificial scattering structures that match the performance of these organic structures has proven challenging. Typically, sound manipulation relies on active transduction in fluid media rather than passive scattering principles, as often observed in nature. In this work, we use computational morphogenesis to create complex, energy-efficient, wavelength-sized single-material scattering structures that passively decompose radiated sound into its spatio-spectral components. Specifically, we design an acoustic rainbow structure with “above unity” efficiency and an acoustic wavelength splitter. Our work demonstrates what is possible when using computational morphogenesis to tailor the emission and reception of sound fields, with relevance to disciplines concerned with the sensing and emission of wave fields.
In magnetic pyrochlore materials, the interplay of spin-orbit coupling, electronic correlations, and geometrical frustration gives rise to exotic quantum phases, including topological semimetals and spin ice. While these phases have been observed in isolation, the interface-driven phenomena emerging from their interaction have never been realized previously. Here, we report on the discovery of interfacial electronic anisotropy and rotational symmetry breaking at a heterostructure consisting of the Weyl semimetal Eu2Ir2O7and spin ice Dy2Ti2O7. Subjected to magnetic fields, we unveil a sixfold anisotropic transport response that is theoretically accounted by a Kondo-coupled heterointerface, where the spin ice’s field-tuned magnetism induces electron scattering in the Weyl semimetal’s topological Fermi-arc states. Furthermore, at elevated magnetic fields, we reveal a twofold anisotropic response indicative of the emergence of a symmetry-broken many-body state. This discovery showcases the potential of pyrochlore frustrated magnet/topological semimetal heterostructures in search of emergent interfacial phenomena.
The nucleolus is essential for ribosome biogenesis and stress regulation. However, because of its dynamic nature, there is still a lack of methods to specifically visualize nucleolar localization in living cells and to study dynamic changes in protein interaction networks within the cell nucleolus. In this study, we identified and engineered a signal peptide sequence, termed nucleolar beacon, which exhibits robust nucleolar localization and universal applicability across various mammalian cell types. Using this sequence, we established nucleolar indicator cell lines and demonstrated their practicality in studying nucleolar functions in living cells. In addition, by combining the signal peptide with proximity labeling technology, we developed an effective approach for capturing the nucleolar proteome and successfully identified nucleolar-associated proteins. These techniques provide effective and versatile tools for investigating nucleolar functions in living cells and offer a potential strategy for drug delivery applications.
Amyloid aggregates are pathological hallmarks of many human diseases, but how soluble proteins nucleate to form amyloids is poorly understood. Here, we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid-β (Aβ42), the protein that aggregates in Alzheimer’s disease. In total, we measure the nucleation rates of >140,000 variants of Aβ42 to accurately quantify the changes in free energy of activation of the reaction for all possible amino acid substitutions in a protein and, in addition, to quantify >600 energetic interactions between mutations. Strong energetic couplings suggest that the Aβ42 nucleation reaction transition state is structured in a short C-terminal region, providing a structural model for the reaction that may initiate Alzheimer’s disease. Using this approach it should be possible to reveal the energetic structures of additional amyloid transition states and, in combination with additional selection assays, protein transition states more generally.
Optoretinography is an emerging method for detecting and measuring functional responses from neurons in the living human retina. Its potential applications are compelling and broad, spanning clinical assessment of retinal disease, investigation of fundamental scientific questions, and rapid evaluation of experimental therapeutics for blinding retinal diseases. Progress in all these domains hinges on the development of robust methods for quantifying observed responses in relation to visible stimuli. In this work, we describe an optoretinographic imaging platform: full-field swept-source optical coherence tomography with adaptive optics, measure cone responses in two healthy volunteers to a variety of stimulus patterns, and propose a simple model for predicting and quantifying responses to those stimuli.
Eosinophil-rich granulomas, formed around tissue-trapped parasite eggs, are hallmarks of schistosomiasis mansoni, a prevalent neglected tropical disease. How eosinophils populate and affect the complexSchistosomagranulomas remains unclear. Here, we mapped eosinophils across evolutional hepatic granulomas in a mouse model and in a primary wild reservoir for human schistosomiasis in Brazil (water ratNectomys squamipes). With in-depth quantitative image analysis and three-dimensional histological reconstructions of entire granulomas, we find that eosinophils are spatially organized and occupy a major, peripheral niche conserved across space and time in all granuloma stages and both experimental and natural infections. Within this niche, immature and mature eosinophils coinhabit, compartmentalize their major basic protein-1 content, robustly interact with other immune cells, and secrete through piecemeal degranulation. This unveiled niche, unrelated to parasite eggs, challenges the concept of eosinophil as a “helminth killer” cell and invigorates its view as an immunoregulatory cell of the tissue microenvironment inSchistosomagranulomas.
Trial-and-error approaches in chemistry generate abundant unsuccessful experiments, yet the potential of these so-called negative results remains largely underutilized. Here, we demonstrate that information from negative chemical reactions can be leveraged to improve reactivity-prediction models, offering advantages in scenarios with a limited volume of successful data. We extend the tuning of language models with reinforcement learning to the chemistry domain, training a transformer model for chemical reaction prediction. Our approach is evaluated using both a rigorously controlled dataset and a realistic high-throughput dataset comprising extensive reaction screenings across diverse catalysts sets and experimental conditions. The model achieves state-of-the-art performance by leveraging information from as few as 20 positive data points in the controlled dataset, supported by a negative dataset at least 40 times larger. Consistent results on both datasets demonstrate that, with an appropriate optimization strategy and the inclusion of unsuccessful experimental data, models can be effectively trained even when successful reactions are underrepresented.
The electrified interface between a liquid and a solid underpins diverse phenomena, from ion-transfer during battery operation to action potentials enabling biological communication. However, conventional tools are blind to the nanoscale dynamics of this metastable interface. Here, we leverage electrified cryo–electron microscopy (eCryo-EM), a technique that rapidly freezes and kinetically traps these dynamic, nonequilibrium states during battery operation for nanoscale characterization. Collective snapshots of the electrified interface at controlled time intervals quantifies early-stage growth kinetics of the solid electrolyte interphase (SEI), a passivation film that governs electron and ion transport. Unexpectedly, the diffusivity of charged species of the two SEI films with differing chemistry and performance are estimated to be within 10% of the other, indicated by the slope of their diffusion-limited SEI growth regimes. Instead, the slope of the reaction-limited SEI growth regimes differs by a factor of 3, suggesting that lowered reactivity of the high-performance electrolyte is largely responsible for its high coulombic efficiency.
Earth is the only known rocky planet to support complex life forms that use oxygen and to have a strong intrinsic magnetic field in much of its history, prompting speculation that Earth’s magnetic field and habitability are related on geological timescales. We search for possible observational evidence for such a relationship by examining evolutions of the virtual geomagnetic axial dipole moment and the atmospheric oxygen level over the past 540 million years. We find that both exhibit strong linearly increasing trends, coupled with a large surge in magnitude between 330 and 220 million years ago. Our time series analysis and statistical tests show that both are highly correlated, with the maximum correlation reached when there is no time lag between the two. Our findings suggest unexpected strong connections between the geophysical processes in Earth’s deep interior, the surface redox budget, and biogeochemical cycling.
DNA damage arises from various environmental stresses, and ABA is well known for its roles in plant stress resistance. However, its function in plant DNA damage tolerance remains unclear. In this study, we showed that ABA supplementation significantly enhances plant tolerance to DNA-damaging treatments. SnRK2.2 and SnRK2.3 kinases in the ABA signaling pathway are pivotal in this process. These kinases interact with clathrin light chain 2 (CLC2), facilitating its phosphorylation and nuclear translocation in response to Zeocin and ABA treatment. In the nucleus, CLC2 interacts with ADA2b, an adaptor protein crucial for recruiting SMC5/6 complex to the double-strand break (DSB) sites. The enhanced nuclear localization of CLC2 is essential for the accurate localization of ADA2b at DSB sites. Collectively, our study uncovers that ABA enhances plant DNA damage tolerance with a distinct function of CLC2 in genomic stability maintaining, thereby improving our understanding of DNA damage tolerance mechanisms in plants.
It is widely held that identical systems tend to behave similarly under comparable conditions. Yet, for systems that interact through a network, symmetry breaking can lead to scenarios in which this expectation does not hold. Prominent examples are chimera states in multistable phase-oscillator networks. Here, we show that for a broad class of such networks, asynchronous states can be converted into frequency-synchronized states when identical oscillators are detuned to have different intrinsic frequencies. We show that frequency synchronization is achieved over a range of intrinsic frequency detuning and is thus a robust effect. These results, which are supported by theory, simulations, and electrochemical oscillator experiments, reveal a counterintuitive opportunity to use parameter heterogeneity to promote synchronization.
Noninvasive transcranial neuromodulation of deep brain regions is a longstanding goal in neuroscience. While optogenetics enables remote neural control, it is constrained by shallow tissue penetration of visible light and delayed onset due to required opsin expression. Here, we introduce a neuromodulation technique using hybrid upconversion and photovoltaic (HUP) nanoparticles, which eliminates the need for genetic modification and affords near-infrared (NIR) activation of neurons in wild-type mice. This method converts deeply penetrating NIR light into localized electrical stimuli, enabling immediate and precise modulation in deep brain. In vitro patch-clamp experiments confirm neuronal activation upon HUP application. In vivo, we achieve remote NIR neuromodulation in the medial septum and ventral tegmental area 7 days postinjection, effectively modulating neuronal activity, suppressing seizures, and triggering dopamine release. This minimally invasive approach offers a versatile tool kit for investigating neural processes in mammals, with potential applications across diverse brain regions through customizable nanoparticle engineering.
In plants, ATP-binding cassette (ABC) transporters are crucial for nutrient uptake, phytohormone transport, and environmental response. It is of great interest to understand the mechanisms of these transporters and develop small-molecule modulators to regulate plant growth.ArabidopsisABCB19 was recently shown to transport brassinosteroid, shaping hormone dynamics and plant architecture. However, the conformational cycle and inhibitor mechanism of ABCB transporters remain elusive. We reconstituted ABCB19 into lipid nanodiscs, where activity was drastically higher than in detergents, and determined its cryo–electron microscopy structures in substrate-free, substrate-bound, vanadate-trapped, and inhibitor-bound states. Inward-facing ABCB19 moved inward upon substrate binding and fully closed with vanadate trapping, unexpectedly temperature dependent. Two inhibitor molecules locked ABCB19 in the inward-facing conformation. Mutagenesis identified key residues for substrate and inhibitor binding, revealing differential contributions to transporter function and inhibition. These results deepen knowledge of plant ABCB transporters, laying a foundation for targeted manipulation to enhance plant resilience and productivity.
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Maintaining reactive oxygen species (ROS) homeostasis is essential for balancing growth-defense trade-offs in plants. Although the transcription factors (TFs) that regulate ROS production and scavenging genes have been studied, the regulation of these TFs to control ROS accumulation remains poorly understood. Here, we demonstrate that during N nucleotide-binding leucine-rich repeat–mediated immunity, Alfin-like 7 (AL7) is ubiquitinated by the ubiquitin protein ligase E3 component N-recognin 7 (UBR7). UBR7 interacts with AL7 and acts as a molecular brake to mediate the ubiquitination of AL7 at lysine-20, leading to its subsequent proteasomal degradation. UBR7 functions upstream of AL7 to reduce AL7-induced ROS accumulation duringN-mediated defense. The phosphorylation of AL7 at serine-174 enhances its interaction with UBR7, thereby increasing AL7 ubiquitination and reducing AL7 stability. Our findings reveal a mechanism by which ROS accumulation is regulated through the phosphorylation and ubiquitination of a TF during the immune response. This ensures precise switching of ROS signaling to prevent excessive defense responses.
Resolving partial waves, including their amplitudes and phases, is crucial for understanding the intricate structure and dynamics of the photoelectron released. However, the knowledge is limited because of the complexities of the multiphoton interactions with molecules in the nonperturbative regime. Here, we address these challenges using an orthogonal two-color (OTC) scheme, which combines different photon energies and polarizations of the laser fields to produce characteristic photoelectron angular distributions (PADs) that vary with the laser phase. By analyzing the phase-dependent PADs, the partial waves, including their individual amplitudes and phases, involved in the nondissociative and dissociative single ionization of H2are unambiguously resolved. In addition, the interaction phases accumulated during the absorption of multiple photons of different polarizations are revealed. The OTC scheme works as a powerful tool to achieve a partial-wave decomposition of the photoelectron wave packet launched via multiphoton ionization and explore attosecond electron dynamics in strong laser fields.
α-Chiral phosphorus compounds have broad applications as organic catalysts or ligands in organic chemistry and related areas. Herein, we disclose a Ni-catalyzed enantioselective cross-hydrodimerization of alkenyl phosphine sulfides with unactivated alkenes to access α-chiral phosphine sulfides, representing the first example of asymmetric hydrodimerization of electron-deficient alkenes with electron-rich alkenes. Key to success is the precise recognition between electron-deficient alkenes and electron-rich alkenes and streamlined alkyl-alkyl bond forming with the control of chemo-, regio-, and enantioselectivity. This strategy requires alkenes as sole precursors for asymmetric alkyl-alkyl cross-coupling, circumventing the use of stoichiometric amounts of alkyl electrophiles or alkyl nucleophiles as coupling partners. The mild conditions tolerate a wide range of functional groups, providing direct access to α-chiral phosphines through a carbon-carbon bond-forming process without prefunctionalized coupling precursors.
Bone morphogenetic protein (BMP) signaling patterns secondary body axes throughout Bilateria and in the bilaterally symmetric corals and sea anemones. Chordin-mediated “shuttling” of BMP ligands is responsible for the BMP signaling gradient formation in many bilaterians and, possibly, also in the sea anemoneNematostella, making BMP shuttling a candidate ancestral mechanism for generating bilaterality. However,NematostellaChordin might be a local inhibitor of BMP rather than a shuttle. To choose between these options, we tested whether extracellular mobility of Chordin, a hallmark of shuttling but dispensable for local inhibition, is required for patterning inNematostella. By generating localized Chordin sources in the Chordin morphant background, we showed that mobile Chordin is necessary and sufficient to establish a peak of BMP signaling opposite to Chordin source. These results provide evidence for BMP shuttling in a bilaterally symmetric cnidarian and suggest that BMP shuttling may have been functional in the potentially bilaterally symmetric cnidarian-bilaterian ancestor.
Materials with low thermal conductivity are important for a variety of applications such as thermal barrier coatings and thermoelectrics, and understanding the underlying mechanisms of low heat transport, as well as relating them to structural features, remains a central goal within material science. Here, we report on the ultralow thermal conductivity of the quarternary crystalline silver chalcogenide AgGaGe3Se8, with a remarkable value of only 0.2 watts per meter per kelvin at room temperature and an unusual glass-like thermal behavior from 2 to 700 kelvin. The ultralow thermal conductivity is linked to a disordered nature of silver in the structure, displaying extremely large silver atomic displacement parameters obtained from multitemperature synchrotron powder x-ray scattering measurements and silver ionic conductivity at elevated temperatures. In addition, a low-temperature Boson peak in the heat capacity and a low Debye temperature of 158 kelvin reveal signs of structural anharmonicity and soft bonding.
Effective memory formation declines in human aging. Diminished neural selectivity—reduced differential responses to preferred versus nonpreferred stimuli—may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer’s disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During learning, neural selectivity in place- and, to a lesser extent, face-selective regions was greater for subsequently remembered than forgotten events; positively scaled with variability in dorsal attention network activity, within and across individuals; and negatively related to AD pathology, evidenced by elevated plasma phosphorylated Tau181(pTau181). Path analysis revealed that neural selectivity mediated the effects of age, attention, and pTau181on memory. These data reveal multiple pathways that contribute to memory differences among older adults—AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.
Spatial transcriptomics enables multiplex profiling of gene cellular expression and location within the tissue context. Although large volumes of spatial transcriptomics data have been generated, the lack of systematic curation and analysis limits biological discovery. We present Spatial transcriptOmics Analysis Resource (SOAR), a comprehensive spatial transcriptomics platform with 3461 uniformly processed samples across 13 species, 42 tissue types, and 19 different spatial transcriptomics technologies. Using SOAR, we found thatCXCL16/SPP1macrophage polarity characterizes the coordination of immune cell polarity in the tumor microenvironment. SOAR’s integrative approach toward drug discovery revealed sirolimus and trichostatin A as potential anticancer agents targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin growth and proliferation pathway and identified Janus kinase/signal transducers and activators of transcription inhibitors for ulcerative colitis treatment. SOAR’s results demonstrate its broad application to data generated from diverse spatial technologies and pathological conditions. SOAR will support future benchmarking studies and method development, facilitating discoveries in molecular functions, disease mechanisms, and potential therapeutic targets.
Josephson junctions (JJs) are key to superconducting quantum technologies and the search for self-conjugate quasiparticles potentially useful for fault-tolerant quantum computing. In topological insulator (TI)–based JJs, measuring the current-phase relation (CPR) can reveal unconventional effects such as Majorana bound states (MBS) and nonreciprocal transport. However, reconstructing CPR as a function of magnetic field has not been attempted. Here, we present a platform for field-dependent CPR measurements in planar JJs made of NbSe2and few-layer Bi2Se3. When a flux quantumΦ0threads the junction, we observe anomalous peak-dip CPR structure and nonreciprocal supercurrent flow. We show that these arise from a nonuniform supercurrent distribution that also leads to a robust and tunable Josephson diode effect. Furthermore, despite numerous previous studies, we find no evidence of MBS. Our results establish magnetic field–dependent CPR as a powerful probe of TI-based superconducting devices and offer design strategies for nonreciprocal superconducting electronics.
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling of host-pathogen interactions has enhanced our understanding of drug resistance. However, how combinations of drug resistance mutations affect dose-response curves remains underappreciated in PK-PD studies. The fitness seascape model addresses this by extending the fitness landscape model to map genotypes to dose-response functions, enabling the study of evolution under fluctuating drug concentrations. Here, we present an empirical fitness seascape inE. coliharboring all combinations of four drug resistance mutations. Incorporating these data into PK-PD simulations of antibiotic treatment, we find that higher mutation supply increases the probability of resistance, and early adherence to the drug regimen is critical. In vitro studies further support the finding that the second dose in a drug regimen is important for preventing resistance. This work bridges empirical fitness seascapes and computational PK-PD studies, revealing insights into drug resistance.
Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of function or increased levels of the essential activation factorAscl1reveal thatAscl1promotes the activation of hippocampal neural stem cells by driving these cells out of deep quiescence, despite its low protein expression in this state. Subsequently, during the transition from deep to shallow quiescence,Ascl1induces the expression ofMycn, which drives progression through shallow quiescent states toward a proliferating state. Together, these results define the required sequence of transcription factors during hippocampal neural stem cell activation and establish a combinatorial code for classifying these cells into deep and shallow quiescence.
Self-powered sensing related to triboelectric nanogenerator (TENG) as a sustainable self-sufficient power source for environmental monitoring by harvesting energy from a living environment is critical in the field of energy and environmental science. However, features of small energy-density and irregularity of environmental energy make it difficult to use directly for real-time environmental monitoring. Here, we report a self-powered and self-calibrated environmental monitoring system (SSEMS) composed of TENG, a calibration resistor, and a sensor network in parallel for real-time temperature and humidity monitoring. The calibration resistor can monitor in real time the irregular output of TENG from the irregularity of rainfalls. SSEMS uses this calibrating signal to calibrate the sensing signal in real time, achieving accurate sensing with an error margin less than 5.0%. We applied SSEMS under waterfalls and rainfalls to monitor in real time the environmental temperature and relative humidity with a sensing error as low as 1.0%. This work promotes self-powering technology one step further to practical applications.
The impact of anaerobic oxidation of methane (AOM) coupled with denitrification on the emission of the denitrification intermediate N2O remains poorly understood. Here, we investigated the influence of AOM coupled with nitrate and nitrite reduction on soil N2O emissions and the associated microbial interactions. We show that AOM coupled with denitrification markedly reduces soil N2O emissions, with the type I methanotrophMethylobacterspecies collaborating with the Methylophilaceae and Gemmatimonadaceae families to perform key roles. The suppression of N2O emissions by AOM primarily stems from its role in supplying electrons and carbon sources, fueling complete denitrification by associated bacteria. In addition, we uncovered distinct microbial interaction strategies for AOM-coupled nitrate and nitrite reduction. While nitrite reduction necessitates both bacterial cooperation and extracellular electron transfer during its initial stages, nitrate reduction predominantly depends on methanotrophic bacteria alone at the outset. These findings advance our understanding of carbon-nitrogen cycle coupling and underscore AOM’s potential to simultaneously mitigate both CH4and N2O emissions.
Unraveling the mechanisms underlying the maintenance of species diversity is a central pursuit in ecology. It has been hypothesized that ectomycorrhizal (EcM) in contrast to arbuscular mycorrhizal fungi can reduce tree species diversity in local communities, which remains to be tested at the global scale. To address this gap, we analyzed global forest inventory data and revealed that the relationship between tree species richness and EcM tree proportion varied along environmental gradients. Specifically, the relationship is more negative at low latitudes and in moist conditions but is unimodal at high latitudes and in arid conditions. The negative association of EcM tree proportion on species diversity at low latitudes and in humid conditions is likely due to more negative plant-soil microbial interactions in these regions. These findings extend our knowledge on the mechanisms shaping global patterns in plant species diversity from a belowground view.
Scattering-type scanning near-field optical microscopy (s-SNOM) allows for the observation of the optical response of material surfaces with a resolution far below the diffraction limit. Based on amplitude-modulation atomic force microscopy (AFM) with typical tapping amplitudes of tens of nanometers, a spatial resolution of 10 to 100 nm is routinely achieved in s-SNOM. However, optical imaging and spectroscopy of atomic-scale structures remain a substantial challenge. Here, we developed ultralow tip oscillation amplitude s-SNOM (ULA-SNOM), where the ultraconfined field localized at a 1-nm-scale gap between a plasmonic tip and sample is combined with frequency-modulation (noncontact) AFM in a stable cryogenic ultrahigh vacuum environment. Using a silver tip under visible laser illumination with a constant 1-nm amplitude oscillation, we obtain a material-contrast image of silicon islands on a silver surface with 1-nm lateral resolution, which surpasses the conventional limits of s-SNOM. ULA-SNOM paves the way for the acquisition of optical information from atomic-scale structures, such as single photo-active defects and molecules.
The coherent vibrational dynamics of gold nanorods with varying aspect ratios have been extensively studied by time-resolved spectroscopy to reveal their mechanical properties, but quantum-sized rods (transverse diameter < 2 nanometers) remain unexplored. Here, we present a comprehensive study on the coherent vibrations of atomically precise gold quantum rods with distinct energy gaps (0.6 to 1.3 electron volts), all sharing the same radial dimension but with increasing aspect ratios. Time-resolved spectroscopy reveals ultrafast internal conversion and intersystem crossing, along with oscillatory features superimposed on transient signals that unveil coherent vibrational dynamics. Two dominant modes are identified: a longitudinal mode scaling with rod length and a transverse mode independent of aspect ratio. Theoretical simulations support these findings and clarify the structural origins of the observed vibrational behavior. Our study provides a framework for designing atomically precise gold quantum rods with tailored optical and vibrational properties, advancing the understanding and application of anisotropic quantum materials.
Flat optical components, or metasurfaces, have transformed optical imaging, data storage, information processing, and biomedical applications by providing unprecedented control over light-matter interactions. These nano-engineered structures enable compact, multidimensional manipulation of light’s amplitude, phase, polarization, and wavefront, producing scalar and vector beams with unique properties such as orbital angular momentum and knotted topologies. This flexibility has potential applications in optical communication and imaging, particularly in complex environments such as atmospheric turbulence and undersea scattering. However, designing metasurfaces for shorter wavelengths, such as visible and ultraviolet light, remains challenging due to fabrication limitations and material absorption. Here, we introduce an innovative concept called topology imprinting using judiciously designed all-dielectric nonlinear optical metasurfaces to replicate desired waveforms at fundamental and harmonic frequencies, opening promising avenues for advanced photonic applications.
Programming microorganism adhesions to engineer multicellular microbial communities holds promise for synthetic biology and medicine. Current chemical and genetic engineering approaches often lack specificity or require engineered bacteria, making the design of responsive interactions challenging. Here, we demonstrate the use of functional DNA as programmable surface receptors to regulate the patterns and behaviors of microbial communities. Using metabolic labeling and hydrophobic insertion, we modified various microorganisms with DNA, including Gram-positive and Gram-negative bacteria, and dormant spores. By incorporating distinct sequences, we achieved precise spatial control of bi- and tricomponent microbial assemblies, forming diverse morphologies like core-shell and selective clusters. Stimuli-responsive clustering was successfully realized using aptamers, strand displacement, and reverse-Hoogsteen base pairing, with oligonucleotides or small molecules as exogenous cues. This work extends the use of functional DNA to control microbial interactions, enabling living communities with dynamic biofunctions, such as biofilm formation, antibiotic sensitivity, and quorum sensing, in response to biological triggers.
The accurate targeting of proteins to their designated cellular compartments is essential for maintaining proper cellular architecture and function. However, interpreting and sorting the highly variable targeting sequences in secreted and membrane proteins present a substantial challenge for achieving precise localization within the secretory pathway. In this study, we demonstrate that atypical signal sequences, characterized by high hydrophobicity and/or the absence of characteristic charges, are recognized by the signal recognition particle and targeted to the endoplasmic reticulum in a reverse orientation. These misoriented signal sequences are subsequently dislocated by the P5A-ATPase ATP13A1 and delivered to SEC61 for further translocation. Using cryo–electron microscopy, we determined the structures of human ATP13A1 in multiple conformations (3.40- to 3.87-angstrom resolution), revealing key residues within its substrate-binding pocket that engage signal sequences through polar interactions. Collectively, our findings elucidate a comprehensive, substrate-specific translocation pathway that ensures both high efficiency and fidelity in protein subcellular localization.
PIEZOs form trimeric calcium-permeable nonselective cationic channels that serve mechanical sensing needs across eukaryotic biology. Forces act on the channels by causing their curved blades to flatten and decompact, leading to an activated state, but it is unclear how this is regulated to enable the channels to adapt to different contexts. To identify potential mechanisms, we performed coarse-grained and all-atom molecular dynamics simulations on human PIEZO1. We observed an interblade handshake interaction mediated by basic amino acid residues in two flexible helices coordinated with regulated anionic lipid phosphatidylinositol 4,5-bisphosphate. The interaction determined the resting configuration of the channel, blade curvature, compactness, and ion pore structure. In experiments, disruption of the handshake by neutralization of helix amino acids or phosphatidylinositol 4,5-bisphosphate depletion increased the channel’s sensitivity to membrane tension. Structural and amino acid sequence analysis for multiple PIEZOs predicted helix amino acid arrangements for varied handshaking intensity. We suggest a dynamic interaction in PIEZO channels that regulates force sensitivity.
Bacteria, the smallest and most abundant life forms on Earth, have been a source of insights that have had a considerable impact on human health.Helicobacter pylorihas captured substantial attention due to its role in provoking an array of gastrointestinal ailments and other human diseases. Here, we report thatH. pylorireleases the protein CagA (cytotoxin-associated gene A) that strongly inhibits formation of both functional (bacterial biofilm) and pathogenic amyloid assemblies by targeting various stages during fibril formation. CagA’s broad substrate specificity reveals a mechanism wherebyH. pyloriinterferes with other bacteria and humans, offering approaches to combat bacterial infections and human protein misfolding diseases.
Influenza A virus (IAV) enters host cells via endocytosis, and fusion of the viral particles (VPs) at endosomes releases the viral ribonucleoproteins (vRNPs) into the cytoplasm. This uncoating step that is vital for IAV infection remains to be fully understood. The aggresome processing machinery (APM) plays a relevant but not essential role in this. Here, we reveal a mechanism in which light chain 3 proteins (LC3s) and pericentrin (PCNT) form an adaptor complex that is required for vRNPs binding to the dynein 1 and IAV uncoating at endosomes. This function of LC3s and PCNT is independent from their established role in autophagy and centrosome assembly, respectively. LC3s or PCNT depletion severely impairs IAV cytoplasm entry and infection, which can be further inhibited by additional silencing of histone deacetylase 6, an APM component. Collectively, our results show that IAV has adopted two redundant strategies to hijack the dynein biomolecular motors and facilitate VP uncoating.
Behavioral fever, a thermoregulatory response in which ectothermic animals seek warmer environments to elevate body temperature and combat parasite infections, is well documented against microparasites. However, its role and mechanisms against macroparasites remain largely unknown. Here, we show thatDrosophilahosts use behavioral fever to defend againstLeptopilinaparasitoid wasps. This thermal preference increases wasp mortality and enhances host survival. We find that behavioral fever is mediated by up-regulation ofHeat shock protein 70(Hsp70) genes in infected hosts asHsp70loss abolishes behavioral fever, whereas its overexpression induces heat-seeking behavior. We further find that behavioral fever up-regulates immune genes in infected hosts, including 12antimicrobial peptide(AMP) genes, which disrupt the gut microbiota homeostasis of parasitoid wasps and, in turn, lead to substantial wasp mortality. Our findings elucidate the detailed mechanisms of behavioral fever inDrosophilahosts, advancing our understanding of ectothermic animal defenses against macroparasites.
The proper assembly of light-harvesting complexes (LHCs) is critical for photosynthesis and requires the biogenesis of light-harvesting chlorophylla,b-binding proteins (LHCPs) to be coordinated with chlorophyll (Chl) biosynthesis. The mechanism underlying this coordination is not well understood. Here, we show that a conserved molecular chaperone, chloroplast signal recognition particle 43-kDa protein (cpSRP43), provides a molecular thermostat that helps maintain this coordination. cpSRP43 undergoes a conformational rearrangement between a well-folded closed state and a partially disordered open state. Closed cpSRP43 is dedicated to the biogenesis of LHCPs, whereas open cpSRP43 protects multiple Chl biosynthesis enzymes from heat-induced destabilization. Rising temperature shifts cpSRP43 to the open state, enabling it to protect heat-destabilized Chl biosynthesis enzymes. Our results reveal the molecular basis of a posttranslational mechanism for the thermoadaptation of LHC biogenesis. They also demonstrate how an adenosine triphosphate–independent chaperone uses conformational dynamics to switch its activity and client selectivity, thereby adapting to different proteostatic demands under shifting environmental conditions.
An emerging family of metal-halide perovskite semiconductors is highly attractive for optoelectronic applications because of their tunable light absorption, long-lived photogenerated carriers, and high defect tolerance. However, their inherent bandgaps limiting the photoabsorption below 1000 nanometers greatly constrain the further development of these materials and their optoelectronic devices. Here, we reported a straightforward strategy to achieving visible-to-infrared photoabsorption covering 630 to 2000 nanometers in inorganic perovskites by incorporating supramolecular crown ethers. Crown ethers enable supramolecular host-guest complexation and the formation of self-organizing Turing structures composed of original perovskites and supramolecular hybrid crystals. The visible-to-infrared photoabsorption is attributed to the interphase electron transitions in the Turing-structured perovskite hybrid matter system. Such visible-to-infrared photoabsorption is successfully translated into a photoelectronic response in an interdigitated photodetector. Our research extends the light absorption and detection capabilities of the perovskite hybrid semiconductors into the infrared region.
Billions of people rely upon groundwater for drinking water and agriculture, yet predicting how climate change may affect aquifer storage remains challenging. To gain insight beyond the short historical record, we reconstruct changes in groundwater levels in western North America during the last glacial termination (LGT, ~20 to 11 thousand years ago) using noble gas isotopes. Our reconstructions indicate remarkable stability of water table depth in a Pacific Northwest aquifer throughout the LGT despite increasing precipitation, closely matching independent Earth system model (ESM) simulations. In the American Southwest, ESM simulations and noble gas isotopes both suggest a pronounced LGT decline in water table depth in in response to decreasing precipitation, indicating distinct regional groundwater responses to climate. Despite the hydrologic simplicity of ESMs, their agreement with proxy reconstructions of past water table depth suggests that these models hold value in understanding groundwater dynamics and projecting large-scale aquifer responses to climate forcing.
The origin and function of chirality in DNA, proteins, and other building blocks of life represent a central question in biology. Observations of spin polarization and magnetization associated with electron transport through chiral molecules, known collectively as the chiral induced spin selectivity effect, suggest that chirality improves electron transfer. Using reconfigurable nanoscale control over conductivity at the LaAlO3/SrTiO3interface, we create chiral electron potentials that explicitly lack mirror symmetry. Quantum transport measurements on these chiral nanowires reveal enhanced electron pairing persisting to high magnetic fields (up to 18 tesla) and oscillatory transmission resonances as functions of both magnetic field and chemical potential. We interpret these resonances as arising from an engineered axial spin-orbit interaction within the chiral region. The ability to create one-dimensional electron waveguides with this specificity creates opportunities to test, via analog quantum simulation, theories about chirality and spin-polarized electron transport in one-dimensional geometries.
Regulatory T cell (Tregcell) therapy has been transformed through the use of chimeric antigen receptors (CARs). We previously found that human Tregcells minimally produce IL-10 and have a limited capacity to control innate immunity compared to type 1 regulatory T cells (Tr1 cells). To create “hybrid” CAR Tregcells with Tr1 cell-like properties, we examined whether thePDCD1locus could be exploited to endow Tregcells with CAR-regulated IL-10 expression. CRISPR-mediated PD1 deletion increased CAR Tregcell activation, and knock-in ofIL10under control of the PD1 promoter resulted in CAR-induced IL-10 secretion.IL10knock-in improved CAR Tregcell function, as determined by increased suppression of dendritic cells and alloantigen- and islet autoantigen–specific T cells. In vivo,IL10knock-in CAR Tregcells were stable, safe, and suppressed dendritic cells and xenogeneic graft-versus-host disease. CRISPR-mediated engineering to simultaneously remove an inhibitory signal and enhance a suppressive mechanism is a previously unexplored approach to improve CAR Tregcell potency.
Endothelial barrier dysfunction and the resulting vascular injury are responsible for multiorgan failure in sepsis. Myeloid C-type lectin domain family 5 member A (CLEC5A) is a pattern recognition receptor involved in host defense against infection. Mice lacking CLEC5A were resistant to cecal ligation and puncture (CLP)–induced polymicrobial sepsis and lipopolysaccharide (LPS)–induced endotoxemia, as observed by decreased mortality. Single-cell RNA sequencing revealed transcriptomic heterogeneity of vascular endothelial cells in CLEC5A-deficient lungs following CLP. Endothelial-specific knockdown of CLEC5A improved survival of CLP-challenged mice, which was completely ineffective with reexpression of endothelial CLEC5A. The survival benefits were attributed to alleviated inflammatory storm and vascular leakage. Furthermore, endothelial CLEC5A deficiency protected mice againstEscherichia coli–induced pneumonia. In vitro, CLEC5A deletion maintained trans-endothelial electrical resistance, and inhibited adhesion and trans-endothelial migration of monocytes/neutrophils under LPS stimulation. The study unveils the importance of CLEC5A in regulating endothelial barrier function and suggests endothelial CLEC5A as a therapeutic target for pneumonia or sepsis-causing bacterial infection.
Mineral-associated organic carbon (MAOC) is the largest terrestrial pool of organic carbon, yet controls on its formation remain unresolved. Existing MAOC is thought to preclude additional C storage on minerals, but this perspective is difficult to reconcile with observations that MAOC stacks in multilayers, suggesting that existing MAOC could promote greater C retention. Here, in a manipulative experiment using 118 soils from 15 agricultural sites across the United States, we show that MAOC formation is promoted by both existing MAOC and its counterpart—MAOC saturation deficit. The positive effect of existing MAOC on the formation of new MAOC persists after accounting for soil physicochemical properties that covary with MAOC. In contrast with current theory, we found that MAOC formation was not clearly influenced by microbial carbon-use efficiency (CUE). Our findings demonstrate that existing MAOC and saturation deficit, not microbial CUE, are key to determining new MAOC formation in agricultural soils.
The impact of chemotherapy-induced tumor cell pyroptosis on fibroblasts, a key stromal cell type within the tumor microenvironment (TME), remains unexplored. Here, we report morphologically and molecularly distinct subtypes of cancer-associated fibroblasts (CAFs) in bladder cancer, including αSMA+IL-6−myofibroblastic CAFs (myCAFs), αSMA−IL-6+inflammatory CAFs (iCAFs), and hybrid i/myCAFs. Caspase-1–dependent tumor pyroptosis releases several inflammatory chemokines, converting αSMA+CAF into iCAFs in a CCR6-dependent manner. This is clinically relevant, as a fibroblast gene signature driven by iCAF markers and collagen type III is enriched in patients with chemoresistant bladder cancer after neoadjuvant chemotherapy. Contrary to the current notion, iCAFs, rather than myCAFs, produce collagen III in response to chemotherapy, supporting the expansion of cancer stem cells (CSCs). Thus, tumor cell pyroptosis initiates an iCAF-CSC feedforward loop that drives chemoresistance, indicating that inflammatory cell death is not universally beneficial to anticancer therapy, depending on the target cell type.
Earth’s continental margins are dissected by submarine canyons that convey sediments, carbon, and nutrients to the deep ocean, regulating global biogeochemical fluxes. Despite their importance in the Earth system, the controls on canyon occurrence remain poorly understood. We report results from a spatial statistical model that explains global canyon distribution. By analyzing >2000 canyons, we show that canyon occurrence correlates with the inclination of continental slopes. Onshore orogeny and associated surface processes, long considered key controls on canyon formation, play a subordinate role. Instead, our results suggest slope inclination as the primary control on submarine canyon density. Because continental slope morphology is fundamentally shaped by marine tectonic and thermal processes, these large-scale forces indirectly govern canyon formation and distribution globally. As a result, they influence the presence of pathways that facilitate the transfer of sediments, carbon, and nutrients to the deep ocean, with implications for biogeochemical cycles over geological timescales.
Femtosecond lasers with extremely high peak intensity have driven remarkable advancements in manufacturing across science, medicine, and industry. However, the problem of notably low machining speed remains unsolved. Here, we demonstrate that by transiently exciting electrons in a transparent material, the laser drilling speed is increased by a factor of 1 million compared to that in multishot percussion drilling. By irradiating with a single shot of a spatially shaped ultrashort laser pulse, the optical properties are momentarily changed on the picosecond scale, making the material considerably easier to machine by a successive laser pulse. The selective absorption of laser energy in regions with excited electrons leads to the rapid heating and evaporation of material at an extraordinarily high speed. Furthermore, the machining is achieved using a low-power light source, four orders of magnitude lower than conventional femtosecond lasers. The concept of transiently altering material properties is expected to usher in a paradigm shift in research and development for manufacturing.
Edholm’s law predicts exponential growth in data rate and spectrum bandwidth for communications. Owing to exponentially increasing deep neural network computing demands and the slowing of Moore’s law, new computing paradigms are required for future advanced communications like 6G. Optical neural networks (ONNs) are promising accelerators but struggle with scalability and system overhead. Here, we introduce our multiplicative analog frequency transform optical neural network (MAFT-ONN), an artificial intelligence hardware accelerator that experimentally computes fully analog deep learning on raw radio frequency (RF) signals, performing modulation classification that quickly converges to 95% accuracy. MAFT-ONN also exhibits scalability with nearly 4 million fully analog operations for MNIST digit classification. Because of the Shannon capacity–limited analog data movement, MAFT-ONN is also hundreds of times faster than traditional RF receivers.
B cell epitope prediction tools are crucial for designing vaccines and disease diagnostics. However, predicting which antigens a specific antibody binds to and their exact binding sites (epitopes) remains challenging. Here, we present AbEpiTope-1.0, a tool for antibody-specific B cell epitope prediction, using AlphaFold for structural modeling and inverse folding for machine learning models. On a dataset of 1730 antibody-antigen complexes, AbEpiTope-1.0 outperforms AlphaFold in predicting modeled antibody-antigen interface accuracy. By creating swapped antibody-antigen complex structures for each antibody-antigen complex using incorrect antibodies, we show that predicted accuracies are sensitive to antibody input. Furthermore, a model variant optimized for antibody target prediction—differentiating true from swapped complexes—achieved an accuracy of 61.21% in correctly identifying antibody-antigen pairs. The tool evaluates hundreds of structures in minutes, providing researchers with a resource for screening antibodies targeting specific antigens. AbEpiTope-1.0 is freely available as a web server and software.
Pacinian corpuscles are among the most sensitive mechanoreceptors found in vertebrates, and they are tuned to vibrations in the highest perceptible frequency range (100 to 2000 Hz). One of their anatomical hallmarks is the onion-like cell layers surrounding the central axon. The innermost layers consist of ~60 densely packed lamellar Schwann cells (LSCs), whose function remains largely unknown. Using high-resolution three-dimensional electron microscopy, we found that LSCs do not form concentric rings, but complex, multilayered, and intertwining assemblies that are connected via a high density of desmosomes and gap junctions. LSCs make multiple converging contacts with the afferent axon via desmosomes. Using optogenetic manipulations of LSCs, we demonstrate not only that their activation drives reliable time-locked spiking in the axon but also that their inactivation significantly elevates the thresholds in situ and increases perceptual thresholds behaviorally. Together, these findings provide evidence that LSCs are a key element of somatosensory processing, actively potentiating mechanosensitivity in Pacinian corpuscles.
Mercury compounds are potent neurotoxins that pose threats to human health, primarily through fish consumption. Rivers, critical for drinking water and food supply, have seen rapid increases in mercury concentrations and export to coastal margins since the Industrial Revolution (~1850). However, patterns of these changes remain understudied, limiting assessments of environmental policies. Here, we develop a global model to simulate preindustrial riverine total mercury and assess human perturbations by comparing it to present-day conditions. We find that global rivers transported ~390 megagrams annually of mercury to the oceans in the preindustrial era, with spatial variability. Human activities have elevated riverine mercury budgets by two to three times in the present day. Establishing a baseline riverine mercury level, our findings reveal rapid responses of riverine mercury to human perturbations and could be used to inform targets for global riverine mercury restoration. Total riverine mercury concentrations could also be used as indicators to comprehensively understand the effectiveness of mercury pollution governance.
Carbon cycling between surface and mantle reservoirs is pivotal in fostering habitability of Earth. A critical yet poorly constrained parameter is whether crustal carbon can “survive” devolatilization processes that accompany slab subduction and therefore influence deep carbon budgets. Carbonatites provide a key record to address this important topic. Here, we present high-precision potassium isotope data for a large set of carbonatite samples from both continental and oceanic settings, spanning from 2 billion years ago to the present. Modeling suggests that the heavy potassium isotopic compositions of carbonatites are inherited from their mantle sources, rather than resulting from magmatic and postmagmatic processes. Our results demonstrate a strong link between the subduction of oceanic crust and the recycling of carbonates into the mantle sources of carbonatites. These findings support the hypothesis that subduction of carbonate-bearing altered oceanic crust has been a critical mechanism for transferring carbon into the deep Earth through time.
Tissue atlases provide foundational knowledge on the cellular organization and molecular distributions across molecular classes and spatial scales. Here, we construct a comprehensive spatiomolecular lipid atlas of the human kidney from 29 donor tissues using integrated multimodal molecular imaging. Our approach leverages high-spatial-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry for untargeted lipid mapping, stained microscopy for histopathological assessment, and tissue segmentation using autofluorescence microscopy. With a combination of unsupervised, supervised, and interpretable machine learning, the atlas provides multivariate lipid profiles of specific multicellular functional tissue units (FTUs) of the nephron, including the glomerulus, proximal tubules, thick ascending limb, distal tubules, and collecting ducts. In total, the atlas consists of tens of thousands of FTUs and millions of mass spectrometry measurements. Detailed patient, clinical, and histopathologic information allowed molecular data to be mined on the basis of these features. As examples, we highlight the discovery of how lipid profiles are altered with sex and differences in body mass index.
Oceanic mesoscale eddies play a crucial but underexplored role in regulating carbon fluxes and climate change. While they redistribute heat, salt, nutrients, and other tracers, their effects on CO2uptake remain uncertain. Using observation-based machine learning to estimate CO2fluxes throughout the lifetimes of thousands of eddies, we show that anticyclonic eddies substantially enhance CO2uptake on average, while cyclonic eddies marginally diminish it. This asymmetry yields an overall net increase in CO2absorption by 9.98 ± 2.28 and 13.82 ± 9.94% in the Kuroshio Extension and Gulf Stream, respectively, major carbon sequestration regions. The primary driver of this enhanced uptake is the downward pumping of dissolved inorganic carbon within anticyclonic eddies. Asymmetric biological responses between anticyclonic and cyclonic eddies contribute to the overall eddy-induced CO2flux imbalance. The finding suggests a potential underestimation of the ocean’s capacity for carbon sequestration because of insufficient incorporation of eddies in current observations, emphasizing the need for expanded monitoring in eddy-rich, undersampled regions.
Biomolecular condensates formed via phase separation of proteins, and nucleic acids regulate crucial cellular processes. However, such liquid-like membraneless bodies can undergo aberrant liquid-to-solid transitions into amyloid-like pathological species, which necessitates their efficient clearance by the cellular protein quality control machinery comprising molecular chaperones. We present a unique case to demonstrate that a heat shock protein 40 (Ydj1) promotes the heterotypic phase separation of intrinsically disordered tau via a multitude of interactions. Using multicolor imaging, time-resolved fluorescence anisotropy, vibrational Raman spectroscopy, and single-molecule Förster resonance energy transfer, we unmask the crucial molecular events associated with heterotypic phase separation of tau. We show that the presence of Ydj1 within condensates abolishes phase transitions into amyloids, unlike tau-only droplets that spontaneously mature into amyloid fibrils. We identify the amyloidogenic hexapeptide motifs located in the hydrophobic microtubule-binding region of tau that interacts with the peptide-binding regions of Ydj1 promoting tau-Ydj1 condensate formation. Our results provide mechanistic underpinnings of condensate-mediated protein homeostasis.
Disruption in neuronal and synaptic metabolic homeostasis is a key driver of neurodegeneration in Parkinson’s disease (PD). Mitochondrial activity, biomass, and efficiency are critical to this balance. While activity and biomass are well characterized in PD pathology, mitochondrial metabolic efficiency remains insufficiently explored. Our previous studies showed that the protein product of PD-associated gene DJ-1 modulates metabolic efficiency through its interaction with the F1Fo-ATP-synthase β subunit (β-sub). Here, using proximity ligation assay (PLA), we compared mitochondrial DJ-1-β-sub association in distinct mesencephalic dopaminergic (mesDA) neuronal subpopulations and their intracellular compartments of PD and control postmortem brains. In PD brains, DJ-1-β-sub-PLA was lower than control in substantia nigra pars compacta (SNpc) somata and neurites but unchanged in ventral tegmental area (VTA) neurons. In PD and control cases, the PLA signal was reduced in distal neurites of SNpc compared to VTA neurons. These intracellular and region-specific differences suggest that impaired mitochondrial efficiency may contribute to the differential vulnerability of mesDA neurons in PD.
Many animals can regenerate tissues after injury. While the initiation of regeneration has been studied extensively, how the damage response ends and normal gene expression returns is unclear. We found that inDrosophilawing imaginal discs, the pioneer transcription factor Zelda controls the exit from regeneration and return to normal gene expression. Optogenetic inactivation of Zelda during regeneration disrupted patterning, induced cell fate errors, and caused morphological defects yet had no effect on normal wing development. Using Cleavage Under Targets & Release Using Nuclease, we identified targets of Zelda important for the end of regeneration, including genes that control wing margin and vein specification, compartment identity, and cell adhesion. We also found that GAGA factor and Fork head similarly coordinate patterning after regeneration and that chromatin regions bound by Zelda increase in accessibility during regeneration. Thus, Zelda orchestrates the transition from regeneration to normal gene expression, highlighting a fundamental difference between developmental and regeneration patterning in the wing disc.
Conventional dendritic cells (cDCs) regulate adaptive immunity. Although most cDCs are of myeloid origin (M-cDCs), some cDCs originate from pro–plasmacytoid DCs (pro-pDCs) via pDC-like cells [lymphoid cDCs (L-cDCs)]. Using lymphoid progenitor–tracking systems, we report tissue segregation, a unique differentiation pathway, and the functions of L-cDCs. Notably, L-cDC2s are predominantly distributed in barrier tissues such as the lungs and skin. Single-cell RNA-sequencing analysis revealed the enrichment of lymphocyte signature genes in L-cDCs. We identified lymphocyte-primed cDC precursors, which are distinct from pDC-like cells, as sources of L-cDCs. Compared with M-cDC2s, L-cDC2s weakly primed T cells under low-dose antigen stimulation and preferentially promoted T helper 2 (TH2) differentiation under sufficient antigenic stimulation. These results suggest the diverse developmental pathways of L-cDCs and imply the contribution of L-cDCs to tolerance and hyperresponses to TH2-related antigens in barrier tissues.
Photocatalytic hydrogen production has emerged as a promising strategy to mitigate the environmental impact of carbon-intensive chemical industries. Loading single atoms is known to enhance photocatalytic efficiency, as their activity is heavily influenced by the microenvironment. Therefore, achieving precise control over the microenvironment of single atoms is crucial but remains a substantial challenge. Here, we reported a unique Pt–C/TiO2photocatalyst with Pt quantum dots (PtQD) and C-coordinated Pt single atoms (PtSA). Under the given experimental conditions, the hydrogen production rate reaches 43.2 mmol hour−1with 70 mg of the photocatalyst. Notably, the hydrogen molecules generated per incident photon (H2/photon) reach 0.92. The special coordination environment influenced by C not only provides a direct transmission channel for photogenerated electrons but also activates surrounding Ti, thus improving the separation of the electron-hole pairs and H2production performance. This research provides a prospect of efficient on-site hydrogen production.
Ocean change leaves a potentially important imprint on ocean colorimetry. Here, we present an overview and current evaluation of the global ocean color variability from 1998 to 2022, and satellites observe that 36% of oceans (~122 million square kilometers, derived from valid observations) have experienced changes (P< 0.1). In this context, 25% of the area (formerly blue hue) is turning light blue or green, while the remaining 11% becomes bluer, mainly concentrating in the low-latitude oceans. This study further identifies a “direct” notable impact of both sea surface temperature (SST) and climate on ocean colorimetry tendency and anomaly, especially in the low-latitude oceans. Extreme SST events cause “distinct” ocean colorimetry anomalies, although 94% of cases involve relatively small SST fluctuations. Causal analysis reveals important impacts of climate change on equatorial ocean dynamics, particularly ENSO events. Our findings prove the low-latitude oceans as one of the core changing regions that respond to climate change in the early 21st century.
Membrane-based processes, such as reverse osmosis (RO) and nanofiltration (NF), are widely used for water purification and desalination due to their high energy efficiency and exceptional solute-water selectivity. Nevertheless, the fundamental, molecular-level mechanisms governing ion selectivity are still not fully understood. This study explores ion selectivity in polyamide desalination membranes, focusing on the partitioning and diffusion mechanisms of co-ions and counterions. Our experimental and molecular simulation results reveal that electrostatic interactions play a key role in impeding co-ion partitioning while enhancing their diffusion. The results further suggest that ion selectivity is predominantly controlled by the partitioning step, particularly the selective partitioning of co-ions. This finding highlights the importance of focusing on ion partitioning at the water-membrane interface to improve membrane ion-ion selectivity. In addition, our results point out to a trade-off between partitioning and diffusion, requiring careful tuning of these processes. Overall, this study provides the scientific foundation for molecular design of membranes with high ion-ion selectivity.
Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing group of virus-encoded transmembrane oligomeric proteins that allow passage of small molecules across the membrane. Despite sparsity in viroporin structures, recent work has revealed diversity in both the number of transmembrane helices and oligomeric states. Here, we provide evidence that the small hydrophobic protein (SH) from mumps virus is a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracellular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expression of wild-type SH and variants inXenopus laevisoocytes reveals the viroporin as a chloride channel, with transport facilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by the small-molecule BIT225, highlighting the potential for antiviral targeting through SH.
Tropical cyclones regularly form above the ocean’s largest subsurface oxygen minimum zone (OMZ) in the eastern tropical North Pacific Ocean (ETNP), yet how these powerful storms affect this biogeochemically important region remains unknown. We captured multiple direct and potentially interactive oceanographic effects of a Category 4 hurricane (Bud) during a 2018 research cruise in the ETNP. Profiles and samples collected directly beneath Bud’s wake revealed rapid OMZ shoaling of 29 to 50 meters, reaching depths as shallow as 41 meters. Untargeted mass spectrometry–based characterization of organic matter, along with elevated particulate organic carbon and chlorophyll concentrations, demonstrated production and accumulation of distinct organic compounds—including phytoplankton biomarkers—within a hurricane-generated phytoplankton bloom. 16SrRNA transcripts from active microbes were dominated by degraders of phytoplankton-derived organic matter near the surface and by anaerobic bacteria (including sulfate-reducing bacteria) within the shoaled OMZ—indicating rapid microbial responses. Tropical cyclones therefore severely disrupt OMZ biogeochemistry through vertical OMZ expansion and altered carbon cycling.
In contrast to global warming, the subpolar North Atlantic has experienced long-term cooling throughout the 20th century. This cooling, known as the North Atlantic cold blob, has been hypothesized to arise from reduced poleward oceanic heat transport associated with a slowdown of the Atlantic meridional overturning circulation (AMOC). Here, by diagnosing historical simulations from multiple coupled climate models, we find that ocean heat transport is not the only pathway through which the AMOC modulates sea surface temperature variability. A weakened AMOC is also associated with colder, drier lower atmospheric conditions, which lead to a reduction in surface warming expected from increasing amounts of heat-trapping gases by reducing downward clear-sky longwave radiation at the surface. This radiative pathway and the oceanic processes contribute equally to the North Atlantic cold blob. These results highlight the importance of the AMOC’s impact on atmospheric properties and their radiative effects.
Structural materials for protective applications are exposed to complex environments including impacts under a wide range of loading velocities. Bioinspired Bouligand-type structural materials show high impact resistance under quasi-static and low-velocity impacts. However, their protective performance under high-velocity impact is lacking investigation. Herein, we expand the Bouligand-type structure family by synergistically considering structural design and compositional regulation and highlight a double-twisted Bouligand structure with gradient composition (DT-Bou-G) for enhancing impact resistance under a wide range of loading velocities. As one demonstration, the DT-Bou-G structural material was fabricated by multimaterial fused deposition with stiff polylactic acid and soft thermoplastic polyurethane as raw materials. Experimental investigations show its superior impact-resistant capability under multiple loading velocities (0.5 millimeters per minute, 2.1 meters per second, 4.3 meters per second, and 120 meters per second). Finite element simulations further prove the mechanical result and reveal the underlying mechanisms. The DT-Bou-G structure will inspire the design of engineering protective materials capable of withstanding complex working conditions.
The excitation-inhibition ratio is a key functional property of cortical microcircuits which changes throughout an individual’s lifespan. Adolescence is considered a critical period for maturation of excitation-inhibition ratio. This has primarily been observed in animal studies. However, there is limited human in vivo evidence for maturation of excitation-inhibition ratio at the individual level. Here, we developed an individualized in vivo marker of regional excitation-inhibition ratio in human adolescents, estimated using large-scale simulations of biophysical network models fitted to resting-state functional imaging data from both cross-sectional (n= 752) and longitudinal (n= 149) cohorts. In both datasets, we found a widespread decrease in excitation-inhibition ratio in association areas, paralleled by an increase or lack of change in sensorimotor areas. This developmental pattern was aligned with multiscale markers of sensorimotor-association differentiation. Although our main findings were robust across alternative modeling configurations, we observed local variations, highlighting the importance of methodological choices for future studies.
The escalating data volume and complexity resulting from the rapid expansion of artificial intelligence (AI), Internet of Things (IoT), and 5G/6G mobile networks is creating an urgent need for energy-efficient, scalable computing hardware. Here, we demonstrate a hypermultiplexed tensor optical processor that can perform trillions of operations per second using space-time-wavelength three-dimensional optical parallelism, enabling O(N2) operations per clock cycle with O(N) modulator devices. The system is built with wafer-fabricated III/V micrometer-scale lasers and high-speed thin-film lithium niobate electro-optics for encoding at tens of femtojoules per symbol. Lasing threshold incorporates analog inline rectifier (ReLU) nonlinearity for low-latency activation. The system scalability is verified with machine learning models of 405,000 parameters. A combination of high clock rates, energy-efficient processing, and programmability unlocks the potential of light for low-energy AI accelerators for applications ranging from training of large AI models to real-time decision-making in edge deployment.
We assess how quantum-mechanical effects associated with high-frequency chromophore vibrations influence excitation energy transfer in biological light-harvesting complexes. After defining a classical nuclear limit that is consistent with the quantum-classical equilibrium, we include nuclear quantum effects through a variational polaron transformation of the high-frequency vibrational modes. This approach is validated by comparison with fully quantum-mechanical benchmark calculations and applied to three prototypical light-harvesting complexes. For light-harvesting complex 2 of purple bacteria, the inter-ring transfer is 1.5 times slower in the quantum treatment than in the classical treatment. For the Fenna-Matthews-Olson complex, the transfer rate is the same in both cases, whereas for light-harvesting complex II of spinach, the transfer is 1.7 times slower in the quantum treatment. The effect is most pronounced for systems with large excitonic energy gaps and strong vibronic coupling to high-frequency modes. In all cases, nuclear quantum effects are found to be unimportant for the directionality of energy transfer.
High-entropy oxides (HEOs) have attracted attention due to their unique elemental synergistic effect and lattice distortion. However, mixing elements’ vastly different radii and valences leads to substantial element segregation during the reaction. In addition, the requirement for a harsh temperature (1100°C) to achieve entropy stabilization results in the volatilization of low–melting point components. Here, we propose a strategy for synthesizing functionalized Ga-based HEOs (GHEOs) at a low temperature (400°C) by the Ga integration mechanism. The negative mixing enthalpy between Ga and other metals reduces the Gibbs free energy, enabling the creation of homogeneous GHEOs through a hydrothermal process at a lower temperature. The Ga integration mechanism is supported by thermodynamic and density functional theory analyses. In particular, the perovskite, spinel, and rock salt crystal can be precisely tuned by choosing metal ions, enabling tailored applications in electrocatalysis, energy-saving materials, and methane sensors. Hence, this GHEOs strategy can be extended to realize many ideal GHEOs adjusted for specific applications.
Bacteriophages use receptor-binding proteins (RBPs) to adhere to bacterial hosts, yet their sequence and structural diversity remain poorly understood. Tail fibers, a major class of RBPs, are elongated and flexible trimeric proteins, making their full-length structures difficult to resolve experimentally. Advances in deep learning–based protein structure prediction, such as AlphaFold2-multimer (AF2M) and ESMFold, provide opportunities for studying these challenging proteins. Here, we introduce RBPseg, a method that combines monomeric ESMFold predictions with a structural-based domain identification approach, to divide tail fiber sequences into manageable fractions for high-confidence modeling with AF2M. Using this approach, we generated complete tail fiber models, validated by single-particle cryo–electron microscopy of five fibers from three phages. A structural classification of 67 fibers identified 16 distinct classes and 89 domains, revealing patterns of modularity, convergence, divergence, and domain swapping. Our findings suggest that these structural classes represent at least 24% of the known tail fiber universe, providing key insights into their evolution and functionality.
Itaconate, derived from the tricarboxylic acid cycle, is recognized as a key regulator of the immune response in mammals. Despite this well-characterized role, its presence and functions within plants have remained largely unexplored. Here, we identify itaconate as an endogenous metabolite in maize andArabidopsisand investigate its impact on development. Itaconate treatment has dose-dependent effects on growth in maize andArabidopsisseedlings. To characterize the mechanisms responsible for itaconate’s regulation of plant development, we investigated its effects onArabidopsisroots using analysis of mutants and reporter lines, RNA sequencing, and two forms of protein-metabolite interaction assays. Our results demonstrate that itaconate covalently binds to proteins and substantially influences critical pathways in plants, including central carbon metabolism, phytohormone signaling, and oxidative stress response. This study expands the current understanding of itaconate’s roles beyond the animal kingdom, providing a foundation for further research into its complex functions in plants.
The two-dimensional (2D) thermoacoustic emitter excels in producing a flat sound spectrum above 5 kilohertz but struggles with reduced sound pressure at lower frequencies. To address this, we designed a wearable acoustic device that combines graphene with a 3D-printed cavity, enabling tunable resonant frequency and enhanced sound amplification based on thermoacoustic resonance. The design features laser-scribed graphene as a 2D flexible thermoacoustic source attached onto the cavity, with a specialized chamber above to facilitate air vibration through Joule heat release. The inversely proportional relationship between the operating resonant frequency and the path distance of sound propagation is verified, the sound pressure level increases from 32 to 71 decibels at 5.4 kilohertz when the cavity height increases from 0 to 10 millimeters. Last, a wearable conch-like spiral cavity with graphene is tested under a commercial artificial ear system, demonstrating an effective amplification at approximately 1 and 10 kilohertz, offering insights for developing flexible loudspeakers.
Classically, chemokines coordinate leukocyte trafficking; however, many chemokines also have direct antibacterial activity. The bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. We report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill bacteria and that they exert rapid bacteriostatic and bactericidal effects with a higher potency than the antimicrobial peptide β-defensin 3. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics,Escherichia colifailed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as binding partners for chemokines responsible for chemokine antimicrobial action.
We present the class of extreme nuclear transients (ENTs), including the most energetic single transient yet found, Gaia18cdj. Each ENT is coincident with its host-galaxy nucleus and exhibits a smooth (<10% excess variability), luminous (2 × 1045to 7 × 1045erg per second), and long-lived (>150 days) flare. ENTs are extremely rare (≥1 × 10–3cubic gigaparsec per year) compared to any other known class of transients. They are at least twice as energetic (0.5 × 1053to 2.5 × 1053erg) as any other known transient, ruling out supernova origins. Instead, the high peak luminosities, long flare timescales, and immense radiated energies of the ENTs are most consistent with the tidal disruption of high-mass (≳3M⊙) stars by massive (≳108M⊙) supermassive black holes (SMBHs). ENTs will be visible to high redshifts (z~ 4 to 6) in upcoming surveys, providing an avenue to study the high-mass end of the SMBH mass distribution, complementing recent studies of actively accreting SMBHs at high redshifts with the James Webb Space Telescope.
Two kinds of multidimensional atom interferometers are demonstrated that are capable of measuring both the magnitude and direction of applied inertial forces. These interferometers, built from ultracold Bose-Einstein condensed rubidium atoms, use an original design that operates entirely within the Bloch bands of an optical lattice. Through time-dependent lattice position control, we realize Bloch oscillations in two dimensions and a vector atomic Michelson interferometer. Fits to the observed Bloch oscillations demonstrate the measurement of an applied acceleration of 2galong two axes, wheregis Earth’s gravitational acceleration. For the Michelson interferometer, we perform Bayesian inferencing from a 49-channel output by repeating experiments for two-axis accelerations and demonstrate vector parameter estimation. Accelerations can be measured from single experimental runs and do not require repeated shots to construct a fringe. The performance of our device is near the quantum limit for the interferometer size and quantum detection efficiency of the atoms.
Despite advances in machine learning and computer vision for biomedical imaging, machine reading and learning of colors remain underexplored. Color consistency in computer vision, color constancy in human perception, and color accuracy in biomedical imaging are intertwined, complicating digital color–based diagnostics. Existing color reference charts and correction algorithms are inadequate for mobile health (mHealth) and telemedicine in digital health applications where detecting subtle color changes is critical. We present a machine reading and learning platform for color recognition and quantification to extract diagnostic information from colors. A unique combination of spectroscopic gamut determination, reference color optimization, nonsubjective quantification metrics, and neural network–based color recovery retrieves absolute colors of biological tissue. Studies on inflammation bioimaging of photocarcinogenesis and mHealth blood hemoglobin assessment demonstrate accuracy and precision in color recovery across diverse acquisition scenarios. The reported framework overcomes limitations of conventional colorimetric detection, enabling machine-compatible color-based bioassays and bioimaging, advancing digital diagnostics.
Quantum light sources, especially single-photon emitters, are crucial for advancing quantum technologies. Despite extensive research, the behavior of defect-localized excitons in monolayer WSe2under external perturbations, such as magnetic fields, remain underexplored. This study investigates the nature and dynamics of defect-localized excitons under in-plane magnetic fields using steady-state and time-resolved photoluminescence (PL) spectroscopy. Observations reveal a sharp PL peak, indicative of single-photon emission, with doublet peaks from hybridized spin–state excitons. Notably, magnetic brightening of the PL peak was detected at a low magnetic field (<1 tesla), and the dynamics of hybridized-state excitons under magnetic fields indicated field-induced state mixing, explaining the magnetic brightening. These findings advance tunable single-photon emitters controlled by magnetic fields, with implications for quantum optics applications.
The subcellular localization of neurotransmitter receptors is strictly regulated in neurons. Changes in the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–type glutamate receptors (AMPARs) play an essential role in synaptic plasticity, which is the cellular basis of learning and memory. To explore receptor trafficking, genetically encoded approaches (e.g., the fusion of fluorescent proteins to receptors) are often used. However, concerns remain that genetic approaches cannot fully reproduce the receptor functions that are inherent to neurons. Herein, we report on PFQX1(AF488), a fluorescent probe for the visualization of cell-surface AMPARs without any genetic manipulation to neurons. The rapid and reversible staining features of this probe enabled snapshot imaging, which showed the accumulation of native AMPARs in dendritic spines during synaptic plasticity. Moreover, the mechanism of this synaptic accumulation, for which genetically encoded approaches have given controversial results, was revealed by integrating two chemical methods: PFQX1(AF488) and covalent chemical labeling.
Alloys, solid solutions, and doped systems are essential in technologies such as energy generation and catalysis, but predicting their properties remains challenging because of compositional disorder. As the concentration of components changes in a binary solid solutionA(1−x)Bx, the number of possible configurations becomes computationally intractable. Algorithms used in classical optimization methods cannot avoid assessing high-energy states where, for example, simulated annealing is designed to initially spend computational effort. We introduce a scalable, practical, and accurate approach using quantum annealing to efficiently sample low-energy configurations of disordered materials, avoiding the need for excessive high-energy calculations. Our method includes temperature and simulates large unit cells, producing a Boltzmann-like distribution to identify thermodynamically relevant structures. We demonstrate this by predicting bandgap bowing inAl1−xGaxNand bulk modulus variations inTa1−xWx, with results in excellent agreement with experiments.
Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons is known to reduce maladaptive host responses during endotoxemia, only selective vagal afferent neuron stimulation inhibited TLR7-induced macrophage activation and neutrophil recruitment to the lung. These anti-inflammatory actions are dependent on adrenal gland–derived epinephrine, as adrenalectomy or inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the β2-adrenergic receptor (β2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in β2AR knockout mice and with pharmacological inhibition of the β2AR. These findings demonstrate a previously unidentified neuroimmune circuit elicited by VNS that can control acute lung inflammation.
Laser-induced air fluorescence in the ultraviolet regime is primarily attributed to transitions between the C and B states in excited neutralN2molecules and between the B and X states inN2+ions. However, the mechanism underlying the former remains contentious, as direct population to the C state by light fields is forbidden by electron spin constraints. In this work, we investigate the mechanism of air fluorescence from excited neutralN2molecules by carrier-envelope phase–stabilized sub–4 femtosecond pulses. Our results show that fluorescence fromN2+ions reaches a maximum with cosine-like pulses, while fluorescence from excited neutralN2molecules peaks with sine-like pulses. In addition, by scanning the chirp of the driving pulse, we find that ionic fluorescence is maximized with chirp-free pulses, whereas neutral fluorescence favors negatively chirped pulses. These observations, supported by classical trajectory Monte Carlo simulations, support the mechanism of intersystem crossing from excited spin-singlet states, which are populated via recollision-induced strong-field excitation.
Several landmark studies over the past decade have uncovered a critical role of the CRL3KBTBD4ubiquitin ligase complex in regulating stability of corepressor of repressor element 1 silencing transcription factor (CoREST) complex proteins and normal hematopoietic stem cell self-renewal. There is now mounting evidence that the CoREST complex plays oncogenic roles, although the contributions of its catalytic versus noncatalytic functions remain unclear. Here, we summarize and discuss mechanisms whereby the CoREST complex coopts tissue-specific transcription factors to elicit pathogenic activity in cancer and neurodegenerative disease. We also identify tumor types with selective dependencies on the scaffolding properties of the CoREST complex. We argue that these tumor types may benefit from a KBTBD4-activating/CoREST complex degrader therapy, which could also enhance antitumor immunity and sensitize resistant tumors to immunotherapy. Overall, understanding how the CoREST complex operates abnormally and differences between its targeting through catalytic inhibitors or protein degraders will help discern all possible applications for targeting therapies now in clinical development.
The autophagosomal SNARE (solubleN-ethylmaleimide–sensitive factor attachment protein) Syntaxin17 (Syx17) plays a pivotal role in autophagosome-lysosome fusion, yet the broader impact of its loss remains elusive. Our investigation of Syx17 function inDrosophilanephrocytes and salivary gland cells revealed unexpected effects. We find that Syx17 loss induces the formation of autophagosome-lysosome clusters in a HOPS (homotypic fusion and vacuole protein sorting)–dependent manner, entrapping this tether, autophagosomes, and lysosomes. While locked in clusters, these organelles cannot participate in other vesicle fusions, impeding endosomal progression and autophagosome secretion. Therefore, the absence of Syx17 not only inhibits autophagosome-lysosome fusion but also prevents HOPS release from autophagosome-lysosome tethering sites causing a “tethering lock.” Preventing autophagosome formation or removing the HOPS adaptor Plekhm1 (pleckstrin homology domain–containing family M member 1) leads to release of HOPS and lysosomes from these clusters, thus rescuing secondary effects of Syx17 loss. Our findings show that a tethering lock can disrupt multiple vesicle trafficking routes.
Fibroblastic reticular cells (FRCs) are specialized fibroblasts that construct secondary lymphoid organs where they provide crucial signals for immune cell homeostasis and migration. While splenic FRCs are thought to support antiviral T cell responses, their role remains unclear. Here, we found that ablation of splenic FRCs impaired virus-specific CD8+T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Immunofluorescence imaging revealed that FRCs promote CD8+T cell clustering with type 1 conventional dendritic cells (cDC1) in the T cell zone before migration to the infected marginal zone. Without FRCs, T cells instead clustered with cDC1 and virus-infected cells in the marginal zone, leading to suboptimal priming. Mechanistically, FRCs coordinated early viral replication and the inflammatory milieu for optimal DC activation, and an intact FRC network was crucial for generating effector T cells and maintaining protective memory T cells. Thus, splenic FRCs provide essential lymphoid niches for antiviral T cell responses.
More than 90% of the world’s hydrogen (H2) is produced from fossil fuel sources, which requires energy-intensive separation and purification to produce high-purity H2fuel and to capture the carbon dioxide (CO2) by-product. While membranes can decarbonize H2/CO2separation, their moderate H2/CO2selectivity requires secondary H2purification by pressure swing adsorption. Here, we report hyperselective carbon molecular sieve hollow fiber membranes showing H2/CO2selectivity exceeding 7000 under mixture permeation at 150°C, which is almost 30 times higher than the most selective nonmetallic membrane reported in the literature. The membrane is able to maintain an ultrahigh H2/CO2selectivity over 1400 under mixture permeation at 400°C. Pore structure characterization suggests that highly refined ultramicropores are responsible for effectively discriminating the closely sized H2and CO2molecules in the hyperselective carbon molecular sieve membrane. Modeling shows that the unprecedented H2/CO2selectivity will potentially allow one-step enrichment of fuel-grade H2from shifted syngas for decarbonized H2production.
The Fe-Ni alloy is believed to be the main component of Earth’s core. Yet, a comprehensive understanding of phase equilibria near the melting point of this alloy under core conditions is still lacking, leaving the effect of nickel inconclusive. Using ab initio simulations, we computed Gibbs free energy and phase diagram for liquid and solid solutions of the Fe-Ni alloy under conditions close to the inner core. The Fe-Ni phase diagram provides crucial insights for understanding previous experimental observations and crystallization simulations of the Fe-Ni alloy under core conditions. It also presents complex scenarios for inner core structures, suggesting body-centered cubic (bcc)–liquid coexistence at the inner core boundary and the possibility of multilayer structures consisting of bcc–hexagonal close-packed (hcp) composites within the inner core. Our work clarifies nickel’s substantial impact on the inner core structure, providing additional constraints for studying the core’s composition and formation.
Climate change is decimating habitat-forming species in ecosystems around the world. Yet, the impacts of habitat loss on the energetics of the wider food web remain uncertain for many iconic ecosystems, including cold-water kelp forests. Here, we assessed how the loss of kelp forests and the subsequent proliferation of low-lying turf algae in the Gulf of Maine have altered the trophic niches of, and energy acquired by, predatory reef fishes. Bulk tissueδ13C andδ15N analysis showed that fishes in kelp forests had larger trophic niches and greater interspecific niche separation than fishes on turf reefs. Moreover,δ13C analysis of essential amino acids revealed that kelp-derived energy accounted for most of the energy used by kelp forest fishes (> 50% on average), whereas fishes on turf reefs compensated for kelp decline via greater reliance on a phytoplankton-based energy channel. Therefore, ecosystem state shifts to turf algae—now a global phenomenon—may have far-reaching impacts on food web energetics and resilience.
Anemotaxis behaviors inspired by rats have tremendous potential in efficiently processing perilous search and rescue operations in the physical world, but there is still lack of hardware components that can efficiently sense, encode, and recognize wind signal. Here, we report an artificial vibrissal system consisting of a self-powered carbon black sensor and threshold-switching HfO2memristor. By integrating a forming HfO2memristor with a self-powered angle-detecting hydro-voltaic sensor, the spiking sensory neuron can synchronously perceive and encode wind, humidity, and temperature signals into spikes with different frequencies. Furthermore, to validate the self-powered artificial vibrissal system with anemotaxis behavior, a robotic car with equipped artificial vibrissal system tracks trajectory toward the air source has been demonstrated. This design not only addresses the high energy consumption and low computing issues of traditional sensory system but also introduces the multimode functionalities, therefore promoting the construction of neuromorphic perception systems for neurorobotics.
Past coral range expansions suggest that high-latitude environments may serve as refugia, potentially buffering coral biodiversity loss due to climate change. We explore this possibility for corals globally, using a dynamic metacommunity model incorporating temperature, photosynthetically available radiation, pH, and four distinct, interacting coral assemblages. This model reasonably reproduces the observed distribution and recent decline of corals across the Indo-Pacific and Caribbean. Our simulations suggest that there is a mismatch between the timescales of coral reef decline and range expansion under future predicted climate change. Whereas the most severe declines in coral cover will likely occur within 40 to 80 years, large-scale coral reef expansion requires centuries. The absence of large-scale coral refugia in the face of rapid anthropogenic climate change emphasizes the urgent need to reduce greenhouse gas emissions and mitigate nonthermal stressors for corals, both in the tropics and in higher latitudes.
SalmonellaTyphi assembles and secretes two forms of typhoid toxin by using two receptor-binding subunits, PltB and PltC. Unlike PltB typhoid toxin, little is known about the tropism and functional consequences of PltC typhoid toxin. Here, we report that PltC typhoid toxin has hepatobiliary tropism through the binding of PltC subunit to sulfated glycans on liver sinusoidal endothelial cells and gallbladder epithelial cells. Critical bacterial and mammalian cell factors involved are PltC R109 residue and carbohydrate sulfotransferases CHST2/4. One notable effect associated with the hepatobiliary tropism of PltC typhoid toxin is a reduction in bile acids, consequently promotingS.Typhi pathogenicity in infected mice. Similarly, bile acids serve as anti–S.Typhi infectivity agents at the cellular level, as bile acids inhibit invasion of mammalian cells. These findings highlight a distinct mechanism used by a bacterial exotoxin promoting the pathogenicity of the cognate bacteria and offer insights into the development of antivirulence agents against PltC typhoid toxin and/orS.Typhi.
The endolysosomal pathway plays an evolutionarily conserved role in pathogen clearance, and viruses have evolved complex mechanisms to evade this host defense system. Here, we describe a previously unidentified aspect of coronaviral infection, whereby the master transcriptional activator of lysosomal homeostasis—TFEB—is targeted for proteasomal-mediated degradation upon viral infection. Through mass spectrometry analysis and an unbiased small interfering RNA screen, we identify that TFEB protein stability is coordinately regulated by the E3 ubiquitin ligase subunit DCAF7 and the PAK2 kinase. We derive a series of novel small molecules that interfere with the DCAF7-TFEB interaction. These agents inhibit virus-induced TFEB degradation and demonstrate broad antiviral activities including attenuating severe acute respiratory syndrome coronavirus 2 infection in two animal models. Together, these results delineate a virally triggered pathway that impairs lysosomal homeostasis in the host. Small molecule E3 ubiquitin ligase DCAF7 inhibitors that restore lysosomal function represent a novel class of host-directed, antiviral therapies useful for current and potentially future coronaviral variants.
Learning disabilities affect a substantial proportion of children worldwide, with far-reaching consequences for their academic, professional, and personal lives. Here we develop digital twins—biologically plausible personalized deep neural networks (pDNNs)—to investigate the neurophysiological mechanisms underlying learning disabilities in children. Our pDNN reproduces behavioral and neural activity patterns observed in affected children, including lower performance accuracy, slower learning rates, neural hyperexcitability, and reduced neural differentiation of numerical problems. Crucially, pDNN models reveal aberrancies in the geometry of manifold structure, providing a comprehensive view of how neural excitability influences both learning performance and the internal structure of neural representations. Our findings not only advance knowledge of the neurophysiological underpinnings of learning differences but also open avenues for targeted, personalized strategies designed to bridge cognitive gaps in affected children. This work reveals the power of digital twins integrating artificial intelligence and neuroscience to uncover mechanisms underlying neurodevelopmental disorders.
Ice-jam floods are a unique yet understudied hydrological hazard, occurring in cold-region rivers when upstream thawing and downstream freezing create ice blockages. Despite their severe impacts, their atmospheric drivers and future trends remain unclear. Using a 160-year documentary record, historical reanalysis datasets, and statistical modeling, we examine the climatic and hydrological controls of ice-jam floods in the lower Yellow River, one of the world’s most flood-prone rivers. Our findings show that ice-jam floods are strongly influenced by large-scale atmospheric teleconnections, including the Arctic Oscillation, Siberian High, and Ural Blocking, which regulate regional thermal contrasts and cold-air intrusions. Over the past century, ice-jam flood frequency has declined, with hot spots shifting toward the river estuary due to weakening upstream-to-downstream temperature gradients under climate warming. Projections using bias-corrected CMIP6 multimodel ensemble indicate a continued decline in ice-jam flood occurrences by 2100. Our study bridges historical and future perspectives, emphasizing the need for adaptive flood management as climate change shifts hydrological risks worldwide.
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Scarmeas & Noriega De La Colina use the ancient Greek concepts of nosos (biological disease) and asthenia (functional decline) to frame the shift in Alzheimer’s disease diagnosis from clinical symptoms to biomarkers, calling for better public understanding of both biological presence and lived experience.
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AbstractEssential tremor (ET) is a highly prevalent movement disorder characterized by high heritability. However, the genetic basis of this disease remains largely unknown. Understanding the genetic causes of ET is crucial for unraveling its pathogenesis and developing targeted therapies. In this study, we aimed to investigate tandem repeats in a Chinese cohort of ET pedigrees.To explore the genetic causes of ET, we enrolled 165 Chinese ET pedigrees and performed whole-exome sequencing (WES) as well as long-read sequencing (LRS) within this cohort. Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analyses were employed to assess HSF1 expression levels. Transgenic Drosophila model and induced pluripotent stem cells (iPSCs) were constructed to investigate the pathogenic role of HSF1 in ET.Our study identified the expanded variable number of tandem repeats (VNTRs) in intron 10 of HSF1. LRS revealed two repeat configurations consisting of CCCCGCNCCGCCT and CCNCGCCT in this VNTR loci. Expanded VNTRs alleles were highly enriched in ET affected individuals, and VNTRs length was positively correlated with disease severity. We found the intronic repeat expansions downregulated HSF1 expression in affected individuals, indicating its loss-of-function in ET. Consistently, RNAi knockdown of HSF1 homolog in Drosophila led to leg and head shaking and age-dependent movement deficits, recapitulating the ET phenotype in fly model. iPSCs derived from the ET affected individual carrying expanded VNTRs in the HSF1 gene exhibited significantly reduced expression of HSF1 compared to control iPSCs. Bulk RNA-sequencing analysis of these iPSCs revealed that diminished HSF1 expression resulted in the downregulation of genes associated with GABAergic synapse function.In conclusion, our study suggests that impaired GABAergic signaling may play a critical role in the pathogenesis of HSF1-related ET. These findings provide new information on the etiology of ET and highlight the role of HSF1 in human genetic disorder.
AbstractAssessing disease progression and informing clinical trials in peripheral neuropathy would benefit from objective and responsive fluid biomarkers closely linked to disease biology. This is particularly important in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS), the most common inflammatory neuropathies, where reliable biomarkers of peripheral demyelination would help identify, and potentially measure, active disease and responses to treatment. We postulated that periaxin, a protein exclusively expressed by myelinating Schwann cells, could serve as a fluid biomarker of demyelinating peripheral neuropathy.We developed a Simoa-based immunoassay to measure plasma periaxin in patients with CIDP (n = 45, including longitudinal samples across a discovery cohort and a validation cohort, for a total of 77 time points), GBS (n = 30, 66 time points), Charcot-Marie-Tooth disease (CMT, n = 20), central nervous system (CNS) disease controls with multiple sclerosis (MS, n = 30), and healthy controls (HC, n = 30). We also evaluated whether periaxin is released in myelinating cocultures following immune-mediated demyelination and axonal damage, comparing results with uninjured cultures.Plasma periaxin effectively distinguishes peripheral from central nervous system diseases, with significantly elevated levels in CIDP, GBS, and CMT, but not in CNS disease or healthy controls (all P < 0.01). In CIDP, periaxin discriminates patients with active disease from those with inactive disease (P < 0.0001), and plasma levels decrease following treatment with intravenous immunoglobulin (IVIg). Elevated periaxin strongly predicts clinical worsening at 1 year [sensitivity 99%, specificity 72%, area under the curve (AUC) 0.86 (95% C.I. 0.67–1)]. In GBS, peak levels of plasma periaxin and the ratio of periaxin to axonal biomarkers [neurofilament light chain (NfL) and peripherin] discriminate most cases of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) from acute motor axonal neuropathy (AMAN), as classified by electrophysiology (sensitivity 100%, specificity 86%, AUC = 0.94, 95% CI 0.81-1). Serial measurements showed that plasma periaxin levels peak 2 to 3 weeks after GBS symptom onset, followed by a gradual decline in the weeks thereafter. In vitro, periaxin is higher following immune-mediated demyelination compared to axonal damage and control conditions.Plasma periaxin is a biomarker of peripheral nerve demyelination. Combined with axonal fluid biomarkers and existing clinical scales, periaxin has the potential to improve the clinical management of peripheral neuropathies, accelerating advances in care and experimental research.
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AbstractTemporal lobe epilepsy is the most common focal epilepsy in adults. While temporal lobe epilepsy was historically perceived to have a largely acquired aetiology, growing evidence points to important genetic contributions. There are several temporal lobe epilepsy subtypes, including mesial temporal lobe epilepsy with or without hippocampal sclerosis, but the relative genetic contributions to each of these subtypes have not been directly studied.In this study, we use the classical twin model in 80 twin pairs where at least one twin had temporal lobe epilepsy. We assessed the genetic contribution to various subtypes [lesional temporal lobe epilepsy, non-lesional temporal lobe epilepsy, mesial temporal lobe epilepsy (with or without hippocampal sclerosis), lateral temporal lobe epilepsy, and non-localized temporal lobe epilepsy], by analysing the concordance for temporal lobe epilepsy in monozygotic twins compared to dizygotic twins. In the 10 monozygotic pairs where at least one twin had hippocampal sclerosis, we searched for within-pair acquired differences between affected and unaffected individuals.There was an excess of monozygotic pairs concordant for temporal lobe epilepsy compared to dizygotic pairs (17/47 concordant monozygotic vs 0/33 concordant dizygotic, p<0.05). This supports a genetic contribution to temporal lobe epilepsy, but notably this concordance was driven by non-lesional temporal lobe epilepsy cases, particularly mesial temporal lobe epilepsy without hippocampal sclerosis (14/22 concordant monozygotic vs 0/11 concordant dizygotic, p<0.05). No concordant monozygotic or dizygotic pairs were observed in the lesional temporal lobe epilepsy (n=8) and non-localized temporal lobe epilepsy (n=15) groups.The concordance for temporal lobe epilepsy in monozygotic twins with mesial temporal lobe epilepsy with hippocampal sclerosis was much lower (2/10 concordant monozygotic vs 0/9 concordant dizygotic, p=1), suggesting a lesser contribution from germline genetic causes to mesial temporal lobe epilepsy with hippocampal sclerosis. Eight monozygotic twin pairs were discordant for hippocampal sclerosis. In four of these pairs, both twins had febrile seizures, but hippocampal sclerosis was only present in the twin who had prolonged seizures.The two monozygotic twin pairs concordant for hippocampal sclerosis had clinical neurofibromatosis type 1 with pathogenic germline NF1 variants.Our findings confirm a germline genetic component in temporal lobe epilepsy, strongest in mesial temporal lobe epilepsy without hippocampal sclerosis and present in lateral temporal lobe epilepsy but absent in lesional and non-localized temporal lobe epilepsy. In our mesial temporal lobe epilepsy with hippocampal sclerosis twins, we found both genetic factors (NF1) and prolonged febrile seizures contributed to the aetiology of hippocampal sclerosis.
Neuroscientific research into mental imagery often relies on David Hume’s view of visual imagination as weak perception. Arcangeli & Bartolomeo argue that Jean-Paul Sartre’s alternative framework—supported by recent findings on aphantasia—offers a more conceptually and empirically robust approach.
AbstractAmyotrophic lateral sclerosis (ALS) is thought to be caused by interaction between genetic and environmental factors leading to motor neuron (MN) degeneration. Physical exercise has been linked to ALS but controversy remains. A key question is to determine which individuals might be at risk of exercise-associated ALS, because unnecessary avoidance of exercise could be harmful.We implemented complementary strategies including Mendelian randomization and multiple questionnaire-based measures of physical exercise in different cohorts. We include a prospective study in UK Biobank participants where we could test for a relationship between exercise and the timing of future ALS symptom onset. To interrogate the molecular basis of our observations we performed a genetic association study of ‘extreme’ exercise, equivalent to >6 hours of strenuous exercise or >12 hours of any leisure-time exercise per week.Our data suggest that the link between increased physical exercise and ALS is particularly important for males who perform the most activity; with no evidence of a link in females. We determined that extreme exercise in males is associated with loss-of-function genetic variants within a number of mammalian target of rapamycin (mTOR) signalling genes that are also differentially expressed in ALS spinal cord.Activity-induced mTOR signalling has been shown to selectively benefit MN. Therefore, our findings could imply that moderate exercise is neuroprotective via enhanced mTOR signalling, but extreme exercise in men is associated with neurotoxicity and ALS via a failure of this mechanism. There was no significant overlap between genes associated with extreme exercise and those associated with ALS risk, consistent with a true gene-environment interaction rather than a shared genetic basis. We are not yet able to make individual-level recommendations regarding exercise and risk of ALS, but our conclusions should focus future investigation.
AbstractLearning is a fundamental aspect of human behaviour and is essential for adapting to new environments and situations. The ventral tegmental area is a critical brain area containing neurons that release dopamine to signal reward, drive learning, and bias decision-making. Human data on ventral tegmental area’s effects on cognition are scarce, and no studies have causally manipulated the human ventral tegmental area. Here we studied a unique group of patients who had deep brain stimulation surgery in the ventral tegmental area, to improve pain due to trigeminal autonomic cephalalgias refractory to medical therapy.In this study, we asked how deep brain stimulation, which aimed to inhibit the ventral tegmental area, affected reward-related learning and decision-making. Patients performed a reversal learning task while their deep brain stimulation was switched on vs. off, in a powerful within-subject design. In the task, patients learned to choose between two options to win money, based on previous outcomes, but also made post-decision bets based on whether they thought they were likely to win. This allowed us to also investigate the effect of electrical stimulation within the ventral tegmental area on betting behaviour.We found that stimulation did not affect learning in this group of patients but led to a more strategic betting behaviour. First, stimulation reduced the bias where healthy people tend to bet similarly to the previous trial. Second, when on stimulation, bets were more strongly linked to the actual value of the choice. The data indicate that disrupting ventral tegmental area signals by electrical stimulation reduces the perseverative betting bias, permitting more strategic decision-making. We interpret this to mean that mesolimbic dopaminergic signals in humans may be important in producing persistence of reward-driven behaviours over time.
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AbstractLimbic-predominant age-related TAR-DNA binding protein (TDP-43) encephalopathy neuropathological change (LATE-NC) refers to the aberrant accumulation of TDP-43 in the brains of aging individuals either in isolation or in combination with neurodegenerative disease. LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease. Since LATE-NC can only be diagnosed post-mortem, there is a need for pathology-validated neuroimaging biomarkers for LATE-NC. In the current study we assessed MRI-measured amygdalar and hippocampal volume in brain donors with Alzheimer’s disease or Lewy Body diseases with and without co-occurring LATE-NC pathology.Post-mortem in-situ 3D-T1 3T-MRI data were collected for 51 cases (27 Alzheimer’s disease and 24 Lewy Body Disease) of whom 17 had post-mortem confirmed LATE-NC and 34 were non-LATE-NC (matched on age, sex, and neurodegenerative disease). Amygdalar and hippocampal volumes were calculated using FreeSurfer. Within-subject amygdalar and hippocampal tissue sections were immunostained for TDP-43 (pTDP-43), phosphorylated tau (AT8), amyloid-β (4G8) and α-synuclein (pSer129). Positive cell density (TDP-43 and α-synuclein) and area percentage immunoreactivity (p-tau and amyloid-β) outcome measures were quantified using QuPath. Group differences between LATE-NC and non-LATE-NC donors were assessed with univariate analyses and correlations were assessed with linear regression models, all adjusting for intracranial volume and post-mortem delay and if applicable for primary pathology.Brain donors with LATE-NC showed significantly lower amygdalar (-26%, p=.014) and hippocampal (-19%, p=.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden. These group differences remained significant in the Alzheimer’s disease group (amygdala -24%, p=.028; hippocampus -21%, p=.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared to non-LATE-NC donors (18%, p=.030). These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology. This study proposes that exceptionally low amygdalar and hippocampal volumes could indicate LATE-NC and that this may serve as a potential biomarker for in-vivo studies.
AbstractGait problems in people with Parkinson’s (PD) are increasingly common as disease progresses. Symptoms include freezing of gait (FoG), and a predisposition to falls. The causative pathophysiology is still not completely understood. In this study, Positron Emission Tomography (PET) with 18F-fluoro-ethoxy-benzovesamicol (18F-FEOBV), a presynaptic marker of cholinergic terminal density, and 18F-fluoro-deoxy-glucose (18F-FDG) was performed in a cohort of people with PD and gait disorder to derive spatial covariance networks of cholinergic and metabolic activity, and to evaluate the correlation of such networks against frequency of FoG and other gait measures.Fourteen patients with PD and FoG in the ON motor state underwent PET using 18F-FEOBV and 18F-FDG on two separated days. Following spatial normalization, functional networks were derived by Principal Component Analysis (PCA). The individual expression of linear combinations of principal components (PCs) was subsequently correlated with measures of FoG in the ON motor state (ON-FoG) and a lower body and gait (LBG) subsection of the Unified Parkinsons Disease Rating Scale (UPDRS) part III. Gait measures were derived from home-worn measures using a triaxial accelerometer.We found a derived pattern of 18F-FEOBV binding that correlated with ON-FoG (R2= 0.46975, p = 0.045) as well as other lower body and gait signs (R2 = 0.78591, p = 0.0077). Lower levels of cholinergic activity in the thalamus, hippocampus, striatum, anterior cingulate as well as areas of the brainstem consistent with the mesencephalic locomotor region were associated with worse ON-FoG and gait disturbances. The derived pattern was not associated with overall disease duration or progression as assessed by standard motor scores. There was no correlation between 18F-FEOBV and OFF-FoG. For 18F-FDG, no correlation between covariance patterns and gait assessments could be found. However, a statistically significant correlation was found for a subset of lower body and gait symptoms (R2 = 0.78306, p = 0.002).These results exhibit a correlation between lower levels of cholinergic function in locomotor-related areas of the brainstem and objective measures of dopamine medication ON-FoG, potentially indicating a causative link between the two. No association was found with OFF-FoG. Taken together our results provide support for the role of the cholinergic system in the occurrence of dopamine medication ON-FoG.
AbstractPerineuronal nets are specialized extracellular matrix structures forming preferentially around parvalbumin interneurons to regulate plasticity. While cortical perineuronal nets have been implicated in sensory plasticity and memory modulation, perineuronal nets of the primary motor cortex have been largely overlooked. We found that transient reduction of primary motor cortex perineuronal nets by ChABC treatment in otherwise healthy adult mice resulted in temporary deficits in motor function. In a mouse model of Parkinson's disease based on unilateral 6-hydroxydopamine lesions of the midbrain, perineuronal net levels were decreased in both primary motor cortex hemispheres 2 weeks post-lesion, yet returned to baseline within 5 weeks. We discovered that subsequent transient reduction of primary motor cortex perineuronal nets through ChABC treatment could unlock motor recovery when coupled with motor stimulation. This recovery was associated with a bilateral increase in perineuronal-net-enwrapped parvalbumin interneurons and a rebalancing of parvalbumin cell soma excitatory synaptic markers. These findings reveal distinct roles of perineuronal net plasticity – first in response to the initial midbrain lesion and then during rescue after ChABC treatment – suggesting that primary motor cortex perineuronal nets play a nuanced role in regulating motor function. This duality positions perineuronal nets as potential therapeutic targets for motor rehabilitation strategies in Parkinson's disease.
AbstractIn the intensive care unit (ICU), management of unresponsive patients with brain injury focuses on preventing secondary brain damage. Therapeutic strategies that directly promote the recovery of consciousness are urgently needed. In an investigator-initiated, randomized, placebo-controlled, double-blind, cross-over trial, we studied the effects of apomorphine and methylphenidate in ICU patients with acute disorders of consciousness (DoC). We hypothesized that these stimulants would improve consciousness biomarkers assessed by automated pupillometry (primary outcome) and clinical signs of consciousness (secondary outcome).We randomized 50 ICU patients with DoC (14 women; mean age 63 ± 10 years; 48 with non-traumatic brain injuries) to strata consisting of three consecutive treatment sessions during which apomorphine, methylphenidate or placebo were administered. In total, we administered 112 study medications, including 36 doses of apomorphine, 39 doses of methylphenidate and 37 doses of placebo. Missing administrations were due to death, ICU discharge, or spontaneous consciousness recovery. Plasma concentrations of stimulants confirmed drug exposure. We found no adverse events related to the trial drugs.Pupillometry recordings of sufficient quality (n = 590) were available from 48 (96%) patients. A pupillary response to a verbal arithmetic command (i.e., ≥3 pupillary dilations on five verbal arithmetic tasks) was identified during 70 (12%) of these recordings. Seven (15%) patients without any other observable response to spoken commands also passed a stricter threshold of ≥4 pupillary dilations, suggesting cognitive motor dissociation. Apomorphine (OR 1.35, 95% CI: 0.93 to 1.96) and methylphenidate (OR 1.29, 95% CI: 0.89 to 1.86) did not significantly increase pupillary responses. However, after study drug administration, 10 (20%) patients showed improved clinical arousal at least once. Signs of arousal were noted after one dose of placebo, four doses of apomorphine (OR 5.04, 95% CI: 0.56 to 120.7), and seven doses of methylphenidate (OR 9.96, 95% CI: 1.36 to 235.8). Changes toward higher consciousness level categories were observed once after placebo, four times after apomorphine (OR 5.67, 95% CI 0.63 to 169.46), and three times after methylphenidate (OR 3.41, 95% CI 0.34 to 88.00). In a post-hoc analysis, patients with greater pupillary responsiveness showed better arousal, suggesting that this condition may predict stimulant drug effects.In conclusion, while pupillometry revealed no direct drug effects on overall pupillary responses, stimulants may have triggered clinical arousal in some patients, particularly in those with greater pupillary responsiveness. These findings require replication but should guide future pharmacological trials aimed at improving consciousness recovery after brain injury.
AbstractIndividuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear.Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings, and behavioral analysis of zebrafish and multiple mouse models.We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein, and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within down-regulated genes. Lastly using both zebrafish and mouse models, we found behavioral disruptions that include developmental deficits and sex-specific social behavioral changes.Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology, and behavior across multiple models and systems.
AbstractDystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e).We investigated patients diagnosed with congenital myopathy using exome or genome sequencing. In 19 affected individuals from 14 unrelated families, we identified nine different variants in biallelic state located in exons 40-41, specific to DST-b. Affected individuals presented with severe neonatal myopathy characterized by arthrogryposis, hypotonia, and dilated cardiomyopathy. Postnatal CPAP ventilation was required in nine patients, and seven died within the first three years of life. Survivors showed an improvement of symptoms, with the oldest three patients, now over 25 years old, exhibiting normal cognition and being ambulatory.RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue, and cultured fibroblasts, but not in brain matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Muscle biopsies from four patients aged 1 month to 3 years revealed mild, non-specific myopathic changes. Ultrastructural analysis in three individuals showed mild and focal myofibrillar disruption and non-specific undulating nuclear membranes, with these changes observed in two cases each.Additionally, we identified two homozygous variants affecting both DST-a and DST-b isoforms in four patients from two unrelated families; all presented with severe arthrogryposis and died intrauterine or shortly after birth. Genotype-Phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome.Our findings demonstrate that biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. The location of the variant within DST allows for phenotype prediction. We propose redefining DST as a disease-associated gene linked to four distinct allelic disease phenotypes.
AbstractLoss-of-function mutations in the transcription factor POU3F2 have been identified in individuals with neurodevelopmental disorders.To elucidate the mechanistic role of POU3F2 in human neurodevelopment, we induced POU3F2 disruption in human neural progenitor cells (NPCs).Mutation of POU3F2 in NPCs causes reduced baseline canonical Wnt signalling and decreased proliferation, resulting in premature specification of radial glia. Additionally, POU3F2 levels across genetically diverse NPCs significantly associate positively with baseline canonical Wnt signalling and negatively with markers of radial glia specification. Through a series of unbiased analyses, we show that SOX13 and ADNP are transcriptional targets of POU3F2 which mediate POU3F2’s effects on Wnt signalling in human NPCs. Finally, we describe five individuals with autism spectrum disorder that harbor loss-of-function mutations in POU3F2, enhancing the genetic evidence for its critical role in human neurodevelopment.Together, these studies define POU3F2 as an activator of canonical Wnt signalling and mechanistically link two high-confidence autism genes, ADNP and POU3F2, in the regulation of neurodevelopment.
AbstractDe novo or autosomal dominant BAG3 gene variants cause a wide range of skeletal and cardiac muscle diseases encompassing Charcot–Marie–Tooth disease, myofibrillar myopathy, cardiomyopathy or a combination of them. Given the severity and rarity of BAG3-neuromuscular diseases (NMD), series of patients are lacking. Our aim was to characterize the clinical and genetic spectrum as well as the natural history of BAG3-NMD in Europe.In this multicentre retrospective study, we collected clinical, ancillary, and genetic data of patients with NMD and BAG3 variants, identified from European paediatric and adult neuromuscular reference centres from May to December 2023 following a call circulated through the European Reference Network EURO-NMD and other partners. Responses were received from 35 centres in 17 countries. Twenty-six patients (65.4% males, 34.6% females) with BAG3-NMD from 18 different families were included in the study. The c.626C>T p.(Pro209Leu) variant, carried by 16 patients, was the only recurrent variant and was associated with a homogeneous and severe phenotype, with predominantly lower-limb motor weakness (n=13, 81.25%) or heart failure (n=3, 18.75%) as the presenting feature, and a mean age at symptom onset of 7.8±3.4 years. Where available (n=13), electroneuromyography showed a polyneuropathy with demyelinating features and a frequently associated myopathy. Eleven (68.8%) patients had restrictive cardiomyopathy on initial assessment. Orthopaedic manifestations were common, with contractures (n=15, 93.8%), foot deformities (n=11, 84.6%), and scoliosis and/or rigid spine (n=12, 80%). At last follow-up (age 21.5±8.6 years), of the patients carrying the p.(Pro209Leu) variant, 10 (62.5%) had lost ambulation, 14 (93.3%) had respiratory insufficiency (11 requiring ventilation), and 12 (75%) had a restrictive cardiomyopathy, leading to heart failure and heart transplantation in five and four patients, respectively. Eight (50%) patients died prematurely at a mean age of 22.5±9.6 years, most frequently from sudden death (n=5). The other 10 patients carried three other BAG3 variants, and showed a milder disease course, with all patients remaining ambulatory, without cardiorespiratory manifestations at last follow-up. The p.(Arg309*) nonsense variant, known to cause isolated dilated cardiomyopathy, as well as the p.(Val505Glyfs*6) frameshift variant resulting in a premature stop codon, caused distal hereditary motor neuropathy.This is the largest study of patients with BAG3-NMD, delineating the frequency, specific presentation, and the natural history in patients with the recurrent BAG3 p.(Pro209Leu) missense variant, crucial for informing patient management in the context of a rapidly progressive disease. All other BAG3 variants were rare and caused milder clinical presentations.
AbstractRemote digital monitoring of Huntington’s disease (HD) has potential to enhance the development of therapeutics, but no data-driven digital motor score exists to quantify the diversity of disease manifestations and track their progression.The HD Digital Motor Score (HDDMS), co-designed with people with HD and neurologists, is a composite score for measuring motor progression of HD in clinical research. It is derived from smartphone sensor-based motor tests included in a remote HD digital monitoring platform. Developing the HDDMS involved selecting features that quantify test performance according to desired measurement properties and combining these features in a weighted composite score using factor analysis. It was developed and subsequently validated using data from four separate studies [HD Natural History Study (NCT03664804), open-label extension (OLE) of the tominersen phase I/IIa study (NCT03342053), GENERATION HD1 (NCT03761849) and Digital-HD].Based on data from 1048 (the total number of individuals whose data contributed to the construction of the score includes the 40 gene-negative volunteers) individuals, the HDDMS encompasses balance, chorea, speeded tapping and gait. It has favourable characteristics, including reliability (intraclass correlation coefficient > 0.95), correlation with the composite Unified Huntington’s Disease Rating Scale (cUHDRS) (r = −0.5), and better sensitivity to change (STC) than the cUHDRS. In a post hoc analysis of GENERATION HD1, the STC of HDDMS at Week 20 was comparable to that of the cUHDRS at Week 68. The HDDMS promises substantial reduction in sample size in clinical trials.
This scientific commentary refers to ‘The association of seizure control with neuropathology in dementia’ by Zawar et al. (https://doi.org/10.1093/brain/awaf017).
Pansieri et al. argue that bureaucracy is suffocating research, as an ever increasing administrative burden consumes researchers’ time and diverts focus from discovery to compliance. They highlight ways in which red tape delays progress, wastes funding, and drives researchers out of academia, and call for systemic change.
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AbstractCharcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E.Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity.Twenty-four presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes.Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.
This scientific commentary refers to ‘Interferon-γ causes myogenic cell dysfunction and senescence in immune myopathies’ by Hou et al. (https://doi.org/10.1093/brain/awaf153).
AbstractAlzheimer’s disease (AD) is characterized by the accumulation of pathogenic proteins, notably amyloid-beta and hyperphosphorylated tau, which disrupt neuronal function and contribute to cognitive decline. Although proteotoxic stress is well-established in AD, the role of the ubiquitin-proteasome system (UPS) in maintaining neuronal proteostasis, and how it becomes compromised during disease progression remains incompletely understood.Here we integrated multiple approaches to characterize proteasome function, composition, and regulation in post-mortem human AD brain tissue compared to age-matched controls. These included proteasome kinetic assays, affinity purification of intact 26S proteasomes, in-gel activity assays and proteomics. According to Braak staging, we further interrogated bulk RNA-seq and single-nucleus RNA-seq (sn-RNA-seq) datasets spanning the progression of AD pathology. Finally, we examined Nrf1/NFE2L1 binding and subcellular localization to understand the transcriptional regulation of proteasome genes in AD.We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes. This reduction in proteolytic capacity persisted after proteasome purification, implicating intrinsic defects within the proteasome complex. Proteomic profiling of isolated proteasomes revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g., tau, α-synuclein and SQSTM1/p62), suggesting proteasome entrapment in pathological aggregates. Transcriptomic analyses showed progressive downregulation of constitutive proteasome subunit genes in individuals along the Braak stage axis, with downregulation apparent even at the earliest Braak stages, in tissue without overt tau aggregation. Neurons were disproportionately affected, whereas non-neuronal cells did not show substantial differences in proteasome-related gene expression, possibly through immunoproteasome induction. Despite elevated NFE2L1 expression, a key transcription factor normally driving proteasome gene transcription, AD brains exhibited impaired Nrf1 nuclear localization, preventing the expected compensatory upregulation of proteasome components.Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course. Intrinsic alterations in proteasome complexes, coupled with early transcriptional downregulation of proteasome subunits and disrupted Nrf1-mediated regulatory pathways, contribute to a vicious cycle of proteotoxic stress and neuronal vulnerability. Restoring proteasome function and enhancing Nrf1-driven transcriptional responses may represent promising therapeutic strategies to preserve proteostasis and mitigate neurodegeneration in AD.
AbstractRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an incurable microvascular disease caused by C-terminus truncation of the TREX1 exonuclease. There is a pressing need to understand disease mechanisms and identify therapeutic targets.We evaluated TREX1 sequencing data from 469 229 UK Biobank participants together with RVCL-S-related microvascular clinical and imaging outcomes. We show that mono-allelic truncating mutations in TREX1 require intact nuclease activity in order to cause endothelial disease. Differential proteomics identifies loss of interaction with endoplasmic reticulum insertion proteins such as Guided Entry of Tail-Anchored Proteins Factor 3 as a major consequence of pathogenic TREX1 truncation, and this altered trafficking results in the unregulated presence of enzymatically active TREX1 in the nucleus. In endothelial cells with a patient mutation, mislocalized yet enzymatically active TREX1 causes accumulation of a spectrum of DNA damage. These pathological changes can be rescued by inhibiting exonuclease activity.In summary, our data implicate exonuclease-dependent DNA damage in endothelial cells as a key therapeutic target in the pathogenesis of RVCL-S.
AbstractHow do brain networks limit seizure activity? In the Interictal Suppression Hypothesis, we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression. If broad networks appear to be responsible for interictal SOZ suppression, what changes during seizure initiation, spread, and termination? For patients with drug-resistant epilepsy, intracranial monitoring offers a view into the electrographic networks which organize around and in response to the SOZ.In this manuscript, we investigate network dynamics in the peri-ictal periods to assess possible mechanisms of seizure suppression and the consequences of this suppression being overwhelmed. Peri-ictal network dynamics were derived from stereo electroencephalography recordings from 75 patients with drug-resistant epilepsy undergoing pre-surgical evaluation at Vanderbilt University Medical Center. We computed directed connectivity from 5-second windows in the periods between, immediately before, during, and after 668 seizures. We aligned connectivity matrices across seizures and patients, then calculated net connectivity changes from the SOZ, propagative zone, and NIZ.Across all seizure types, we observed two phases: a rapid increase in directed communication towards the SOZ followed by a collapse in network connectivity. During this first phase, SOZs could be distinguished from all other regions (One-Way ANOVA, P-value = 8.32x10-19-2.22x10-7). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (One-Way ANOVA, P-value = 2.58x10-10-1.66x10-2). NIZs appeared to drive increased SOZ connectivity while intra-NIZ connectivity concordantly decreased. Stratifying by seizure subtype, we found that consciousness-impairing seizures decrease inward connectivity from the NIZ earlier than consciousness-sparing seizures (one-way ANOVA, p<0.01 after false discovery correction). Tracking network reorganization against a surrogate for seizure involvement highlighted a possible antagonism between seizure propagation and the NIZ’s ability to maintain high connectivity to the SOZ. Finally, we found that inclusion of peri-ictal connectivity improved SOZ classification accuracy from previous models to a combined area under the curve of 93%.Overall, NIZs appear to actively increase inhibitory signaling towards the SOZ during seizure onset, possibly to thwart seizure activity. While inhibition appears insufficient to prevent seizure onset, the inability to restrict seizure propagation may contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work may: i) facilitate accurate delineation of surgical targets in focal epilepsy, ii) reveal why interictal suppression of SOZs may be insufficient to prevent all seizures, and iii) provide insight into mechanisms of loss of consciousness during certain seizures.
AbstractT-type/Cav3 calcium channels are key in neuronal excitability and pain processing with Cav3.2 being the prominent isoform in primary sensory neurons of the dorsal root ganglion (DRG). Cav3.2 pharmacological inhibition or gene silencing induces analgesia in several preclinical models of inflammatory and neuropathic pain. However, the presence of Cav3.2, encoded by the CACNA1H gene, in human DRG neurons remains unresolved.Using RNA in-situ hybridization and electrophysiological recordings, we show that human DRGs express Cav3.2 in a subset of neurons positive for the neurotrophic factor receptor TrkB (NTRK2 gene). The Cav3.2 current exhibits typical biophysical and pharmacological properties, including inhibition by a low concentration of nickel and by Z944, a specific T-type calcium channel blocker in advanced clinical development. Conversely, ABT-639, a T-type calcium channel inhibitor that failed in Phase 2 trials for pain relief, does not inhibit Cav3.2 currents in human DRG neurons. Importantly, Cav3.2 currents are prominent in neurons from female organ donors, supporting the presence of sex differences in pain mechanisms in humans.These findings underscore the potential of continued exploration of Cav3.2 as a therapeutic target for pain treatment and highlight a specific subset of human neurons that likely rely on this channel to modulate their excitability.
AbstractPathogenic variants in GABAA receptor subunits genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations, and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review. Our cohort included 19 individuals (7 males, 12 females) from 15 families harboring 13 different GABRB1 variants (11 missense, 1 indel, 1 stop). Functional analysis was performed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes. For all eleven missense variants, α1β1γ2 GABAA receptors with a single mutant β1 subunit were used. Four missense variants were selected for further functional analysis using α5β1γ2 GABAA receptors with two mutant β1 subunits.Gain-of-function (GoF) effects, characterised by increased GABA-sensitivity, were observed for eight missense variants. Loss-of-function (LoF) effects were observed for one, and no functional effects for two variants. Clinically, GoF variants were only observed in individuals with severe early-onset disease including profound intellectual disability, hypotonia, and early mortality. Additionally, cortical visual impairment, dysmorphisms and cortical atrophy were exclusive to this cohort. By integrating previously reported clinical data for variants in other GABR* genes we validated that these features were associated with GoF variants more broadly. The only LoF variant was identified in a nuclear family with the relatively milder syndrome of genetic epilepsy with febrile seizures plus.Seizures were therapy-resistant in all individuals with GoF variants, and in a single individual with a LoF variant. The GABAergic anti-seizure medication (ASM) vigabatrin caused life-threatening side-effects in two individuals with GoF variants, while the sodium-channel blocker (SCB) lamotrigine exacerbated seizures in a single individual carrying a LoF variant. By integrating data from literature on all GABR* variants, we observed a potential dichotomy in treatment responses: GABAergic and broad-spectrum ASMs, such as valproate and levetiracetam, were more effective for individuals with LoF variants in GABR* genes, while SCBs showed greater benefit for GoF variants. Additionally, there is an increased risk of adverse effects of SCBs in LoF and vigabatrin in GoF variants. Our results highlight the importance of functional characterisation of variants and clinical predictors in guiding treatment strategies for individuals with GABRB1 and other GABR* variants, though larger prospective studies are needed to confirm these observations.
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AbstractThere has been a rapid growth in research on peripheral fluid biomarkers for Alzheimer’s Disease and Alzheimer’s Disease related dementias (AD/ADRD) because they are non-invasive, relatively inexpensive, and easily accessible. The most commonly used plasma biomarkers include β-amyloid (Aβ), phosphorylated tau (p-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The extent to which distinct profiles of multiple plasma biomarkers correlate with common neuropathologies is unclear.Using clinicopathologic data from 405 community-dwelling older adults, we applied latent profile analysis on 4 plasma biomarkers, i.e., Aβ42/40 ratio, p-tau217, NfL and GFAP, and examined the correlates of the latent profiles with 4 degeneration measures of AD, Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy (LATE), hippocampal sclerosis, and 5 vascular measures including chronic macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriosclerosis.On average, participants died at the age of 89 and blood samples for plasma biomarkers were measured 3.9 years before death. Over 75% were female and 24% were non-Latino Black. We observed 3 distinct biomarker profiles. Profile #1, characterized by low p-tau217, low GFAP, low NfL and high Aβ42/40, represents most participants (55.6%) with better than average biomarker levels. Both Profile #2 and Profile #3 showed worse than average biomarker levels. Profile #2, representing 34.8% of the participants, was high in p-tau217 and GFAP. By contrast, Profile #3, representing 9.6% of the participants, was high in NfL and GFAP. Examination of neuropathologic correlates of these plasma biomarker profiles revealed that Profile #2 exemplifies older adults with a high burden of neurodegeneration; almost all participants (92.9%) in Profile #2 had a diagnosis of pathologic AD, and the group also had the highest percentage of participants with Lewy bodies (41.1%). In comparison, Profile #3 exemplifies older adults with more severe vascular conditions; participants in this group had the highest percentage of macroscopic infarcts (31.6%) and moderate or severe atherosclerosis (42.1%).Together, these findings suggest that common plasma biomarkers may exhibit profiles reflective of distinct pathophysiologic processes.
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AbstractMonoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture of LGI1–ADAM22/23 pathway-related diseases remains incompletely understood.Through international genetic data sharing, we identified the first ultra-rare biallelic LGI1 variants in six individuals from four consanguineous families. Affected individuals presented DEE with neonatal/infantile-onset epilepsy (6/6), global developmental delay/intellectual disability (6/6), and infant/premature death (5/6). Brain MRI showed mild cerebral atrophy in a subset of patients (3/6).Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes. Further, we observed epileptic discharges from the isolated whole hippocampus of Lgi1–/– knockout mice, experimentally modelling the hippocampal origin of LGI1-related epilepsy. Automated behavioural analysis of a mouse model for ADAM22-related DEE revealed its impaired cognitive function. Furthermore, we report the first ADAM23 variant associated with lethal neonatal-onset epilepsy and myopathy. Collectively, this study defines the LGI1–ADAM22/23 pathway-related disease spectrum.
AbstractApathy is a common neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD) but can emerge earlier in prodromal and even preclinical stages as part of mild behavioural impairment (MBI-apathy), a syndrome defined by emergent and persistent NPS. In dementia, apathy is associated with higher morbidity, mortality, and caregiver distress. However, the significance of MBI-apathy in dementia-free persons, including its associations with AD biomarkers, remains unclear. This study aimed to determine whether MBI-apathy is associated with biomarker evidence of amyloid beta (Aβ) and tau (phosphorylated [p-tau], total [t-tau]) in CSF. Because MBI predicts incident dementia better than NPS without MBI, we aimed to determine the association between apathy and AD biomarkers when it occurred as part of the MBI syndrome and when it did not.Dementia-free participants with mild cognitive impairment (MCI) or normal cognition from the Alzheimer’s Disease Neuroimaging Initiative were stratified by NPS status – MBI-apathy, non-apathy MBI, non-MBI NPS, and no-NPS – based on the Neuropsychiatric Inventory (NPI) or NPI-Questionnaire (NPI-Q). Linear regressions modelled cross-sectional associations between NPS status (predictor) and CSF biomarker ratios (Aβ42/Aβ40, p-tau181/Aβ42, and t-tau/Aβ42; primary outcomes) and levels (Aβ40, Aβ42, p-tau181, t-tau; exploratory outcomes), adjusting for age, sex, Apolipoprotein E4, education, Mini Mental State Examination, and NPI version. Hierarchical linear mixed-effects (LME) models assessed longitudinal associations over two years incorporating random intercepts and slopes to account for repeated measures. Fixed effects included NPS status, all covariates from the linear regression model, as well as an interaction term between NPS status and time.Among 477 participants (176 cognitively normal), 52 had MBI-apathy. Primary cross-sectional analyses showed that, compared to the no-NPS group, MBI-apathy was associated with higher CSF p-tau181/Aβ42 (11.25% [2.56% – 20.68%]; adjusted p = 0.018) and t-tau181/Aβ42 (10.26% [2.42% – 18.70%]; adjusted p = 0.018). Exploratory analyses revealed that MBI-apathy was associated with higher CSF p-tau181 (5.98% [0.50% – 11.77%]; p = 0.032). Primary LMEs showed that MBI-apathy was associated with higher CSF p-tau181/Aβ42 (11.34% [2.55% – 20.88%]; adjusted p = 0.022) and t-tau181/Aβ42 (10.34% [2.41–18.88%]; adjusted p = 0.022) over two years. Exploratory LMEs revealed that MBI-apathy was associated with higher CSF p-tau181 (6.03% [0.56% – 11.81%]; p = 0.032) and t-tau (4.96% [0.07% – 10.09%]; p = 0.049) over two years.MBI-apathy was significantly associated with core AD biomarkers cross-sectionally and longitudinally, over two years, underscoring its relevance as a marker of AD pathological burden. An overall MBI composite score may reflect a broader spectrum of pathology and warrants further investigation.
AbstractFragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a preCGG repeat expansion in the FMR1 gene. Individuals with the FMR1 premutation often exhibit neuropsychiatric symptoms before FXTAS onset, leading to the identification of fragile X-associated neuropsychiatric disorders (FXAND). Rodent models of FXTAS show motor impairments, pathological intranuclear inclusions, and heightened anxiety. However, the early onset of neuropsychiatric features and underlying mechanisms remain poorly understood.To address the above issues, we used the doxycycline (dox)-inducible 90CGG mouse model, with transgene activation at two developmental stages: adolescence and young adulthood. Mice were evaluated in a behavioural battery to assess anxiety-like behaviour, exploration, and motor coordination and learning. Next, we conducted a combination of ex vivo extracellular local field potential recordings to measure synaptic physiology and oscillatory activity in the limbic system, particularly in the basolateral amygdala (BLA) and ventral hippocampus (vH) regions. Parvalbumin interneurons and intranuclear inclusions in the amygdala and hippocampus were investigated by immunofluorescence, while mass spectrometry and gene set enrichment were used to identify differentially expressed proteins molecular pathways.Adolescent 90CGG mice displayed early-onset hyperactivity, transitioning to heightened anxiety in young adulthood, coinciding with the accumulation of intranuclear inclusions in the BLA and vH. Electrophysiological analysis revealed augmented gamma oscillations in the vH, emerging during adolescence and persisting in young adulthood. These changes correlated with a reduction in parvalbumin interneurons in these regions, and together likely contribute to enhanced BLA excitability and impaired vH plasticity. Finally, proteomic analysis of the vH revealed altered proteins linked to attention deficit hyperactivity disorder in adolescence and anxiety/depression in adulthood, aligning well with behavioural findings. Importantly, these behavioural, electrophysiological, and cellular alterations were reversible upon transgene inactivation.This study reveals a temporal progression of CGG premutation effects on behaviour, from hyperactivity to heightened anxiety to late onset motor dysfunction. Moreover, these findings provide altered network activity in the limbic system as a putative mechanism in neuropsychiatric features of premutation carriers.
AbstractThe historical understanding of cerebrospinal fluid (CSF) production and flow comprises CSF production primarily in the choroid plexus of the 1st-3rd ventricles, flow through the aqueduct of Sylvius en route to the 4th ventricle, circulation around the subarachnoid space, and ultimately resorption into the blood circulation through arachnoid granulations. Since the discovery of a perivascular CSF clearance system in 2012 and in 2015 of lymphatic vessels localized to the dura mater of mice, there has been a growing interest in characterizing the structure and function of the tissues surrounding the dural sinuses, or the parasagittal dural (PSD) space. This work is now being pursued with increasing frequency to understand how the PSD space may relate to impaired neurofluid egress or neuroimmune function, with the intent of further informing our understanding of neurodegenerative proteinopathies and associated therapeutic avenues in disease. This review summarizes (i) our current understanding of neurofluid (comprised of CSF and interstitial fluid) circulation within the brain, as well as the (ii) anatomy and (iii) function of the PSD space in the context of neurofluid circulation and neuroimmune surveillance. With this context in place, we report on recent (iv) abilities to quantify the PSD volume and function in humans, (v) large-scale studies of PSD evolution across the human lifespan, and (vi) evidence for PSD structural variation in the setting of neurodegenerative disease.
Matt Butler, runner up in the Brain Essay Competition 2024, considers what happens when memories fragment and certainties fade in this fictional tale of a professor of literature who loses her grasp on time.
Drawing on two decades of clinical experience with affective disorders, Jesús Ramírez-Bermúdez— runner up in the Brain Essay Competition 2024—explores the cultural significance of melancholy, with the aid of historical archives from the Inquisition and the introspections of a 17th century poet.
The response of an atom to external electric and magnetic fields can reveal fundamental atomic properties. It has long been verified that, in a static magnetic field, those atomic energy levels with hyperfine interactions shift according to the Breit–Rabi formula, which introduces nonlinear dependence on the magnetic field. On the other hand, the corresponding Breit–Rabi dependence on a static electric field has not been observed before due to a combination of experimental challenges. Here, we precisely measure the Stark shift of the6s21S0↔6s6p1P1transition of171Yb (I= 1/2) with cold atoms held by an optical dipole trap in a static electric field up to 120 kV/cm. We observe the electric Breit–Rabi effect displaying high-order (E4andE6) DC Stark shifts. These effects arise from the influence of the strong electric field on hyperfine interactions.
Collective cooperation maintains the function of many natural and social systems, making understanding the evolution of cooperation a central question of modern science. Although human interactions involve complex contact networks, current explorations are limited to static networks, where social ties are permanent and do not change over time. In reality, human activities often involve temporal interactions, where links are impermanent, and understanding the evolution of cooperation on such temporal networks is an open problem. Here, we systematically analyze how cooperation spreads on arbitrary temporal networks, and we distill our results down to a concise condition, which integrates evolutionary game dynamics with both static and temporal interactions. We find that the emergence of cooperation is facilitated by a simple rule of thumb: Hubs (individuals with many social ties) should be temporally deprioritized in interactions. For empirical applications, we further provide a quantitative metric capturing the priority of hubs, which is validated on empirical datasets based on its effectiveness in orchestrating the ordering of interactions to best promote cooperation. Our findings unveil the fundamental advantages conferred by temporal interactions for promoting collective cooperation, transcending the specific insights gleaned from studying static networks.
D-peptides hold great promise as therapeutics by alleviating the challenges of metabolic stability and immunogenicity in L-peptides. However, current D-peptide discovery methods are severely limited by specific size, structure, and the chemical synthesizability of their protein targets. Here, we describe a computational method for de novo design of D-peptides that bind to an epitope of interest on the target protein using Rosetta’s hotspot-centric approach. The approach comprises identifying hotspot sidechains in a functional protein–protein interaction and grafting these side chains onto much smaller structured peptide scaffolds of opposite chirality. The approach enables more facile design of D-peptides and its applicability is demonstrated by design of D-peptidic binders of influenza A virus hemagglutinin, resulting in identification of multiple D-peptide lead series. The X-ray structure of one of the leads at 2.38 Å resolution verifies the validity of the approach. This method should be generally applicable to targets with detailed structural information, independent of molecular size, and accelerate development of stable, peptide-based therapeutics.
Light controls important biological processes in fungi by regulating transcriptional gene activation. Here, we found that beyond the regulation of mRNA transcript abundance, light regulates alternative splicing (AS) in the filamentous fungiAspergillus nidulans,Trichoderma guizhouense,andNeurospora crassa. Blue light-regulated AS was involved in ergothioneine biosynthesis and conidiation inT. guizhouense, which required the blue light receptor BLR1. Blue light activated the MAPK HOG (Sak) pathway which then transmitted the signal via the serine/threonine kinase SRK1 to the AS key regulator SRP1. SRK1 and SRP1 are important for light-induced conidiation. The light-activated HOG pathway led to an increase of the SRK1 protein level and its phosphorylation status. Phosphorylated SRK1 translocated from the cytoplasm to the nucleus to interact with SRP1, thereby regulating AS efficiency. This study unravels another level of complexity of fungal environmental sensing and responses and also first describes the entire cascade from an environmental signal to the splicing machinery.
Multiple sclerosis (MS) is an immune-mediated disease with no current cure. Drug discovery and repurposing are essential to enhance treatment efficacy and safety. We utilized summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma and 1,443 brain proteins, a genome-wide association study of MS susceptibility with 14,802 cases and 26,703 controls, both bulk and cell-type specific transcriptome data, and external pQTL data in blood and brain. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization to determine potential causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing all analyses were prioritized as potential drug targets. We further conducted pathway annotations and protein–protein interaction network analysis (PPI) and verified our findings at mRNA and protein levels. We tested hundreds of MS-associated proteins and confirmed 18 potential causal proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also identified intricateAQ PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. We identified two targets using bulk mRNA expression data and four targets expressed in MS-related cell types. We finally verified 10 targets using external pQTL data. We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for potential drug discovery and repurposing in MS.
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A long-standing fundamental open problem in mathematical fluid dynamics and nonlinear partial differential equations is to determine whether solutions of the 3D incompressible Euler equations can develop a finite-time singularity from smooth, finite-energy initial data. Leonhard Euler introduced these equations in 1757 [L. Euler,Mémoires de l’Académie des Sci. de Berlin11, 274–315 (1757).], and they are closely linked to the Navier–Stokes equations and turbulence. While the general singularity formation problem remains unresolved, we review a recent computer-assisted proof of finite-time, nearly self-similar blowup for the 2D Boussinesq and 3D axisymmetric Euler equations in a smooth bounded domain with smooth initial data. The proof introduces a framework for (nearly) self-similar blowup, demonstrating the nonlinear stability of an approximate self-similar profile constructed numerically via the dynamical rescaling formulation.
Retinoic acid (RA) is a morphogen that contributes to inner ear development. Gain and loss of function experiments have indicated retinoic acid’s critical role in cochlear hair cell development. However, the underlying molecular mechanisms are unclear. Here, we hypothesized that RA receptor alpha (RARA) has a dual role in cochlear organogenesis: First, during embryonic development, in the presence of RA, RARA functions as a transcriptional activator that induces prosensory gene expression in progenitor cells and supports differentiation of the organ of Corti; later during postnatal development, when RA is absent, the function of RARA switches, thereby repressing prosensory genes in postnatal hair cells and hindering trans-differentiation into supporting cells. This hypothesis was supported by demonstration that RARA forms a complex with either the coactivator NCOA1 or the corepressor NCOR1 depending on the developmental stage. In addition, modulation of RA levels was found to govern recruitment of the coactivator and corepressor to the RARA complex, and the expression of prosensory genes was validated to depend on RARA complex composition. Together, our results provide insights supporting the potential of harnessing RA signaling to induce prosensory progenitors in stem cell–based strategies for hearing loss.
The formation of bilateral testes in animals is critical for puberty, reproductive capacity, and testosterone production across the life course. In humans, testis development begins in embryonic life in the first trimester, with considerable effort focused on the cell and developmental events associated with testis cell specification, leaving limited knowledge on testicular organogenesis during the second and third trimesters. To fill this knowledge gap, we evaluated testicular cell maturation at weeks 5 (W5), W6, W8, W15, and W19 postconception using a rhesus macaque model. Our data identify a major transcriptional change in the somatic cells of the testis (Sertoli cells, interstitial cells and fetal Leydig cells) between W8 and W15, and this is associated with the maturation of seminiferous cords and maturation of PGCs into fetal spermatogonia. Through this work, we identified cellular changes and differential protein expression between W5 and W19 that can be used to holistically define testis development across the time course of embryonic and fetal life. This study provides important insights necessary to recreate the testicular niche from stem cells for biomedical research.
Darwinian evolution results from an interplay between stochastic diversification of heritable phenotypes, impacting the chance of survival and reproduction, and fitness-based selection. The ability of populations to evolve and adapt to environmental changes depends on rates of mutational diversification and the distribution of fitness effects of random mutations. In turn, the distribution of fitness effects of stochastic mutations can be expected to depend on the adaptive state of a population. To systematically study the impact of the interplay between the adaptive state of a population on the ability of asexual populations to adapt, we used a spatial agent-based model of a neoplastic population adapting to a selection pressure of continuous exposure to targeted therapy. We found favorable mutations were overrepresented at the extinction bottleneck but depleted at the adaptive peak. The model-based predictions were tested using an experimental cancer model of an evolution of resistance to a targeted therapy. Consistent with the model’s prediction, we found that enhancement of the mutation rate was highly beneficial under therapy but moderately detrimental under the baseline conditions. Our results highlight the importance of considering population fitness in evaluating the fitness distribution of random mutations and support the potential therapeutic utility of restricting mutational variability.
The rapid evolution of RNA viruses implies that their evolutionary and ecological processes occur on the same time scale. Genome sequences of these pathogens therefore can contain information about the processes that govern their transmission and dispersal. Landscape phylogeographic approaches use phylogeographic reconstructions to investigate the impact of environmental factors and variables on the spatial spread of viruses. Here, we extend and improve existing approaches and develop three novel landscape phylogeographic methods that can test the impact of continuous environmental factors on the diffusion velocity of viral lineages. In order to evaluate the different methods, we also implemented two simulation frameworks to test and compare their statistical performance. The results enable us to formulate clear guidelines for the use of three complementary landscape phylogeographic approaches that have sufficient statistical power and low rates of false positives. Our open-source methods are available to the cientific community and can be used to investigate the drivers of viral spread, with potential benefits for understanding virus epidemiology and designing tailored intervention strategies.
Drimenol synthase fromAquimarina spongiae(AsDMS) is a highly unusual chimera that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol. The AsDMS structure exhibits a didomain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase-like phosphatase domain, with two distinct active sites located on opposite sides of the protein. Mechanistic studies show that dephosphorylation of the drimenyl diphosphate intermediate proceeds through stepwise hydrolysis such that two equivalents of inorganic phosphate rather than inorganic pyrophosphate are coproducts of the reaction sequence. When the AsDMS reaction is performed in H218O,18O is not incorporated into drimenol, indicating that the hydroxyl oxygen of drimenol originates from the prenyl oxygen of FPP rather than a water molecule from bulk solution. These results correct a mechanistic proposal previously advanced by another group. Surprisingly, AsDMS exhibits substrate promiscuity, catalyzing the conversion of the slowly reactive substrate mimic farnesyl-S-thiolodiphosphate into cyclic and linear sesquiterpene products. Structural and mechanistic insights gained from AsDMS illustrate the functional diversity of terpene biosynthetic enzymes and provide a foundation for engineering “designer cyclase” assemblies capable of generating a wide variety of terpenoid products.
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Insects frequently form associations with maternally transmitted symbiotic bacteria. This transmission mode ensures that symbiont-conferred effects, both beneficial and negative, are passed onto offspring. Here, we report an extreme example of symbiont-mediated temperature sensitivity imposed by a vertically transmitted, defensive symbiont. Pea aphids infected with the bacterial endosymbiont,Fukatsuia symbiotica,resist infection by fungal pathogens but produce few or no offspring when moved from cool (15 °C) to mildly warmer temperatures (20 °C). This temperature-dependent reduction in host fitness is associated with increased symbiont abundance, disordered symbiont localization, and high expression of a horizontally acquired nonribosomal peptide synthetase (NRPS) locus. This NRPS operon is syntenic with the locus responsible for the production of Herbicolin A, a known antifungal produced by some plant-associatedErwiniaceae. Activity of chemical extracts from infected aphids is predictive of in vivo protection against entomopathogenic fungi, indicating that an Herbicolin A–like molecule is the likely source ofFukatsuia’sprotective effects against fungal pathogens. Injection of the same chemical extracts into naive aphids partially recapitulates developmental defects observed in natural infections at 20 °C, suggesting that increased levels of this compound contribute to disrupted embryonic development. Finally, the purification of the causal agent revealedFukatsuiaproduces a compound similar but not identical to Herbicolin A, that exhibits both antifungal and hemolytic activity. These results suggest thatF. symbioticainfection imposes a trade-off between antifungal defense and disrupted embryonic development, mediated by a single genetic locus.
Antagonistic interactions are critical determinants of microbial community stability and composition, offering host benefits such as pathogen protection and providing avenues for antimicrobial control. While the ability to eliminate competitors confers an advantage to antagonistic microbes, it often incurs a fitness cost. Consequently, many microbes only produce toxins or engage in antagonistic behavior in response to specific cues like quorum sensing molecules or environmental stress. In laboratory settings, antagonistic microbes typically dominate over sensitive ones, raising the question of why both antagonistic and nonantagonistic microbes are found in natural environments and host microbiomes. Here, using both theoretical models and experiments with killer strains ofSaccharomyces cerevisiae, we show that “boom-and-bust” dynamics—periods of rapid growth punctuated by episodic mortality events—caused by temporal environmental fluctuations can favor nonantagonistic microbes that do not incur the growth rate cost of toxin production. Additionally, using control theory, we derive bounds on the competitive performance and identify optimal regulatory toxin-production strategies in various boom-and-bust environments where population dilutions occur either deterministically or stochastically over time. Our mathematical investigation reveals that optimal toxin regulation is much more beneficial to killers in stochastic, rather than deterministic, boom-and-bust environments. Overall, our findings show how both antagonistic and nonantagonistic microbes can thrive under varying environmental conditions.
Polyploid organisms evolve from their initial doubled genomic condition through a number of processes collectively termed diploidization, whose tempo and mode remain poorly understood mainly due to the difficulty of discriminating de novo evolution subsequent to polyploidy from variation inherited from progenitors. Here, we generated chromosome-scale genome assemblies for the wild rice allopolyploidOryza minutaand its two diploid progenitors,Oryza punctataandOryza officinalis, and employed a population genomic approach to investigate the diploidization process inO. minutaat the sequence and transcriptomic level. We show that this wild rice allopolyploid originated around 0.7 Mya, and during subsequent diploidization, its two subgenomes have retained highly conserved synteny with the genomes of its extant diploid progenitors. This populational approach allowed us to distinguish parental legacy of inherited variation from postpolyploidy evolution, and our analyses revealed that whereas gene fractionation occurred in an early burst, accumulation of transposable elements (TEs) and homoeologous exchanges has been gradual. Patterns of homoeolog expression bias are highly variable across tissues, with no consistent subgenome expression bias. Our assessments of the impact of DNA methylation, TE distribution, and parental legacy on expression patterns provide some support for the TE load theory (the theory that the TE densities in flanking regions surrounding genes strongly influence expression levels), while also illustrating the complexity of transcription regulation.
Currently, catalytic recycling of polyethylene (PE) into high-value chemicals using solar energy often faces poor product selectivity and low efficiency. This is mainly due to the difficulty in effectively controlling the intermediates during PE photoreforming and the long-standing challenge of inefficient charge dynamics. Here, we present a solar-driven photothermal catalytic approach for the selective conversion of PE waste into propionic acid and hydrogen under ambient conditions. Atomically dispersed Ni sites supported on CeO2(NiSA/CeO2) achieve a propionic acid yield of 331 μmol h–1with 94.8% selectivity in the photothermal reaction. This performance is 1.6 times higher than that of catalysts supported by Ni clusters (NiNP/CeO2). Additionally, NiSA/CeO2exhibits a hydrogen yield of 0.23 mmol h–1with stable long-term performance. Mechanistic studies reveal that single Ni atoms form linear coordination with oxygen atoms in CeO2, introducing unoccupied mid-gap states that effectively capture hot electrons and enhance the photothermal effect through local hotspot formation. In contrast, Ni clusters suffer from inefficient heat accumulation due to multistep phonon scattering. Furthermore, site isolation of Ni single atoms spatially separates the reaction intermediates and suppresses dimerization of the key intermediate COOHCH2CH2*, thereby greatly improving the selectivity for propionic acid. In contrast, closely packed Ni cluster sites promote intermediate coupling and the formation of undesirable byproducts, reducing selectivity. This work provides mechanistic insights into the advantages of atomic-scale catalyst design for selective chemical transformations.
The basal ganglia play a crucial role in action selection by facilitating desired movements and suppressing unwanted ones. The substantia nigra pars reticulata (SNr), a key output nucleus, facilitates movement through disinhibition of the superior colliculus (SC). However, its role in action suppression, particularly in primates, remains less clear. We investigated whether individual SNr neurons in three male macaque monkeys bidirectionally modulate their activity to both facilitate and suppress actions and examined the role of glutamatergic inputs in suppression. Monkeys performed a sequential choice task, selecting or rejecting visually presented targets. Electrophysiological recordings showed that SNr neurons decreased firing rates during target selection and increased firing rates during rejection, demonstrating bidirectional modulation. Pharmacological blockade of glutamatergic inputs to the lateral SNr disrupted saccadic control and impaired suppression of reflexive saccades, providing causal evidence for the role of excitatory input in behavioral inhibition. These findings suggest that glutamatergic projections, potentially originating from sources including the subthalamic nucleus, contribute to the increased SNr activity during action suppression. Our results highlight conserved basal ganglia mechanisms across species and offer insights into the neural substrates of action selection and suppression in primates, with implications for understanding disorders such as Parkinson’s disease.
Chronic pain arises from maladaptive changes in both peripheral and central nervous systems, including the anterior cingulate cortex (ACC), a key region implicated in descending pain modulation. Chronic pain increases the excitability of pyramidal neurons in the ACC. Although a reduction in inhibitory inputs onto pyramidal neurons has been observed in neuropathic conditions, the identity of the specific interneurons responsible remains unclear. We show that chronic pain selectively impairs parvalbumin (PV), but not somatostatin, interneurons in the rostral ACC. This is characterized by a decrease in the density of PV interneuron processes, a reduction in their surrounding perineuronal net, and a lower expression of PV. Functionally, PV interneurons display diminished inhibitory efficacy in vitro and reduced phasic activation in response to aversive stimuli in vivo. Dopamine (DA) fibers preferentially contact PV interneurons and excite them via D1 dopamine receptor activation, increasing their excitability and enhancing the frequency of inhibitory postsynaptic currents on pyramidal neurons in healthy, but not neuropathic, conditions. Furthermore, we show that this pathway is involved in hunger-induced analgesia: Food deprivation increases DA release in the ACC and consequently decreases pain thresholds in neuropathic mice. Conversely, when mice are not food deprived, neuropathic pain significantly reduces DA release in the ACC. We conclude that the loss of PV interneuron inhibitory efficacy, alongside convergent hypodopaminergic signaling, synergistically contributes to pathological ACC dysfunction and associated symptoms of chronic pain.
Regulation of proteome homeostasis is crucial for the survival and adaptation to changing environments for all species. In eukaryotes, this process is finely tuned through regulation at the level of transcription, translation, protein modification, and protein degradation. The phospholipase A2 activating protein (PLAA) is present in all eukaryotes and believed to be a key player in ubiquitin-dependent protein sorting and degradation via its interactions with ubiquitin and/or the AAA+ ATPase, valosin-containing protein (VCP/p97). PLAA’s molecular targets and interaction network remain unclear. We usedCaenorhabditis elegansand unbiased proteome-scale approaches to investigate neuronal specific interactors of theC. elegansPLAA ortholog UFD-3 (ubiquitin fusion degradation 3), its effect on ubiquitinated proteins, and global protein expression changes in anufd-3mutant. We found that PLAA may play a unique role in cytoplasmic messenger ribonucleic acid (mRNA) processing bodies (P-bodies). Using biochemical analysis in vitro and fluorescence imaging inC. elegans, we show that UFD-3 directly interacts with the mRNA decapping complex regulatory subunit DCAP-1. UFD-3's intrinsic disordered region (IDR), which contains conserved amino acid motifs, is important for the recruitment of DCAP-1 to P-bodies. Finally, we show that loss of the IDR does not affect UFD-3's role in sorting ubiquitinated proteins through the multivesicular body pathway. Collectively, our results suggest that UFD-3's role in P-bodies is distinct from its role in the ubiquitin-dependent protein degradation pathway and the IDR is only critical for UFD-3-regulated P-bodies pathways. Thus, PLAA/UFD-3 might regulate the proteome via two distinct pathways: ubiquitinated protein turnover, as well as mRNA regulation through P-bodies.
In recent years, trust in US public health and science institutions has faced unprecedented declines, particularly among Republicans/conservatives. To what extent might institutional criticism on social media be responsible for such politically polarized declines in institutional trust? Two online survey experiments (totalN= 6,800), using samples roughly reflective of the US adult population, examined the effects of key types of criticism against the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention (CDC). The results suggest that just a single exposure to any of the key types of criticism was sufficient to undermine institutional trust. While an institutional rebuttal was partially able to reverse these effects, residual declines in trust were substantial enough to cause decreased intentions to adhere to the AHRQ/CDC health recommendation featured in the experiments. While institutions should, therefore, be concerned about all types of social media criticism, those featuring morally charged trust-undermining narratives attacking the integrity of the AHRQ/CDC generated dramatically more anger (i.e., moral outrage), which in turn attracted social media engagement preferences likely to promote viral spread and exacerbate preexisting institutional politicization and issue polarization. These results suggest that efforts to bolster institutional trust should pay special attention to criticisms featuring integrity-based trust-undermining narratives.
Hydrocephalus, a neurological condition characterized by an excessive buildup of cerebrospinal fluid (CSF) in the brain, affects millions worldwide and leads to severe consequences. Current treatments, such as ventriculoperitoneal shunts, divert excess CSF from the brain but often face complications, mainly due to shunt obstructions caused by biological matter accumulation. While previous shunt designs aimed to improve fluid flow and reduce occlusion, they often lacked the precision needed for real-world applications due to simplified simulation models that did not fully capture the dynamics of the cerebral ventricular system. Here, we introduce BrainFlow, a computational model that integrates detailed anatomical and physiological features to simulate CSF dynamics in the presence of shunt implants. BrainFlow incorporates patient-specific medical imaging data, pulsatile flow to mimic cardiac cycles, adjustable parameters for various hydrocephalus conditions, and a biomolecule tracking feature to evaluate the long-term risk of shunt occlusion due to flow-mediated biomolecular transport. This model provides a more nuanced understanding of the factors contributing to shunt obstruction, offering insights into optimal shunt placement, design, and materials choice. Through validation against four-dimensional MRI flow data, BrainFlow demonstrates robust accuracy across multiple flow metrics. Our work lays the groundwork for the development of next-generation shunts tailored to individual patient anatomy and pathology, ultimately aiming to improve hydrocephalus treatment through informed, patient-specific design strategies.
Adhesive interfaces store significant energy due to interlocking molecular chain entanglement and van der Waals forces. When two adhesive surfaces are separated, triboelectric effects induce charge transfer, generating a strong electric field at the peeling interface. This effect offers different opportunities for initiating chemical reactions. Here, we report that the stick–slip friction involved in peeling tape produces electric fields on the order of 109V/m, as measured by the vibrational Stark shift observed by confocal Raman spectroscopy during tape peeling. This field is sufficiently strong to ionize water and produce the H4O2+cation, a hydroxyl radical adduct with a hydronium ion. We further demonstrate that this electric field can drive a variety of electron transfer reactions. Our findings suggest that tribocharging presents a promising, energy-efficient avenue for electric-field-driven green chemistry.
Generative AI is poised to revolutionize how humans work, and has already demonstrated promise in significantly improving human productivity. A key question is how generative AI affects learning—namely, how humans acquire new skills as they perform tasks. Learning is critical to long-term productivity, especially since generative AI is fallible and users must check its outputs. We study this question via a field experiment where we provide nearly a thousand high school math students with access to generative AI tutors. To understand the differential impact of tool design on learning, we deploy two generative AI tutors: one that mimics a standard ChatGPT interface (“GPT Base”) and one with prompts designed to safeguard learning (“GPT Tutor”). Consistent with prior work, our results show that having GPT-4 access while solving problems significantly improves performance (48% improvement in grades for GPT Base and 127% for GPT Tutor). However, we additionally find that when access is subsequently taken away, students actually perform worse than those who never had access (17% reduction in grades for GPT Base)—i.e., unfettered access to GPT-4 can harm educational outcomes. These negative learning effects are largely mitigated by the safeguards in GPT Tutor. Without guardrails, students attempt to use GPT-4 as a “crutch” during practice problem sessions, and subsequently perform worse on their own. Thus, decision-makers must be cautious about design choices underlying generative AI deployments to preserve skill learning and long-term productivity.
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Prostate cancer is a global health challenge, particularly for patients resistant to the second-generation anti-androgen receptor pathway inhibitors. The steroidogenic enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) has emerged as a promising therapeutic target and the corresponding inhibitors, biochanin-A (BCA) and its derivatives, suppress tumor growth in preclinical models and patients. However, the poor oral bioavailability of BCA hinders its clinical application. Here, we employed a sophisticated computational approach to refine the structural design of 3βHSD1 inhibitors. AlphaFold2 was utilized to construct detailed models of 3βHSD1 binding to various substrates. These models, in conjunction with the elucidated enzymatic mechanism of 3βHSD1, guided the optimization of a series of BCA-related compounds. Our structure–activity relationship studies identified HEAL-116 as a potent 3βHSD1 inhibitor. HEAL-116 exhibited enhanced binding specificity to the substrate-binding pocket of 3βHSD1 and effectively neutralized the local charge environment. The incorporation of hydrophilic groups in its structure also markedly enhanced its oral bioavailability. HEAL-116 robustly inhibited 3βHSD1 activity and exerted pronounced antitumor effect in biochemical, cellular, and mouse models. Our findings lay the foundation for the clinical translation of 3βHSD1 inhibitors, offering a promising therapeutic strategy for the management of prostate cancer and potentially other diseases.
Trichomonas vaginalisis a common, extracellular, sexually transmitted parasite which is often found in symbiosis with the intracellular bacteriumMycoplasma hominis(Mh), an opportunistic pathogen of the female reproductive tract. How this symbiosis affects infection outcomes and the host cell innate immune response is poorly understood. Here, we show that infection withT. vaginalisin symbiosis withM. hominisorM. hominisalone triggers a noncanonical type I interferon, interferon-epsilon (IFNε), but infection withT. vaginalisalone does not. We also demonstrate that extracellular vesicles (TvEVs) produced by the parasite downregulate host cell IFNε, counteracting this symbiont-driven response and elevating infection. We further demonstrate that IFNε, a hormonally regulated cytokine produced in the human reproductive system, is protective againstT. vaginaliscytoadherence and cytolysis of host cells. These studies provide insight into how a parasite and its bacterial symbiont work in concert to regulate host cell innate immune responses to drive infection.
The aggregation ofα-synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation ofα-synuclein. Using this framework, we find thatα-synuclein fibrils form via a two-step primary nucleation mechanism and that lipid molecules are directly involved in both the nucleation and fibril elongation steps, giving rise to lipid–protein coaggregates. To illustrate the applicability of this kinetic approach to drug discovery, we identify the mechanism of action of squalamine, a known inhibitor of lipid-inducedα-synuclein aggregation, revealing that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design ofα-synuclein aggregation inhibitors.
There is overwhelming evidence that forest trees are locally adapted to climate. Thus, genecological models based on population phenotypes have been used to measure local adaptation, infer genetic maladaptation to climate, and guide assisted migration. However, instead of phenotypes, there is increasing interest in using genomic data for gene resource management. We used whole-genome resequencing and common-garden experiments to understand the genetic architecture of adaptive traits in black cottonwood. We studied the potential of using genome-wide association studies (GWAS) and genomic prediction to detect causal loci, identify climate-adapted phenotypes, and inform gene resource management. We analyzed population structure by partitioning phenotypic and genomic (single-nucleotide polymorphism) variation among 840 genotypes collected from 91 stands along 16 rivers. Most phenotypic variation (60 to 81%) occurred among populations and was strongly associated with climate. Population phenotypes were predicted well using genomic data (e.g., predictive abilityr> 0.9) but almost as well using climate or geography (r> 0.8). In contrast, genomic prediction within populations was poor (r< 0.2). We identified many GWAS associations among populations, but most appeared to be spurious based on pooled within-population analyses. Hierarchical partitioning of linkage disequilibrium and haplotype sharing suggested that within-population genomic prediction and GWAS were poor because allele frequencies of causal loci and linked markers differed among populations. Given the urgent need to conserve natural populations and ecosystems, our results suggest that climate variables alone can be used to predict population phenotypes, delineate seed zones and deployment zones, and guide assisted migration.
Chloroplast division, a process tightly linked to the energy demands of plants, is initiated by the formation of the stromal filamenting temperature-sensitive Z (FtsZ) ring. The Z ring is highly dynamic, and its constriction provides the essential force for chloroplast division. However, the regulatory mechanisms governing Z-ring dynamics and constriction remain poorly understood. Here, we report that the chloroplast inner envelope membrane (IEM) protein ACCUMULATION AND REPLICATION OF CHLOROPLASTS6 (ARC6) interacts with the chloroplast stromal protein ARC3, and this interaction is negatively regulated by the conserved J-like domain of ARC6. ARC3 is found both distributed throughout the stroma and localized to a ring-like structure at the chloroplast division site. We demonstrate that ARC6 recruits ARC3 to the division site to form a ring-like structure, likely through direct interaction. This ARC6–ARC3 interaction enables ARC3 to bind FtsZs. Furthermore, we show that the ARC6–ARC3 complex significantly promotes the dynamics of chloroplast Z rings reconstituted in a heterologous system. Finally, the constriction of these reconstituted Z rings is markedly enhanced by ARC6–ARC3. Our findings reveal a regulatory mechanism that governs Z-ring dynamics and constriction, shedding light on the molecular mechanisms underlying chloroplast division.
Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance remains a major hurdle. Metabolic reprogramming is a notable phenotype associated with the acquisition of drug resistance. Here, we develop a computational framework that predicts metabolic gene targets capable of reverting the metabolic state of drug-resistant cells to that of drug-sensitive parental cells, thereby sensitizing the resistant cells. The computational framework performs single-gene knockout simulation of genome-scale metabolic models that predicts genome-wide metabolic flux distribution in drug-resistant cells, and clusters the resulting knockout flux data using uniform manifold approximation and projection, followed byk-means clustering. From the clustering analysis, knockout genes that lead to the flux data near that of drug-sensitive cells are considered drug sensitization targets. This computational approach is demonstrated using doxorubicin- and paclitaxel-resistant MCF7 breast cancer cells. Drug sensitization targets are further refined based on proteome and metabolome data, which generateGOT1for doxorubicin-resistant MCF7,GPIfor paclitaxel-resistant MCF7, andSLC1A5as a common target. These targets are experimentally validated where treating drug-resistant cancer cells with small-molecule inhibitors results in increased sensitivity of drug-resistant cells to doxorubicin or paclitaxel. The applicability of the developed framework is further demonstrated using drug-resistant triple-negative breast cancer cells. Taken together, the computational framework predicts drug sensitization targets in an intuitive and cost-efficient manner and can be applied to overcome drug-resistant cells associated with various cancers and other metabolic diseases.
Cancer therapy would benefit from suppressing cancer cell motility in the process of metastasis. Such directed cell migration relies on the propulsive force established by the filamentous actin network within lamellipodia. Proteins of the Ena/VASP family and the WAVE regulatory complex orchestrate lamellar protrusions and therefore provide promising targets for pharmacological interventions. Here, we report a cross-talk between Ena/VASP proteins and WAVE2 that is important for cancer cell extravasation. Mutating the EVH1 domain recognition motif in WAVE2 abrogates chemotaxis of triple-negative MDA-MB-231 breast cancer cells and reduces their extravasation in a zebrafish model. In pilot experiments, orthotopic implantation of these cells into mice led to a reduction in macrometastasis, resulting in prolonged survival. Similarly, intervention by an Ena/VASP-EVH1 inhibitor also reduced metastasis in vivo. Our results suggest that pharmacological interference with the Ena/VASP–WAVE2 interaction may thus reduce metastasis.
The Hantzsch ester (HEH2) has found considerable utility as a photoreductant in synthesis, with photodriven transfer hydrogenation reactions typically limited to activated substrates. We recently established that the addition of an organic buffer of collidinium triflate [(ColH)OTf] and collidine (Col) allows photodriven transfer hydrogenation from HEH2to N2forming NH3(nitrogen reduction; N2R) in the presence of a Mo catalyst. Given the requirements for Mo-catalyzed thermally driven N2R, this result suggested the generation of a significant driving force for proton-coupled electron transfer (PCET) when irradiating HEH2in the presence of Col-buffer. In this study, we probe how Col-buffer enables efficient photodriven proton-coupled reductions with HEH2. Wavelength-dependent NH3yields are consistent with HEH2photoexcitation, and the combination of HEH2with Col-buffer is privileged. Data are presented, suggesting that HEH2is statically quenched via ET to [ColH]OTf through an H-bonded association complex to release ColH•and [HEH2]•+. Transient absorbance data and EPR studies establish that the resulting [HEH2]•+intermediate is rapidly deprotonated by Col to yield HEH•, in net furnishing HEH•and ColH•as potent H-atom donors. Broader utility of this reagent combination is demonstrated in the photoreduction of a range of C=O and N=O π-bonds by HEH2, with a significant boost in rates and yield, and altered reactivity, observed on addition of Col-buffer. ColH•is posited as the most potent PCET donor generated (BDFEN−Hof 28 kcal mol−1).
Perception is fallible. Humans know this, and so do some nonhuman animals like macaque monkeys. When monkeys report more confidence in a perceptual decision, that decision is more likely to be correct. It is not known how neural circuits in the primate brain assess the quality of perceptual decisions. Here, we test two hypotheses. First, that decision confidence is related to the structure of population activity in the sensory cortex. And second, that this relation differs from the one between sensory activity and decision content. We trained macaque monkeys to judge the orientation of ambiguous stimuli and additionally report their confidence in these judgments. We recorded population activity in the primary visual cortex and used decoders to expose the relationship between this activity and the choice-confidence reports. Our analysis validated both hypotheses and suggests that perceptual decisions arise from a neural computation downstream of visual cortex that estimates the most likely interpretation of a sensory response, while decision confidence instead reflects a computation that evaluates whether this sensory response will produce a reliable decision. Our work establishes a direct link between neural population activity in the sensory cortex and the metacognitive ability to introspect about the quality of perceptual decisions.
The contact between two rough surfaces has been a topic of significant interest since early studies on Coulombic friction and remains crucial for numerous technological applications. However, theoretical progress has outpaced experiments due to the challenges in measuring contact areas across scales ranging from subnanometers to macroscopic dimensions. Here, we demonstrate the use of commonly available infrared-based (IR) spectroscopy in combination with finite-difference time-domain (FDTD) optical simulations to measure separation gaps and contact areas for glassy polymers ranging in roughness over two orders in magnitude. With the combined IR and FDTD simulations, we can overcome the optical diffraction limits and take advantage of the chemical specificity of IR spectroscopy to overcome limitations due to scattering. The scaling of the contact area ratio as a function of pressure illustrated the limitations of using pure elastic or plastic deformation in explaining the results. At both low and high pressures, the contact area ratios scale linearly with pressure as expected for purely elastic deformations at low pressures or plastic deformations at high pressures. However, if analyzed over a broad range of pressure, the power laws we observe are much larger than 1, exemplifying the need to consider elastoplastic models in explaining results for softer polymer contacts compared to other brittle, glassy materials. In comparison, the separation gaps scale exponentially with pressure, as expected. These results have important implications for the interpretation of properties such as friction, adhesion, and conductivity for softer, glassy contact interfaces.
RNA recognition motif (RRM) domain proteins are crucial RNA-binding proteins across all domains of life. In cyanobacteria, single RRM domain proteins are involved in mRNA targeting to the thylakoid membrane and acclimation to certain stress conditions, but many details of their physiological functions and molecular targets have remained unknown. The model cyanobacteriumSynechocystissp. PCC 6803 has a family of three genes encoding the RRM domain–containing proteins Rbp1, Rbp2, and Rbp3. Here, we verified the RNA-binding activity of Rbp3 in vivo and show that cells of a Δrbp3deletion strain had a lower photosystem (PS) I:PSII ratio and decreased pigment content and were significantly smaller than wild-type cells. To identify the set of interacting molecules, coimmunoprecipitation experiments were performed with a strain expressing a C-terminally FLAG-tagged Rbp3. Mass spectrometry of the elution fraction suggested physical proximity between Rbp3, ribosomes, and a very small number of other proteins. The most highly enriched transcript in the coeluting RNA fraction was thepsaABmRNA. This was corroborated by fluorescent in situ hybridization analyses showing decreasedpsaAmRNA signals in Δrbp3, and colocalization with Rbp3 fusions to the green fluorescent protein (GFP) in the wild type. Other mRNAs coenriched with Rbp3 encode thylakoid, plasma membrane, and carboxysome proteins. Binding assays using Bio-layer Interferometry validated the Rbp3-psaABmRNA interaction, indicating a preference for folded RNA segments near or overlapping the respective stop codons.
Liquid–liquid phase transitions (LLPTs) are typically characterized as two-state systems, where transitions occur between two distinct liquid phases driven by local structural rearrangements. In this study, we observed a continuous LLPT with an inversion of electronegativity in a K–Rb binary alloy. This uniquely exhibits a three-state system behavior. The transition, induced by pressure-driven reordering of electronic orbital energies, progresses through a sequence froms-metal to electride tod-metal, accompanied by a valence reversal: Potassium transitions from a negative to a positive valence, while rubidium undergoes the opposite shift. This process is marked by two successive anomalies in the alloy’s optical, thermodynamic, and dynamic properties over a broad pressure range. The observation of similar LLPT phenomena in other alkali and alkaline earth metal liquids suggests that this three-state system mechanism may provide broader insights into the nature of continuous phase transitions.
PIK3CA-related disorders are rare genetic disorders due to somatic gain-of-function mutations inPIK3CAduring embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients withPIK3CA-related disorders indicates that peripheral nerves are frequently affected, leading to severe neurological symptoms. However, the exact underlying mechanism of these disorders remains unclear. To address this, we developed a mouse model with aPIK3CAgain-of-function mutation specifically in Schwann cells, which successfully mirrored the clinical features observed in patients. In this model, we observed thatPIK3CA-mutated cells communicate with neighboring healthy cells, such as adipocytes and hair follicles, through a unique crosstalk mechanism that triggers their growth, proliferation, and anagen phase expansion. Additionally, we demonstrated thatPIK3CAmutation in peripheral nerves leads to a metabolic shift through glycolytic activation. We investigated the effects of alpelisib, an approved pharmacological inhibitor of PIK3CA, in the model. Early administration of alpelisib significantly improved the signs and symptoms in the mice. However, when treatment was delayed, its efficacy was diminished due to the drug’s inability to penetrate the myelin sheath effectively. In summary, our study offers a valuable mouse model for studyingPIK3CA-related neuropathy, uncovers a unique communication between healthy and affected tissues, and highlights the potential benefits of early pharmacological intervention using alpelisib.
Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. In this study, we focused on the stability of SAM levels in the fat body (FB) ofDrosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin–proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt level reduction by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated reduction helps maintain SAM levels under SAM shortage conditions.
The outer membrane vesicles (OMVs) produced by diderm bacteria have important roles in cell envelope homeostasis, secretion, interbacterial communication, and pathogenesis. The facultative intracellular pathogenSalmonella entericaTyphimurium (STm) activates OMV biogenesis inside the acidic vacuoles of host cells by upregulating the expression of the OM protein PagC, one of the most robustly activated genes in a host environment. Here, we used solid-state nuclear magnetic resonance (NMR) and electron microscopy (EM), with native bacterial OMVs, to demonstrate that three histidines, essential for the OMV biogenic function of PagC, constitute a key pH-sensing motif. The NMR spectra of PagC in OMVs show that they become protonated around pH 6, and His protonation is associated with specific perturbations of select regions of PagC. The use of bacterial OMVs is a key aspect of this work enabling NMR structural studies in the context of the physiological environment. PagC expression upregulates OMV production inEscherichia coli, replicating its function in STm. Moreover, the presence of PagC drives a striking aggregation of OMVs and increases bacterial cell pellicle formation at acidic pH, pointing to a potential role as an adhesin active in biofilm formation. The data provide experimental evidence for a pH-dependent mechanism of OMV biogenesis and aggregation driven by an OM protein.
Island populations of large vertebrates have experienced higher extinction rates than mainland populations over long timescales due to demographic stochasticity, genetic drift, and inbreeding. While being more susceptible to extinction and as such potentially targeted for conservation interventions such as genetic rescue, small-island populations can experience relatively less anthropogenic habitat degradation than those on larger islands. Here, we determine the consequences and conservation implications of long-term isolation and recent human activities on genetic diversity of island populations of two forest-dependent mammals endemic to the Wallacea archipelago: the anoa (Bubalusspp.) and babirusa (Babyrousaspp.). Using genomic analyses and habitat suitability models, we show that, compared to closely related species, populations on mainland Sulawesi exhibit low heterozygosity, high inbreeding, a high proportion of deleterious alleles, and experience a high rate of anthropogenic disturbance. In contrast, populations on smaller islands occupy higher-quality habitats, possess fewer deleterious mutations despite exhibiting lower heterozygosity and higher inbreeding. Site frequency spectra indicate that these patterns reflect stronger, long-term purging in smaller-island populations. Our results thus suggest that conservation efforts should focus on protecting small-island high-quality habitats and avoiding translocations from mainland populations. This study highlights the crucial role of small offshore islands for the long-term survival of Wallacea’s iconic and indigenous mammals in the face of development on the mainland.
Tissue fibrosis is commonly associated with organ malfunction and is strongly associated with the development of chronic rejection, cardiovascular diseases, and other chronic diseases. Fibrosis also contributes to immune exclusion in tumor tissues. Targeting fibrosis might be a strategy for prolonging allograft survival while suppressing cancer development. Here, single-cell transcriptomes of human and mouse heart allografts showed that macrophages accumulated in grafts with fibrosis were reprogrammed via histone methylation regulated by Setdb1, an H3K9 methyltransferase. Myeloid-specific deletion of Setdb1 prolonged heart allograft survival but reversed immune exclusion in tumor tissues. Interestingly, myeloid-specific Setdb1-knockout led to lower fibrosis in heart allografts and tumor tissues in mice. Our single-cell sequencing data showed that Setdb1 ablation impaired Fn1+and SPP1+profibrogenic macrophage reprogramming. Mechanistically, Fn1, which was induced by the CCR2-Creb/Setdb1 axis, upregulated the expression of genes related to fibrosis in fibroblasts and macrophages via ITGA5 and PIRA receptors. Blocking the interaction between FN1 and these receptors inhibited fibrosis in allograft and tumor tissues. Our results reveal a target, histone methylation in macrophages, for the treatment of fibrosis-related disease.
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The Late Paleozoic Ice Age (~340 to 260 Ma) occurred under peak atmospheric O2(1.2 to 1.7 PIAL, pre-industrial atmospheric levels) for Earth history and CO2concentrations comparable to those of the preindustrial to that anticipated for our near future. The evolution of the marine redox landscape under these conditions remains largely unexplored, reflecting that oceanic anoxia has long been considered characteristic of carbon cycle perturbation during greenhouse times. Despite elevated O2, a 105-y period of CO2-forced oceanic anoxia was recently identified, but whether this short-term interval of widespread oceanic anoxia was anomalous during this paleo-ice age is unexplored. Here, we investigate these issues by building a high-resolution record of carbonate uranium isotopes (δ238Ucarb) from an open-marine succession in South China that permits us to reconstruct the global marine redox evolution through the deep glacial interval (310 to 290 Ma) of near peak O2. Our data reveal repeated, short-term decreases in δ238Ucarbcoincident with negative C isotopic excursions and rises in paleo-CO2, all superimposed on a longer-term rise in δ238Ucarb. A carbon–phosphorus–uranium biogeochemical model coupled with Bayesian inversion is employed to quantitatively explore the interplay between marine anoxia, carbon cycling, and climate evolution during this paleo-glacial period. Although our results indicate that protracted, enhanced organic carbon burial can account for the long-term O2increase, seafloor oxygenation, and overall low CO2, episodic pulses of C emissions had the potential to drive recurring short-term periods of marine anoxia (with 4 to 12% of seafloor anoxia) despite up to 1.7 times higher atmospheric O2than present day.
Inspired by Nature, we present a polypeptide-based organic redox-active material constructed from renewable feedstocks, L-glutamic acid (an amino acid) and riboflavin (vitamin B2), to address challenges with start-to-end-of-life management in energy storage systems (ESSs). The amino acid was utilized to establish a degradable polymer backbone, along which many copies of riboflavin were incorporated to serve as the redox-active pendant groups that enabled energy storage. The overall synthesis involved the ring-opening polymerization (ROP) of anl-glutamic acid-derivedN-carboxyanhydride (NCA) monomer, followed by side chain activation with azides and, finally, click coupling to achieve installation of alkyne-functionalized riboflavin moieties. The steric bulkiness and rich chemical functionality of riboflavin resulted in synthetic complexities that required reaction optimization to achieve the desired polymer structure. Electrochemical characterization of the resultant riboflavin polypeptide, in organic electrolyte, showed quasireversible redox activity with a half-wave potential (E1/2) ofca.−1.10 Vvs.ferrocene/ferrocenium (Fc/Fc+). Cell viability assays revealed biocompatibility, as indicated by negligible cytotoxicity for fibroblast cells. The polypeptide design, consisting of labile amide backbone linkages and side-chain ester functionalities that tethered the riboflavin units to the backbone, enabled hydrolytic degradation to recover building blocks for future upcycling or recycling. This bioinspired strategy advances the development of degradable redox-active polymers and promotes sustainable materials design for circular energy storage technologies.
Equine infectious anemia virus (EIAV) is an important model for the study of pathogenesis in lentiviruses. Studies of viral genome organization and replication mechanisms are fundamental to the understanding of virus pathogenicity. In this study, we identified an unique transcript from EIAV in vivo and in vitro by Sanger sequencing and Northern blotting. The transcript contains a complete open reading frame and has length 369 nt. We named the protein encoded by this transcript S4 and demonstrated its expression in EIAV-infected cells. An S4-deficient EIAV infectious clone displayed obviously impaired virion release and attenuated virus replication in vitro, demonstrating that S4 plays a role in the release step of EIAV. The host restriction factor tetherin has broad-spectrum antiviral activity and prevents the release of a wide range of enveloped viruses, including lentiviruses. Here, we demonstrated that S4 enhances the release of the EIAV-like particle by counteracting the equine tetherin (eqTHN). S4 interacts with the eqTHN and sequesters it within intracellular membrane compartments, attenuating eqTHN expression on the cell surface and thereby disrupting its antiviral activity. Further investigation revealed that S4 retains eqTHN in the endoplasmic reticulum and trans-Golgi network through impacting its anterograde transport to the cell surface and may interfere with the posttranslational modification of this membrane protein. Collectively, our findings uncover an accessory protein, S4, of EIAV and reveal its ability to promote virion release by antagonizing the antiviral activity of the host restriction factor tetherin.
Scholars have long been concerned about gender representation in scientific research but there has been little work on gender differences in participation and performance in climate science, a field that engages with both male-majority disciplines (e.g., geosciences, engineering) and female-majority disciplines (e.g., life sciences, medical science). This has implications for both gender equity and viewpoint representation. Sampling over 400,000 publications and a similar number of authors, we examine gender differences in several scholarly outcomes including publication count, career survival, coauthor gender, journal status, and mean citation count. We find men and women are similarly productive, successful, and connected, though women have shorter research careers and thus fewer papers. We also find gender homophily effects in collaboration, but no evidence of gender bias in peer review.
Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
Freshwater resources are fundamental to supporting humanity, and measures of water scarcity have been critical for identifying where water requirements and water availability are imbalanced. Existing water scarcity metrics typically account for blue water withdrawals (i.e., from surface-/groundwater), while the contribution of green water (i.e., soil moisture) and water quality—dimensions with important implications for multiple societal sectors—to water scarcity remains unclear. Here, we introduce the concept of multidimensional water scarcity that explicitly assesses all three of these dimensions of water scarcity and evaluates their individual and combined effects. We find that 22 to 26% of the global land area and 58 to 64% of the global population are exposed to some form of water scarcity annually, with multidimensional (i.e., blue, green, and quality) water scarcity particularly high in India, China, and Pakistan. Examining seasonal water scarcity, we estimate that 5.9 billion people (or 80% of the world’s population in 2015) were exposed to at least one dimension of water scarcity for at least 1 mo per year and that 1-in-10 people (10%) were exposed to multidimensional water scarcity at least 1 mo per year. Our findings demonstrate that the challenges of water scarcity are far more widespread than previously understood. As such, our assessment provides a more holistic view of global water scarcity issues and points to overlooked scarcity where action needs to bring human pressure on freshwater resources into balance with water quantity and quality.
The Qinghai–Tibet Plateau (QTP) harbors extraordinarily high levels of biodiversity and endemism. The region is warming at a rate twice the global average, yet the evolutionary dynamics of its unique biota are poorly understood. Here, we used the endemic land plant genera of the QTP to investigate how its floristic endemism was shaped over time by Cenozoic geoclimatic changes. We first clarified that the QTP hosts 82 endemic land plant genera; we found that the origins of these endemic genera were most likely driven by ecological niche and elevation differentiation, caused by the uplift of the QTP and associated climate change. By sampling 37 land plant clades that together encompass 1,740 species, covering all 82 endemic genera, we show that QTP floristic endemism had emerged by the Early Eocene. Furthermore, the unique biodiversity of the QTP comprises a mix of indigenous elements and immigrants. Among the three subregions of the QTP (Plateau Platform, Himalaya, and the Hengduan Mountains), the processes associated with floristic endemism are asynchronous, reflecting different geoclimatic events with the Miocene as a particularly critical period. The relative contributions of in situ speciation and immigration to the unique biodiversity of the three subregions are also markedly different; in situ speciation dominated in the Hengduan Mountains, which hosts the oldest endemic components of the flora and has served as an important “pump” and “sink” of unique biodiversity. These findings provide insights into how past geoclimatic events may have shaped floristic endemism on the QTP and also have important conservation implications.
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Indirect reciprocity is a compelling explanation for stable cooperation in a large society: Those who cooperate appropriately earn a good standing, so that others are more likely to cooperate with them. However, this mechanism requires a population to agree on who has good standing and who has bad standing. Consensus can be provided by a central institution that monitors and broadcasts reputations. But how might such an institution be maintained, and how can a population ensure that it is effective and incorruptible? Here, we explore a simple mechanism to sustain an institution for judging reputations: a tax collected from each member of the population. We analyze the possible tax rate that individuals will rationally pay to sustain an institution of judgment, which provides a public good in the form of information, and we derive necessary conditions for individuals to resist the temptation to evade their tax payment. We also consider the possibility that institution members may be corrupt and subject to bribery, and we analyze how strong the incentives against corruption need to be. Our analysis has implications for establishing robust public institutions that provide social information to support cooperation in large populations—and the potential negative consequences associated with wealth or income inequality.
Cyclin F, a noncanonical member of the cyclin protein family, plays a critical role in regulating transitions in the cell division cycle. Unlike canonical cyclins, which bind and activate cyclin-dependent kinases (CDKs), Cyclin F functions as a substrate receptor protein within the Skp1–Cullin-F-box E3 ubiquitin ligase complex, enabling the ubiquitylation of target proteins. The structural features that distinguish Cyclin F as a ligase adaptor and the mechanisms underlying its selective substrate recruitment over Cyclin A, which functions in complex with CDK2 at a similar time in the cell cycle, remain largely unexplored. We utilized single-particle cryoelectron microscopy to elucidate the structure of a Cyclin F–Skp1 complex bound to an E2F1 peptide. The structure and biochemical analysis reveal important differences in the substrate-binding site of Cyclin F compared to Cyclin A. Our findings expand on the canonical cyclin-binding motif (Cy or RxL) and highlight the importance of electrostatics at the E2F1 binding interface, which varies between Cyclin F and Cyclin A. These results advance our understanding of E2F1 regulation and may inform strategies for selectively targeting Cyclin F in cancer or neurodegeneration.
Thiamine (vitamin B1) deficiency in marine systems is a globally significant threat to marine life. In 2020, newly hatched Chinook salmon (Oncorhynchus tshawytscha) fry in California’s Central Valley (CCV) hatcheries swam in corkscrew patterns and died at unusually high rates due to a lack of this essential vitamin. We subsequently investigated the impacts and causes of thiamine deficiency in California’s anadromous salmonids. Our laboratory studies defined the relationship between thiamine concentrations in Chinook salmon eggs and early life-stage survival in offspring; we used these data to develop a model that estimated 26 to 48% thiamine-dependent fry mortality across consecutive years (2020–2021) for winter-run Chinook salmon. We established an egg surveillance effort that found widespread thiamine deficiency in CCV Chinook salmon in 2020 and 2021, and emerging thiamine deficiency in Klamath River and Trinity River coho salmon (Oncorhynchus kisutch) in 2021. We determined that thiamine injections into adults raised egg thiamine concentrations above levels found to impact early life-stage survival and swimming behavior. Ocean surveys, prey nutrition, salmon gut contents, and stable isotope data link thiamine deficiency to an ocean diet dominated by a booming population of northern anchovy (Engraulis mordax). This forage fish had low thiamine, high lipid, and high thiaminase activity levels consistent with both a thiaminase and oxidative stress hypothesis for causing thiamine deficiency in California salmon. Our research suggests California’s already stressed anadromous salmonids will continue to be impacted by thiamine deficiency as long as their ocean forage base and diet are dominated by northern anchovy.
Salt marshes provide valuable ecosystem services but are vulnerable to drowning with accelerated sea-level rise (SLR). Marsh belowground biomass (BGB) production helps avoid drowning by building marsh surface elevation. Reductions in BGB can serve as an early warning sign of marsh deterioration, as they often precede decreases in aboveground biomass (AGB). However, landscape-scale BGB assessments to predict broad trends in marsh deterioration have not been previously available. We applied the Belowground Ecosystem Resiliency Model (BERM) to assess standing stocks and trends in both BGB and AGB over the past decade (2014–2023) across US Georgia coastSpartina alternifloramarshes (691 km2). Over this time period, BGB and AGB averaged 841 ± 323 and 221 ± 14 g m−2, respectively, but showed opposite trends. BGB decreased on average by 0.94% per year and over most of the marsh area (72%), while AGB increased on average by 0.66% per year and showed a net increase across most of the marsh area (88%). This disconnect suggests that AGB is not a good indicator of marsh resilience, and we highlight two areas with similar AGB but different BGB. Inundation intensity, an important predictor of BGB, rose through time and was negatively related to BGB. SLR trends suggest continuing increases in inundation, which will result in further declines in BGB followed by widespread marsh drowning. Landscape BGB assessments are a valuable tool to identify ecosystem vulnerability and proactively manage salt marshes and the services they provide under rising sea levels.
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Fire is a pivotal aspect of human involvement in the carbon cycle. However, the precise timing of the large-scale human fire use remains uncertain. Here, we report a pyrogenic carbon record of East Asian fire history over the past 300,000 y from the East China Sea. This record suggests a rapid increase in fire activity since approximately 50,000 y ago, indicating a decoupling from the monsoon climate, and this pattern is consistent with fire histories in Europe, Southeast Asia, and Papua New Guinea-Australia regions. By integrating extensive archaeological data, we propose that the intensified global expansion of modern human and population growth, coupled with the rising demand for fire use during cold glacial periods, resulted in a significant increase in fire utilization from 50,000 y onward. This suggests that a measurable human imprint on the carbon cycle via fire likely predates the Last Glacial Maximum.
Each new mammalian life begins with the fusion of an oocyte and a sperm to produce a fertilized egg containing two sets of genomes, one from the mother and one from the father. Androgenesis, a way for producing offspring solely from male genetic material, is limited in mammals, presumably due to barriers arising from genomic imprinting, an epigenetic mechanism leading to monoallelic gene expression. Here, we report adult mammalian offspring derived from the genetic material of two sperm cells. These mice, which we refer to as androgenetic mice, were produced via targeted DNA methylation editing of seven imprinting control regions (ICRs) through CRISPR-based epigenome engineering. Two sperm cells were injected into an enucleated oocyte to form putatively diploid embryos. Allele-specific epigenetic editing was achieved by injecting guide RNAs with protospacer adjacent motif (PAM) sequences designed to match one allele but not the other. The birth of androgenetic mice that were able to develop to adulthood demonstrates that mammalian androgenesis is achievable by targeted epigenetic remodeling of a few defined ICRs.
Tree species worldwide face increasing exposure to unprecedented macroclimatic conditions due to anthropogenic climate change, which may trigger biome shifts and ecosystem disruptions. We quantified climate change exposure–shifts to species’ currently unoccupied climate zones–for 32,089 tree species globally by 2100, assessing both species-level and local tree diversity risks. On average, 69% of species are predicted to experience macroclimatic shifts in at least 10% of their range, while 14% face exposure in over 50% of their range under a high-emission (4 °C warming) future scenario. This suggests that most species retain substantial climate refugia within their current range. However, local tree diversity exposure is predicted to be severe in vast regions, including Eurasia, the northwestern United States and Canada, northern Chile, and the Amazon Delta. Under a moderate (2 °C warming) scenario, high tree diversity exposure is mostly restricted to taiga regions in the Northern Hemisphere. These findings provide conservative estimates of climate-driven biodiversity risk, as our approach focuses solely on macroclimate and does not account for additional stressors such as land-use change or species interactions. Identifying tree species and areas of high macroclimatic shift exposure allows for targeted conservation strategies, including species stability monitoring, assisted migration, and the protection of climate refugia. Our results offer a foundation for prioritizing conservation actions in a rapidly changing climate, ensuring long-term ecosystem resilience.
TheHTLV-1 bZIP factor(HBZ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia–lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1–infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1–infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-β activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-β stimulation.JUNBknockdown inhibits cell proliferation in vitro and in vivo and promotes apoptosis in ATL cells but not in HTLV-1–infected nonleukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-β-induced nuclear translocation of HBZ–JunB complexes is associated with ATL oncogenesis.
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A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA—leaked from mitochondria or nuclei during infection—remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid–sensing pathways.
Estrogen receptor β (ERβ) plays an important role in both the mouse and human prostate. The endogenous ligand for ERβ is the dihydrotestosterone metabolite, 5β-androstane-3β, 17β-diol (3β-Adiol). Thus, treatment with 5-α reductase inhibitor (5-ARI) should produce a phenotype similar to that seen in ERβ−/−mice. By comparing RNA-Seq of the ventral prostates (VP) of ERβ knockout mice (ERβcrispr−/−) and wild-type (WT) mice, we confirmed that ERβ modulates androgen receptor (AR) signaling indirectly by suppressing AR coactivators. Compared to WT mice, basal cell genes from ERβcrispr−/−mouse VP were significantly upregulated. A population of abnormal basal cells coexpressing P63 and AR was identified in the ERβcrispr−/−mouse VP by immunohistochemistry. In men treated with 5-ARI for treatment of benign prostatic hyperplasia (BPH), there was induction of a P63-positive intermediate cell population characterized by down regulation of Krt14 without significant change in the expression of Krt15, upregulation of AR and NKX3.1, and increased proliferation. In both VP of aging ERβcrispr−/−mice and in human prostates after 5-ARI treatment, there was substantial immune infiltration. Testosterone treatment inhibited immune infiltration in the VP of ERβcrispr−/−mice. We conclude that ERβ is a gene critical in maintaining normal basal cells and modulating immune environment in the prostate. Its loss leads to histological changes suggesting prostatitis and increases the number of intermediate cells, which are considered to be the cells of origin of prostate cancers. We suggest that an ERβ agonist could protect against 5-ARI-induced inflammatory cell infiltration and defects in the basal cell layer in BPH.
Motivated by recent data pointing to the existence of homo-oligomeric assemblies of membrane proteins called higher-order transient structures, and their apparent role in connecting components of membrane signal pathways, we examine here by cryoelectron microscopy some of the protein–protein interactions that occur in cluster formation. Metabotropic glutamate receptors and HCN ion channels inside clusters contact their neighbors through structured extracellular and intracellular domains, respectively. Other ion channels, including Kv2.1 and Slo1, appear to form clusters through prominent intrinsically disordered sequences in the cytoplasm. These distinct modes of interaction are associated with clusters exhibiting varying degrees of compactness and order. We conclude that nature utilizes a variety of ways to form connections between membrane proteins in self-assembled clusters.
Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we demonstrate a role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings reveal that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.
Recently, extensive evidence has demonstrated that the brain operates close to a critical state, characterized by dynamic patterns known as neuronal avalanches. The critical state, reflecting the delicate balance between neural excitation and inhibition, offers numerous advantages in information processing. However, the role of genetics in shaping brain criticality is not fully understood. Whether there is any shared genetic factor influencing the critical state and cognitive functions remains elusive. Here, we aimed to address these questions by examining the heritability of brain criticality and its relation to cognitive function by analyzing resting-state functional magnetic resonance imaging (rs-fMRI) in 250 monozygotic twins, 142 dizygotic twins, and 437 Not-twin subjects. We found that genetic factors substantially influenced brain criticality across various scales, encompassing brain regions, functional networks, and the whole brain. These genetic influences exhibited heterogeneity, with the criticality of the primary sensory cortex being more strongly influenced by genetic factors compared to that of the association cortex. Furthermore, we combined rs-fMRI data with transcriptional microarray data from the Allen Brain Atlas: Human Brain (ABHB) dataset and found that the organization of regional critical dynamics was highly explained by a specific gene expression profile. Finally, our results showed that the critical state was correlated with total cognition and had a genetic link with it. These findings provide empirical evidence that brain criticality is a biological phenotype and suggest a shared genetic foundation underlying brain criticality and cognitive functions. Our results pave the way toward revealing specific biological mechanisms contributing to critical dynamics and their associations with brain function and dysfunction.
The mutual antagonistic signaling of abscisic acid (ABA) and ROP GTPases highlights an intersection between stress responses and pattern formation. Previously, we have shown that signaling of ABA in the endodermis leads to protoxylem (PX) differentiation. In this study, we demonstrate that ROPs suppress PX differentiation in the roots of bothArabidopsisand tomato. Fourier transform and Shannon’s entropy show that endodermal ABA signaling controls the periodicity and overall order of PX secondary cell wall (SCW) coils in an ROP-dependent manner. Correspondingly, in the PX, GFP-ROP11 is initially dispersed and gradually becomes distributed in an oscillatory fashion with a periodicity corresponding to that of the SCW coils. Oryzalin treatments disrupt the frequency and increase the entropy of the GFP-ROP11 signal, suggesting that microtubules delimit ROP distribution. Signaling of ABA in the endodermis encourages the enlargement of metaxylem SCW pits, while ABA signaling in the stele limits this enlargement. Pit size and density are decreased in ROP mutants while ABA enhances ROP11 expression in the stele and broadens its distribution in the endodermis. Taken together, non-cell-autonomous and cell-autonomous interactions between ABA and ROPs regulate xylem differentiation and SCW patterning.
Gastrointestinal (GI) neuroimmune interactions are crucial sensors and regulators of tissue homeostasis. Most enteric neurons reside within the myenteric plexus of the enteric nervous system in the muscular region, forming a structure called themuscularis externa. Despite established interactions between muscularis macrophages and neurons, the presence and function of other immune cell types remains poorly characterized. Here, we mapped the muscularis immune cell landscape, revealing that diverse cell types are present within distinct locations of the GI tract, and they lie in proximity to neuronal cell bodies and their axons. Using a hypothesis-free computational approach, we identify putative ligand–receptor interactions from publicly available single-cell RNA datasets and further validate one of these (App-CD74). This study provides a valuable reference to encourage new avenues of research underpinning enteric neuroimmune interactions as key contributors to GI homeostasis and diseases.
Climate change pushes species toward higher latitudes and altitudes, but the proximate drivers of range expansions vary, and it is unclear whether evolution facilitates climate change–induced range changes. In a temporally replicated field experiment, we translocated wall brown butterflies (Lasiommata megera) descending from range interior and range margin populations to sites at 1) the range interior, 2) the range margin, and 3) beyond the current northern range edge. Thereby, we tested for local adaptation in seasonal timing and winter survival and evaluated to what extent local adaptation influences the ongoing, climate-driven range expansion. Almost all individuals from all populations entered diapause at an appropriate time, despite previously identified among-population variation in diapause induction thresholds. Caterpillars of northern descent, however, grew faster than those from southern populations at all field sites. This may be a countergradient adaptation to compensate for the short, northern growing seasons, but we found no evidence for prewinter body mass affecting winter survival. In fact, winter survival was low overall—extremely so at the beyond range site—regardless of population origin, indicating that the primary constraint to range expansion is an inability to adapt to winter conditions. Hence, although range-expanding wall browns show clear local evolution of two traits related to seasonal timing, these putative local adaptations likely do not contribute to range expansion, which is instead limited by winter survival. To predict future range changes, it will be important to distinguish between the traits that evolve during range expansion and those that set the range limit.
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Neisseria meningitidisis a human commensal bacterium that can opportunistically invade the bloodstream and cross the blood–brain barrier, where it can cause septicemia and meningitis. These diseases, if left untreated, can be lethal within hours. HyperinvasiveN. meningitidisstrains often express a genomically encoded filamentous bacteriophage called MDAΦ, which promotes colonization of mucosal host surfaces to facilitate bacterial invasion. How this phage is organized and how it promotes biofilm formation and infection at the molecular level is unclear. Here, we present an electron cryomicroscopy structure of the MDA phage, showing that MDAΦ is a class I filamentous inovirus, with the major capsid protein (MCP) arranged within the phage as a highly curved and densely packed α-helix. Comparison with other filamentous bacteriophages offers clues about inoviral genome encapsidation mechanisms, providing a framework for understanding the evolutionary diversity of inoviruses. A disordered, N-terminal segment in the MCP presents hydrophobic patches on the surface of assembled phage particles, which, together with electron cryotomography data of phage bundles, furnishes a structural rationale for phage–phage interactions that were seen previously in an epithelium adhesion infection model ofN. meningitidis. Taken together, our results shed light on the structure, organization, and higher-order assembly of a biomedically relevant phage encoded in the genome of a human pathogen. Molecular insights gleaned from this study increase our understanding of phage evolution, phage-mediated bacterial adhesion, and pathogenicity.
It is increasingly recognized that participation bias can pose problems for genetic studies. Recently, to overcome the challenge that genetic information of nonparticipants is unavailable, it is shown that by comparing the IBD (identity by descent) shared and not-shared segments between participating relative pairs, one can estimate the genetic component underlying participation. That, however, does not directly address how to adjust estimates of heritability and genetic correlation for phenotypes correlated with participation. Here, we demonstrate a way to do so by adopting a statistical framework that separates the genetic and nongenetic correlations between participation and these phenotypes. Crucially, our method avoids making the assumption that the effect of the genetic component underlying participation is manifested entirely through these other phenotypes. Applying the method to 12 UK Biobank phenotypes, we found eight that have significant genetic correlations with participation, including body mass index, educational attainment, and smoking status. For most of these phenotypes, without adjustments, estimates of heritability and the absolute value of genetic correlation would have underestimation biases.
Water molecules at the solid–liquid interface display intricate behaviors sensitive to small changes. The presence of different interfacial components, such as cations or functional groups, shapes the physical and chemical properties of the hydrogen-bond network. Understanding such interfacial hydrogen-bond networks is essential for a large range of applications and scientific questions. To probe the interfacial hydrogen-bond network, atmospheric water capture is a powerful tool. Here, we experimentally observe that a calcium ion on a calcium-intercalated graphene oxide aerogel (Ca-GOA) surface captures 3.2 times more water molecules than in its freestanding state. From experimental Van’t Hoff estimation and density functional theory (DFT) calculations, we uncover the synergistically enhanced hydrogen-bond network of the calcium ion–epoxide complex due to significantly larger polarizations and hydrogen bond enthalpies. This study reveals valuable insights into the interfacial water hydrogen-bond network on functionalized carbon–cation complexed surfaces and potential pathways for future atmospheric water generation technologies.
The gut microbiome has emerged as a key factor influencing a wide range of host physiological processes and behaviors, though the mechanisms behind these effects remain only partially understood. In this study, we explored the role of the gut microbiome in memory regulation using a parasitoid wasp-induced oviposition depression paradigm inDrosophila melanogaster. Our findings show that flies with depleted gut microbiota, either through axenic culture or antibiotic treatment, exhibited significant memory impairments. However, reintroducing the commensal bacteriumLactobacillus plantarumalone was sufficient to restore memory, while coinoculation withAcetobacter pomorumfurther enhanced memory performance. Hemolymph metabolomic analyses revealed reduced amino acid levels in antibiotic-treated flies, which were linked to impairedDrosophilatarget of rapamycin (dTOR) signaling. Additionally, genetic manipulation of dTOR or dietary supplementation with branched-chain amino acids either mimicked or rescued the memory deficits caused by antibiotic treatments. These results suggest that the gut microbiome is essential for regulating memory function by maintaining amino acid homeostasis and proper dTOR signaling, with profound implications for advancing knowledge of cognitive regulation.
The vertical transport of solid material in a stratified medium is fundamental to a number of environmental applications, with implications for the carbon cycle and nutrient transport in marine ecosystems. In this work, we study the diffusion-limited settling of highly porous particles in a density-stratified fluid through a combination of experiment, analysis, and numerical simulation. By delineating and appealing to the diffusion-limited regime wherein buoyancy effects due to mass adaptation dominate hydrodynamic drag, we derive a simple expression for the steady settling velocity of a sphere as a function of the density, size, and diffusivity of the solid, as well as the density gradient of the background fluid. In this regime, smaller particles settle faster, in contrast with most conventional hydrodynamic drag mechanisms. Furthermore, we outline a general mathematical framework for computing the steady settling speed of a body of arbitrary shape in this regime and compute exact results for the case of general ellipsoids. Using hydrogels as a highly porous model system, we validate the predictions with laboratory experiments in linear stratification for a wide range of parameters. Last, we show how the predictions can be applied to arbitrary slowly varying background density profiles and demonstrate how a measured particle position over time can be used to reconstruct the background density profile.
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As large language models (LLMs) become more widely used, people increasingly rely on them to make or advise on moral decisions. Some researchers even propose using LLMs as participants in psychology experiments. It is, therefore, important to understand how well LLMs make moral decisions and how they compare to humans. We investigated these questions by asking a range of LLMs to emulate or advise on people’s decisions in realistic moral dilemmas. In Study 1, we compared LLM responses to those of a representative U.S. sample (N= 285) for 22 dilemmas, including both collective action problems that pitted self-interest against the greater good, and moral dilemmas that pitted utilitarian cost–benefit reasoning against deontological rules. In collective action problems, LLMs were more altruistic than participants. In moral dilemmas, LLMs exhibited stronger omission bias than participants: They usually endorsed inaction over action. In Study 2 (N= 474, preregistered), we replicated this omission bias and documented an additional bias: Unlike humans, most LLMs were biased toward answering “no” in moral dilemmas, thus flipping their decision/advice depending on how the question is worded. In Study 3 (N= 491, preregistered), we replicated these biases in LLMs using everyday moral dilemmas adapted from forum posts on Reddit. In Study 4, we investigated the sources of these biases by comparing models with and without fine-tuning, showing that they likely arise from fine-tuning models for chatbot applications. Our findings suggest that uncritical reliance on LLMs’ moral decisions and advice could amplify human biases and introduce potentially problematic biases.
AI is increasingly replacing human decision-makers across domains. AI-based tools have become particularly common in assessment decisions, such as when recruiting employees or admitting students. Calls for transparency and new legislation require organizations to disclose the use of AI assessment tools, thus making people under assessment aware of its use. We investigate whether this shift from human to AI assessment affects people’s behavior during the assessment. We propose that people emphasize their analytical characteristics and downplay their intuitive and emotional ones under AI (vs. human) assessment, a phenomenon we label “the AI assessment effect.” Twelve studies (eight in text and four in the Supporting Information;N= 13,342) document the AI assessment effect and its underlying mechanism: the lay belief that AI prioritizes analytical characteristics in its assessment. Whereas prior work has studied perceptions of AI assessment tools and their productivity gains, the current research demonstrates systematic behavioral changes because of AI assessment. The findings offer theoretical contributions to the psychology of AI and practical insights for organizations using AI assessment.
Determining how people behave in contexts governed by social norms can clarify both how norms influence human behavior and how norms evolve. We examined cooperative farming harvest division among the Derung, a Tibeto-Burman-speaking horticultural society in southwestern China. In the village of Dizhengdang, the norm dictates that cofarming harvests should be divided equally among participating households. This contrasts with an alternative norm followed in some other Derung villages that holds that harvests should be divided equally among participating laborers. Rational choice theory and evolutionary models of norm-based cooperation assume that individuals weigh the material and social payoffs of different actions and follow norms because doing so maximizes their payoff. However, the behavior of the Derung in Dizhengdang is not consistent with payoff maximization. Using interviews on co-farming behaviors and attitudes, along with an ultimatum game experiment framed as co-farming harvest division, we found that most respondents preferred divisions based on labor contribution. They also accurately guessed that others shared this preference and would approve of such divisions. Nonetheless, they still followed the prevailing norm of dividing by household. Their self-reported explanation for this behavior was that they desired to follow their traditional practices. Such a normative decision-making algorithm can allow individually consequential norms to persist without costly policing by other group members.
Despite over a century of studies, fundamental questions remain about the processes governing crystal nucleation from melts or solutions. Research over the past three decades has presented mounting evidence for kinetic pathways of crystal nucleation that are more complex than envisioned by the simplest forms of classical theory. Such observations have been presented for colloidal and elemental systems with covalent and metallic bonding. Despite the technological and geochemical importance of molten salts, similar studies for these ionically bonded systems are currently lacking. Here we develop a machine learning interatomic potential for a model ionic system: LiF. The potential features quantum-level accuracy for both liquid and multiple solid polymorphs over wide temperature and pressure ranges and accurately reproduces experimentally measured properties. Thanks to the efficiency of the potential, which enables microsecond-scale molecular dynamics simulations, induction times for nucleation of LiF solids from their melts are computed over a range of undercoolings. With the aid of a set of robust local order parameters established here, the simulations reveal that homogeneous crystal nucleation in undercooled melts preferentially initiates from liquid regions showing slow dynamics and high bond orientational order simultaneously, and the second-shell order of both precritical nuclei and the surface of postcritical nuclei is dominated by hexagonal close packing and body-centered cubic local structure, even though the nucleus core is dominated by face-centered cubic structure corresponding to the stable rocksalt crystal structure. Finally, we establish a connection between the crystallization pathway and the equilibrium crystal–melt interface structure.
We investigate the hypothesis that family resemblance on school performance can be fully explained by additive genetic effects and assortative mating. Our sample consists of all schoolchildren who took Norwegian national standardized tests between 2007 and 2019 (N = 936,708). These tests measure aptitude in math and reading comprehension, and are taken the years children turn 10, 13, and 14 y old. We identify millions of pairs of relatives within our sample (82 different kinds, in total), including not only conventional biological relatives such as siblings and cousins, but also relatives-in-law, relatives through adoption, twins, and relatives connected through twins. When fitting models which assume that family resemblance arises solely from additive genetic effects and assortative mating, we find that they describe much of our data well, but that they systematically underestimate the similarity of close relatives (particularly monozygotic twins), maternal relatives, relatives-in-law, and relatives through adoption. We discuss potential explanations for these deviations, including shared-environmental effects, nonadditive genetic effects, and gene–environment interplay.
Negative feedback of the cochlear efferent system plays a critical role in control of hearing sensitivity and protection from noise trauma. Type II auditory nerves (ANs) innervate outer hair cells (OHCs) in the cochlea and provide an input to the cochlear efferent system to achieve hearing sensitivity controlling and protection; in particular, medial olivocochlear efferent nerves innervate OHCs to control OHC electromotility, which is an active cochlear amplifier in mammals. However, little is known about channel information underlying type II AN activity and consequent function. Here, we report that ATP-gated P2x7 receptor had a predominant expression at type II spiral ganglion (SG) neurons and the synaptic areas under inner hair cells and OHCs with lateral and medial olivocochlear efferent nerves. Knockout (KO) of P2x7 increased hearing sensitivity with enhanced acoustic startle response, auditory brainstem response, and cochlear microphonics by increasing OHC electromotility. P2x7 KO also increased susceptibility to noise and exacerbated ribbon synapse degeneration. Middle-level noise exposure could impair active cochlear mechanics resulting in hearing loss in P2x7 KO mice. These data demonstrate that P2x7 receptors have a critical role in type II SG neuron’s function and the cochlear efferent system to control hearing sensitivity; deficiency of P2x7 receptors can impair type II SG neuron’s function and the cochlear efferent suppression leading to increase of active cochlear amplification and hearing oversensitivity, i.e., hyperacusis, and susceptibility to noise, which may also associate with other hearing disorders, such as tinnitus.
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The thymus is one of the most important organs of the immune system. It is responsible for both the production of T cells and the prevention of their autoimmunity. It comprises two types of tissue: The cortex, where nascent T cells (thymocytes) are generated; and the medulla, embedded within the cortex, where autoreactive thymocytes are eliminated through negative selection. In mice, the medulla exhibits a complex, convoluted morphology, which has raised the question of whether its form impacts its function. Intriguingly, experiments also reveal a reverse dependency: The interactions between medullary stroma and thymocytes shape the medullary structure. However, an understanding of the underlying mechanisms of medulla morphogenesis emerging from these interactions remains elusive. Here, we present a conceptual theoretical model showing that central, experimentally verified signaling pathways suffice to shape the convoluted medullary structure. The mathematical analysis of the model explains the observed effects of chemotaxis on thymocyte localization, and the reported morphological changes resulting from the modulation of thymocyte production. Our findings reveal that the cross-talk between medulla growth and negative selection of thymocytes not only regulates medullary volume but also orchestrates the morphology of the thymus medulla. This mechanism of structure formation robustly organizes the medulla in a way that accelerates thymocyte negative selection by improving their chemotactic migration into the medulla. Thereby, we identify a feedback between the function of the thymus medulla and its form. Our theoretical study motivates further experimental analysis of the spatial distribution of thymic cell populations and predicts morphological changes under genetic perturbations.
Computational theories of reinforcement learning suggest that two families of algorithm—model-based and model-free—tightly map onto the classic distinction between automatic and deliberate systems of control: Deliberate evaluative responses are thought to reflect model-based algorithms, which are accurate but computationally expensive, whereas automatic evaluative responses are thought to reflect model-free algorithms, which are error-prone but computationally cheap. This framework has animated research on psychological phenomena ranging from habit formation to social learning, moral decision-making, and cognitive development. Here, we propose that model-based and model-free algorithms may not be as aligned with deliberate and automatic evaluative processing as prevailing theories suggest. Across three preregistered behavioral experiments involving adult human participants (totaln= 2,572), we show that model-based algorithms shape not only deliberate but also automatic evaluations. Experiment 1 numerically replicates past findings suggesting that deliberate (but not automatic) evaluative responses are uniquely shaped by model-based algorithms but, critically, also reveals confounds that render interpretation of this evidence equivocal. Experiments 2 to 3 eliminate these confounds and reveal robust model-based contributions to automatic evaluative processing across two measures of automatic evaluation, supported by multinomial processing tree modeling. Together, these results suggest that dominant frameworks may considerably underestimate both the ubiquity of model-based algorithms and the computational sophistication of automatic evaluative processing.
Using machine learning (ML) to construct interatomic interactions and thus potential energy surface (PES) has become a common strategy for materials design and simulations. However, those current models of machine-learning interatomic potential (MLIP) consider no relevant physical constraints or global scaling and thus may owe intrinsic out-of-domain difficulty which underlies the challenges of model generalizability and physical scalability. Here, by incorporating the global universal scaling law, we develop an ultrasmall parameterized MLIP with superlinear expressive capability, named SUS2-MLIP. Due to the global scaling derived from the universal equation of state (UEOS), SUS2-MLIP not only has significantly reduced parameters by decoupling the element space from coordinate space but also naturally outcomes the out-of-domain difficulty and endows the model with inherent generalizability and scalability even with relatively small training dataset. The non-linearity-embedding transformation in radial function endows the model with superlinear expressive capability. SUS2-MLIP outperforms the state-of-the-art MLIP models with its exceptional computational efficiency, especially for multiple-element materials and physical scalability in property prediction. This work not only presents a highly efficient universal MLIP model but also sheds light on incorporating physical constraints into AI–aided materials simulation.
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A charge density wave (CDW) is a phase of matter characterized by a periodic modulation of valence electron density coupled with lattice distortion. Its formation is closely tied to the dynamical charge susceptibility,χ(q,ω), which reflects the collective electron dynamics of the material. Despite decades of study,χ(q,ω)near a CDW transition has never been measured at nonzero momentum,q, with meV energy resolution. Here, we investigate the canonical CDW transition in ErTe3using momentum-resolved electron energy loss spectroscopy, a technique uniquely sensitive to valence band charge excitations. Unlike phonons, which soften via the Kohn anomaly, we find the electronic excitations exhibit purely relaxational dynamics well described by a diffusive model, with the diffusivity peaking just below the critical temperature,TC1. Additionally, we report for the first time a divergence in the real part ofχ(q,ω)in the static limit (ω→0), a long-predicted hallmark of CDWs. Unexpectedly, this divergence occurs asT→0, with only a weak thermodynamic signature atT=TC1. Our study necessitates a reexamination of the traditional description of CDW formation in quantum materials.
Protein structure–function relationships are critical for understanding molecular mechanisms and the impacts of genetic variation. Mutational scanning approaches can deliver scalable analysis, usually through the study of loss-of-function variants. Rarer dominant negative and gain-of-function variants can be more information rich, as they retain a stable proteoform and can be used to dissect molecular function while retaining biological context. Dominant variant proteoforms can still engage substrates and interact with binding partners. Here, we probe the structure–function relationships of the Mus81 endonuclease by ectopic expression of deep mutational scanning libraries to find amino acid variants that confer dominant sensitivity to genotoxic stress and dominant synthetic lethality. Screening more than 2,200MUS81variants at 100 positions identified 13 amino acids that can be altered to elicit a dominant phenotype. The dominant phenotype of these variants required the presence of the obligate Mus81 binding protein, Mms4. The dominant variants affect amino acids in a contiguous surface on Mus81 and fall into two distinct classes: residues that bind the catalytic magnesium atoms and residues that form the hydrophobic wedge. Most of the variant amino acids were conserved across species and cognate variants expressed in human cell lines resulted in dominant sensitivity to replication stress and synthetic growth defects in cells lacking BLM helicase. The dominant variants in both yeast and humanMUS81resulted in phenotypes distinct from aMUS81knockout. These data demonstrate the utility of dominant genetics using ectopic expression of amino acid site saturation variant libraries to link function to protein structure providing insight into molecular mechanisms.
The surface layer or “S-layer” is a two-dimensional lattice of proteins that coats a wide range of archaea and bacteria in place of a cell wall or capsular polysaccharides. S-layers are thought to play an important role in chemically and physically insulating cells from the external environment. Here, we show that the integrity of the S-layer inSulfolobus acidocaldariusis maintained as cells grow via a process of self-assembly as SlaA monomers fill gaps in the lattice. Although this lattice which is physically tethered to the membrane might be expected to hinder cell division, we show that the S-layer flattens the membrane at cytokinesis to accelerate ESCRT-III-dependent cell division—and is important for robust, successful cell divisions under conditions of mechanical stress. Taken together, these results define the rules governing S-layer self-assembly and show how a flexible lattice coat that is coupled to the underlying membrane can both provide a cell with mechanical support and help to drive rapid and functionally important changes in cell shape.
Regional collectivism has been observed to contribute to better coping with public crises such as the COVID-19 pandemic. This study poses a reverse question: Does the eruption of public crises increase people’s conformity to the collective? To answer this question, we analyzed real-world transactions on Taobao (the largest e-commerce platform in China), each with a purchase decision and a list of candidates considered before purchasing. Conformity to the collective was measured using two indicators: whether the decision-maker opted for the A) most-sold and B) best-rated options within the candidate option set. The results reveal that both conformity variables were significantly higher in the 10 wk subsequent to January 19, 2020 (when the nationwide COVID-19 crisis erupted in China), than in the 8 wk prior. These shifts were common across subpopulations, regions, and product categories and remained significant after strictly matching across weeks and after using a within-person, longitudinal sample. These shifts were more confidently attributed to the pandemic by further conducting difference-in-differences analyses to compare pandemic-affected regions with their unaffected, comparable counterparts using data from six subsequent regional waves in China. Furthermore, regions with larger increases in conformity during the early stage of the pandemic achieved better antipandemic outcomes. These findings provide real-world evidence for previous theories on behavioral immune systems, terror management, and compensatory control. Additionally, cross-regional comparisons of effect sizes offer exploratory insights into cultural psychology. In summary, these findings capture how human societies dynamically adjust their values to better adapt to unanticipated survival challenges.
In Shannon’s seminal paper, the entropy of printed English, treated as a stationary stochastic process, was estimated to be roughly 1 bit per character. However, considered as a means of communication, language differs considerably from its printed form: i) the units of information are not characters or even words but clauses, i.e., shortest meaningful parts of speech; and ii) what is transmitted is principally the meaning of what is being said or written, while the precise phrasing that was used to communicate the meaning is typically ignored. In this study, we show that one can leverage recently developed large language models to quantify information communicated in meaningful narratives in terms of bits of meaning per clause.
Evolutionary adaptation to new environments likely results from a combination of selective sweeps and polygenic shifts, depending on the genetic architecture of traits under selection. While selective sweeps have been widely studied, polygenic responses are thought to be more prevalent but remain challenging to quantify. The infinitesimal model makes explicit the hypothesis about the dynamics of changes in allele frequencies under selection, where only allelic effect sizes, frequencies, linkage, and gametic disequilibrium matter. Departures from this, like long-range correlations of allele frequency changes, could be a signal of epistasis in polygenic response. We performed an Evolve & Resequence experiment inDrosophila melanogasterexposing flies to a high-sugar diet for over 100 generations. We tracked allele frequency changes in >3000 individually sequenced flies and population pools and searched for loci under selection by identifying sites with allele frequency trajectories that differentiated selection regimes consistently across replicates. We estimate that at least 4% of the genome was under positive selection, indicating a highly polygenic response. The response was dominated by small, consistent allele frequency changes, with few loci exhibiting large shifts. We then searched for signatures of selection on pairwise combinations of alleles in the new environment and found several strong signals of putative epistatic interactions across unlinked loci that were consistent across selected populations. Finally, we measured differentially expressed genes (DEGs) across treatments and show that DEGs are enriched for selected SNPs. Our results suggest that epistatic contributions to polygenic selective response are common and lead to detectable signatures.
The utility of a pure population of highly regenerative satellite stem cells (SSCs) is a prerequisite for successful cell-based muscle therapies. Previous works have reported several methods for the SSC isolation. However, the majority of cells isolated using previous methods are fibroblasts and other nonmyogenic cell types, necessitating further expensive and time-consuming purification steps often affecting the regenerative quality of the isolated SSCs. Here, we describe a simple, time-effective, and robust protocol for the isolation of a pure population of SSCs in a single direct step, eliminating the need for further purification steps. By separating the muscle fascicles from the adjacent connective tissues (i.e., epimysium and perimysium) and utilizing a defined dissociation medium, a cell pool enriched in SSCs was successfully obtained. Immunofluorescent staining confirmed the stemness and the myogenic purity of the isolated cells (~97%). Upon myogenic induction, SSCs gave rise to multinucleated myofibers that exhibited spontaneous contraction in the culture dish for up to 21 d. Efforts to optimize the culture conditions revealed that tissue culture plates (TCPs) coated with a tissue-specific extract significantly enhanced SSCs’ attachment, growth, and differentiation compared to collagen I, Matrigel-coated TCPs, or noncoated TCPs. Further studies confirmed the robust myogenic regenerative capacity of the isolated cells, as evidenced by their ability to display key regenerative characteristics, demonstrating the mild effects of our isolation protocol on their regenerative capacity. The isolation protocol presented herein can potentially be used to obtain SSCs with high myogenic purity for skeletal muscle regenerative engineering and clinical indications.
The freezing of droplets on surfaces is closely relevant with various industrial processes such as aviation, navigation, and transportation. Previous studies mainly focus on physiochemically heterogeneous but electrically homogeneous surfaces, on which the presence of vapor pressure gradient between droplets is the predominant mechanism for interdroplet freezing bridging, propagation, and eventual frosting across the entire surface. An interesting yet unanswered question is whether electrostatic charge on surfaces affects freezing dynamics. Here, we find an interdroplet freezing relay (IFR) phenomenon on electrically heterogeneous surfaces that exhibits a three-dimensional, in-air freezing propagation pathway and an accelerated freezing rate. Theoretical and experimental investigations demonstrate that this phenomenon originates from the presence of surface charge gradient established between the frozen droplet and neighboring water droplet, which leads to a spontaneous shooting of desublimated ice needles from the frozen droplet and then triggers the freezing of neighboring water droplet in in-air manner. We further demonstrate its generality across various dielectric substrates, liquids, and droplet configurations. Our work enriches conventional perspectives on droplet freezing dynamics and emphasizes the pivotal role of electrostatics in designing passive anti-icing and antifrosting materials.
Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of theMYCNoncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming in NB, including upregulation of antioxidant enzymes. Here, we identify peroxiredoxin 6 (PRDX6) as a promising therapeutic target in NB. Pharmacological inhibition of PRDX6 reduces MYCN levels, induces apoptosis, and promotes neuronal differentiation accompanied by lipid droplet accumulation, essential for the phenotypic reprogramming. Moreover, combined inhibition of PRDX6 and glutathione S-transferase Pi 1 (GSTP1), a key antioxidant enzyme needed for PRDX6 activation, demonstrated synergistic effects both in vitro and in vivo. This strategy results in neuronal maturation as well as activity and initiates downstream pathways distinct from the ones triggered by retinoic acid, the differentiation-inducing agent currently used in clinical practice for NB. Notably, bothPRDX6andGSTP1are highly expressed in the developing murine adrenal gland, as well as in high-risk,MYCN-amplified NB, correlating with an undifferentiated state and poor prognosis. Together, our results provide insights into the potential of PRDX6 and GSTP1 as therapeutic targets for differentiation induction for children with NB.
Protein–protein interactions (PPIs) are crucial for comprehending the molecular mechanisms and signaling pathways underlying diverse biological processes and disease progression. However, investigating PPIs involving membrane proteins is challenging due to the complexity and heterogeneity of glycosylation. To tackle this challenge, we developed an approach termed glycan-dependent affinity purification coupled with mass spectrometry (GAP–MS), specifically designed to characterize changes in glycoprotein PPIs under varying glycosylation conditions. GAP–MS integrates metabolic control of glycan profiles in cultured cells using small molecules referred to as glycan modifiers with affinity purification followed by mass spectrometry analysis (AP–MS). Here, GAP–MS was applied to characterize and compare the interaction networks under five different glycosylation states for four bait glycoproteins: BSG, CD44, EGFR, and SLC3A2. This analysis identified a network comprising 156 interactions, of which 131 were determined to be glycan dependent. Notably, the GAP–MS analysis of BSG provided distinct information regarding glycosylation-influenced interactions compared to the commonly used glycosylation site mutagenesis approach combined with AP–MS, emphasizing the unique advantages of GAP–MS. Collectively, GAP–MS presents distinct insights over existing methods in elucidating how specific glycosylation forms impact glycoprotein interactions. Additionally, the glycan-dependent interaction networks generated for these four glycoproteins serve as a valuable resource for guiding future functional investigations and therapeutic developments targeting the glycoproteins discussed in this study.
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Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive experience-dependent reciprocal antagonism that gates cortical feedback regulation of feedforward thalamic refinement.
The evolutionary histories of many polyploid plant species are difficult to resolve due to a complex interplay of hybridization, incomplete lineage sorting, and missing diploid progenitors. In the case of octoploid strawberry with four subgenomes designated ABCD, the identities of the diploid progenitors for subgenomes C and D have been subject to much debate. By integrating new sequencing data from North American diploids with reticulate phylogeny and admixture analyses, we uncovered introgression from an extinct or unsampled species in the clade ofFragaria viridis,Fragaria nipponica, andFragaria nilgerrensisinto the donor of subgenome A of octoploidFragariaprior to its divergence fromF. vescasubsp. bracteata. We also detected an introgression event fromF. iinumaeinto an ancestor ofF. nipponicaandF. nilgerrensis.Using an LTR-age-distribution-based approach, we estimate that the octoploid and its intermediate hexaploid and tetraploid ancestors emerged approximately 0.8, 2, and 3 million years ago, respectively. These results provide an explanation for previous reports ofF. viridisandF. nipponicaas donors of the C and D subgenomes and suggest a greater role than previously thought for homoploid hybridization in the diploid progenitors of octoploid strawberry. The integrated set of approaches used here can help advance polyploid genome analysis in other species where hybridization and incomplete lineage sorting obscure evolutionary relationships.
Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis.UBR4knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.
During vertebrate development, the heart primarily arises from mesoderm, with crucial contributions from cardiac neural crest (CdNC) cells that migrate to the heart and form a variety of cardiovascular derivatives. Here, by integrating bulk and single cell RNA-seq with ATAC-seq, we identify a gene regulatory subcircuit specific to migratory cardiac crest cells composed of key transcription factorsegr1, sox9a, tfap2a,andets1.Notably, we show that cells expressing the canonical neural crest genesox10are essential for proper cardiac regeneration in adult zebrafish. Furthermore, expression of all transcription factors from the migratory cardiac crest gene subcircuit are reactivated after injury at the wound edge. Together, our results uncover a developmental gene regulatory network that is important for CdNC fate determination, with key factors of the program reexpressed during regeneration.
On shallow rocky and coral reefs, cultural and recreational values, like aesthetics, are critical aspects of Nature’s Contributions to People (NCP) that support human well-being and provide billions of dollars in tourism revenue. Quantifying the aesthetic value of reef ecosystems and uncovering the conditions that enhance it could support NCP-based management. Here, we combine a global dataset of reef fish surveys, species-level aesthetic values, and causal modeling to assess the global status and drivers of reef fish assemblage aesthetic value. We find that aesthetic value is inherently linked to species richness, displaying a latitudinal gradient with peaks in the tropics, but varies strongly with the presence of exceptionally beautiful or less-beautiful species. Sea surface temperature, primary productivity, human gravity, and protection status are the strongest drivers of assemblage-level aesthetic value. Protection against human impacts consistently enhances aesthetic value by boosting taxonomic and phylogenetic diversity, and this effect is greatest in species-rich, tropical ecoregions. Economic development has little influence, indicating that low-income countries are not constrained from maintaining beautiful fish assemblages. Our results therefore suggest that marine protected areas (MPAs) can support multiple NCPs simultaneously, particularly in developing tropical countries. While we highlight the effectiveness of MPAs, given the low level of marine protection globally and the sensitivity of aesthetic value to environmental conditions, the beauty of the world’s reefs appears severely threatened. Aesthetic value should be immediately integrated into reef conservation and management plans.
Assessing model uncertainty is crucial to quantitative political science. Yet, most available sensitivity analyses focus only on a few modeling choices, most notably the covariate space, while neglecting to jointly consider several equally important modeling choices simultaneously. In this article, we combine the exhaustive and systematic method of the Extreme Bounds Analysis with the more multidimensional logic underpinning the multiverse approach to develop an approach to sensitivity analyses. This allows us to systematically assess the degree and sources of model uncertainty across multiple dimensions, including the control set, fixed effect structures, SE types, sample selection, and dependent variable operationalization. We then apply this method to four prominent topics in political science: democratization, institutional trust, public good provision, and welfare state generosity. Results from over 3.6 bn estimates reveal widespread model uncertainty, not just in terms of the statistical significance of the effects, but also their direction, with most independent variables yielding a substantive share of statistically significant positive and negative coefficients depending on model specification. We compare the strengths and weaknesses of three distinct approaches to estimating the relative importance of different model specification choices: nearest 1-neighbor; logistic; and deep learning. All three approaches reveal that the impact of the covariate space is relatively modest compared to the impact of sample selection and dependent variable operationalization. We conclude that model uncertainty stems more from sampling and measurement than conditioning and discuss the methodological implications for how to assess model uncertainty in the social sciences.
Unraveling the origin(s) of carbon on Earth has remained challenging, not only because of the multiple isotopic fractionation episodes that may have occurred during planet formation processes but also because the end point of these processes, the current isotopic value of Earth’s deep carbon reservoirs remains poorly constrained. Here, we present carbon isotopic measurements on rare undegassed mid-ocean ridge basalts from the Pacific, Atlantic, and Arctic Oceans that have preserved the isotopic signature of their mantle source. We find that Earth’s present-day convecting upper mantle has variable δ13C value from ~−10 to −4‰, significantly different from the δ13C value of peridotitic diamonds and with the highest values being restricted to the Atlantic. Evidence for significant mantle heterogeneity contrasts with previous assumptions and its origin remains puzzling being uncorrelated with geochemical markers associated with either subduction and surficial recycling processes or lower mantle contributions. The data do not preclude other causes such as primordial mantle heterogeneity. We suggest that the δ13C value of the bulk silicate Earth may need to be revised.
Adaptation to novel environments requires genetic variation, but whether adaptation typically acts upon preexisting genetic variation or must wait for new mutations remains a fundamental question in evolutionary biology. Selection during domestication has been long used as a model to understand evolutionary processes, providing information not only on the phenotypes selected but also, in many cases, an understanding of the causal loci. For each of the causal loci that have been identified in maize, the selected allele can be found segregating in natural populations, consistent with their origin as standing genetic variation. The sole exception to this pattern is the well-characterized domestication locustga1(teosinte glume architecture1), which has long been thought to be an example of selection on a de novo mutation. Here, we use a large dataset of maize and teosinte genomes to reconstruct the origin and evolutionary history oftga1. We first estimated the age oftga1-maizeusing a genealogy-based method, finding that the allele arose approximately 42,000 to 49,000 y ago, predating the beginning of maize domestication. We also identifytga1-maizein teosinte populations, indicating that the allele can survive in the wild. Finally, we compare observed patterns of haplotype structure and mutational age distributions neartga1with simulations, finding that patterns neartga1in maize better resemble those generated under simulated selective sweeps on standing variation. These multiple lines of evidence suggest that maize domestication likely drew upon standing genetic variation attga1and cement the importance of standing variation in driving adaptation during domestication.
Pregnancy- and birth-related factors affect offspring brain development, emphasizing the importance of early life exposures. While most previous studies have focused on a few variables in isolation, here we investigated associations between a broad range of pregnancy- and birth-related variables and multivariate cortical brain MRI features. Our sample consisted of 8,396 children aged 8.9 to 11.1 y from the Adolescent Brain Cognitive Development Study. Through multiple correspondence analysis and factor analysis of mixed data, we distilled numerous pregnancy and birth variables into four overarching dimensions; maternal pregnancy complications, maternal substance use, low birth weight and prematurity, and newborn birth complications. Vertex-wise measures of cortical thickness (CT), surface area (SA), and curvature were fused using linked independent component analysis. Linear mixed-effects models showed that maternal pregnancy complications and low birth weight and prematurity were associated with smaller global SA. Additionally, low birth weight and prematurity was associated with complex regional cortical patterns reflecting bidirectional variations in both SA and CT. Newborn birth complications showed multivariate patterns reflecting smaller occipital- and larger temporal area, bidirectional frontal area variations, and reduced CT across the cortex. Maternal substance use showed no associations with child cortical structure. By employing a multifactorial and multivariate morphometric fusion approach, we connected complications during pregnancy and fetal size and prematurity to global SA and specific regional signatures across child cortical MRI features.
Herpesviruses, including Epstein–Barr virus (EBV) – a human oncogenic virus and essential trigger of multiple sclerosis – must bypass host DNA-sensing mechanisms to establish lifelong, latent infection. Therefore, herpesviruses encode viral proteins to disrupt key host factors involved in DNA sensing and viral restriction. The first viral latency protein expressed, EBNA-LP, is essential for transformation of naïve B cells and establishment of viral gene expression, yet its role in evading host defenses remains unclear. Using single-cell RNA sequencing of EBNA-LP Knockout (LPKO)-infected B cells, we reveal an antiviral response landscape implicating the “speckled proteins” as key cellular restriction factors countered by EBNA-LP. Specifically, loss of Sp100 or the primate-specific Sp140L reverses the restriction of LPKO, suppresses a subset of canonically interferon-stimulated genes, and restores transcription of essential latent viral genes and cellular proliferation. Notably, we also identify Sp140L as a restriction target of the herpesvirus saimiri ORF3 protein, implying a role for Sp140L in immunity to other diverse DNA viruses. This study reveals Sp140L as a restriction factor that we propose links sensing and transcriptional suppression of viral DNA to an Interferon-independent innate immune response, likely relevant to all nuclear DNA viruses.
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Emerging theories in cognitive neuroscience propose a third brain pathway dedicated to processing biological motion, alongside the established ventral and dorsal pathways. However, its role in computing dynamic social signals for behavior remains uncharted. Here, participants (N = 10) actively categorized dynamic facial expressions synthesized by a generative model and displayed on different face identities—as “happy,” “surprise,” “fear,” “anger,” “disgust,” “sad”—while we recorded their MEG responses. Using representational interaction measures that link facial features with MEG activity and categorization behavior, we identified within each participant a functional social pathway extending from the occipital cortex to the superior temporal gyrus. This pathway selectively represents, communicates, and integrates facial movements that are essential for the behavioral categorization of emotion, while task-irrelevant identity features are filtered out in the occipital cortex. Our findings uncover how the third pathway selectively computes complex dynamic social signals for emotion categorization in individual participants, offering computational insights into the dynamics of neural activity.
How tick-borne pathogens interact with their hosts has been primarily studied in vertebrates where disease is observed. Comparatively less is known about pathogen interactions within the tick. Here, we report thatIxodes scapularisticks infected with eitherAnaplasma phagocytophilum(causative agent of anaplasmosis) orBorrelia burgdorferi(causative agent of Lyme disease) show activation of the ATF6 branch of the unfolded protein response (UPR). Disabling ATF6 functionally restricts pathogen survival in ticks. When stimulated, ATF6 functions as a transcription factor, but is the least understood out of the three UPR pathways. To interrogate theIxodesATF6 transcriptional network, we developed a custom R script to query tick promoter sequences. This revealedstomatinas a potential gene target, which has roles in lipid homeostasis and vesical transport.Ixodes stomatinwas experimentally validated as a bona fide ATF6-regulated gene through luciferase reporter assays, pharmacological activators, RNA interference transcriptional repression, and immunofluorescence microscopy. SilencingstomatindecreasedA. phagocytophilumcolonization inIxodesand disrupted cholesterol dynamics in tick cells. Furthermore, blockingstomatinrestricted cholesterol availability to the bacterium, thereby inhibiting growth and survival. Taken together, we have identified theIxodesATF6 pathway as a contributor to vector competence through Stomatin-regulated cholesterol homeostasis. Moreover, our custom, web-based transcription factor binding site search tool “ArthroQuest” revealed that the ATF6-regulated nature ofstomatinis unique to blood-feeding arthropods. Collectively, these findings highlight the importance of studying fundamental processes in nonmodel organisms.
The nucleobase queuine (q) and its nucleoside queuosine (Q) are micronutrients derived from bacteria that are acquired from the gut microbiome and/or diet in humans. Following cellular uptake, Q is incorporated at the wobble base (position 34) of tRNAs that decode histidine, tyrosine, aspartate, and asparagine codons, which is important for efficient translation. Early studies suggested that cytosolic uptake of queuine is mediated by a selective transporter that is regulated by mitogenic signals, but the identity of this transporter has remained elusive. Here, through a cross-species bioinformatic search and genetic validation, we have identified the solute carrier family member SLC35F2 as a unique transporter for both queuine and queuosine inSchizosaccharomyces pombeandTrypanosoma brucei. Furthermore, gene disruption in human HeLa cells revealed that SLC35F2 is the sole transporter for queuosine (Km174 nM) and a high-affinity transporter for the queuine nucleobase (Km67 nM), with the additional presence of second low-affinity queuine transporter (Km259 nM). Ectopic expression of labeled SLC35F2 reveals localization to the cell membrane and Golgi apparatus via immunofluorescence. Competition uptake studies show that SLC35F2 is not a general transporter for other canonical ribonucleobases or ribonucleosides but selectively imports q and Q. The identification of SLC35F2, an oncogene, as the transporter of both q and Q advances our understanding of how intracellular levels of queuine and queuosine are regulated and how their deficiency contributes to a variety of pathophysiological conditions, including neurological disorders and cancer.
The host–microbiome interface is rich in metabolite exchanges and exquisitely sensitive to diet. Hydrogen sulfide (H2S) is present at high concentrations at this interface and is a product of both microbial and host metabolism. The mitochondrial enzyme, sulfide quinone oxidoreductase (SQOR), couples H2S detoxification to oxidative phosphorylation; its inherited deficiency presents as Leigh disease. Since an estimated two-thirds of systemic H2S metabolism originates in the gut, it raises questions as to whether impaired sulfide clearance in this compartment contributes to disease and whether it can be modulated by dietary sulfur content. In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells perturbs colon bioenergetics that is reversed by antibiotics, revealing a significant local contribution of microbial H2S to host physiology. We also find that a 2.5-fold higher methionine intake, mimicking the difference between animal and plant proteins, synergizes with intestinal SQOR deficiency to adversely impact colon architecture and alter microbiome composition. In serum, increased thiosulfate, a biomarker of H2S oxidation, reveals that intestinal SQOR deficiency combined with higher dietary methionine affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies. The mice exhibit lower exploratory locomotor activity while brain MRI reveals an atypical reduction in ventricular volume, which is associated with lower aquaporin 1 that is important for cerebrospinal fluid secretion. Our study reveals the dynamic interaction between dietary sulfur intake and sulfide metabolism at the host–microbe interface, impacting gut health, and the potential for lower dietary methionine intake to modulate pathology.
Microscopic robots exhibit efficient locomotion in liquids by leveraging fluid dynamics and chemical reactions to generate force asymmetry, thereby enabling critical applications in photonics and biomedicine. However, achieving controllable locomotion of such robots on terrestrial surfaces remains challenging because fluctuating adhesion on nonideal surfaces disrupts the necessary asymmetry for propulsion. Here, we present a microscopic robot composed of three-dimensional nanomembranes, which navigate diverse terrestrial surfaces with omnidirectional motion. We propose a general mechanism employing nonreciprocal shape morphing to generate stable asymmetric forces on surfaces. This nonreciprocal shape morphing is realized through a laser-actuated vanadium dioxide nanomembrane, leveraging the material's inherent hysteresis properties. We demonstrate that these robots can be fabricated in various shapes, ranging from simple square structures to bioinspired "bipedal" helical designs, enabling them to directionally navigate challenging surfaces such as paper, leaves, sand, and vertical walls. Furthermore, their omnidirectional motion facilitates applications in microassembly and microelectronic circuit integration. Additionally, we developed an artificial intelligence control algorithm based on reinforcement learning, enabling these robots to autonomously follow complex trajectories, such as tracing the phrase "hello world". Our study lays a theoretical and technological foundation for microscopic robots with terrestrial locomotion and paves a way for microscopic robots capable of operating on surfaces for advanced nanophotonic, microelectronic, and biomedical applications.
Gonadotropin-releasing hormone receptor (GnRHR) is critical for reproductive health and a key therapeutic target for endocrine disorders and hormone-responsive cancers. Using high-resolution cryoelectron microscopy, we determined the structures ofSus scrofaandXenopus laevisGnRHRs bound to mammal GnRH, uncovering conserved and species-specific mechanisms of receptor activation and G protein coupling. The conserved “U”-shaped GnRH conformation mediates high-affinity binding through key interactions with residues such as K3.32, Y6.51, and Y6.52. Species-specific variations in extracellular loops and receptor–ligand contacts fine-tune receptor function, while ligand binding induces structural rearrangements, including N terminus displacement and TM6 rotation, critical for signaling. Structure–activity relationship analysis demonstrates how D-amino acid substitutions in GnRH analogs enhance stability and receptor affinity. Distinct binding modes of agonists and antagonists elucidate mechanisms of ligand-dependent activation and inactivation. These insights lay the groundwork for designing next-generation GnRHR therapeutics with enhanced specificity and efficacy for conditions like endometriosis, prostate cancer, and infertility.
Mutations that impact splicing play a significant role in disease etiology but are not fully understood. To characterize the impact of exonic variants on splicing in 71 clinically actionable disease genes in asymptomatic people, we analyzed 32,112 exonic mutations from ClinVar and Geisinger MyCode using a minigene reporter assay. We identify 1,733 splice-disrupting mutations, with the most extreme variants likely being deleterious. We report that these variants are not distributed evenly across exons but are mostly concentrated in the ~8% of exons that are most susceptible to splicing mutations (i.e., hotspot exons). We demonstrate how multiple, splice-disrupting mutations in these exons can be reverted by the same ASOs targeting the splice sites of either their upstream or downstream flanking exons. This finding supports the feasibility of developing single therapeutic ASOs that could revert all splice-altering variants localized to a particular exon.
Human society is coordinated by mechanisms that control how prices are agreed, taxes are set, and electoral votes are tallied. The design of robust and effective mechanisms for human benefit is a core problem in the social, economic, and political sciences. Here, we discuss the recent application of modern tools from AI research, including deep neural networks trained with reinforcement learning (RL), to create more desirable mechanisms for people. We review the application of machine learning to design effective auctions, learn optimal tax policies, and discover redistribution policies that win the popular vote among human users. We discuss the challenge of accurately modeling human preferences and the problem of aligning a mechanism to the wishes of a potentially diverse group. We highlight the importance of ensuring that research into “deep mechanism design” is conducted safely and ethically.
Theories on group-bias often posit an internal preparedness to bias one’s cognition to favor the in-group (often envisioned as a product of evolution). In contrast, other theories suggest that group-biases can emerge from nonspecialized cognitive processes. These perspectives have historically been difficult to disambiguate given that observed behavior can often be attributed to innate processes, even when groups are experimentally assigned. Here, we use modern techniques from the field of AI that allow us to ask what group biases can be expected from a learning agent that is a pure blank slate without any intrinsic social biases, and whose lifetime of experiences can be tightly controlled. This is possible because deep reinforcement-learning agents learn to convert raw sensory input (i.e. pixels) to reward-driven action, a unique feature among cognitive models. We find that blank slate agents do develop group biases based on arbitrary group differences (i.e. color). We show that the bias develops as a result of familiarity of experience and depends on the visual patterns becoming associated with reward through interaction. The bias artificial agents display is not a static reflection of the bias in their stream of experiences. In this minimal environment, the bias can be overcome given enough positive experiences, although unlearning the bias takes longer than acquiring it. Further, we show how this style of tabula rasa group behavior model can be used to test fine-grained predictions of psychological theories.
Inspired by the challenges at the intersection of Evolutionary Game Theory and Machine Learning, we investigate a class of discrete-time multiagent reinforcement learning (MARL) dynamics in population/nonatomic congestion games, where agents have diverse beliefs and learn at different rates. These congestion games, a well-studied class of potential games, are characterized by individual agents having negligible effects on system performance, strongly aligned incentives, and well-understood advantageous properties of Nash equilibria. Despite the presence of static Nash equilibria, we demonstrate that MARL dynamics with heterogeneous learning rates can deviate from these equilibria, exhibiting instability and even chaotic behavior and resulting in increased social costs. Remarkably, even within these chaotic regimes, we show that the time-averaged macroscopic behavior converges to exact Nash equilibria, thus linking the microscopic dynamic complexity with traditional equilibrium concepts. By employing dynamical systems techniques, we analyze the interaction between individual-level adaptation and population-level outcomes, paving the way for studying heterogeneous learning dynamics in discrete time across more complex game scenarios.
Theories of the evolution of cooperation through reciprocity explain how unrelated self-interested individuals can accomplish more together than they can on their own. The most prominent theories of reciprocity, such as tit-for-tat or win-stay-lose-shift, are inflexible automata that lack a theory of mind—the human ability to infer the hidden mental states in others’ minds. Here, we develop a model of reciprocity with a theory of mind, the Bayesian Reciprocator. When making decisions, this model does not simply seek to maximize its own payoff. Instead, it also values the payoffs of others—but only to the extent it believes that those others are also cooperating in the same way. To compute its beliefs about others, the Bayesian Reciprocator uses a probabilistic and generative approach to infer the latent preferences, beliefs, and strategies of others through interaction and observation. We evaluate the Bayesian Reciprocator using a generator over games where every interaction is unique, as well as in classic environments such as the iterated prisoner’s dilemma. The Bayesian Reciprocator enables the emergence of both direct-reciprocity when games are repeated and indirect-reciprocity when interactions are one-shot but observable to others. In an evolutionary competition, the Bayesian Reciprocator outcompetes existing automata strategies and sustains cooperation across a larger range of environments and noise settings than prior approaches. This work quantifies the advantage of a theory of mind for cooperation in an evolutionary game theoretic framework and suggests avenues for building artificially intelligent agents with more human-like learning mechanisms that can cooperate across many environments.
Methane seeps harbor uncharacterized animal–microbe symbioses with unique nutritional strategies. Three undescribed sea spider species (family Ammotheidae; genusSericosura) endemic to methane seeps were found along the eastern Pacific margin, from California to Alaska, hosting diverse methane- and methanol-oxidizing bacteria on their exoskeleton. δ13C tissue isotope values of in situ specimens corroborated methane assimilation (−45‰, on average). Live animal incubations with13C-labeled methane and methanol, followed by nanoscale secondary ion mass spectrometry, confirmed that carbon derived from both compounds was actively incorporated into the tissues within five days. Methano- and methylotrophs of the bacterial families Methylomonadaceae, Methylophagaceae and Methylophilaceae were abundant, based on environmental metagenomics and 16S rRNA sequencing, and fluorescence and electron microscopy confirmed dense epibiont aggregations on the sea spider exoskeleton. Egg sacs carried by the males hosted identical microbes suggesting vertical transmission. We propose that these sea spiders farm and feed on methanotrophic and methylotrophic bacteria, expanding the realm of animals known to harness C1 compounds as a carbon source. These findings advance our understanding of the biology of an understudied animal lineage, unlocking some of the unique nutritional links between the microbial and faunal food webs in the oceans.
In multiple sclerosis (MS), cerebellar gray matter atrophy, white matter demyelination, and Purkinje cell (PC) loss have been linked to tremors, impaired motor control, and loss of coordination. Similar pathologies have been observed in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). This study hypothesized that inflammatory demyelination of the cerebellum alters overall mitochondrial function and is a contributor to axon degeneration and PC loss. Postmortem cerebellar tissue from MS patients, particularly those with secondary progressive MS, showed decreased mitochondrial complex IV (COXIV) activity and significant PC loss. Inflammation, PC axon demyelination, axon degeneration, and parallel fiber loss were also evident. These findings were mirrored in late-stage EAE mice, which also showed increased inflammation and demyelination, reduced PC COXIV activity, and overall PC loss. Further analysis of EAE mice revealed altered mitochondrial structure, modified mitochondrial respiration, and reduced levels of mitochondrial genes involved in energy production. These findings indicate that both human MS and mouse EAE share similar cerebellar changes linked to mitochondrial dysfunction. Thus, late-stage EAE is a valuable model for studying MS-related cerebellar pathology, and mitochondria may be a potential therapeutic target for MS treatment.
Iron (Fe) availability limits photosynthesis at a global scale where Fe-rich photosystem (PS) I abundance is drastically reduced in Fe-poor environments. We used single-particle cryoelectron microscopy to reveal a unique Fe starvation-dependent arrangement of light-harvesting chlorophyll (LHC) proteins where Fe starvation–induced TIDI1 is found in an additional tetramer of LHC proteins associated with PSI inDunaliella tertiolectaandDunaliella salina. These cosmopolitan green algae are resilient to poor Fe nutrition. TIDI1 is a distinct LHC protein that co-occurs in diverse algae with flavodoxin (an Fe-independent replacement for the Fe-containing ferredoxin). The antenna expansion in eukaryotic algae we describe here is reminiscent of the iron-starvation induced (isiA-encoding) antenna ring in cyanobacteria, which typically co-occurs withisiB, encoding flavodoxin. Our work showcases the convergent strategies that evolved after the Great Oxidation Event to maintain PSI capacity.
State-of-the-art ice sheet model simulations used in the Ice Sheet Model Intercomparison Project (ISMIP) that informs the Intergovernmental Panel on Climate Change tend to underestimate observed mass loss from the Greenland Ice Sheet, leading to the question of whether future sea-level rise may be larger than projected. We use one of these models, the Ice-sheet and Sea-level System Model, to investigate how transient calibration impacts historical and projection simulations. Transient calibration is an emerging capability in ice flow models; it uses time series of surface observations and time-dependent physics to constrain uncertain model parameters—in this case, the basal friction coefficient in the sliding law. With more constraints than the common snapshot inversion method, transient calibration has been shown to better capture trends in ice dynamics. Here, we apply both methods to northwestern Greenland, a region undergoing rapid changes. For simulations initialized with the snapshot inversion, we find that subsequent modeled velocities are generally too slow, leading to an underestimation of the mass loss. With transient calibration, however, our simulation better matches a time series of observed velocities, bringing it within observational error for mass loss; however, the fit to observed surface elevation is slightly reduced. Together with the ISMIP results, our simulations show that reproducing the high rates of historical mass loss leads to greater projected sea-level contribution from this region over the coming century. Finally, we suggest a path forward for making transient calibration scalable to the entire Greenland Ice Sheet.
Ralph Holloway pioneered and developed the field of hominin paleoneurology. Although Holloway’s undergraduate degrees were in metallurgical engineering and geology, at graduate school his interests switched to the brain. Holloway and his graduate students explored many aspects of the macro- and microstructure of the brain of extant primates but he focused on the recent evolutionary history of the human brain. The infant skull of the first African early hominin discovered at Taungs by Raymond Dart included a natural brain endocast. Natural endocasts as well-preserved as that of the Taungs infant are rare, but Holloway reasoned that if a way could be found to reproduce the endocranial morphology of early hominin crania then he would be able to track brain evolution within the human clade. Holloway realized that if liquid latex was introduced into the cranial cavity and left to cure, it could be extracted via the foramen magnum and then be used to make a facsimile of that individual’s brain. Modern imaging methods have made Holloway’s technique redundant, but for many years, it was the only way to access the endocranial morphology of fossil hominins.
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Evolutionary game theory (EGT) has been pivotal in the study of cooperation, offering formal models that account for how cooperation may arise in groups of selfish, but simple agents. This is done by inspecting the complex dynamics arising from simple interactions between a few strategies in a large population. As such, the strategies at stake are typically hand-picked by the modeler, resulting in a system with many more individuals in the population than strategies available to them. In the presence of noise and with multiple equilibria, the choice of strategies can considerably alter the emergent dynamics. As a result, model outcomes may not be robust to how the strategy set is chosen, sometimes misrepresenting the conditions required for cooperation to emerge. We propose three principles that can lead to a more systematic choice of the strategies in EGT models of cooperation. These are the inclusion of all computationally equivalent strategies; explicit microeconomic models of interactions, and a connection between stylized facts and model assumptions. Further, we argue that new methods arising in AI may offer a promising path toward richer models. These richer models can push the field of cooperation forward together with the principles described above. At the same time, AI may benefit from connecting to the more abstract models of EGT. We provide and discuss examples to substantiate these claims.
A brief global warming event known as the Pre-Onset Excursion (POE) occurred just before the Paleocene–Eocene Thermal Maximum (PETM, 56 Mya). The deconvolution of the evolutionary consequences of these two hyperthermal events is puzzling because of their close temporal proximity and the lack of comprehensive, well-calibrated paleontological records, especially in terrestrial environments. As a consequence, the impact of the POE on mammalian evolution and its role in shaping PETM faunas remains unclear. Here, we report from France a mammalian fauna, named Albas, which is interpreted to postdate the POE and predate the PETM. The absence of artiodactyls, perissodactyls, and euprimates at Albas lends support to the controversial hypothesis that these “modern” mammal groups appeared in the European fossil record during the PETM. In contrast, Albas yielded the European first definitive Paleocene record of metatherians, paromomyid primates, “creodonts,” and rodents, challenging the assumption that these groups migrated into Europe during the PETM. Because the majority of them originated from North American pre-POE species, we tentatively suggest that these “precursor” dispersers entered Europe during the POE. Similar to the modern orders during the PETM, these “precursor” dispersers likely entered Europe through corridors in the continuous evergreen forest belt at high latitudes. Our findings highlight how a brief warming event in the Arctic during the latest Paleocene, such as the POE (which could result in a release of carbon into the atmosphere similar to cumulative ongoing anthropogenic emissions), significantly influenced the evolutionary dynamics of European mammals.
Multiagent learning is challenging when agents face mixed-motivation interactions, where conflicts of interest arise as agents independently try to optimize their respective outcomes. Recent advancements in evolutionary game theory have identified a class of “zero-determinant” strategies, which confer an agent with significant unilateral control over outcomes in repeated games. Building on these insights, we present a comprehensive generalization of zero-determinant strategies to stochastic games, encompassing dynamic environments. We propose an algorithm that allows an agent to discover strategies enforcing predetermined linear (or approximately linear) payoff relationships. Of particular interest is the relationship in which both payoffs are equal, which serves as a proxy for fairness in symmetric games. We demonstrate that an agent can discover strategies enforcing such relationships through experience alone, without coordinating with an opponent. In finding and using such a strategy, an agent (“enforcer”) can incentivize optimal and equitable outcomes, circumventing potential exploitation. In particular, from the opponent’s viewpoint, the enforcer transforms a mixed-motivation problem into a cooperative problem, paving the way for more collaboration and fairness in multiagent systems.
Choosing social partners is a potentially demanding task which involves paying attention to the right information while disregarding salient but possibly irrelevant features. The resultant trade-off between cost of evaluation and quality of decisions can lead to undesired bias. Information-processing abilities mediate this trade-off, where individuals with higher ability choose better partners leading to higher performance. By altering the salience of features, technology can modulate the effect of information-processing limits, potentially increasing or decreasing undesired biases. Here, we use game theory and multiagent reinforcement learning to investigate how undesired biases emerge, and how a technological layer (in the form of a perceptual intervention) between individuals and their environment can ameliorate such biases. Our results show that a perceptual intervention designed to increase the salience of outcome-relevant features can reduce bias in agents making partner choice decisions. Individuals learning with a perceptual intervention showed less bias due to decreased reliance on features that only spuriously correlate with behavior. Mechanistically, the perceptual intervention effectively increased the information-processing abilities of the individuals. Our results highlight the benefit of using multiagent reinforcement learning to model theoretically grounded social behaviors, particularly when real-world complexity prohibits fully analytical approaches.
Antarctic krill is a keystone species in the Antarctic marine ecosystem and the target of a growing fishery. Given the ecological importance of krill, concerns have been raised about potential negative impacts of fishing on the Southern Ocean ecosystem. Resource-efficient approaches to fisheries monitoring are particularly valuable in this context due to the high costs associated with data collection in Antarctica. In this study, we trained a segmentation model (U-Net) to extract dives of air-breathing krill predators from more than 30,000 h of active acoustic data collected by three krill fishing vessels over six years. We were able to characterize the temporal and spatial dynamics of predator-vessel co-occurrences, which aligned well with the findings from more costly tracking studies. For example, we found that encounters with whales consistently peaked in autumn around the Antarctic Peninsula, when whales are building up fat reserves for their migration to breeding grounds. We also demonstrated that protection measures, introduced to protect breeding penguins at the Antarctic Peninsula, have simply shifted penguin-vessel encounters to the South Orkney Islands, where the affected colonies are not currently monitored. Our approach, results, and application example demonstrate how acoustic data from fishing vessels can provide important information to support fisheries management. As a by-product of fishing operations, these data are cost-effective, offering unique temporal and spatial coverage and providing a useful basis for rapid, low-level assessments of the fishery’s interaction with the wider ecosystem. This is particularly important given the unpredictable dynamics of krill fishery management decision-making.
We use crowd-sourced assessments from X’s Community Notes program to examine whether there are partisan differences in the sharing of misleading information. Unlike previous studies, misleadingness here is determined by agreement across a diverse community of platform users, rather than by fact-checkers. We find that 2.3 times more posts by Republicans are flagged as misleading compared to posts by Democrats. These results are not base rate artifacts, as we find no meaningful overrepresentation of Republicans among X users. Our findings provide strong evidence of a partisan asymmetry in misinformation sharing which cannot be attributed to political bias on the part of raters, and indicate that Republicans will be sanctioned more than Democrats even if platforms transition from professional fact-checking to Community Notes.
Symbioses with microorganisms expand the genetic and metabolic repertoire of many insects. The lac insectKerria lacca(Hemiptera: Sternorrhyncha) is a phloem-feeding scale insect that is brightly colored due to the presence of natural polyhydroxy-anthraquinone pigments called laccaic acids. The deep red pigments possibly provide defense against pathogens and predators and are commercially important as dyes in textiles, lacquerware, and cosmetics. Laccaic acids are categorized as polyketides comprising an anthraquinone backbone decorated with tyrosine or its derivatives. However, the genetic basis of these pigments remains unknown, as insects are not known to produce aromatic polyketides or tyrosine de novo. Here, we sequence the genome of the lac insect and its two endosymbionts—Wolbachiaand a hitherto unidentified, transovarially transmitted yeast-like symbiont (YLS). We found no evidence for the host orWolbachiato be able to synthesize the pigments. The pigments and their precursors were also not detected in the host plant. Genomic, transcriptomic, and metabolomic analyses combined with fluorescence microscopy identified and characterized YLS as the sole producer of the pigment’s polyketide backbone and tyrosine moiety, demonstrating an endosymbiotic origin of the lac pigments. A nonreducing polyketide synthase gene cluster encoding the laccaic acid backbone was identified. Furthermore, the YLS genome encoded essential amino acids and vitamins that are deficient in the insect’s phloem diet. Experimental fungicide-treated insects exhibited reduced concentrations of laccaic acids and tyrosine, along with decreased body size and weight, indicating a mutualistic association between the lac insect and its YLS.
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Vertebrate scavengers play a critical role in ecosystem functioning worldwide. Through the cascading effects of their ecological role, scavengers can also alleviate the burden of zoonotic diseases on people. This importance to human health fuels a growing need to understand how vertebrate scavengers and their ecosystem services are faring globally in the Anthropocene. We reviewed the conservation status of 1,376 vertebrate scavenging species and examined the implications for human health. We uncovered that 36% of these species are threatened or decreasing in population abundance and that apex (large-bodied or obligate) scavengers are disproportionately imperiled. In contrast, mesoscavengers (small-bodied or facultative) are thriving from anthropogenic food subsidies and ecological release. We posit that this global shift in scavenger community structure increases carrion persistence enabling zoonotic pathogens to propagate. Our analysis also indicates that the release of mesoscavengers is associated with reservoir host proliferation, potentially further exacerbating human disease burdens. Urgently tackling the key threats to scavengers—intensive livestock production, land use change, wildlife trade, and the interactions among them—is critical to securing the long-term public health benefits of the world’s diverse scavenger communities.
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Removing CO2from the atmosphere is emerging as a viable strategy to mitigate global warming, yet the responses of the climate system to CO2reduction remain uncertain. One of the most uncertain aspects of El Niño behavior is the change in periodicity in response to CO2forcing [O. Alizadeh,Earth-Sci. Rev.235, 104246 (2022)]. In this study, we show that climate models consistently project an abrupt shortening of El Niño periodicity once CO2reductions commence in ramp-up and ramp-down CO2experiments. Besides the contribution of slow mean state changes, this phenomenon is shown to be driven by a southward shift of the Intertropical Convergence Zone (ITCZ) [J.-S. Kug,et al.,Nat. Clim. Chang.12, 47–53 (2022)] and the consequent narrowing of El Niño’s spatial pattern, which enhances the effectiveness of ocean heat recharge/discharge processes, thereby shortening its periodicity. This suggests that the abrupt shift in El Niño periodicity results from a cascading reaction involving ITCZ dynamics and El Niño’s spatial configuration. These findings highlight the critical role of the global energy balance in shaping El Niño characteristics.
The physics of the heat-trapping properties of CO2were established in the mid-19th century, as fossil fuel burning rapidly increased atmospheric CO2levels. To date, however, research has not probed when climate change could have been detected if scientists in the 19th century had the current models and observing network. We consider this question in a thought experiment with state-of-the-art climate models. We assume that the capability to make accurate measurements of atmospheric temperature changes existed in 1860, and then apply a standard “fingerprint” method to determine the time at which a human-caused climate change signal was first detectable. Pronounced cooling of the mid- to upper stratosphere, mainly driven by anthropogenic increases in carbon dioxide, would have been identifiable with high confidence by approximately 1885, before the advent of gas-powered cars. These results arise from the favorable signal-to-noise characteristics of the mid- to upper stratosphere, where the signal of human-caused cooling is large and the pattern of this cooling differs markedly from patterns of intrinsic variability. Even if our monitoring capability in 1860 had not been global, and high-quality stratospheric temperature measurements existed for Northern Hemisphere mid-latitudes only, it still would have been feasible to detect human-caused stratospheric cooling by 1894, only 34 y after the assumed start of climate monitoring. Our study provides strong evidence that a discernible human influence on atmospheric temperature has likely existed for over 130 y.
We demonstrate a tripling in the frequency of planetary wave resonance events over the past halfcentury, coinciding with the rise in persistent boreal summer weather extremes. This increase aligns with changes in the underlying climate conditions favoring these events, including amplified Arctic warming and land–sea thermal contrast. We also observe increased prevalence of resonant amplification events following the mature phase of strong El Niño events, suggesting that such events may precondition the mean state conditions in ways that favor large-scale quasi-stationary wave patterns and quasi-resonant wave amplification. Since the impact of anthropogenic warming on quasi-resonant amplification is not well captured by current-generation climate models, it is likely that models are underpredicting the potential increase, indicating even greater risk of persistent extreme summer weather events with ongoing warming.
Circulating monocytes are recruited to the tumor microenvironment, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate and migrate through the type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by a higher loss tangent or faster stress relaxation rate. Here, we studied how changes in matrix stiffness and viscoelasticity impact the three-dimensional (3D) migration of monocytes through stromal-like matrices. Interpenetrating networks of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining matrices for 3D culture of monocytes. Increased stiffness and faster stress relaxation independently enhanced the 3D migration of monocytes. Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Matrix adhesions were dispensable for monocyte migration in 3D, but migration did require actin polymerization and myosin contractility. Mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that open a path for the monocytes to migrate through in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal how monocytes use pushing forces at the leading edge mediated by actin polymerization to generate migration paths in confining viscoelastic matrices.
In an era increasingly influenced by autonomous machines, it is only a matter of time before strategic individual decisions that impact collective goods will also be made virtually through the use of artificial delegates. Through a series of behavioral experiments that combine delegation to autonomous agents and different choice architectures, we pinpoint what may get lost in translation when humans delegate to algorithms. We focus on the collective-risk dilemma, a game where participants must decide whether or not to contribute to a public good, where the latter must reach a target in order for them to keep their personal endowments. To test the effect of delegation beyond its functionality as a commitment device, participants are asked to play the game a second time, with the same group, where they are given the chance to reprogram their agents. As our main result we find that, when the action space is constrained, people who delegate contribute more to the public good, even if they have experienced more failure and inequality than people who do not delegate. However, they are not more successful. Failing to reach the target, after getting close to it, can be attributed to precision errors in the agent’s algorithm that cannot be corrected amid the game. Thus, with the digitization and subsequent limitation of our interactions, artificial delegates appear to be a solution to help preserving public goods over many iterations of risky situations. But actual success can only be achieved if humans learn to adjust their agents’ algorithms.
Pure siderite [FeIICO3] was recently discovered in abundant quantities (4.8 to 10.5 wt.%) by the Curiosity rover at Gale crater, Mars. Diagenetic alteration of siderite likely caused the carbonate-sequestered CO2to be released back into the atmosphere and consequently produced ferric [Fe(III)] oxyhydr(oxide) minerals. Here, using laboratory experimentation, we demonstrate that while closed system acid diagenesis—as proposed for Gale crater—is incapable of effective siderite alteration in Mars-relevant fluids, oxyhalogen compounds (chlorate and bromate) can weather siderite not only at acidic pH but also in near-neutral Mars-relevant solutions. The ferric oxyhydroxide minerals produced as a consequence are controlled by the diagenetic fluid composition. While photooxidation is possible, the mutually exclusive products of alteration—magnetite (Fe3O4) during ultraviolet irradiation and ferric oxyhydroxide (FeOOH) by oxyhalogens—demonstrate that siderite at Gale crater underwent chemical weathering by chlorate and bromate brines owing to the complete absence of magnetite in drill samples containing siderite. We propose a top–down oxyhalogen brine percolation model to explain the iron mineralogy of the sulfate-rich unit at Gale crater. We conclude that siderite alteration by acidic fluids alone cannot explain the redox disequilibrium witnessed in Gale crater sediments as promulgated before and siderite weathering by oxyhalogen brines is the most likely explanation. It is highly likely that the halogen cycle on Mars is interlinked to the iron and the carbon cycle on early and current Mars.
Cooperation at scale is critical for achieving a sustainable future for humanity. However, achieving collective, cooperative behavior—in which intelligent actors in complex environments jointly improve their well-being—remains poorly understood. Complex systems science (CSS) provides a rich understanding of collective phenomena, the evolution of cooperation, and the institutions that can sustain both. Yet, much of the theory in this area fails to fully consider individual-level complexity and environmental context—largely for the sake of tractability and because it has not been clear how to do so rigorously. These elements are well captured in multiagent reinforcement learning (MARL), which has recently put focus on cooperative (artificial) intelligence. However, typical MARL simulations can be computationally expensive and challenging to interpret. In this perspective, we propose that bridging CSS and MARL affords new directions forward. Both fields can complement each other in their goals, methods, and scope. MARL offers CSS concrete ways to formalize cognitive processes in dynamic environments. CSS offers MARL improved qualitative insight into emergent collective phenomena. We see this approach as providing the necessary foundations for a proper science of collective, cooperative intelligence. We highlight work that is already heading in this direction and discuss concrete steps for future research.
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Intermediate filaments are key regulators of cell mechanics. Vimentin, a type of intermediate filament expressed in mesenchymal cells and involved in migration, forms a dense network in the cytoplasm that is constantly remodeling through filament transport, elongation/shortening, and subunit exchange. While it is known that filament elongation involves end-to-end annealing, the reverse process of filament shortening by fragmentation remains unclear. Here, we use a combination of in vitro reconstitution, probed by fluorescence imaging and atomic force microscopy, with theoretical modeling to uncover the molecular mechanism involved in filament breakage. We first show that vimentin filaments are composed of two populations of subunits, half of which are exchangeable and half immobile. We also show that the exchangeable subunits are tetramers. Furthermore, we reveal a mechanism of continuous filament self-repair, where a soluble pool of vimentin tetramers in equilibrium with the filaments is essential to maintain filament integrity. Filaments break due to local fluctuations in the number of tetramers per cross-section, induced by the constant subunit exchange. We determine that a filament tends to break if approximately four tetramers are removed from the same filament cross-section. Finally, we analyze the dynamics of association/dissociation and fragmentation to estimate the binding energy of a tetramer to a complete versus a partially disassembled filament. Our results provide a comprehensive description of vimentin turnover and reveal the link between subunit exchange and fragmentation.
The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17–iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.
Positive-strand RNA viruses are important pathogens of humans and plants. These viruses built viral replication organelles (VROs) with the help of co-opted host proteins and intracellular membranes to support robust virus replication in infected cells. Tomato bushy stunt virus (TBSV), a model (+)RNA virus, assembles membranous VROs, which are associated with vir-condensate substructures driven by TBSV p33 replication-associated protein. In this work, we provide evidence that the peroxisome-associated TBSV and the mitochondria-associated carnation Italian ringspot virus hijack the host small ubiquitin-like modifier (SUMO) machinery in yeast model host and plants. Based on knockdown of components of the SUMO pathway, we show that SUMO machinery acts as a cellular proviral dependency factor during TBSV replication. The sumoylation machinery was found to be partially retargeted from the nucleus into vir-condensate associated with membranous VROs through direct interactions with TBSV p33. We developed a yeast-based sumoylation assay that demonstrated p33 sumoylation. Absence of sumoylation or mutations in SIM SUMO-interacting motif in p33 replication protein reduced the ability of p33 to form droplets in vitro via phase separation. We demonstrate that p33 sumoylation and its intrinsically disordered region play noncomplementary roles in droplet formation. Mutations in p33 sumoylation sites and p33-SIM sequence resulted in reduced-sized VROs, which showed diminished protection of TBSV p33 and the viral RNA from degradation and also reduced viral RNA recombination. Altogether, the co-opted host sumoylation machinery promotes viral replication and RNA recombination. This finding could provide opportunities for antiviral interventions via targeting protein posttranslational modifications.
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The wave-like behavior of matter in quantum physics has spurred insightful analogies between the dynamics of particles and waves in classical systems. In this study, drawing inspiration from synchrotrons that resonate to accelerate ions along a closed path, we introduce a synchrowave: a waveguide designed to generate and sustain traveling water waves within an annular channel. In analogy to unavoidable energy losses in conventional particle accelerators due to electromagnetic radiation and inelastic collisions, the system displays undesired water-wave dampening, which we address through the synchronized action of underwater wavemakers. Our analogies extend the resonance mechanisms of synchrotrons to generate and sustain gravity waves in closed waveguides efficiently. A proof-of-concept experiment at a laboratory scale demonstrates the unique capability of this technique to build up anomalously large traveling waves displaying a flat response in the long-wave limit. Besides quantifying the performance of wave generation, our findings offer a framework for both industrial and computational applications, opening up unexplored possibilities in hydraulics, coastal science, and engineering. In a broader context, our experimental apparatus and methods highlight the versatility of a simple yet powerful concept: a closed-path continuous-energy-pumping scheme to effectively harvest prominent resonant responses within wave-supporting systems displaying weak dissipation.
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Many dynamical systems can exist in alternative regimes for which small changes in an environmental driver can cause sudden jumps between regimes. In ecology, predicting the regime of population fluctuations under unobserved levels of an environmental driver has remained an unsolved challenge with important implications for conservation and management. Here, we show that integrating time-series data and information on a putative driver into a Gaussian Process regression model for the system’s dynamics allows us to predict dynamical regimes without the need to specify the equations of motion of the system. As a proof of concept, we demonstrate that we can accurately predict fixed-point, cyclic, or chaotic dynamics under unseen levels of a control parameter for a range of simulated population dynamics models. For a model with an abrupt population collapse, we show that our approach goes beyond an early warning signal by characterizing the regime that follows the tipping point. We then apply our approach to data from an experimental microbial food web and from a lake planktonic food web. We find that we can reconstruct transitions away from chaos in the microbial food web and anticipate the dynamics of the oligotrophic regime in the planktonic food web. These results lay the groundwork for making rational decisions about preventing, or preparing for, regime shifts in natural ecosystems and other dynamical systems.
AI systems, particularly large language models (LLMs), are increasingly being employed in high-stakes decisions that impact both individuals and society at large, often without adequate safeguards to ensure safety, quality, and equity. Yet LLMs hallucinate, lack common sense, and are biased—shortcomings that may reflect LLMs’ inherent limitations and thus may not be remedied by more sophisticated architectures, more data, or more human feedback. Relying solely on LLMs for complex, high-stakes decisions is therefore problematic. Here, we present a hybrid collective intelligence system that mitigates these risks by leveraging the complementary strengths of human experience and the vast information processed by LLMs. We apply our method to open-ended medical diagnostics, combining 40,762 differential diagnoses made by physicians with the diagnoses of five state-of-the art LLMs across 2,133 text-based medical case vignettes. We show that hybrid collectives of physicians and LLMs outperform both single physicians and physician collectives, as well as single LLMs and LLM ensembles. This result holds across a range of medical specialties and professional experience and can be attributed to humans’ and LLMs’ complementary contributions that lead to different kinds of errors. Our approach highlights the potential for collective human and machine intelligence to improve accuracy in complex, open-ended domains like medical diagnostics.
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Reflection and refraction are ubiquitous phenomena with extensive applications, yet minimizing energy loss and information distortion during these processes remains a significant challenge. This study examines the behavior of structurally stable solitons, known as directrons, in nematic liquid crystals interacting with an interface where the director field orientation changes, despite identical physical properties, external potentials, and boundary anchoring in the two regions. During reflection and refraction, the directrons maintain nearly constant structure and velocity, ensuring energy conservation and information integrity. Microscopic analyses of the director field and macroscopic evaluations of effective potential are employed to elucidate the dependence of reflection and refraction probabilities on the directron’s incident angle and the orientation difference across the interface. The findings provide valuable insights into the dynamics of solitary waves in structured liquid crystal systems, offering significant implications for the development of tunable photonic devices, reconfigurable optical systems, and nanoscale material engineering.
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We give an explicit counterexample to the bunkbed conjecture introduced by Kasteleyn in 1985. The counterexample is given by a planar graph on 7,222 vertices and is built on the recent work of Hollom (2024).
Ryanodine receptors (RyRs) are intracellular Ca2+channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca2+. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.
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Lipoprotein retention in Bruch’s membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch’s membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch’s membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.
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The discovery of transgenerational epigenetic inheritance and the unraveling of its molecular mechanisms are currently solving previously puzzling challenges that Mendelian genetics based solely on DNA could not explain, leading to significant paradigm shifts across various fields of biology. There has been a long-standing controversy over the factors determining the caste fate of individuals in social insects. Increasing evidence supports heritable influences on division of labor. Here, we provide evidence that transgenerational epigenetic inheritance influences caste determination in a termite. We demonstrate that the age of the king influences the caste fate of offspring, with young kings’ progeny showing a higher tendency for reproductive differentiation compared to offspring from older kings (under controlled conditions). Then, we conducted a high-quality chromosome-level genome assembly for the Japanese subterranean termiteReticulitermes speratus. Genome-wide methylome analysis of kings’ sperm reveals a drastic change in DNA methylation patterns with aging. Among 39,399,411 CpG sites, 21,611 sites showed significant age differences in methylation levels. We identified 13 genes whose methylation levels are significantly different between young and old kings and suggestively correlated with the offspring’s differentiation into the reproductive pathway. Our results suggest that sperm DNA methylation, which changes with the age of kings, is a potential transgenerational epigenetic factor involved in offspring caste differentiation in a termite. These findings may have broad applicability to caste differentiation in social insects and to phenotypic plasticity more generally.
Resource fluctuations are ubiquitous in nature and yet are generally assumed to play a limited role in the maintenance of biodiversity. We challenge this assumption by analyzing resource competition dynamics under conditions where prevailing theory does not hold. We show that multispecies coexistence can be sustained when species are able to specialize on different temporal patterns of resource variability, including the asymmetries and periodic extremes commonly observed in natural systems. We further show how this partitioning of the statistical moments of the resource distribution provides a unified framework for explaining coexistence in variable resource environments. The multiplicity of niches we find in a single fluctuating resource highlights the potential for anthropogenic changes in resource regimes to drive cascading biodiversity losses.
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Alveolar macrophages (AMs) are indispensable to prevent pulmonary alveolar proteinosis and clear inhaled pathogens. Receptor for activated C kinase 1 (RACK1) is a versatile adaptor protein that regulates multiple signaling pathways. Whether RACK1 is implicated in AM alterations remains elusive. Alveolar type 2 cells-derived granulocyte-macrophage colony-stimulating factor and autocrine transforming growth factor-β1 drive the transcription ofPparg, the gene encoding AM signature transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). The regulation of PPARγ stability during AM development and maintenance remains unexplored. Here, we report that myeloid RACK1 deficiency results in the scarcity of mature AMs and pulmonary alveolar proteinosis. A mixed bone marrow chimera approach reveals a cell-intrinsic role of RACK1 in AM differentiation. Bulk RNA-sequencing indicates a considerable loss of AM identity, impaired PPAR signaling, but a largely unchangedPpargmessenger RNA (mRNA) level in the absence of RACK1. Indeed, myeloid deletion ofRack1halts AM differentiation in vivo and blocks the ability of PPARγ agonist to induce AM-like cells in vitro. Mechanistically, RACK1 directly binds to and stabilizes PPARγ by preventing its ubiquitination and degradation. Moreover, myeloid RACK1 deficiency renders mice susceptible toStreptococcus pneumoniaeinfection.
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Fluorinated compounds are used for agrochemical, pharmaceutical, and numerous industrial applications, resulting in global contamination. In many molecules, fluorine is incorporated to enhance the half-life and improve bioavailability. Fluorinated compounds enter the human body through food, water, and xenobiotics including pharmaceuticals, exposing gut microbes to these substances. The human gut microbiota is known for its xenobiotic biotransformation capabilities, but it was not previously known whether gut microbial enzymes could break carbon–fluorine bonds, potentially altering the toxicity of these compounds. Here, through the development of a rapid, miniaturized fluoride detection assay for whole-cell screening, we identified active gut microbial defluorinases. We biochemically characterized enzymes from diverse human gut microbial classes including Clostridia, Bacilli, and Coriobacteriia, with the capacity to hydrolyze (di)fluorinated organic acids and a fluorinated amino acid. Whole-protein alanine scanning, molecular dynamics simulations, and chimeric protein design enabled the identification of a disordered C-terminal protein segment involved in defluorination activity. Domain swapping exclusively of the C-terminus conferred defluorination activity to a nondefluorinating dehalogenase. To advance our understanding of the structural and sequence differences between defluorinating and nondefluorinating dehalogenases, we trained machine learning models which identified protein termini as important features. Models trained on 41-amino acid segments from protein C termini alone predicted defluorination activity with 83% accuracy (compared to 95% accuracy based on full-length protein features). This work is relevant for therapeutic interventions and environmental and human health by uncovering specificity-determining signatures of fluorine biochemistry from the gut microbiome.
The correlation between synonymous codon usage and secondary structure in translated proteins has been widely demonstrated. This usage plays a capital role in tuning translational rates and protein folding kinetics, indirectly influencing multiple biological processes. A recent report [A. A. Rosenberg, A. Marx, A. M. Bronstein,Nat. Commun.13, 2815 (2022).] suggests that the translated synonymous codon influences the(ϕ,ψ)dihedral angles within secondary structure elements. If true, this conclusion would have strong consequences in several scientific fields, including structural biology and protein design, where results would depend on DNA sequence rather than protein sequence. Here, we show that the original statistical methodology used in the referred study was formally incorrect. Furthermore, when using a correct approach, we demonstrate that the influence of the codon on the distribution of the dihedral angles is not statistically significant for any type of secondary structure.
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The growth of populations and organisms often depends on their previous history of environmental exposure: a phenomenon referred to as “phenotypic memory.” The field of ecology presently lacks a mechanistic theory describing phenotypic memory and, as such, evaluating the ecological consequences of this phenomenon is a major challenge. Here, we show that internal nutrient storage connects past thermal experience to current growth in phytoplankton. We develop a mechanistic model showing that delays in the response of nutrient stores to changing temperatures produces phenotypic memory. By testing this model against experimental data of phytoplankton growth rates following temperature perturbations, we find general patterns in the population consequences of phenotypic memory: Prior exposure to warm temperatures depletes nutrient stores, and, in doing so, slows growth during subsequent temperature exposure and restricts the breadth of the thermal niche (i.e., the range of acute temperature exposures yielding a positive growth rate). Our model reveals how phenotypic memory produces temporal variation in critical thermal minima and maxima and predicts that the thermal niche is constricted by long-term exposure to warm temperatures (e.g., during summer months), but that high frequency temperature fluctuations can expand a population’s thermal niche. This work provides a mechanistic framework for considering the ecological implications of phenotypic memory.
Recent studies suggest large language models (LLMs) can generate human-like responses, aligning with human behavior in economic experiments, surveys, and political discourse. This has led many to propose that LLMs can be used as surrogates or simulations for humans in social science research. However, LLMs differ fundamentally from humans, relying on probabilistic patterns, absent the embodied experiences or survival objectives that shape human cognition. We assess the reasoning depth of LLMs using the 11-20 money request game. Nearly all advanced approaches fail to replicate human behavior distributions across many models. The causes of failure are diverse and unpredictable, relating to input language, roles, safeguarding, and more. These results warrant caution in using LLMs as surrogates or for simulating human behavior in research.
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A cure for chronic hepatitis B requires eliminating or permanently silencing covalently closed circular DNA (cccDNA). A pivotal target of this approach is the hepatitis B virus (HBV) X protein (HBx), which is a key factor that promotes transcription from cccDNA. However, the HBx structure remains unsolved. Here, we present the cryoelectron microscopy structure of HBx in complex with DDB1, which is an essential complex for cccDNA transcription. In this structure, hydrophobic interactions within HBx were identified, and mutational analysis highlighted their importance in the HBV life cycle. Our biochemical analysis revealed that the HBx–DDB1 complex directly interacts simultaneously with NSE3, which is a component of the SMC5/6 complex, and Spindlin1. Additionally, HBx–DDB1 complex dynamics were explored via high-speed atomic force microscopy. These findings provide comprehensive insights into the structure and function of HBx in HBV replication.
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Antlers, a male deer secondary sex characteristic, are unique mammalian appendages that fully regenerate annually, under androgen regulation. Stem cells located in the antlerogenic periosteum (AP), a tissue overlaying the frontal crest of both male and female deer, play a crucial role in antlerogenesis. Nonetheless, the underlying molecular mechanisms as to how antlerogenesis is regulated by androgens remain largely unexplored. Here, we show that androgens regulate antler growth via macrophages. Bulk RNA sequencing revealed a significant enrichment of immune-related factors in the androgen-activated antlerogenic periosteum (AAP), and single-cell RNA sequencing identified a cluster of AAP cells overexpressing macrophage chemokine CCL2. Additionally, the presence of a substantial number of monocytes/macrophages was detected in the skin overlying the AAP. Histological examination confirmed macrophage accumulation in the AAP. Removal of macrophages with clodronate effectively inhibited antler generation in male sika deer as well as in nude mice engrafted with the AP. Furthermore, testosterone up-regulated CCL2 expression in the AP cells (APCs), thus enhancing their chemotactic effect on recruitment of macrophages. Remarkably, female sika deer developed antlers following local injection of CCL2, autologous macrophages, or even immune response inducer lipopolysaccharide (LPS). Therefore, macrophages play an essential role in deer antler generation.
Hydrogen embrittlement (HE) remains a critical scientific challenge in building reliable infrastructure for a carbon-free hydrogen economy. Predictive models for hydrogen-induced material failure are still lacking, largely due to an incomplete understanding of hydrogen’s effects on deformation behavior, especially in multiphase alloys with complex compositions and microstructures. Here, we demonstrate a synergistic hydrogen embrittlement (SHE) phenomenon in high-strength martensitic steels, where hydrogen interacts with carbon in solution to activate hydrogen-enhanced localized plasticity (HELP). Microcantilever bending tests revealed greater hydrogen susceptibility with higher carbon content, evidenced by a significant reduction in work-hardening capacity, promoting slip localization and reduced ductility. First-principles calculations and theoretical modeling revealed that carbon intensifies hydrogen–dislocation interactions and amplifies hydrogen redistribution around screw dislocations, inhibiting cross-slip. This work integrates experimental and modeling approaches to elucidate the synergistic interactions between hydrogen and solute elements, providing critical insights for designing high-strength, hydrogen-tolerant structural materials.
Plague continues to pose a public health problem in multiple regions of the world, including Madagascar, where it is characterized by a pronounced seasonal pattern. The drivers of plague seasonality remain poorly understood. Using a deterministic compartmental model, calibrated to rat and flea capture data, serological data collected in active rural foci, and human plague surveillance data, we analyzed the effects of seasonal rat and flea population dynamics on plague transmission. The models that incorporated seasonal fluctuations in rat and flea populations provided better predictive performances than those that did not. We found that a simpler mass-action model also performed well. Driven by these seasonal changes, the effective reproduction number (Re) between rats peaks at 1.45 [95% credible interval (CI): 1.41, 1.48] in October and falls to 0.6 (95% CI: 0.57, 0.63) in March. We estimated that 0.5% (95% CI: 0.2%, 0.9%) of rats are infected annually, indicating that plague is not the main driver of rat population changes. Using our model, we evaluated intervention strategies and found that targeting both rats and their fleas at the start of the epidemic season (July–September) was the most effective approach for reducing human plague cases. Such an approach contrasts with the reactive strategy currently employed in Madagascar. Our findings highlight the role of flea and rat populations in plague seasonality and identify strategies that could be deployed in Madagascar to better control plague epidemics.
Cancer therapy is limited by resistance to standard-of-care chemotherapeutic and/or by treatment-associated toxicity. Identifying molecular mechanisms that modulate cellular toxicity is crucial for enhancing treatment efficacy. We characterize CDADC1, a vertebrate-specific orphan enzyme, as an unprecedented eukaryotic dCTP deaminase. CDADC1 catalyzes the conversion of dCTP into dUTP. While bacteria use this activity to sustain proliferation, CDADC1 evolved independently and is not required for mammalian cell proliferation, as demonstrated in cell lines and by the normal growth and standard lifespan of Cdadc1-deficient mice. However, we uncover a role of CDADC1 in metabolizing nucleotide analogs gemcitabine and decitabine. Gain- and loss-of-function assays in cancer cell lines, along with ectopic mouse models of pancreatic cancer, show that CDADC1 reduces these drugs’ efficacy. By the same token,Cdadc1−/−mice are hypersensitive to gemcitabine. Mechanistically, CDADC1 deaminates the active triphosphate form of gemcitabine and decitabine, rendering them susceptible to inactivation by deoxyuridine triphosphatase. In contrast, the dCMP deaminase DCTD contributes to cell proliferation and promotes gemcitabine and decitabine toxicity. Thus, CDADC1 underpins a previously unrecognized mechanism of intrinsic chemoresistance in cancer cells and has a nonredundant role in protecting from gemcitabine toxicity. CDADC1 reveals a clinically relevant metabolic pathway that might be exploited to enhance the efficacy of deoxycytidine analogs but calls for assessing CDADC1 status to avoid lethal toxicities.
Grain growth in polycrystals is traditionally considered a capillarity-driven process, where grain boundaries (GBs) migrate toward their centers of curvature (i.e., mean curvature flow) with a velocity proportional to the local curvature (including extensions to account for anisotropic GB energy and mobility). Experimental and simulation evidence shows that this simplistic view is untrue. We demonstrate that the failure of the classical mean curvature flow description of grain growth mainly originates from the shear deformation naturally coupled with GB motion (i.e., shear coupling). Our findings are built on large-scale microstructure evolution simulations incorporating the fundamental (crystallography-respecting) microscopic mechanism of GB migration. The nature of the deviations from curvature flow revealed in our simulations is consistent with observations in recent experimental studies on different materials. This work also demonstrates how to incorporate the mechanical effects that are essential to the accurate prediction of microstructure evolution.
The α-hemolysin (HlyA) of uropathogenicEscherichia coli(UPEC) is a pore-forming toxin (PFT) that is thought to function by disrupting the host cell plasma membrane. Although CD18 (LFA-1) has been implicated as a receptor on myeloid cells, the mechanisms underlying HlyA cytotoxicity to epithelial cells are poorly defined. Here, we show that HlyA secretion by UPEC markedly intensifies renal tubular epithelial injury in a murine model of ascending pyelonephritis. A CRISPR-Cas9 loss-of-function screen in renal collecting duct cells revealed an unexpected requirement for clathrin-mediated endocytosis in HlyA-induced cytotoxicity. Following internalization, HlyA triggered lysosomal permeabilization, resulting in protease leakage, cytoplasmic acidification, and mitochondrial impairment, culminating in rapid epithelial cell death—a pathway distinct from canonical membrane-disrupting mechanisms of other PFTs. Moreover, we identify the low-density lipoprotein receptor (LDLR) as a critical epithelial receptor for HlyA; genetic ablation or competitive inhibition of the HlyA–LDLR interaction fully abrogated cytotoxicity. Our findings detail a paradigm for HlyA function in which epithelial toxicity relies on LDLR-mediated endocytic uptake rather than plasma membrane poration. These mechanistic insights illuminate potential therapeutic strategies to attenuate HlyA-mediated tissue damage during UPEC infections.
Isoprene is the most abundant nonmethane biogenic hydrocarbon emitted by some plants, mostly trees. It plays critical roles in atmospheric chemistry by contributing to ozone and aerosol formation. Isoprene also benefits plants, particularly under stress, through its signaling roles. Legume crops like soybean were thought to have evolutionarily lost isoprene synthase (ISPS) and are typically considered nonemitters. Here, we report that damage to soybean leaves by wounding or burning triggered a burst of isoprene emission from the undamaged part of the leaves. In silico analysis identified intactISPSgenes in the soybean genome, with features similar to known ISPSs. Protein made from these gene sequences catalyzed isoprene production in the presence of dimethylallyl diphosphate. Isoprene emission in soybeans was linked to reduced photosynthesis rates and stomatal conductance. Metabolomic analysis showed that leaf damage caused a surge in glyceraldehyde 3-phosphate and pyruvate levels, leading to an increase of most of the methylerythritol 4-phosphate pathway metabolites.
Biological microswimmers exhibit intricate taxis behaviors in response to environmental stimuli and swim in complex trajectories to navigate their environment. How microswimmers respond to stimulus instantaneously, and how adaptation to stimulus influences their long-term behavioral changes, remains largely unclear. Here, we report an oscillatory phototaxis observed inChlamydomonas reinhardtiiat intermediate light intensities, where cells swim back-and-forth under a constant, unidirectional light stimulus due to alternation between positive and negative phototaxis. The phototaxis switching can be captured by the change in phase relationship between eyespot and helical swimming. Oscillatory phototaxis of individual cells leads to a global pattern of millimeter-scale propagating density bands that persists for∼30 min. High-speed imaging and long-time tracking experiments at single-cell level verify a unified phototaxis mechanism that couples light detection, light adaptation, flagella responses, and behavioral switching. By experimentally tracking steady swimming and transient turning states, we verify that phototaxis transition is achieved via the modulation of flagella waveforms and flagella phase difference, which can be captured by a hydrodynamic model accounting for photoresponses. Adaptation acts effectively as an oscillator damper to mediate multipurpose tasking across multiple system levels (subcellular flagella beats, oscillatory phototaxis, colonial pattern formation) and timescales (from milliseconds to over 30 min). This adaptive phototaxis mechanism provides a comprehensive understanding of how microswimmers achieve complex behavioral changes across multiple temporal scales with a single sensor–actuator circuit featuring relatively simple adaptive feedback responses.
PKD2 is a member of the polycystin subfamily of transient receptor potential (TRP) ion channel subunits which traffic and function in primary cilia organelle membranes. Millions of individuals carry pathogenic genetic variants in PKD2 that cause a life-threatening condition called autosomal dominant polycystic kidney disease (ADPKD). Although ADPKD is a common monogenetic disorder, there is no drug cure or available therapeutics which address the underlying channel dysregulation. Furthermore, the structural and mechanistic impacts of most disease-causing variants are uncharacterized. Using direct cilia electrophysiology, cryogenic electron microscopy (cryo-EM), and superresolution imaging, we have found mechanistic differences in channel dysregulation caused by three germline missense variants located in PKD2’s pore helix 1. Variant C632R reduces protein thermal stability, resulting in impaired channel assembly and abolishes primary cilia trafficking. In contrast, variants F629S and R638C retain native cilia trafficking but exhibit gating defects. Cryo-EM structures (2.7 to 2.8 Å resolution) indicate loss of critical pore helix interactions which precipitate allosteric collapse of the channels inner gate. Results demonstrate how ADPKD-causing mutations cause mechanistically divergent and ranging impacts on PKD2 function, despite their shared structural proximity. These unexpected findings highlight the need for structural and biophysical characterization of polycystin variants, which will guide rational drug development of ADPKD therapeutics.
Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated viaOvgp1-driven Cre recombinase effecting CRISPR/Cas9-mediated deletion ofTrp53, Rb1, andNf1tumor suppressors in mouse oviductal epithelium (m-sgPRNmodel). Cyclin-dependent kinase 12 (CDK12) inactivation—frequently observed in human HGSC—is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation ofCdk12(m-sgPRN;Cdk12KO) recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated)Trp53/Nf1/Rb1triple knockout model with concurrentCdk12ablation (PRN;Cdk12KOmice), we observed T cell–rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts ofCDK12-inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/Cas9 synthetic lethality screen inPRN;Cdk12KO-derived cell lines identified CDK13—an essential paralog of CDK12—as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from bothm-sgPRN;Cdk12KOandPRN;Cdk12KOmodels. Our results defineCDK12as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach inCDK12-inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.
Mass-independent isotope fractionation (MIF) enables powerful geochemical tracers for various geological and planetary problems, yet the mechanisms driving MIF for tin (Sn) remain ambiguous. Here, we demonstrate that distinct Sn isotope fractionation signatures were produced during photolysis of organic Sn species (i.e., methyltin) under laboratory UV irradiation and natural sunlight. UV irradiation of methyltin induced pronounced Sn-MIF in all odd Sn isotopes (Δ115Sn up to 21.82‰, Δ117Sn up to 23.16‰, Δ119Sn up to 24.01‰), with their ratios (Δ117Sn/Δ115Sn = 1.069; Δ119Sn/Δ115Sn = 1.099; Δ119Sn/Δ117Sn = 1.028) strongly correlating with nuclear magnetic moments. This unambiguously identifies the magnetic isotope effect (MIE) as the driving mechanism, ruling out other causes such as the nuclear volume effect (NVE). Methyl radicals (•CH3) were detectable during the methyltin photolysis experiments, and the magnitude of MIF for Sn was suppressed by the presence of electron spin trapping agent (DMPO) for radicals, supporting that the pronounced Sn-MIF originated from radical-mediated singlet-triplet state transitions of Sn species. Furthermore, the magnitude of Sn-MIF depended nonmonotonically on external magnetic fields (peak suppression at 100 to 180 G), implying competition between hyperfine coupling and Zeeman interactions. Notably, Sn-MIF was absent during photolysis of methyltin by natural sunlight despite significant mass-dependent Sn isotope fractionation (e.g., >3‰ in δ122/116Sn), attributed to atmospheric ozone shielding of short-wavelength UV (<290 nm) required for radical generation. Our results register Sn-MIF as a sensitive tracer of UV-driven photochemistry in low-oxygen environments, underlining the potential of Sn isotopes in studies of early Earth’s atmosphere and planetary environments.
Evolution of complexity in human languages has been vigorously debated, including the proposal that complexity can build in small, isolated populations but is often lost in situations of language contact. If it is generally true that small, isolated languages can build morphological complexity over time, but complexity tends to be lost in situations of language contact, then we should find that forms of language complexity that have evolved multiple times will tend to be associated with population size, isolation, and language age. We test this hypothesis by focusing on one particular form of morphological complexity, polysynthesis, where words built from many parts embody complex phrases. By assembling a global database of polysynthetic languages and conducting phylospatial analyses, we show that languages with highly complex word morphology are more likely to have small population sizes, less likely to occur with many other languages in direct contact, and have a greater tendency to be on long phylogenetically isolated lineages. These findings are consistent with the hypothesis that languages that evolve in isolation for long periods may be more likely to accrue morphological complexity. Polysynthetic languages also tend to have higher levels of endangerment. Our results provide phylogenetically informed evidence that one particular form of complex language morphology is more likely to occur in small, isolated languages and is prone to loss in contact.
Cushing’s syndrome (CS) is an abnormal condition characterized by elevated cortisol levels, often resulting from genetic alterations in thePRKACAgene, which encodes the catalytic subunit of cAMP-dependent protein kinase A (PKA-C). The most common CS mutation, L205R, lies at the P + 1 loop. Understanding how this mutation alters the internal allosteric network within PKA-C and changes nucleotide and substrate cooperativity is a major goal. Using molecular dynamics (MD) simulations and protein residue networks based on local spatial pattern (LSP) method, we compare crystal structures of wild-type PKA-C and L205R. Our findings indicate that L205R not only locally disrupts the P + 1 hydrophobic pocket, leading to the displacement of the P + 1-residue and altered substrate specificity, but also has long-range effects in the linker connecting the A helix to β strand 1. The MD simulations and LSP analyses also reveal critical changes at the phosphoryl transfer site. Some of these changes are captured in the L205R crystal structure while others are not. With this strategy, we also show how the dynamics of local and distal allosteric networks are differentially influenced by backbone and side-chain dynamics.
To decide how to move around the world, we must determine which locomotive actions (e.g., walking, swimming, or climbing) are afforded by the immediate visual environment. The neural basis of our ability to recognize locomotive affordances is unknown. Here, we compare human behavioral annotations, functional MRI (fMRI) measurements, and deep neural network (DNN) activations to both indoor and outdoor real-world images to demonstrate that the human visual cortex represents locomotive action affordances in complex visual scenes. Hierarchical clustering of behavioral annotations of six possible locomotive actions show that humans group environments into distinct affordance clusters using at least three separate dimensions. Representational similarity analysis of multivoxel fMRI responses in the scene-selective visual cortex shows that perceived locomotive affordances are represented independently from other scene properties such as objects, surface materials, scene category, or global properties and independent of the task performed in the scanner. Visual feature activations from DNNs trained on object or scene classification as well as a range of other visual understanding tasks correlate comparatively lower with behavioral and neural representations of locomotive affordances than with object representations. Training DNNs directly on affordance labels or using affordance-centered language embeddings increases alignment with human behavior, but none of the tested models fully captures locomotive action affordance perception. These results uncover a type of representation in the human brain that reflects locomotive action affordances.
Polygenic risk scores (PRS) are essential tools for estimating individual susceptibility to complex diseases by aggregating the effects of many genetic variants. With the advent of whole-genome sequencing (WGS), rare and de novo variants can now be detected at scale, presenting new opportunities to enhance PRS performance. Additionally, regulatory mechanisms that govern gene expression play a critical role in disease manifestation, suggesting further potential for improvement. However, most existing PRS methods are not well-equipped to incorporate nonlinear variant effects, rare variant contributions, or regulatory context. To address these limitations, we developed Epi-PRS, a novel framework that leverages large language models (LLMs) to impute cell-type-specific epigenomic signals from personal diploid genotypes. These imputed signals act as informative intermediates between genotype and phenotype, allowing for more accurate modeling of variant impact. Our simulation studies demonstrate that Epi-PRS improves predictive accuracy by incorporating nonlinear relationships, rare variant effects, and regulatory information across large genomic regions. When applied to real data from the UK Biobank, Epi-PRS significantly outperforms existing PRS approaches in predicting risk for both breast cancer and type 2 diabetes. These results underscore the advantages of integrating WGS data, epigenomic context, and advanced LLMs framework to enhance both the predictive power and interpretability of PRS. Overall, Epi-PRS represents a promising step toward more precise and biologically informed disease risk prediction, with broad implications for advancing personalized medicine and understanding complex genetic architectures.
The relationship between genotype and phenotype remains an outstanding question for organism-level traits because these traits are generallycomplex. The challenge arises from complex traits being determined by a combination of multiple genes (or loci), which leads to an explosion of possible genotype–phenotype mappings. The primary techniques to resolve these mappings are genome/transcriptome-wide association studies, which are limited by their lack of causal inference and statistical power. Here, we develop an approach that combines transcriptional data endowed with causal information and a generative machine learning model designed to strengthen statistical power. Our implementation of the approach—dubbed transcriptome-wide conditional variational autoencoder (TWAVE)—includes a variational autoencoder trained on human transcriptional data, which is incorporated into an optimization framework. Given a trait phenotype, TWAVE generates expression profiles, which we dimensionally reduce by identifying independently varying generalized pathways (eigengenes). We then conduct constrained optimization to find causal gene sets that are the gene perturbations whose measured transcriptomic responses best explain trait phenotype differences. By considering several complex traits, we show that the approach identifies causal genes that cannot be detected by the primary existing techniques. Moreover, the approach identifies complex diseases caused by distinct sets of genes, meaning that the disease is polygenicandexhibits distinct subtypes driven by different genotype–phenotype mappings. We suggest that the approach will enable the design of tailored experiments to identify multigenic targets to address complex diseases.
Characterizing the feedback linking human behavior and the transmission of infectious diseases (i.e., behavioral changes) remains a significant challenge in computational and mathematical epidemiology. Existing behavioral epidemic models often lack real-world data calibration and cross-model performance evaluation in both retrospective analysis and forecasting. In this study, we systematically compare the performance of three mechanistic behavioral epidemic models across nine geographies and two modeling tasks during the first wave of COVID-19, using various metrics. The first model, a Data-Driven Behavioral Feedback Model, incorporates behavioral changes by leveraging mobility data to capture variations in contact patterns. The second and third models are Analytical Behavioral Feedback Models, which simulate the feedback loop either through the explicit representation of different behavioral compartments within the population or by utilizing an effective nonlinear force of infection. Our results do not identify a single best model overall, as performance varies based on factors such as data availability, data quality, and the choice of performance metrics. While the Data-Driven Behavioral Feedback Model incorporates substantial real-time behavioral information, the Analytical Compartmental Behavioral Feedback Model often demonstrates superior or equivalent performance in both retrospective fitting and out-of-sample forecasts. Overall, our work offers guidance for future approaches and methodologies to better integrate behavioral changes into the modeling and projection of epidemic dynamics.
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Clostridium thermocellum, a cellulolytic thermophilic anaerobe, is considered by many to be a prime candidate for the realization of consolidated bioprocessing (CBP) and is known as an industry standard for biofuel production.C. thermocellumis among the best biomass degraders identified to date in nature and produces ethanol as one of its main products. Many studies have helped increase ethanol titers in this microbe; however, ethanol production usingC. thermocellumis still not economically viable. Therefore, a better understanding of its ethanol synthesis pathway is required. The main pathway for ethanol production inC. thermocelluminvolves the bifunctional aldehyde-alcohol dehydrogenase (AdhE). To better understand the function of theC. thermocellumAdhE, we used cryo-electron microscopy (cryo-EM) to obtain a 3.28 Å structure of the AdhE complex. This high-resolution structure, in combination with molecular dynamics simulations, provides insight into the substrate channeling of the toxic intermediate acetaldehyde, indicates the potential role ofC. thermocellumAdhE to regulate activity and cofactor pools, and establishes a basis for future engineering studies. The containment strategy found in this enzyme offers a template that could be replicated in other systems where toxic intermediates need to be sequestered to increase the production of valuable biochemicals.
Neurons in the brain are known to encode diverse information through their spiking activity, primarily reflecting external stimuli and internal states. However, whether individual neurons also embed information about their own anatomical location within their spike patterns remains largely unexplored. Here, we show that machine learning models can predict a neuron’s anatomical location across multiple brain regions and structures based solely on its spiking activity. Analyzing high-density recordings from thousands of neurons in awake, behaving mice, we demonstrate that anatomical location can be reliably decoded from neuronal activity across various stimulus conditions, including drifting gratings, naturalistic movies, and spontaneous activity. Crucially, anatomical signatures generalize across animals and even across different research laboratories, suggesting a fundamental principle of neural organization. Examination of trained classifiers reveals that anatomical information is enriched in specific interspike intervals as well as responses to stimuli. Within the visual isocortex, anatomical embedding is robust at the level of layers and primary versus secondary but does not robustly separate individual secondary structures. In contrast, structures within the hippocampus and thalamus are robustly separable based on their spike patterns. Our findings reveal a generalizable dimension of the neural code, where anatomical information is multiplexed with the encoding of external stimuli and internal states. This discovery provides new insights into the relationship between brain structure and function, with broad implications for neurodevelopment, multimodal integration, and the interpretation of large-scale neuronal recordings. Computational approximations of anatomy have the potential to support in vivo electrode localization.
Clostridium thermocellum, a cellulolytic thermophilic anaerobe, is considered by many to be a prime candidate for the realization of consolidated bioprocessing (CBP) and is known as an industry standard for biofuel production.C. thermocellumis among the best biomass degraders identified to date in nature and produces ethanol as one of its main products. Many studies have helped increase ethanol titers in this microbe; however, ethanol production usingC. thermocellumis still not economically viable. Therefore, a better understanding of its ethanol synthesis pathway is required. The main pathway for ethanol production inC. thermocelluminvolves the bifunctional aldehyde-alcohol dehydrogenase (AdhE). To better understand the function of theC. thermocellumAdhE, we used cryo-electron microscopy (cryo-EM) to obtain a 3.28 Å structure of the AdhE complex. This high-resolution structure, in combination with molecular dynamics simulations, provides insight into the substrate channeling of the toxic intermediate acetaldehyde, indicates the potential role ofC. thermocellumAdhE to regulate activity and cofactor pools, and establishes a basis for future engineering studies. The containment strategy found in this enzyme offers a template that could be replicated in other systems where toxic intermediates need to be sequestered to increase the production of valuable biochemicals.
Neurons in the brain are known to encode diverse information through their spiking activity, primarily reflecting external stimuli and internal states. However, whether individual neurons also embed information about their own anatomical location within their spike patterns remains largely unexplored. Here, we show that machine learning models can predict a neuron’s anatomical location across multiple brain regions and structures based solely on its spiking activity. Analyzing high-density recordings from thousands of neurons in awake, behaving mice, we demonstrate that anatomical location can be reliably decoded from neuronal activity across various stimulus conditions, including drifting gratings, naturalistic movies, and spontaneous activity. Crucially, anatomical signatures generalize across animals and even across different research laboratories, suggesting a fundamental principle of neural organization. Examination of trained classifiers reveals that anatomical information is enriched in specific interspike intervals as well as responses to stimuli. Within the visual isocortex, anatomical embedding is robust at the level of layers and primary versus secondary but does not robustly separate individual secondary structures. In contrast, structures within the hippocampus and thalamus are robustly separable based on their spike patterns. Our findings reveal a generalizable dimension of the neural code, where anatomical information is multiplexed with the encoding of external stimuli and internal states. This discovery provides new insights into the relationship between brain structure and function, with broad implications for neurodevelopment, multimodal integration, and the interpretation of large-scale neuronal recordings. Computational approximations of anatomy have the potential to support in vivo electrode localization.
Liquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions, including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives the formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around p130Cas-coated beads allowed their isolation, which were enriched in a subset of focal adhesion proteins, mRNAs, and RNA binding proteins, including those implicated in inhibiting mRNA translation. Plating cells on very high concentrations of fibronectin to induce large focal adhesions inhibited message translation which required p130Cas and correlated with droplet formation. Photo-induction of p130Cas condensates using the Cry2 system also reduced translation. These results identify a novel regulatory mechanism in which high adhesion limits message translation via induction of p130Cas-dependent cytoplasmic LLPS. This mechanism may contribute to the quiescent state of very strongly adhesive myofibroblasts and senescent cells.
Background:An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.Methods:In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.Results:From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor's immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.Conclusions:These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.Funding:This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).Clinical trial number:ChiCTR2200066117.
Background:An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.Methods:In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.Results:From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor's immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.Conclusions:These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.Funding:This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).Clinical trial number:ChiCTR2200066117.
Liquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions, including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives the formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around p130Cas-coated beads allowed their isolation, which were enriched in a subset of focal adhesion proteins, mRNAs, and RNA binding proteins, including those implicated in inhibiting mRNA translation. Plating cells on very high concentrations of fibronectin to induce large focal adhesions inhibited message translation which required p130Cas and correlated with droplet formation. Photo-induction of p130Cas condensates using the Cry2 system also reduced translation. These results identify a novel regulatory mechanism in which high adhesion limits message translation via induction of p130Cas-dependent cytoplasmic LLPS. This mechanism may contribute to the quiescent state of very strongly adhesive myofibroblasts and senescent cells.
In electroreceptive jawed fishes and amphibians, individual lateral line placodes form lines of neuromasts on the head containing mechanosensory hair cells, flanked by fields of ampullary organs containing electroreceptors - modified hair cells that respond to weak electric fields. Extensively shared gene expression between neuromasts and ampullary organs suggests that conserved molecular mechanisms are involved in their development, but a few transcription factor genes are restricted either to the developing electrosensory or mechanosensory lateral line. Here, we used CRISPR/Cas9-mediated mutagenesis in G0-injected sterlet embryos (Acipenser ruthenus, a sturgeon) to test the function of three such genes. We found that the 'hair cell' transcription factor geneAtoh1is required for both hair cell and electroreceptor differentiation in sterlet, and forPou4f3andGfi1expression in both neuromasts and ampullary organs. These data support the conservation of developmental mechanisms between hair cells and electroreceptors. Targeting ampullary organ-restrictedNeurod4did not yield any phenotype, potentially owing to redundancy with otherNeurodgenes that we found to be expressed in sterlet ampullary organs. After targeting mechanosensory-restrictedFoxg1, ampullary organs formed within neuromast lines, suggesting that Foxg1 normally represses their development, whether directly or indirectly. We speculate that electrosensory organs may be the 'default' developmental fate of lateral line primordia in electroreceptive vertebrates.
Patients with cerebellar damage experience various motor impairments, but the specific sequence of primary and compensatory processes that contribute to these deficits remains unclear. To clarify this, we reversibly blocked cerebellar outflow in monkeys engaged in planar reaching tasks. This intervention led to a spatially selective reduction in hand velocity, primarily due to decreased muscle torque, especially in movements requiring high inter-joint torque coupling. When examining repeated reaches to the same target, we found that the reduced velocity resulted from both an immediate deficit and a gradually developing compensatory slowing to reduce passive inter-joint interactions. However, the slowed hand velocity did not account for the fragmented and variable movement trajectories observed during the cerebellar block. Our findings indicate that cerebellar impairment results in motor deficits due to both inadequate muscle torque and an altered motor control strategy for managing impaired limb dynamics. Additionally, impaired motor control elevates noise, which cannot be entirely mitigated through compensatory strategies.
It is widely accepted that more time and information yield better decisions. However, some decisions manage to be extremely fast and yet accurate. The trick of such highspeed decisions appears to be the use of simplifying heuristics that works well for the most common condition but lacks flexibility otherwise. Here, we describe an unexpected level of flexibility in a complex highspeed decision that is made faster than an Olympic sprinter can respond to the start gun. In this decision, archerfish observe the initial speed, direction, and height of falling prey and then use these initial values to turn right towards where ballistically falling prey would later land. To analyze the limits in flexibility of this highspeed decision, we developed and critically tested a system that allowed us to replace the usual ballistic relation between initial prey motion and the expected landing point with another deterministic rule. We discovered that, surprisingly, adult fish could reprogram their highspeed decision to the new rule. Moreover, after reprogramming their decision fish were immediately able to generalize their decision to novel untrained settings, showing a remarkable degree of abstraction in how the decision circuit represented the novel rule. The decision circuit is even capable of simultaneously using two distinct sets of rules, one for each of two visually distinct objects. The flexibility and level of cognition are unexpected for a decision that lacks a speed-accuracy tradeoff and is made in less than 100 ms. Our findings demonstrate the enormous potential highspeed decision making can have and strongly suggest that we presently underappreciate this form of decision making.
Insect wings, a key innovation that contributed to the explosive diversification of insects, are recognized for their remarkable variation and many splendid adaptations. Classical morphological work subdivides insect wings into several distinct domains along the anteroposterior (AP) axis, each of which can evolve relatively independently to produce the myriad forms we see in nature. Important insights into AP subdivision of insect wings come from work inDrosophila melanogaster; however, they do not fully explain the diversity of AP domains observed across broad-winged insects. Here, we show that the transcription factormirroracts as a selector gene to differentiate a far posterior domain in the butterfly wing, classically defined as the vannus, and has effects on wing shape, scale morphology, and color pattern. Our results support models of how selector genes may facilitate evolutionarily individuation of distinct AP domains in insect wings outside ofDrosophilaand suggest that theD. melanogasterwing blade has been reduced to represent only a portion of the archetypal insect wing.
Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which depends on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies, or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3’s crucial role in NNV entry and its potential as an antiviral target.
It is widely accepted that more time and information yield better decisions. However, some decisions manage to be extremely fast and yet accurate. The trick of such highspeed decisions appears to be the use of simplifying heuristics that works well for the most common condition but lacks flexibility otherwise. Here, we describe an unexpected level of flexibility in a complex highspeed decision that is made faster than an Olympic sprinter can respond to the start gun. In this decision, archerfish observe the initial speed, direction, and height of falling prey and then use these initial values to turn right towards where ballistically falling prey would later land. To analyze the limits in flexibility of this highspeed decision, we developed and critically tested a system that allowed us to replace the usual ballistic relation between initial prey motion and the expected landing point with another deterministic rule. We discovered that, surprisingly, adult fish could reprogram their highspeed decision to the new rule. Moreover, after reprogramming their decision fish were immediately able to generalize their decision to novel untrained settings, showing a remarkable degree of abstraction in how the decision circuit represented the novel rule. The decision circuit is even capable of simultaneously using two distinct sets of rules, one for each of two visually distinct objects. The flexibility and level of cognition are unexpected for a decision that lacks a speed-accuracy tradeoff and is made in less than 100 ms. Our findings demonstrate the enormous potential highspeed decision making can have and strongly suggest that we presently underappreciate this form of decision making.
Tissue-resident memory T cells (TRM) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection are defined at minimum by three quantities: the rate at which new TRMare generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quantifying these processes individually is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4+TRMin the skin and gut lamina propria (LP) of healthy adult mice. We show that CD69+CD4+TRMin skin reside for ∼24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks, and approximately 2% of cells are replaced daily from precursors. CD69+CD4+TRMin LP have shorter residencies (∼14 days) and are maintained largely by immigration (4–6% per day). We also find evidence that the continuous replacement of CD69+CD4+TRMat both sites derives from circulating effector-memory CD4+T cells, in skin possibly via a local CD9−intermediate. Our approach maps the ontogeny of CD4+TRMin skin and LP and exposes their dynamic and distinct behaviours, with continuous seeding and erosion potentially impacting the duration of immunity at these sites.
SalmonellaDublin is a host-adapted, invasive nontyphoidalSalmonella(iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1303 genomes, coupled with in vitro assays, we examined the evolutionary, resistance, and virulence characteristics ofS. Dublin. Our analysis revealed strong geographical associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci, includingSalmonellapathogenicity island (SPI)-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies forS.Dublin infections. Collectively, this study represents the most comprehensive investigation ofS. Dublin to date and, importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinctS.Dublin lineages highlight the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.
Patients with cerebellar damage experience various motor impairments, but the specific sequence of primary and compensatory processes that contribute to these deficits remains unclear. To clarify this, we reversibly blocked cerebellar outflow in monkeys engaged in planar reaching tasks. This intervention led to a spatially selective reduction in hand velocity, primarily due to decreased muscle torque, especially in movements requiring high inter-joint torque coupling. When examining repeated reaches to the same target, we found that the reduced velocity resulted from both an immediate deficit and a gradually developing compensatory slowing to reduce passive inter-joint interactions. However, the slowed hand velocity did not account for the fragmented and variable movement trajectories observed during the cerebellar block. Our findings indicate that cerebellar impairment results in motor deficits due to both inadequate muscle torque and an altered motor control strategy for managing impaired limb dynamics. Additionally, impaired motor control elevates noise, which cannot be entirely mitigated through compensatory strategies.
Tissue-resident memory T cells (TRM) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection are defined at minimum by three quantities: the rate at which new TRMare generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quantifying these processes individually is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4+TRMin the skin and gut lamina propria (LP) of healthy adult mice. We show that CD69+CD4+TRMin skin reside for ∼24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks, and approximately 2% of cells are replaced daily from precursors. CD69+CD4+TRMin LP have shorter residencies (∼14 days) and are maintained largely by immigration (4–6% per day). We also find evidence that the continuous replacement of CD69+CD4+TRMat both sites derives from circulating effector-memory CD4+T cells, in skin possibly via a local CD9−intermediate. Our approach maps the ontogeny of CD4+TRMin skin and LP and exposes their dynamic and distinct behaviours, with continuous seeding and erosion potentially impacting the duration of immunity at these sites.
Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which depends on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies, or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3’s crucial role in NNV entry and its potential as an antiviral target.
Insect wings, a key innovation that contributed to the explosive diversification of insects, are recognized for their remarkable variation and many splendid adaptations. Classical morphological work subdivides insect wings into several distinct domains along the anteroposterior (AP) axis, each of which can evolve relatively independently to produce the myriad forms we see in nature. Important insights into AP subdivision of insect wings come from work inDrosophila melanogaster; however, they do not fully explain the diversity of AP domains observed across broad-winged insects. Here, we show that the transcription factormirroracts as a selector gene to differentiate a far posterior domain in the butterfly wing, classically defined as the vannus, and has effects on wing shape, scale morphology, and color pattern. Our results support models of how selector genes may facilitate evolutionarily individuation of distinct AP domains in insect wings outside ofDrosophilaand suggest that theD. melanogasterwing blade has been reduced to represent only a portion of the archetypal insect wing.
SalmonellaDublin is a host-adapted, invasive nontyphoidalSalmonella(iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1303 genomes, coupled with in vitro assays, we examined the evolutionary, resistance, and virulence characteristics ofS. Dublin. Our analysis revealed strong geographical associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci, includingSalmonellapathogenicity island (SPI)-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies forS.Dublin infections. Collectively, this study represents the most comprehensive investigation ofS. Dublin to date and, importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinctS.Dublin lineages highlight the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.
A growing body of research suggests that dopamine is involved in working memory updating and that the striatum takes up a critical role in the subprocess of working memory gating . In this study, we investigated subcortical – in particular, possible dopaminergic – involvement in working memory updating subprocesses using the reference-back task and ultrahigh field 7 Tesla functional magnetic resonance imaging (fMRI). Using a scanning protocol optimized for BOLD sensitivity in the subcortex, we found no evidence of subcortical activation during working memory gate opening, predominantly activations in frontoparietal network regions, which challenges the idea of a striatal gating mechanism. However, during gate closing, subcortical activation was observed. Furthermore, a ready-to-update mode demonstrated large-spread subcortical activation, including basal ganglia nuclei, suggesting that the basal ganglia are engaged in general updating processes rather than specifically controlling the working memory gate. Moreover, substituting new information into working memory elicited activation in dopamine-producing midbrain regions along with the striatum, thalamus, and prefrontal cortex, indicating engagement of the basal ganglia-thalamo-cortical loop possibly driven by (potential) dopaminergic activity. These findings expand our understanding of subcortical regions involved in working memory updating, shifting the focus from gate opening to substitution as a midbrain-driven updating process.
A growing body of research suggests that dopamine is involved in working memory updating and that the striatum takes up a critical role in the subprocess of working memory gating . In this study, we investigated subcortical – in particular, possible dopaminergic – involvement in working memory updating subprocesses using the reference-back task and ultrahigh field 7 Tesla functional magnetic resonance imaging (fMRI). Using a scanning protocol optimized for BOLD sensitivity in the subcortex, we found no evidence of subcortical activation during working memory gate opening, predominantly activations in frontoparietal network regions, which challenges the idea of a striatal gating mechanism. However, during gate closing, subcortical activation was observed. Furthermore, a ready-to-update mode demonstrated large-spread subcortical activation, including basal ganglia nuclei, suggesting that the basal ganglia are engaged in general updating processes rather than specifically controlling the working memory gate. Moreover, substituting new information into working memory elicited activation in dopamine-producing midbrain regions along with the striatum, thalamus, and prefrontal cortex, indicating engagement of the basal ganglia-thalamo-cortical loop possibly driven by (potential) dopaminergic activity. These findings expand our understanding of subcortical regions involved in working memory updating, shifting the focus from gate opening to substitution as a midbrain-driven updating process.
The risk for developing primary open-angle glaucoma (POAG) correlates with the magnitude of ocular hypertension (OHT) and the concentration of transforming growth factor-β2 (TGFβ2) in the aqueous humor. Effective treatment of POAG requires a detailed understanding of the interaction between pressure sensing mechanisms in the trabecular meshwork (TM) and biochemical risk factors. Here, we employed molecular, optical, electrophysiological, and tonometric strategies to establish the role of TGFβ2 in transcription and functional expression of mechanosensitive channel isoforms alongside studies of TM contractility in biomimetic hydrogels and intraocular pressure (IOP) regulation in a mouse model of TGFβ2-induced OHT. TGFβ2 upregulated expression ofTrpv4andPiezo1transcripts and time-dependently augmented functional TRPV4 activation. TRPV4 agonists induced contractility of TM-seeded hydrogels, whereas pharmacological inhibition suppressed TGFβ2-induced hypercontractility and abrogated OHT in eyes overexpressing TGFβ2.Trpv4-deficient mice resisted TGFβ2-driven increases in IOP, but nocturnal OHT was not additive to TGFβ-evoked OHT. Our study establishes the fundamental role of TGFβ as a modulator of mechanosensing in nonexcitable cells, identifies the TRPV4 channel as the final common mechanism for TM contractility and circadian and pathological OHT, and offers insights for future treatments that can lower IOP in the sizeable cohort of hypertensive glaucoma patients that resist current treatments.
Recent studies have provided evidence for the concurrent encoding of sensory percepts and visual working memory (VWM) contents across visual areas; however, it has remained unclear how these two types of representations are concurrently present. Here, we reanalyzed an open-access fMRI dataset where participants memorized a sensory stimulus while simultaneously being presented with sensory distractors. First, we found that the VWM code in several visual regions did not fully generalize between different time points, suggesting a dynamic code. A more detailed analysis revealed that this was due to shifts in coding spaces across time. Second, we collapsed neural signals across time to assess the degree of interference between VWM contents and sensory distractors, specifically by testing the alignment of their encoding spaces. We find that VWM and feature-matching sensory distractors are encoded in coding spaces that do not fully overlap, but the separation decreases when distractors negatively impact behavioral performance in recalling the target. Together, these results indicate a role of dynamic coding and temporally stable coding spaces in helping multiplex perception and VWM within visual areas.
Group identification may influence collective behaviors and result in variations in collective performance. However, the evidence for this hypothesis and the neural mechanisms involved remain elusive. To this end, we conducted a study using both single-brain activation and multi-brain synchronization analyses to investigate how group identification influences collective problem-solving in a murder mystery case. Our results showed that groups with high levels of identification performed better individually compared to those with low identification, as supported by single-brain activation in the dorsolateral prefrontal cortex (DLPFC). Furthermore, high-identification groups also showed enhanced collective performance, supported by within-group neural synchronization in the orbitofrontal cortex (OFC). The DLPFC–OFC connectivity played a crucial role in linking individual and collective performance. Overall, our study provides a two-in-one neural model to explain how group identification affects collective decision-making processes, offering valuable insights into the dynamics of group interactions.
Understanding the complex three-dimensional structure of cells is crucial across many disciplines in biology and especially in neuroscience. Here, we introduce a set of models including a 3D transformer (SwinUNetR) and a novel 3D self-supervised learning method (WNet3D) designed to address the inherent complexity of generating 3D ground truth data and quantifying nuclei in 3D volumes. We developed a Python package called CellSeg3D that provides access to these models in Jupyter Notebooks and in a napari GUI plugin. Recognizing the scarcity of high-quality 3D ground truth data, we created a fully human-annotated mesoSPIM dataset to advance evaluation and benchmarking in the field. To assess model performance, we benchmarked our approach across four diverse datasets: the newly developed mesoSPIM dataset, a 3D platynereis-ISH-Nuclei confocal dataset, a separate 3D Platynereis-Nuclei light-sheet dataset, and a challenging and densely packed Mouse-Skull-Nuclei confocal dataset. We demonstrate that our self-supervised model, WNet3D – trained without any ground truth labels – achieves performance on par with state-of-the-art supervised methods, paving the way for broader applications in label-scarce biological contexts.
Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore,Il1r1-/-LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32°C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.
Group identification may influence collective behaviors and result in variations in collective performance. However, the evidence for this hypothesis and the neural mechanisms involved remain elusive. To this end, we conducted a study using both single-brain activation and multi-brain synchronization analyses to investigate how group identification influences collective problem-solving in a murder mystery case. Our results showed that groups with high levels of identification performed better individually compared to those with low identification, as supported by single-brain activation in the dorsolateral prefrontal cortex (DLPFC). Furthermore, high-identification groups also showed enhanced collective performance, supported by within-group neural synchronization in the orbitofrontal cortex (OFC). The DLPFC–OFC connectivity played a crucial role in linking individual and collective performance. Overall, our study provides a two-in-one neural model to explain how group identification affects collective decision-making processes, offering valuable insights into the dynamics of group interactions.
The attentional blink reflects a ubiquitous bottleneck with selecting and processing the second of two targets that occur in close temporal proximity. An extensive literature has examined the attention blink as a unitary phenomenon. As a result, which specific component of attention – perceptual sensitivity, choice bias, or both – is compromised during the attentional blink, and their respective neural bases, remains unknown. Here, we address this question with a multialternative task and novel signal detection model, which decouples sensitivity from bias effects. We find that the attentional blink impairs specifically one component of attention – sensitivity – while leaving the other component – bias – unaffected. Distinct neural markers of the attentional blink were mapped onto distinct subcomponents of the sensitivity deficits. Parieto-occipital N2p and P3 potential amplitudes characterized target detection deficits, whereas long-range high-beta band (20–30 Hz) coherence between frontoparietal electrodes signaled target discrimination deficits. We synthesized these results with representational geometry analysis. The analysis revealed that detection and discrimination deficits were encoded along separable neural dimensions, whose configural distances robustly correlated with the neural markers of each. Overall, these findings provide detailed insights into the subcomponents of the attentional blink and reveal dissociable neural bases underlying its detection and discrimination bottlenecks.
Understanding the complex three-dimensional structure of cells is crucial across many disciplines in biology and especially in neuroscience. Here, we introduce a set of models including a 3D transformer (SwinUNetR) and a novel 3D self-supervised learning method (WNet3D) designed to address the inherent complexity of generating 3D ground truth data and quantifying nuclei in 3D volumes. We developed a Python package called CellSeg3D that provides access to these models in Jupyter Notebooks and in a napari GUI plugin. Recognizing the scarcity of high-quality 3D ground truth data, we created a fully human-annotated mesoSPIM dataset to advance evaluation and benchmarking in the field. To assess model performance, we benchmarked our approach across four diverse datasets: the newly developed mesoSPIM dataset, a 3D platynereis-ISH-Nuclei confocal dataset, a separate 3D Platynereis-Nuclei light-sheet dataset, and a challenging and densely packed Mouse-Skull-Nuclei confocal dataset. We demonstrate that our self-supervised model, WNet3D – trained without any ground truth labels – achieves performance on par with state-of-the-art supervised methods, paving the way for broader applications in label-scarce biological contexts.
We explored neural mechanisms underlying sighing in mice. Photostimulation of parafacial (pF) neuromedin B (NMB) or gastrin-releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.
We explored neural mechanisms underlying sighing in mice. Photostimulation of parafacial (pF) neuromedin B (NMB) or gastrin-releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.
Chromosome segregation is essential for cellular proliferation. Unlike eukaryotes, bacteria lack cytoskeleton-based machinery to segregate their chromosomal DNA (nucleoid). The bacterial ParABS system segregates the duplicated chromosomal regions near the origin of replication. However, this function does not explain how bacterial cells partition the rest (bulk) of the chromosomal material. Furthermore, some bacteria, includingEscherichia coli, lack a ParABS system. Yet,E. colifaithfully segregates nucleoids across various growth rates. Here, we provide theoretical and experimental evidence that polysome production during chromosomal gene expression helps compact, split, segregate, and position nucleoids inE. colithrough nonequilibrium dynamics that depend on polysome synthesis, degradation (through mRNA decay), and exclusion from the DNA meshwork. These dynamics inherently couple chromosome segregation to biomass growth across nutritional conditions. Halting chromosomal gene expression and thus polysome production immediately stops sister nucleoid migration, while ensuing polysome depletion gradually reverses nucleoid segregation. Redirecting gene expression away from the chromosome and toward plasmids causes ectopic polysome accumulations that are sufficient to drive aberrant nucleoid dynamics. Cell width enlargement experiments suggest that limiting the exchange of polysomes across DNA-free regions ensures nucleoid segregation along the cell length. Our findings suggest a self-organizing mechanism for coupling nucleoid compaction and segregation to cell growth without the apparent requirement of regulatory molecules.
Chromosome segregation is essential for cellular proliferation. Unlike eukaryotes, bacteria lack cytoskeleton-based machinery to segregate their chromosomal DNA (nucleoid). The bacterial ParABS system segregates the duplicated chromosomal regions near the origin of replication. However, this function does not explain how bacterial cells partition the rest (bulk) of the chromosomal material. Furthermore, some bacteria, includingEscherichia coli, lack a ParABS system. Yet,E. colifaithfully segregates nucleoids across various growth rates. Here, we provide theoretical and experimental evidence that polysome production during chromosomal gene expression helps compact, split, segregate, and position nucleoids inE. colithrough nonequilibrium dynamics that depend on polysome synthesis, degradation (through mRNA decay), and exclusion from the DNA meshwork. These dynamics inherently couple chromosome segregation to biomass growth across nutritional conditions. Halting chromosomal gene expression and thus polysome production immediately stops sister nucleoid migration, while ensuing polysome depletion gradually reverses nucleoid segregation. Redirecting gene expression away from the chromosome and toward plasmids causes ectopic polysome accumulations that are sufficient to drive aberrant nucleoid dynamics. Cell width enlargement experiments suggest that limiting the exchange of polysomes across DNA-free regions ensures nucleoid segregation along the cell length. Our findings suggest a self-organizing mechanism for coupling nucleoid compaction and segregation to cell growth without the apparent requirement of regulatory molecules.
The risk for developing primary open-angle glaucoma (POAG) correlates with the magnitude of ocular hypertension (OHT) and the concentration of transforming growth factor-β2 (TGFβ2) in the aqueous humor. Effective treatment of POAG requires a detailed understanding of the interaction between pressure sensing mechanisms in the trabecular meshwork (TM) and biochemical risk factors. Here, we employed molecular, optical, electrophysiological, and tonometric strategies to establish the role of TGFβ2 in transcription and functional expression of mechanosensitive channel isoforms alongside studies of TM contractility in biomimetic hydrogels and intraocular pressure (IOP) regulation in a mouse model of TGFβ2-induced OHT. TGFβ2 upregulated expression ofTrpv4andPiezo1transcripts and time-dependently augmented functional TRPV4 activation. TRPV4 agonists induced contractility of TM-seeded hydrogels, whereas pharmacological inhibition suppressed TGFβ2-induced hypercontractility and abrogated OHT in eyes overexpressing TGFβ2.Trpv4-deficient mice resisted TGFβ2-driven increases in IOP, but nocturnal OHT was not additive to TGFβ-evoked OHT. Our study establishes the fundamental role of TGFβ as a modulator of mechanosensing in nonexcitable cells, identifies the TRPV4 channel as the final common mechanism for TM contractility and circadian and pathological OHT, and offers insights for future treatments that can lower IOP in the sizeable cohort of hypertensive glaucoma patients that resist current treatments.
In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism underlying the ULK complex assembly have yet to be fully clarified. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 engages the bases of the two UBL domains in the FIP200 dimer via two phenylalanines and also binds the tandem microtubule-interacting and transport domain of ULK1, thereby yielding the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13–FIP200 triadic interaction is crucial for autophagosome formation and provides a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.
In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism underlying the ULK complex assembly have yet to be fully clarified. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 engages the bases of the two UBL domains in the FIP200 dimer via two phenylalanines and also binds the tandem microtubule-interacting and transport domain of ULK1, thereby yielding the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13–FIP200 triadic interaction is crucial for autophagosome formation and provides a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.
Striatal cholinergic interneurons (SCINs) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors (D2Rs), though the underlying membrane currents remain unknown. Moreover, the role of D5 receptors (D5Rs) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCINs, followed by a pause mediated by the activation of a Kv1-dependent delayed rectifier current. Endogenous dopamine promotes this pause through D2R stimulation, while pharmacological stimulation of D5Rs suppresses it. Remarkably, this pause is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In contrast, the D2-type receptor agonists quinpirole and sumanirole failed to reinstate a pause in dyskinetic mice. In conclusion, stimulation of thalamic inputs induces excitation followed by a pause in SCINs, which is lost in parkinsonian mice that have been rendered dyskinetic. This pause is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinson’s disease.
Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore,Il1r1-/-LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32°C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.
Recent studies have provided evidence for the concurrent encoding of sensory percepts and visual working memory (VWM) contents across visual areas; however, it has remained unclear how these two types of representations are concurrently present. Here, we reanalyzed an open-access fMRI dataset where participants memorized a sensory stimulus while simultaneously being presented with sensory distractors. First, we found that the VWM code in several visual regions did not fully generalize between different time points, suggesting a dynamic code. A more detailed analysis revealed that this was due to shifts in coding spaces across time. Second, we collapsed neural signals across time to assess the degree of interference between VWM contents and sensory distractors, specifically by testing the alignment of their encoding spaces. We find that VWM and feature-matching sensory distractors are encoded in coding spaces that do not fully overlap, but the separation decreases when distractors negatively impact behavioral performance in recalling the target. Together, these results indicate a role of dynamic coding and temporally stable coding spaces in helping multiplex perception and VWM within visual areas.
The attentional blink reflects a ubiquitous bottleneck with selecting and processing the second of two targets that occur in close temporal proximity. An extensive literature has examined the attention blink as a unitary phenomenon. As a result, which specific component of attention – perceptual sensitivity, choice bias, or both – is compromised during the attentional blink, and their respective neural bases, remains unknown. Here, we address this question with a multialternative task and novel signal detection model, which decouples sensitivity from bias effects. We find that the attentional blink impairs specifically one component of attention – sensitivity – while leaving the other component – bias – unaffected. Distinct neural markers of the attentional blink were mapped onto distinct subcomponents of the sensitivity deficits. Parieto-occipital N2p and P3 potential amplitudes characterized target detection deficits, whereas long-range high-beta band (20–30 Hz) coherence between frontoparietal electrodes signaled target discrimination deficits. We synthesized these results with representational geometry analysis. The analysis revealed that detection and discrimination deficits were encoded along separable neural dimensions, whose configural distances robustly correlated with the neural markers of each. Overall, these findings provide detailed insights into the subcomponents of the attentional blink and reveal dissociable neural bases underlying its detection and discrimination bottlenecks.
Striatal cholinergic interneurons (SCINs) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors (D2Rs), though the underlying membrane currents remain unknown. Moreover, the role of D5 receptors (D5Rs) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCINs, followed by a pause mediated by the activation of a Kv1-dependent delayed rectifier current. Endogenous dopamine promotes this pause through D2R stimulation, while pharmacological stimulation of D5Rs suppresses it. Remarkably, this pause is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In contrast, the D2-type receptor agonists quinpirole and sumanirole failed to reinstate a pause in dyskinetic mice. In conclusion, stimulation of thalamic inputs induces excitation followed by a pause in SCINs, which is lost in parkinsonian mice that have been rendered dyskinetic. This pause is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinson’s disease.
Serial dependence describes the phenomenon that current object representations are attracted to previously encoded and reported representations. While attractive biases have been observed reliably in behavior, a direct neural correlate has not been established. Previous studies have either shown a reactivation of past information without observing a neural signal related to the bias of the current information, or a repulsive distortion of current neural representations contrasting the behavioral bias. The present study recorded neural signals with magnetoencephalography (MEG) during a working memory task to identify neural correlates of serial dependence. Participants encoded and memorized two sequentially presented motion directions per trial, one of which was later retro-cued for report. Multivariate analyses provided reliable reconstructions of both motion directions. Importantly, the reconstructed directions in the current trial were attractively shifted toward the target direction of the previous trial. This neural bias mirrored the behavioral attractive bias, thus reflecting a direct neural signature of serial dependence. The use of a retro-cue task in combination with MEG allowed us to determine that this neural bias emerged at later, post-encoding time points. This timing suggests that serial dependence in working memory affects memorized information during read-out and reactivation processes that happen after the initial encoding.
Sensorimotor computations for learning and behavior rely on precise patterns of synaptic connectivity. Yet, we typically lack the synaptic wiring diagrams for long-range connections between sensory and motor circuits in the brain. Here, we provide the synaptic wiring diagram for sensorimotor circuits involved in learning and production of male zebra finch song, a natural and ethologically relevant behavior. We examined the functional synaptic connectivity from the 4 main sensory afferent pathways onto the three known classes of projection neurons of the song premotor cortical region HVC. Recordings from hundreds of identified projection neurons reveal rules for monosynaptic connectivity and the existence of polysynaptic ensembles of excitatory and inhibitory neuronal populations in HVC. Circuit tracing further identifies novel connections between HVC’s presynaptic partners. Our results indicate a modular organization of ensemble-like networks for integrating long-range input with local circuits, providing important context for information flow and computations for learned vocal behavior.
Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell–cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
Serial dependence describes the phenomenon that current object representations are attracted to previously encoded and reported representations. While attractive biases have been observed reliably in behavior, a direct neural correlate has not been established. Previous studies have either shown a reactivation of past information without observing a neural signal related to the bias of the current information, or a repulsive distortion of current neural representations contrasting the behavioral bias. The present study recorded neural signals with magnetoencephalography (MEG) during a working memory task to identify neural correlates of serial dependence. Participants encoded and memorized two sequentially presented motion directions per trial, one of which was later retro-cued for report. Multivariate analyses provided reliable reconstructions of both motion directions. Importantly, the reconstructed directions in the current trial were attractively shifted toward the target direction of the previous trial. This neural bias mirrored the behavioral attractive bias, thus reflecting a direct neural signature of serial dependence. The use of a retro-cue task in combination with MEG allowed us to determine that this neural bias emerged at later, post-encoding time points. This timing suggests that serial dependence in working memory affects memorized information during read-out and reactivation processes that happen after the initial encoding.
Sensorimotor computations for learning and behavior rely on precise patterns of synaptic connectivity. Yet, we typically lack the synaptic wiring diagrams for long-range connections between sensory and motor circuits in the brain. Here, we provide the synaptic wiring diagram for sensorimotor circuits involved in learning and production of male zebra finch song, a natural and ethologically relevant behavior. We examined the functional synaptic connectivity from the 4 main sensory afferent pathways onto the three known classes of projection neurons of the song premotor cortical region HVC. Recordings from hundreds of identified projection neurons reveal rules for monosynaptic connectivity and the existence of polysynaptic ensembles of excitatory and inhibitory neuronal populations in HVC. Circuit tracing further identifies novel connections between HVC’s presynaptic partners. Our results indicate a modular organization of ensemble-like networks for integrating long-range input with local circuits, providing important context for information flow and computations for learned vocal behavior.
Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell–cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
Cognitive control tasks require using one class of information while ignoring competing classes of information. The central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cognitive control, as inferred, typically from the task design. In prior work, we used an active place avoidance task where a rat or mouse on a rotating arena is required to avoid the stationary task-relevant locations of a mild shock and ignore the rotating task-irrelevant locations of those shocks. The task is impaired by hippocampal manipulations, and the discharge of hippocampal place cell populations judiciously alternates between representing stationary locations near the shock zone and rotating locations far from the shock zone, demonstrating cognitive control concurrently in behavior and the hippocampal representation of spatial information. Here, we test whether rat mPFC lesion impairs the active place avoidance task to evaluate two competing hypotheses, a ‘central-computation’ hypothesis that the mPFC is essential for the computations required for cognitive control and an alternative ‘local-computation’ hypothesis that other brain areas can perform the computations required for cognitive control, independent of mPFC. Ibotenic acid lesion of the mPFC was effective, damaging the cingulate, prelimbic, and infralimbic cortices. The lesion also altered the normal coordination of metabolic activity across remaining structures. The lesion did not impair learning to avoid the initial location of shock or long-term place avoidance memory, but impaired avoidance after the shock was relocated. The lesion also did not impair the alternation between task-relevant and task-irrelevant hippocampal representations of place information. These findings support the local-computation hypothesis that computations required for cognitive control can occur locally in brain networks independently of the mPFC.
Understanding neural activity organization is vital for deciphering brain function. By recording whole-brain calcium activity in larval zebrafish during hunting and spontaneous behaviors, we find that the shape of the neural activity space, described by the neural covariance spectrum, is scale-invariant: a smaller,randomly sampledcell assembly resembles the entire brain. This phenomenon can be explained by Euclidean Random Matrix theory, where neurons are reorganized from anatomical to functional positions based on their correlations. Three factors contribute to the observed scale invariance: slow neural correlation decay, higher functional space dimension, and neural activity heterogeneity. In addition to matching data from zebrafish and mice, our theory and analysis demonstrate how the geometry of neural activity space evolves with population sizes and sampling methods, thus revealing an organizing principle of brain-wide activity.
Cognitive control tasks require using one class of information while ignoring competing classes of information. The central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cognitive control, as inferred, typically from the task design. In prior work, we used an active place avoidance task where a rat or mouse on a rotating arena is required to avoid the stationary task-relevant locations of a mild shock and ignore the rotating task-irrelevant locations of those shocks. The task is impaired by hippocampal manipulations, and the discharge of hippocampal place cell populations judiciously alternates between representing stationary locations near the shock zone and rotating locations far from the shock zone, demonstrating cognitive control concurrently in behavior and the hippocampal representation of spatial information. Here, we test whether rat mPFC lesion impairs the active place avoidance task to evaluate two competing hypotheses, a ‘central-computation’ hypothesis that the mPFC is essential for the computations required for cognitive control and an alternative ‘local-computation’ hypothesis that other brain areas can perform the computations required for cognitive control, independent of mPFC. Ibotenic acid lesion of the mPFC was effective, damaging the cingulate, prelimbic, and infralimbic cortices. The lesion also altered the normal coordination of metabolic activity across remaining structures. The lesion did not impair learning to avoid the initial location of shock or long-term place avoidance memory, but impaired avoidance after the shock was relocated. The lesion also did not impair the alternation between task-relevant and task-irrelevant hippocampal representations of place information. These findings support the local-computation hypothesis that computations required for cognitive control can occur locally in brain networks independently of the mPFC.
Phosphoprotein phosphatase 1 (PP1) relies on association with PP1-interacting proteins (PIPs) to generate substrate-specific PIP/PP1 holoenzymes, but the lack of well-defined substrates has hindered elucidation of the mechanisms involved. We previously demonstrated that the Phactr1 PIP confers sequence specificity on the Phactr1/PP1 holoenzyme by remodelling the PP1 hydrophobic substrate groove. Phactr1 defines a group of ‘RVxF-ΦΦ-R-W’ PIPs that all interact with PP1 in a similar fashion. Here, we use a PP1-PIP fusion approach to address sequence specificity and identify substrates of the RVxF-ΦΦ-R-W family PIPs. We show that the four Phactr proteins confer identical sequence specificities on their holoenzymes. We identify the 4E-BP and p70 S6K translational regulators as substrates for the Neurabin/Spinophilin PIPs, implicated in neuronal plasticity, pointing to a role for their holoenzymes in mTORC1-dependent translational control. Biochemical and structural experiments show that in contrast to the Phactrs, substrate recruitment and catalytic efficiency of the PP1-Neurabin and PP1-Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining their RVxF-ΦΦ-R-W motifs, rather than by recognition of the remodelled PP1 hydrophobic groove. Thus, even PIPs that interact with PP1 in a similar manner use different mechanisms to ensure substrate selectivity.
Phosphoprotein phosphatase 1 (PP1) relies on association with PP1-interacting proteins (PIPs) to generate substrate-specific PIP/PP1 holoenzymes, but the lack of well-defined substrates has hindered elucidation of the mechanisms involved. We previously demonstrated that the Phactr1 PIP confers sequence specificity on the Phactr1/PP1 holoenzyme by remodelling the PP1 hydrophobic substrate groove. Phactr1 defines a group of ‘RVxF-ΦΦ-R-W’ PIPs that all interact with PP1 in a similar fashion. Here, we use a PP1-PIP fusion approach to address sequence specificity and identify substrates of the RVxF-ΦΦ-R-W family PIPs. We show that the four Phactr proteins confer identical sequence specificities on their holoenzymes. We identify the 4E-BP and p70 S6K translational regulators as substrates for the Neurabin/Spinophilin PIPs, implicated in neuronal plasticity, pointing to a role for their holoenzymes in mTORC1-dependent translational control. Biochemical and structural experiments show that in contrast to the Phactrs, substrate recruitment and catalytic efficiency of the PP1-Neurabin and PP1-Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining their RVxF-ΦΦ-R-W motifs, rather than by recognition of the remodelled PP1 hydrophobic groove. Thus, even PIPs that interact with PP1 in a similar manner use different mechanisms to ensure substrate selectivity.
Understanding neural activity organization is vital for deciphering brain function. By recording whole-brain calcium activity in larval zebrafish during hunting and spontaneous behaviors, we find that the shape of the neural activity space, described by the neural covariance spectrum, is scale-invariant: a smaller,randomly sampledcell assembly resembles the entire brain. This phenomenon can be explained by Euclidean Random Matrix theory, where neurons are reorganized from anatomical to functional positions based on their correlations. Three factors contribute to the observed scale invariance: slow neural correlation decay, higher functional space dimension, and neural activity heterogeneity. In addition to matching data from zebrafish and mice, our theory and analysis demonstrate how the geometry of neural activity space evolves with population sizes and sampling methods, thus revealing an organizing principle of brain-wide activity.
Streptococcus suis(S. suis) is an important zoonotic pathogen causing substantial economic losses in the swine industry.S. suisserotype 2 (SS2) is often isolated from the diseased.S. suisexpresses capsular polysaccharide (CPS), a virulence factor crucial for their survival in the blood. However, the role of CPS in the pathogenesis ofS. suisis incomplete. Here, we showed that thin CPS or no CPS was associated with efficient binding of an SS2 strain, 05ZYH33, to respiratory epithelial cells, while thick CPS increased resistance of 05ZYH33 to blood clearance. In a mouse infection model, 05ZYH33 was detected in the nasal-associated lymphoid tissue (NALT) and cerebrospinal fluid (CSF) as early as 30 min after intranasal inoculation without bacteremia. Histological analysis revealed that 05ZYH33 in the nasal cavity invaded the olfactory epithelium, resulting in early brain inflammation. Transmission electron microscopy showed that 05ZYH33 isolated from NALT and CSF at early infection time had a thin layer of CPS, and those detected in the blood 5 hr post-inoculation showed a much thicker CPS. In addition, adoptive transfer of anti-CPS restricted 05ZYH33 in the blood but not in NALT or CSF. However, an antiserum directed to multiple non-CPS virulence factors (anti-V5) efficiently inhibited 05ZYH33 in NALT, CSF, and blood. Thus, 05ZYH33 colonizes NALT more efficiently without CPS and subsequently invades the meninges through the olfactory nerve system. These findings provide valuable information for the treatment ofS. suisinfection and the development of vaccines across serotypes ofS. suisby targeting CPS-independent immunity.
Streptococcus suis(S. suis) is an important zoonotic pathogen causing substantial economic losses in the swine industry.S. suisserotype 2 (SS2) is often isolated from the diseased.S. suisexpresses capsular polysaccharide (CPS), a virulence factor crucial for their survival in the blood. However, the role of CPS in the pathogenesis ofS. suisis incomplete. Here, we showed that thin CPS or no CPS was associated with efficient binding of an SS2 strain, 05ZYH33, to respiratory epithelial cells, while thick CPS increased resistance of 05ZYH33 to blood clearance. In a mouse infection model, 05ZYH33 was detected in the nasal-associated lymphoid tissue (NALT) and cerebrospinal fluid (CSF) as early as 30 min after intranasal inoculation without bacteremia. Histological analysis revealed that 05ZYH33 in the nasal cavity invaded the olfactory epithelium, resulting in early brain inflammation. Transmission electron microscopy showed that 05ZYH33 isolated from NALT and CSF at early infection time had a thin layer of CPS, and those detected in the blood 5 hr post-inoculation showed a much thicker CPS. In addition, adoptive transfer of anti-CPS restricted 05ZYH33 in the blood but not in NALT or CSF. However, an antiserum directed to multiple non-CPS virulence factors (anti-V5) efficiently inhibited 05ZYH33 in NALT, CSF, and blood. Thus, 05ZYH33 colonizes NALT more efficiently without CPS and subsequently invades the meninges through the olfactory nerve system. These findings provide valuable information for the treatment ofS. suisinfection and the development of vaccines across serotypes ofS. suisby targeting CPS-independent immunity.
Human Immunodeficiency Virus type 1 (HIV-1) RNA genome organization remains a critical knowledge gap in understanding its replication cycle. To address this, we developed HiCapR, a psoralen crosslinking-based RNA proximity ligation method coupled with post-library hybridization, enabling high-resolution mapping of RNA-RNA interactions across the HIV-1 genome. This approach confirmed canonical structural motifs, including stem-loop architectures in the 5’-untranslated region (5’-UTR) and Rev Response Element (RRE), as well as dimerization sites within the 5’-UTR critical for viral packaging. Notably, HiCapR identified novel homodimerization events distributed along the genome, suggesting an expanded regulatory role of RNA multimerization in splicing regulation and selective encapsidation. Intriguingly, while infected cells exhibited extensive long-range RNA interactions—particularly within the 5’-UTR—virion-packaged genomes displayed a marked reduction in such interactions, indicative of a structural transition from a loosely organized state to a condensed conformation. This spatial reorganization coincided with the preservation of stable genomic domains essential for dimerization, which persisted throughout virion assembly. These domains, enriched at homodimer interfaces, likely serve as structural scaffolds ensuring fidelity during genome packaging. This work establishes HiCapR as a robust tool for probing RNA interactomes and provides mechanistic insights into how HIV-1 exploits RNA topological heterogeneity to regulate its life cycle. The identification of conserved structural domains and transient interaction networks opens avenues for targeting RNA conformation in antiviral strategies.
Perceptual updating has been hypothesised to rely on a network reset modulated by bursts of ascending neuromodulatory neurotransmitters, such as noradrenaline, abruptly altering the brain’s susceptibility to changing sensory activity. To test this hypothesis at a large-scale, we analysed an ambiguous figures task using pupillometry and functional magnetic resonance imaging (fMRI). Behaviourally, qualitative shifts in the perceptual interpretation of an ambiguous image were associated with peaks in pupil diameter, an indirect readout of phasic bursts in neuromodulatory tone. We further hypothesised that stimulus ambiguity drives neuromodulatory tone, leading to heightened neural gain, hastening perceptual switches. To explore this hypothesis computationally, we trained a recurrent neural network (RNN) on an analogous perceptual categorisation task, allowing gain to change dynamically with classification uncertainty. As predicted, higher gain accelerated perceptual switching by transiently destabilising the network’s dynamical regime in periods of maximal uncertainty. We leveraged a low-dimensional readout of the RNN dynamics to develop two novel macroscale predictions: perceptual switches should occur with peaks in low-dimensional brain state velocity and with a flattened egocentric energy landscape. Using fMRI, we confirmed these predictions, highlighting the role of the neuromodulatory system in the large-scale network reconfigurations mediating adaptive perceptual updates.
Human Immunodeficiency Virus type 1 (HIV-1) RNA genome organization remains a critical knowledge gap in understanding its replication cycle. To address this, we developed HiCapR, a psoralen crosslinking-based RNA proximity ligation method coupled with post-library hybridization, enabling high-resolution mapping of RNA-RNA interactions across the HIV-1 genome. This approach confirmed canonical structural motifs, including stem-loop architectures in the 5’-untranslated region (5’-UTR) and Rev Response Element (RRE), as well as dimerization sites within the 5’-UTR critical for viral packaging. Notably, HiCapR identified novel homodimerization events distributed along the genome, suggesting an expanded regulatory role of RNA multimerization in splicing regulation and selective encapsidation. Intriguingly, while infected cells exhibited extensive long-range RNA interactions—particularly within the 5’-UTR—virion-packaged genomes displayed a marked reduction in such interactions, indicative of a structural transition from a loosely organized state to a condensed conformation. This spatial reorganization coincided with the preservation of stable genomic domains essential for dimerization, which persisted throughout virion assembly. These domains, enriched at homodimer interfaces, likely serve as structural scaffolds ensuring fidelity during genome packaging. This work establishes HiCapR as a robust tool for probing RNA interactomes and provides mechanistic insights into how HIV-1 exploits RNA topological heterogeneity to regulate its life cycle. The identification of conserved structural domains and transient interaction networks opens avenues for targeting RNA conformation in antiviral strategies.
Perceptual updating has been hypothesised to rely on a network reset modulated by bursts of ascending neuromodulatory neurotransmitters, such as noradrenaline, abruptly altering the brain’s susceptibility to changing sensory activity. To test this hypothesis at a large-scale, we analysed an ambiguous figures task using pupillometry and functional magnetic resonance imaging (fMRI). Behaviourally, qualitative shifts in the perceptual interpretation of an ambiguous image were associated with peaks in pupil diameter, an indirect readout of phasic bursts in neuromodulatory tone. We further hypothesised that stimulus ambiguity drives neuromodulatory tone, leading to heightened neural gain, hastening perceptual switches. To explore this hypothesis computationally, we trained a recurrent neural network (RNN) on an analogous perceptual categorisation task, allowing gain to change dynamically with classification uncertainty. As predicted, higher gain accelerated perceptual switching by transiently destabilising the network’s dynamical regime in periods of maximal uncertainty. We leveraged a low-dimensional readout of the RNN dynamics to develop two novel macroscale predictions: perceptual switches should occur with peaks in low-dimensional brain state velocity and with a flattened egocentric energy landscape. Using fMRI, we confirmed these predictions, highlighting the role of the neuromodulatory system in the large-scale network reconfigurations mediating adaptive perceptual updates.
Babesiosis is a disease brought on by intraerythrocytic parasites of the genusBabesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs againstBabesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyPlasmodiumandToxoplasma. This study evaluated the growth-inhibiting properties of CIP againstBabesiaspp. and investigated the mechanism of CIP onB. gibsoni. The half inhibitory concentration (IC50) values of CIP against the in vitro growth ofB. bovisandB. gibsoniwere 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofB. microtiandB. rodhainiin vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4L921Vand BgATP4L921I, respectively, compared to that of BgATP4WT. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4L921Vand BgATP4L921Icompared to BgATP4WT. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC50values. Combining CIP with TQ effectively eliminatedB. microtiinfection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.
Salmonellais a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections.Salmonellamust utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellularSalmonellagrowth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical forSalmonellareplication inside macrophages. The concentration of β-alanine is decreased inSalmonella-infected macrophages, while the addition of exogenous β-alanine enhancesSalmonellareplication in macrophages, suggesting thatSalmonellacan uptake host-derived β-alanine for intracellular growth. Moreover, the expression ofpanD,the rate-limiting gene required for β-alanine synthesis inSalmonella,is upregulated whenSalmonellaenters macrophages. Mutation ofpanDimpairedSalmonellareplication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellularSalmonellagrowth and systemic infection. Additionally, we revealed that β-alanine influencesSalmonellaintracellular replication and in vivo virulence partially by increasing expression of the zinc transporter genesznuABC, which in turn facilitates the uptake of the essential micronutrient zinc bySalmonella. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence ofSalmonella, andpanDis a promising target for controlling systemicSalmonellainfection.
Salmonellais a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections.Salmonellamust utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellularSalmonellagrowth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical forSalmonellareplication inside macrophages. The concentration of β-alanine is decreased inSalmonella-infected macrophages, while the addition of exogenous β-alanine enhancesSalmonellareplication in macrophages, suggesting thatSalmonellacan uptake host-derived β-alanine for intracellular growth. Moreover, the expression ofpanD,the rate-limiting gene required for β-alanine synthesis inSalmonella,is upregulated whenSalmonellaenters macrophages. Mutation ofpanDimpairedSalmonellareplication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellularSalmonellagrowth and systemic infection. Additionally, we revealed that β-alanine influencesSalmonellaintracellular replication and in vivo virulence partially by increasing expression of the zinc transporter genesznuABC, which in turn facilitates the uptake of the essential micronutrient zinc bySalmonella. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence ofSalmonella, andpanDis a promising target for controlling systemicSalmonellainfection.
Babesiosis is a disease brought on by intraerythrocytic parasites of the genusBabesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs againstBabesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyPlasmodiumandToxoplasma. This study evaluated the growth-inhibiting properties of CIP againstBabesiaspp. and investigated the mechanism of CIP onB. gibsoni. The half inhibitory concentration (IC50) values of CIP against the in vitro growth ofB. bovisandB. gibsoniwere 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofB. microtiandB. rodhainiin vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4L921Vand BgATP4L921I, respectively, compared to that of BgATP4WT. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4L921Vand BgATP4L921Icompared to BgATP4WT. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC50values. Combining CIP with TQ effectively eliminatedB. microtiinfection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.
Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher- and lower-level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA receptors and recurrent processing in humans has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively improved decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings suggest that NMDA inhibition through memantine enhances recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.
Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher- and lower-level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA receptors and recurrent processing in humans has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively improved decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings suggest that NMDA inhibition through memantine enhances recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.
In mammals, olfactory sensory neurons (OSNs) are born throughout life, ostensibly solely to replace neurons lostviaturnover or injury. This assumption follows from the hypothesis that olfactory neurogenesis is stochastic with respect to neuron subtype, as defined by the single odorant receptor that each neural precursor stochastically chooses out of hundreds of possibilities. This assumption is challenged, however, by recent findings that the birthrates of a fraction of OSN subtypes are selectively reduced by olfactory deprivation. These findings raise questions about how, and why, olfactory stimuli are required to accelerate the neurogenesis rates of some subtypes, including whether the stimuli are specific (e.g. discrete odorants) or generic (e.g. broadly activating odors or mechanical stimuli). Based on previous findings that the exposure of mice to sex-specific odors can increase the representations of subtypes responsive to those odors, we hypothesized that the neurogenic stimuli comprise discrete odorants that selectively stimulate OSNs of the same subtypes whose birthrates are accelerated. In support of this, we have found, using scRNA-seq and subtype-specific OSN birthdating, that exposure to male and exogenous musk odors can accelerate the birthrates of subtypes responsive to those odors. These findings reveal that certain odor experiences can selectively ‘amplify’ specific OSN subtypes and suggest that persistent OSN neurogenesis serves, in part, an adaptive function.
Radiotherapy resistance in nasopharyngeal carcinoma (NPC) is a major cause of recurrence and metastasis. Identifying radiotherapy-related biomarkers is crucial for improving patient survival outcomes. This study developed the nasopharyngeal carcinoma radiotherapy sensitivity score (NPC-RSS) to predict radiotherapy response. By evaluating 113 machine learning algorithm combinations, the glmBoost+NaiveBayes model was selected to construct the NPC-RSS based on 18 key genes, which demonstrated good predictive performance in both public and in-house datasets. The study found that NPC-RSS is closely associated with immune features, including chemokine factors and their receptor families and the major histocompatibility complex (MHC). Gene functional analysis revealed that NPC-RSS influences key signaling pathways such as Wnt/β-catenin, JAK-STAT, NF-κB, and T cell receptors. Cell line validation confirmed that SMARCA2 and CD9 gene expression is consistent with NPC-RSS. Single-cell analysis revealed that the radiotherapy-sensitive group exhibited richer immune infiltration and activation states. NPC-RSS can serve as a predictive tool for radiotherapy sensitivity in NPC, offering new insights for precise screening of patients who may benefit from radiotherapy.
Larvae of the ascidianCionainitiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowingCionato maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator ofCionametamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation.
In the past, immune memory was considered an exclusive feature of the adaptive immune system. However, accumulating evidence suggests that the innate immune system, the most primitive and fundamental component of immunity, can mount more robust responses to non-specific stimuli following prior exposure to different types of initial stimuli, a phenomenon known as trained immunity. Trained immunity has been extensively studied in diverse disease contexts, including infectious diseases, autoimmune disorders, and chronic inflammatory conditions. Notably, significant advancements have been made in recent years in understanding the roles and therapeutic potential of trained immunity in oncology. This review aims to explore the multifaceted roles of trained immunity across different cancer types, providing a comprehensive summary of the pertinent stimuli and associated molecular mechanisms. Additionally, we evaluate the clinical applications of various trained immunity stimuli in cancer therapy and offer perspectives on future directions for integrating trained immunity into cancer treatment strategies.
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Radiotherapy resistance in nasopharyngeal carcinoma (NPC) is a major cause of recurrence and metastasis. Identifying radiotherapy-related biomarkers is crucial for improving patient survival outcomes. This study developed the nasopharyngeal carcinoma radiotherapy sensitivity score (NPC-RSS) to predict radiotherapy response. By evaluating 113 machine learning algorithm combinations, the glmBoost+NaiveBayes model was selected to construct the NPC-RSS based on 18 key genes, which demonstrated good predictive performance in both public and in-house datasets. The study found that NPC-RSS is closely associated with immune features, including chemokine factors and their receptor families and the major histocompatibility complex (MHC). Gene functional analysis revealed that NPC-RSS influences key signaling pathways such as Wnt/β-catenin, JAK-STAT, NF-κB, and T cell receptors. Cell line validation confirmed that SMARCA2 and CD9 gene expression is consistent with NPC-RSS. Single-cell analysis revealed that the radiotherapy-sensitive group exhibited richer immune infiltration and activation states. NPC-RSS can serve as a predictive tool for radiotherapy sensitivity in NPC, offering new insights for precise screening of patients who may benefit from radiotherapy.
In mammals, olfactory sensory neurons (OSNs) are born throughout life, ostensibly solely to replace neurons lostviaturnover or injury. This assumption follows from the hypothesis that olfactory neurogenesis is stochastic with respect to neuron subtype, as defined by the single odorant receptor that each neural precursor stochastically chooses out of hundreds of possibilities. This assumption is challenged, however, by recent findings that the birthrates of a fraction of OSN subtypes are selectively reduced by olfactory deprivation. These findings raise questions about how, and why, olfactory stimuli are required to accelerate the neurogenesis rates of some subtypes, including whether the stimuli are specific (e.g. discrete odorants) or generic (e.g. broadly activating odors or mechanical stimuli). Based on previous findings that the exposure of mice to sex-specific odors can increase the representations of subtypes responsive to those odors, we hypothesized that the neurogenic stimuli comprise discrete odorants that selectively stimulate OSNs of the same subtypes whose birthrates are accelerated. In support of this, we have found, using scRNA-seq and subtype-specific OSN birthdating, that exposure to male and exogenous musk odors can accelerate the birthrates of subtypes responsive to those odors. These findings reveal that certain odor experiences can selectively ‘amplify’ specific OSN subtypes and suggest that persistent OSN neurogenesis serves, in part, an adaptive function.
Larvae of the ascidianCionainitiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowingCionato maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator ofCionametamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation.
Experiments with tools designed to detect DNA damage reveal unique and conserved features of telomeres in cancer cells.
Heterotopic ossification (HO) occurs following mechanical trauma and burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidylinositol 3-kinase alpha (PI3Kα) may be a useful therapy for patients undergoing HO. In this study, using the already marketed BYL719/Alpelisib/Piqray drug, we have further confirmed these results, detailed the underlying mechanisms of action, and optimized the timing of the administration of BYL719. We found that BYL719 effectively prevents HO even when administered up to 3–7 days after injury. We demonstrate in cell cultures and in a mouse model of HO that the major actions of BYL719 are on-target effects through the inhibition of PI3Kα, without directly affecting ACVR1 or FOP-inducing ACVR1R206Hkinase activities. In vivo, we found that a lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification but also reduces the inflammatory response. BYL719 inhibits the migration, proliferation, and expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specificPhosphatase and tensin homologconditional knockout (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway inPten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-outCtnnb1, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.
Contextual fear conditioning (CFC) is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. Few paradigms examine contextual fear in head-fixed mice, and none use freezing—the most common measure of fear in freely moving animals—as the behavioral readout. To address this gap, we developed a CFC paradigm for head-fixed mice using virtual reality (VR). We designed an apparatus to deliver tail shocks while mice navigated a VR environment. We tested three versions of this paradigm and, in all of them, observed increased freezing, particularly on the first trial, in the shock-paired VR compared to a neutral one. These results demonstrate that head-fixed mice can be fear-conditioned in VR and exhibit context-specific freezing behavior. Additionally, using two-photon calcium imaging, we tracked large populations of hippocampal CA1 neurons before, during, and following CFC. As in freely moving mice, CA1 place cells remapped and developed narrower fields following fear conditioning. Thus, our approach enables new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories.
Most of the human gastric cancer (GC) worldwide are ascribed toHelicobacter pyloriinfections, which have a detrimental effect on the immunotherapy’s efficacy. Comprehensively dissecting the key cell players and molecular pathways associated with cancer immunotherapies is critical for developing novel therapeutic strategies againstH. pyloriinfection-associated human GC. We performed a comprehensive single-cell transcriptome analysis of nine GC patients with currentH. pyloriinfection (HpGC), three GC patients with previousH. pyloriinfection (ex-HpGC), six GC patients withoutH. pyloriinfection (non-HpGC), and six healthy controls (HC). We also investigated key cell players and molecular pathways associated with GC immunotherapy outcomes. We revealed the molecular heterogeneity of different cell components in GC, including epithelium, immune cells, and cancer-associated fibroblasts (CAFs) at the single-cell level. The malignant epithelium of HpGC exhibited high expression level of inflammatory and epithelial–mesenchymal transition signature, HpGC and ex-HpGC were enriched with VEGFA+ angiogenic tumor-associated macrophages (Angio-TAM) and IL11+ inflammatory CAF (iCAF), characterized by high expression levels of NECTIN2 and VEGFA/B. Additionally, we found significant correlations between the abundance of iCAF with Angio-TAM and TIGIT+ suppressive T cells, and iCAF interacted with Angio-TAM through the VEGF and ANGPTL angiogenic pathways. We also developed an immune signature and angiogenic signature and demonstrated that the iCAF abundance and angiogenic signature could predict poor immunotherapy outcomes in GC. We revealed the transcriptome characteristics and heterogeneity of various cellular constituents of HpGC patients and demonstrated that a synergistic combination of immunotherapy and anti-angiogenic targeted therapy may be an effective therapeutic modality for HpGC patients.
The nervous system undergoes functional modification independent of cell turnover. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins ofDrosophilaexecutioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near the plasma membrane. We demonstrated thatFas3Goverexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically,Fas3Goverexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly restricted caspase activation, defined by caspase-proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase-proximal proteins.
The nervous system undergoes functional modification independent of cell turnover. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins ofDrosophilaexecutioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near the plasma membrane. We demonstrated thatFas3Goverexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically,Fas3Goverexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly restricted caspase activation, defined by caspase-proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase-proximal proteins.
Contextual fear conditioning (CFC) is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. Few paradigms examine contextual fear in head-fixed mice, and none use freezing—the most common measure of fear in freely moving animals—as the behavioral readout. To address this gap, we developed a CFC paradigm for head-fixed mice using virtual reality (VR). We designed an apparatus to deliver tail shocks while mice navigated a VR environment. We tested three versions of this paradigm and, in all of them, observed increased freezing, particularly on the first trial, in the shock-paired VR compared to a neutral one. These results demonstrate that head-fixed mice can be fear-conditioned in VR and exhibit context-specific freezing behavior. Additionally, using two-photon calcium imaging, we tracked large populations of hippocampal CA1 neurons before, during, and following CFC. As in freely moving mice, CA1 place cells remapped and developed narrower fields following fear conditioning. Thus, our approach enables new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories.
Most of the human gastric cancer (GC) worldwide are ascribed toHelicobacter pyloriinfections, which have a detrimental effect on the immunotherapy’s efficacy. Comprehensively dissecting the key cell players and molecular pathways associated with cancer immunotherapies is critical for developing novel therapeutic strategies againstH. pyloriinfection-associated human GC. We performed a comprehensive single-cell transcriptome analysis of nine GC patients with currentH. pyloriinfection (HpGC), three GC patients with previousH. pyloriinfection (ex-HpGC), six GC patients withoutH. pyloriinfection (non-HpGC), and six healthy controls (HC). We also investigated key cell players and molecular pathways associated with GC immunotherapy outcomes. We revealed the molecular heterogeneity of different cell components in GC, including epithelium, immune cells, and cancer-associated fibroblasts (CAFs) at the single-cell level. The malignant epithelium of HpGC exhibited high expression level of inflammatory and epithelial–mesenchymal transition signature, HpGC and ex-HpGC were enriched with VEGFA+ angiogenic tumor-associated macrophages (Angio-TAM) and IL11+ inflammatory CAF (iCAF), characterized by high expression levels of NECTIN2 and VEGFA/B. Additionally, we found significant correlations between the abundance of iCAF with Angio-TAM and TIGIT+ suppressive T cells, and iCAF interacted with Angio-TAM through the VEGF and ANGPTL angiogenic pathways. We also developed an immune signature and angiogenic signature and demonstrated that the iCAF abundance and angiogenic signature could predict poor immunotherapy outcomes in GC. We revealed the transcriptome characteristics and heterogeneity of various cellular constituents of HpGC patients and demonstrated that a synergistic combination of immunotherapy and anti-angiogenic targeted therapy may be an effective therapeutic modality for HpGC patients.
Heterotopic ossification (HO) occurs following mechanical trauma and burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidylinositol 3-kinase alpha (PI3Kα) may be a useful therapy for patients undergoing HO. In this study, using the already marketed BYL719/Alpelisib/Piqray drug, we have further confirmed these results, detailed the underlying mechanisms of action, and optimized the timing of the administration of BYL719. We found that BYL719 effectively prevents HO even when administered up to 3–7 days after injury. We demonstrate in cell cultures and in a mouse model of HO that the major actions of BYL719 are on-target effects through the inhibition of PI3Kα, without directly affecting ACVR1 or FOP-inducing ACVR1R206Hkinase activities. In vivo, we found that a lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification but also reduces the inflammatory response. BYL719 inhibits the migration, proliferation, and expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specificPhosphatase and tensin homologconditional knockout (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway inPten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-outCtnnb1, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.
Dopaminergic neurons (DANs) play key roles in processing rewards and punishments across species. They evaluate sensory input, store memories, and update them based on relevance. To understand how individual DANs contribute to these functions, we studiedDrosophilalarvae, which have only about 120 DANs. Only eight of these project to the mushroom body (MB), a center for olfactory learning. These eight are divided into the pPAM and DL1 clusters, with four DANs each. We confirmed that pPAM neurons in the MB medial lobe encode sugar rewards. In the DL1 cluster, four neurons—DAN-c1, DAN-d1, DAN-f1, and DAN-g1—each target different MB regions. Notably, optogenetic activation of DAN-f1 and DAN-g1 can substitute for punishment. Additional methods (inhibition, calcium imaging, connectomics) show each DL1 DAN encodes a unique aspect of punishment, with DAN-g1 being pivotal for salt-based signals. Our findings reveal a clear division of labor among larval DL1 DANs for encoding punishment. The striking resemblance in the organizing principle of larval DANs with that of its adult counterpart and the mammalian basal ganglion suggests that there may be a limited number of efficient neural circuit solutions available to address more complex cognitive challenges in nature.
Dopaminergic neurons (DANs) play key roles in processing rewards and punishments across species. They evaluate sensory input, store memories, and update them based on relevance. To understand how individual DANs contribute to these functions, we studiedDrosophilalarvae, which have only about 120 DANs. Only eight of these project to the mushroom body (MB), a center for olfactory learning. These eight are divided into the pPAM and DL1 clusters, with four DANs each. We confirmed that pPAM neurons in the MB medial lobe encode sugar rewards. In the DL1 cluster, four neurons—DAN-c1, DAN-d1, DAN-f1, and DAN-g1—each target different MB regions. Notably, optogenetic activation of DAN-f1 and DAN-g1 can substitute for punishment. Additional methods (inhibition, calcium imaging, connectomics) show each DL1 DAN encodes a unique aspect of punishment, with DAN-g1 being pivotal for salt-based signals. Our findings reveal a clear division of labor among larval DL1 DANs for encoding punishment. The striking resemblance in the organizing principle of larval DANs with that of its adult counterpart and the mammalian basal ganglion suggests that there may be a limited number of efficient neural circuit solutions available to address more complex cognitive challenges in nature.
The brain is thought to construct an optimal internal model representing the probabilistic structure of the environment accurately. Evidence suggests that spontaneous brain activity gives such a model by cycling through activity patterns evoked by previous sensory experiences with the experienced probabilities. The brain’s spontaneous activity emerges from internally driven neural population dynamics. However, how cortical neural networks encode internal models into spontaneous activity is poorly understood. Recent computational and experimental studies suggest that a cortical neuron can implement complex computations, including predictive responses, through soma–dendrite interactions. Here, we show that a recurrent network of spiking neurons subject to the same predictive learning principle provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. In this network, the learning rules minimize probability mismatches between stimulus-evoked and internally driven activities in all excitatory and inhibitory neurons. This learning paradigm generates stimulus-specific cell assemblies that internally remember their activation probabilities using within-assembly recurrent connections. Our model contrasts previous models that encode the statistical structure of sensory experiences into Markovian transition patterns among cell assemblies. We demonstrate that the spontaneous activity of our model well replicates the behavioral biases of monkeys performing perceptual decision making. Our results suggest that interactions between intracellular processes and recurrent network dynamics are more crucial for learning cognitive behaviors than previously thought.
Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening.
Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus respond to multiple metabolic signals and distribute neuroendocrine information to other brain regions such as the paraventricular hypothalamic nucleus (PVH), which plays a central role in metabolic homeostasis. Neural projections from AgRP neurons to the PVH form during the postnatal lactational period in mice and these projections are reduced in offspring of dams that consumed a high-fat diet (HFD) during lactation (MHFD-L). Here, we used immunohistochemistry to visualize microglial morphology in MHFD-L offspring and identified changes that were regionally localized to the PVH and appeared temporally restricted to the period when AgRP neurons innervate this region. In addition, axon labeling experiments revealed that microglia engulf AgRP terminals in the PVH, and that the density of AgRP innervation to the PVH in MHFD-L offspring may be dependent on microglia, because microglial depletion blocked the decrease in PVH AgRP innervation observed in MHFD-L offspring, as well as prevented the increased body weight exhibited at weaning. Together, these findings suggest that microglia are activated by exposure to MHFD-L and interact directly with AgRP axons during postnatal development to permanently alter innervation of the PVH, with implications for developmental programming of metabolic phenotype.
Sensory perception is the ability through which an organism is able to process sensory stimuli from the environment. This stimulus is transmitted from the peripheral sensory organs to the central nervous system, where it is interpreted.Drosophila melanogasterlarvae possess peripheral sense organs on their head, thoracic, and abdominal segments. These are specialized to receive diverse environmental information, such as olfactory, gustatory, temperature, or mechanosensory signals. In this work, we complete the description of the morphology of external larval sensilla and provide a comprehensive map of the ultrastructure of the different types of sensilla that comprise them. This was achieved by 3D electron microscopic analysis of partial and whole body volumes, which contain high-resolution and complete three-dimensional data of the anatomy of the sensilla and adjacent ganglia. Our analysis revealed three main types of sensilla on thoracic and abdominal segments: the papilla sensillum, the hair sensillum, and the knob sensillum. They occur solitary or organized in compound sensilla such as the thoracic keilin’s organ or the terminal sensory cones. We present a spatial map defining these sensilla by their position on thoracic and abdominal segments. Furthermore, we identify and name the sensilla at the larval head and the last fused abdominal segments. We show that mechanosensation dominates in the larval peripheral nervous system, as most sensilla have corresponding structural properties. The result of this work, the construction of a complete structural and neuronal map of the external larval sensilla, provides the basis for following molecular and functional studies to understand which sensory strategies theDrosophilalarva employs to orient itself in its natural environment.
Sensory perception is the ability through which an organism is able to process sensory stimuli from the environment. This stimulus is transmitted from the peripheral sensory organs to the central nervous system, where it is interpreted.Drosophila melanogasterlarvae possess peripheral sense organs on their head, thoracic, and abdominal segments. These are specialized to receive diverse environmental information, such as olfactory, gustatory, temperature, or mechanosensory signals. In this work, we complete the description of the morphology of external larval sensilla and provide a comprehensive map of the ultrastructure of the different types of sensilla that comprise them. This was achieved by 3D electron microscopic analysis of partial and whole body volumes, which contain high-resolution and complete three-dimensional data of the anatomy of the sensilla and adjacent ganglia. Our analysis revealed three main types of sensilla on thoracic and abdominal segments: the papilla sensillum, the hair sensillum, and the knob sensillum. They occur solitary or organized in compound sensilla such as the thoracic keilin’s organ or the terminal sensory cones. We present a spatial map defining these sensilla by their position on thoracic and abdominal segments. Furthermore, we identify and name the sensilla at the larval head and the last fused abdominal segments. We show that mechanosensation dominates in the larval peripheral nervous system, as most sensilla have corresponding structural properties. The result of this work, the construction of a complete structural and neuronal map of the external larval sensilla, provides the basis for following molecular and functional studies to understand which sensory strategies theDrosophilalarva employs to orient itself in its natural environment.
Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.
Motivational deficits are common in several brain disorders, and motivational syndromes like apathy and anhedonia predict worse outcomes. Disrupted effort-based decision-making may represent a neurobiological underpinning of motivational deficits, shared across neuropsychiatric disorders. We measured effort-based decision-making in 994 participants using a gamified online task, combined with computational modelling, and validated offline for test–retest reliability. In two pre-registered studies, we first replicated studies linking impaired effort-based decision-making to neuropsychiatric syndromes, taking both a transdiagnostic and a diagnostic-criteria approach. Next, testing participants withearlyandlatecircadian rhythms in the morning and evening, we find circadian rhythm interacts with time-of-testing to produce parallel effects on effort-based decision-making. Circadian rhythm may be an important variable in computational psychiatry, decreasing reliability or distorting results when left unaccounted for. Disentangling effects of neuropsychiatric syndromes and circadian rhythm on effort-based decision-making will be essential to understand motivational pathologies and to develop tailored clinical interventions.
Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.
Describing morphogenesis generally consists in aggregating the multiple high-resolution spatiotemporal processes involved into reproducible low-dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks as they can be time consuming, hence unfit for scale, and often lack standardization and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardized framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.
Schuster et al.demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (Schuster et al., 2021). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in 1 out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions.
Schuster et al.demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (Schuster et al., 2021). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in 1 out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions.
The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
The brain is thought to construct an optimal internal model representing the probabilistic structure of the environment accurately. Evidence suggests that spontaneous brain activity gives such a model by cycling through activity patterns evoked by previous sensory experiences with the experienced probabilities. The brain’s spontaneous activity emerges from internally driven neural population dynamics. However, how cortical neural networks encode internal models into spontaneous activity is poorly understood. Recent computational and experimental studies suggest that a cortical neuron can implement complex computations, including predictive responses, through soma–dendrite interactions. Here, we show that a recurrent network of spiking neurons subject to the same predictive learning principle provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. In this network, the learning rules minimize probability mismatches between stimulus-evoked and internally driven activities in all excitatory and inhibitory neurons. This learning paradigm generates stimulus-specific cell assemblies that internally remember their activation probabilities using within-assembly recurrent connections. Our model contrasts previous models that encode the statistical structure of sensory experiences into Markovian transition patterns among cell assemblies. We demonstrate that the spontaneous activity of our model well replicates the behavioral biases of monkeys performing perceptual decision making. Our results suggest that interactions between intracellular processes and recurrent network dynamics are more crucial for learning cognitive behaviors than previously thought.
Describing morphogenesis generally consists in aggregating the multiple high-resolution spatiotemporal processes involved into reproducible low-dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks as they can be time consuming, hence unfit for scale, and often lack standardization and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardized framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.
Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are trained and tested on cross-sectional data from primarily Caucasian, adult participants. It is thus unclear how well these models generalize to non-Caucasian participants, especially children. Here, we tested a previously published deep learning model on Singaporean elderly participants (55−88 years old) and children (4−11 years old). We found that the model directly generalized to the elderly participants, but model finetuning was necessary for children. After finetuning, we found that the rate of change in brain age gap was associated with future executive function performance in both elderly participants and children. We further found that lateral ventricles and frontal areas contributed to brain age prediction in elderly participants, while white matter and posterior brain regions were more important in predicting brain age of children. Taken together, our results suggest that there is potential for generalizing brain age models to diverse populations. Moreover, the longitudinal change in brain age gap reflects developing and aging processes in the brain, relating to future cognitive function.
Motivational deficits are common in several brain disorders, and motivational syndromes like apathy and anhedonia predict worse outcomes. Disrupted effort-based decision-making may represent a neurobiological underpinning of motivational deficits, shared across neuropsychiatric disorders. We measured effort-based decision-making in 994 participants using a gamified online task, combined with computational modelling, and validated offline for test–retest reliability. In two pre-registered studies, we first replicated studies linking impaired effort-based decision-making to neuropsychiatric syndromes, taking both a transdiagnostic and a diagnostic-criteria approach. Next, testing participants withearlyandlatecircadian rhythms in the morning and evening, we find circadian rhythm interacts with time-of-testing to produce parallel effects on effort-based decision-making. Circadian rhythm may be an important variable in computational psychiatry, decreasing reliability or distorting results when left unaccounted for. Disentangling effects of neuropsychiatric syndromes and circadian rhythm on effort-based decision-making will be essential to understand motivational pathologies and to develop tailored clinical interventions.
Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus respond to multiple metabolic signals and distribute neuroendocrine information to other brain regions such as the paraventricular hypothalamic nucleus (PVH), which plays a central role in metabolic homeostasis. Neural projections from AgRP neurons to the PVH form during the postnatal lactational period in mice and these projections are reduced in offspring of dams that consumed a high-fat diet (HFD) during lactation (MHFD-L). Here, we used immunohistochemistry to visualize microglial morphology in MHFD-L offspring and identified changes that were regionally localized to the PVH and appeared temporally restricted to the period when AgRP neurons innervate this region. In addition, axon labeling experiments revealed that microglia engulf AgRP terminals in the PVH, and that the density of AgRP innervation to the PVH in MHFD-L offspring may be dependent on microglia, because microglial depletion blocked the decrease in PVH AgRP innervation observed in MHFD-L offspring, as well as prevented the increased body weight exhibited at weaning. Together, these findings suggest that microglia are activated by exposure to MHFD-L and interact directly with AgRP axons during postnatal development to permanently alter innervation of the PVH, with implications for developmental programming of metabolic phenotype.
Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening.
Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are trained and tested on cross-sectional data from primarily Caucasian, adult participants. It is thus unclear how well these models generalize to non-Caucasian participants, especially children. Here, we tested a previously published deep learning model on Singaporean elderly participants (55−88 years old) and children (4−11 years old). We found that the model directly generalized to the elderly participants, but model finetuning was necessary for children. After finetuning, we found that the rate of change in brain age gap was associated with future executive function performance in both elderly participants and children. We further found that lateral ventricles and frontal areas contributed to brain age prediction in elderly participants, while white matter and posterior brain regions were more important in predicting brain age of children. Taken together, our results suggest that there is potential for generalizing brain age models to diverse populations. Moreover, the longitudinal change in brain age gap reflects developing and aging processes in the brain, relating to future cognitive function.
Touch-sensitive neurons in the fingertips take previous physical contacts into account when relaying tactile information to the brain.
Human skin and its underlying tissues constitute a viscoelastic medium, implying that any deformation depends not only on the currently applied force, but also on the recent loading history. The extent to which this physical memory influences the signaling of first-order tactile neurons during natural hand use is not well understood. Here, we examined the effect of past loading on the responses of fast-adapting (FA-1) and slowly-adapting (SA-1 and SA-2) first-order tactile neurons innervating the human fingertip to loadings applied in different directions representative of object manipulation tasks. We found that variation in the preceding loading affected neurons’ overall signaling of force direction. Some neurons kept signaling the current direction, while others signaled both the current and preceding direction, or even primarily the preceding direction. In addition, ongoing impulse activity in SA-2 neurons between loadings signaled information related to the fingertip’s viscoelastic deformation state. We conclude that tactile neurons at the population level signal continuous information about the fingertip’s viscoelastic deformation state, which is shaped by both its recent history and current loading. Such information might be sufficient for the brain to correctly interpret current force loading and help in computing accurate motor commands for interactions with objects in manipulation and haptic tasks.
Complex brain function comprises a multitude of neural operations in parallel and often at different speeds. Each of these operations is carried out across a network of distributed brain regions. How multiple distributed processes are facilitated in parallel is largely unknown. We postulate that such processing relies on a multiplex of dynamic network patterns emerging in parallel but from different functional connectivity (FC) timescales. Given the dominance of inherently slow fMRI in network science, it is unknown whether the brain leverages such multi-timescale network dynamics. We studied FC dynamics concurrently across a breadth of timescales (from infraslow to γ-range) in rare, simultaneously recorded intracranial EEG and fMRI in humans, and source-localized scalp EEG-fMRI data in humans. We examined spatial and temporal convergence of connectome trajectories across timescales. ‘Spatial convergence’ refers to spatially similar EEG and fMRI connectome patterns, while ‘temporal convergence’ signifies the more specific case of spatial convergence at corresponding timepoints in EEG and fMRI. We observed spatial convergence but temporal divergence across FC timescales; connectome states (recurrent FC patterns) with partial spatial similarity were found in fMRI and all EEG frequency bands, but these occurred asynchronously across FC timescales. Our findings suggest that hemodynamic and frequency-specific electrophysiological signals, while involving similar large-scale networks, represent functionally distinct connectome trajectories that operate at different FC speeds and in parallel. This multiplex is poised to enable concurrent connectivity across multiple sets of brain regions independently.
Breast carcinoma amplified sequence 2 (BCAS2), a core component of the hPrP19 complex, plays crucial roles in various physiological and pathological processes. However, whether BCAS2 has functions other than being a key RNA-splicing regulator within the nucleus remains unknown. Here, we show that BCAS2 is essential for primitive hematopoiesis in zebrafish and mouse embryos. The activation of Wnt/β-catenin signaling, which is required for hematopoietic progenitor differentiation, is significantly decreased upon depletion ofbcas2in zebrafish embryos and mouse embryonic fibroblasts. Interestingly, BCAS2 deficiency has no obvious impact on the splicing efficiency of β-catenin pre-mRNA, while significantly attenuating β-catenin nuclear accumulation. Moreover, we find that BCAS2 directly binds to β-catenin via its coiled-coil domains, thereby sequestering β-catenin within the nucleus. Thus, our results uncover a previously unknown function of BCAS2 in promoting Wnt signaling by enhancing β-catenin nuclear retention during primitive hematopoiesis.
Human skin and its underlying tissues constitute a viscoelastic medium, implying that any deformation depends not only on the currently applied force, but also on the recent loading history. The extent to which this physical memory influences the signaling of first-order tactile neurons during natural hand use is not well understood. Here, we examined the effect of past loading on the responses of fast-adapting (FA-1) and slowly-adapting (SA-1 and SA-2) first-order tactile neurons innervating the human fingertip to loadings applied in different directions representative of object manipulation tasks. We found that variation in the preceding loading affected neurons’ overall signaling of force direction. Some neurons kept signaling the current direction, while others signaled both the current and preceding direction, or even primarily the preceding direction. In addition, ongoing impulse activity in SA-2 neurons between loadings signaled information related to the fingertip’s viscoelastic deformation state. We conclude that tactile neurons at the population level signal continuous information about the fingertip’s viscoelastic deformation state, which is shaped by both its recent history and current loading. Such information might be sufficient for the brain to correctly interpret current force loading and help in computing accurate motor commands for interactions with objects in manipulation and haptic tasks.
Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across the occipital cortex and are usually largest when the cortex is inactive. However, recent studies measuring visual receptive fields have reported that local alpha power increases when cortex is excited by visual stimulation. This contrasts with the expectation that alpha oscillations are associated with cortical inactivity. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We hypothesized that stimulus-driven local increases in alpha power result from a mixture of two effects: a reduction in alpha oscillatory power and a simultaneous increase in broadband power. To test this, we implemented a model to separate these components. The two components were then independently fit by population receptive field (pRF) models. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power but are several times larger and exhibit the opposite effect: alpha oscillatory power decreases in response to stimuli within the receptive field, reinforcing the link between alpha oscillations and cortical inactivity, whereas broadband power increases. The results demonstrate that alpha suppression in the human visual cortex can be precisely tuned, but that to measure these effects, it is essential to separate the oscillatory signal from broadband power changes. Finally, we show how the large size and the negative valence of alpha pRFs can explain key features of exogenous visual attention.
Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across the occipital cortex and are usually largest when the cortex is inactive. However, recent studies measuring visual receptive fields have reported that local alpha power increases when cortex is excited by visual stimulation. This contrasts with the expectation that alpha oscillations are associated with cortical inactivity. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We hypothesized that stimulus-driven local increases in alpha power result from a mixture of two effects: a reduction in alpha oscillatory power and a simultaneous increase in broadband power. To test this, we implemented a model to separate these components. The two components were then independently fit by population receptive field (pRF) models. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power but are several times larger and exhibit the opposite effect: alpha oscillatory power decreases in response to stimuli within the receptive field, reinforcing the link between alpha oscillations and cortical inactivity, whereas broadband power increases. The results demonstrate that alpha suppression in the human visual cortex can be precisely tuned, but that to measure these effects, it is essential to separate the oscillatory signal from broadband power changes. Finally, we show how the large size and the negative valence of alpha pRFs can explain key features of exogenous visual attention.
Metazoans detect and differentiate between innocuous (non-painful) and/or noxious (harmful) environmental cues using primary sensory neurons, which serve as the first node in a neural network that computes stimulus-specific behaviors to either navigate away from injury-causing conditions or to perform protective behaviors that mitigate extensive injury. The ability of an animal to detect and respond to various sensory stimuli depends upon molecular diversity in the primary sensors and the underlying neural circuitry responsible for the relevant behavioral action selection. Recent studies inDrosophilalarvae have revealed that somatosensory class III multidendritic (CIII md) neurons function as multimodal sensors regulating distinct behavioral responses to innocuous mechanical and nociceptive thermal stimuli. Recent advances in circuit bases of behavior have identified and functionally validatedDrosophilalarval somatosensory circuitry involved in innocuous (mechanical) and noxious (heat and mechanical) cues. However, central processing of cold nociceptive cues remained unexplored. We implicate multisensory integrators (Basins), premotor (Down-and-Back), and projection (A09e and TePns) neurons as neural substrates required for cold-evoked behavioral and calcium responses. Neural silencing of cell types downstream of CIII md neurons led to significant reductions in cold-evoked behaviors, and neural co-activation of CIII md neurons plus additional cell types facilitated larval contraction (CT) responses. Further, we demonstrate that optogenetic activation of CIII md neurons evokes calcium increases in these neurons. Finally, we characterize the premotor to motor neuron network underlying cold-evoked CT and delineate the muscular basis of CT response. Collectively, we demonstrate howDrosophilalarvae process cold stimuli through functionally diverse somatosensory circuitry responsible for generating stimulus-specific behaviors.
Single-cell RNA-sequencing (scRNA-seq) coupled with robust computational analysis facilitates the characterization of phenotypic heterogeneity within tumors. Current scRNA-seq analysis pipelines are capable of identifying a myriad of malignant and non-malignant cell subtypes from single-cell profiling of tumors. However, given the extent of intra-tumoral heterogeneity, it is challenging to assess the risk associated with individual cell subpopulations, primarily due to the complexity of the cancer phenotype space and the lack of clinical annotations associated with tumor scRNA-seq studies. To this end, we introduce SCellBOW, a scRNA-seq analysis framework inspired by document embedding techniques from the domain of Natural Language Processing (NLP). SCellBOW is a novel computational approach that facilitates effective identification and high-quality visualization of single-cell subpopulations. We compared SCellBOW with existing best practice methods for its ability to precisely represent phenotypically divergent cell types across multiple scRNA-seq datasets, including our in-house generated human splenocyte and matched peripheral blood mononuclear cell (PBMC) dataset. For tumor cells, SCellBOW estimates the relative risk associated with each cluster and stratifies them based on their aggressiveness. This is achieved by simulating how the presence or absence of a specific cell subpopulation influences disease prognosis. Using SCellBOW, we identified a hitherto unknown and pervasive AR−/NElow(androgen-receptor-negative, neuroendocrine-low) malignant subpopulation in metastatic prostate cancer with conspicuously high aggressiveness. Overall, the risk-stratification capabilities of SCellBOW hold promise for formulating tailored therapeutic interventions by identifying clinically relevant tumor subpopulations and their impact on prognosis.
Complex brain function comprises a multitude of neural operations in parallel and often at different speeds. Each of these operations is carried out across a network of distributed brain regions. How multiple distributed processes are facilitated in parallel is largely unknown. We postulate that such processing relies on a multiplex of dynamic network patterns emerging in parallel but from different functional connectivity (FC) timescales. Given the dominance of inherently slow fMRI in network science, it is unknown whether the brain leverages such multi-timescale network dynamics. We studied FC dynamics concurrently across a breadth of timescales (from infraslow to γ-range) in rare, simultaneously recorded intracranial EEG and fMRI in humans, and source-localized scalp EEG-fMRI data in humans. We examined spatial and temporal convergence of connectome trajectories across timescales. ‘Spatial convergence’ refers to spatially similar EEG and fMRI connectome patterns, while ‘temporal convergence’ signifies the more specific case of spatial convergence at corresponding timepoints in EEG and fMRI. We observed spatial convergence but temporal divergence across FC timescales; connectome states (recurrent FC patterns) with partial spatial similarity were found in fMRI and all EEG frequency bands, but these occurred asynchronously across FC timescales. Our findings suggest that hemodynamic and frequency-specific electrophysiological signals, while involving similar large-scale networks, represent functionally distinct connectome trajectories that operate at different FC speeds and in parallel. This multiplex is poised to enable concurrent connectivity across multiple sets of brain regions independently.
Single-cell RNA-sequencing (scRNA-seq) coupled with robust computational analysis facilitates the characterization of phenotypic heterogeneity within tumors. Current scRNA-seq analysis pipelines are capable of identifying a myriad of malignant and non-malignant cell subtypes from single-cell profiling of tumors. However, given the extent of intra-tumoral heterogeneity, it is challenging to assess the risk associated with individual cell subpopulations, primarily due to the complexity of the cancer phenotype space and the lack of clinical annotations associated with tumor scRNA-seq studies. To this end, we introduce SCellBOW, a scRNA-seq analysis framework inspired by document embedding techniques from the domain of Natural Language Processing (NLP). SCellBOW is a novel computational approach that facilitates effective identification and high-quality visualization of single-cell subpopulations. We compared SCellBOW with existing best practice methods for its ability to precisely represent phenotypically divergent cell types across multiple scRNA-seq datasets, including our in-house generated human splenocyte and matched peripheral blood mononuclear cell (PBMC) dataset. For tumor cells, SCellBOW estimates the relative risk associated with each cluster and stratifies them based on their aggressiveness. This is achieved by simulating how the presence or absence of a specific cell subpopulation influences disease prognosis. Using SCellBOW, we identified a hitherto unknown and pervasive AR−/NElow(androgen-receptor-negative, neuroendocrine-low) malignant subpopulation in metastatic prostate cancer with conspicuously high aggressiveness. Overall, the risk-stratification capabilities of SCellBOW hold promise for formulating tailored therapeutic interventions by identifying clinically relevant tumor subpopulations and their impact on prognosis.
Metazoans detect and differentiate between innocuous (non-painful) and/or noxious (harmful) environmental cues using primary sensory neurons, which serve as the first node in a neural network that computes stimulus-specific behaviors to either navigate away from injury-causing conditions or to perform protective behaviors that mitigate extensive injury. The ability of an animal to detect and respond to various sensory stimuli depends upon molecular diversity in the primary sensors and the underlying neural circuitry responsible for the relevant behavioral action selection. Recent studies inDrosophilalarvae have revealed that somatosensory class III multidendritic (CIII md) neurons function as multimodal sensors regulating distinct behavioral responses to innocuous mechanical and nociceptive thermal stimuli. Recent advances in circuit bases of behavior have identified and functionally validatedDrosophilalarval somatosensory circuitry involved in innocuous (mechanical) and noxious (heat and mechanical) cues. However, central processing of cold nociceptive cues remained unexplored. We implicate multisensory integrators (Basins), premotor (Down-and-Back), and projection (A09e and TePns) neurons as neural substrates required for cold-evoked behavioral and calcium responses. Neural silencing of cell types downstream of CIII md neurons led to significant reductions in cold-evoked behaviors, and neural co-activation of CIII md neurons plus additional cell types facilitated larval contraction (CT) responses. Further, we demonstrate that optogenetic activation of CIII md neurons evokes calcium increases in these neurons. Finally, we characterize the premotor to motor neuron network underlying cold-evoked CT and delineate the muscular basis of CT response. Collectively, we demonstrate howDrosophilalarvae process cold stimuli through functionally diverse somatosensory circuitry responsible for generating stimulus-specific behaviors.
Breast carcinoma amplified sequence 2 (BCAS2), a core component of the hPrP19 complex, plays crucial roles in various physiological and pathological processes. However, whether BCAS2 has functions other than being a key RNA-splicing regulator within the nucleus remains unknown. Here, we show that BCAS2 is essential for primitive hematopoiesis in zebrafish and mouse embryos. The activation of Wnt/β-catenin signaling, which is required for hematopoietic progenitor differentiation, is significantly decreased upon depletion ofbcas2in zebrafish embryos and mouse embryonic fibroblasts. Interestingly, BCAS2 deficiency has no obvious impact on the splicing efficiency of β-catenin pre-mRNA, while significantly attenuating β-catenin nuclear accumulation. Moreover, we find that BCAS2 directly binds to β-catenin via its coiled-coil domains, thereby sequestering β-catenin within the nucleus. Thus, our results uncover a previously unknown function of BCAS2 in promoting Wnt signaling by enhancing β-catenin nuclear retention during primitive hematopoiesis.
Zebrafish is an important organism for genetic studies, but its early germ cell types and the mechanism of sex differentiation have not been fully characterized. Here, we profiled single-cell transcriptomes and charted a developmental trajectory going from germline stem cells, through early, committed, and late progenitors, to pre-meiotic and meiotic cells. We showed that transcription factor Foxl2l expressed in the progenitor directed progenitor differentiation toward oocytes. CRISPR-Cas9-mediated mutation offoxl2lproduced 100% male fish with normal fertility. Another single-cell profiling offoxl2l-/-germ cells revealed the arrest of germ cell development at the stage of progenitor commitment. Concomitantly,nanos2transcript (germline stem cell marker) was elevated together with an increase ofnanos2+germ cells infoxl2lmutants, indicating the acquisition of a novel stem cell state. Thus, we have identified developmental stages of germ cells in juvenile zebrafish and demonstrated that zebrafish Foxl2l drives progenitor germ cells toward feminization and prevents them from expressingnanos2.
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Background:Trials of incretins are making it increasingly clear that body mass index (BMI) is linked to several diseases throughout life, but trials cannot easily provide a comprehensive assessment of the role of BMI in health-related attributes for men and women. To systematically investigate the role of BMI, we conducted a sex-specific Mendelian randomization-phenome-wide association study.Methods:We comprehensively examined the associations of genetically predicted BMI in women (n: 194,174) and men (n: 167,020) using health-related attributes from the UK Biobank with inverse variance weighting and sensitivity analysis.Results:BMI impacted 232 of 776 traits considered in women and 203 of 680 traits in men, after adjusting for false discovery; differences by sex were found for 105 traits, and 46 traits remained after adjusting for false discovery. BMI was more strongly positively associated with myocardial infarction, major coronary heart disease events, ischemic heart disease, and heart attack in men than women. BMI was more strongly positively associated with apolipoprotein B (ApoB) and diastolic blood pressure in women than men.Conclusions:Our study revealed that BMI might affect a wide range of health-related attributes and also highlights notable sex differences in its impact, including opposite associations for certain attributes, such as ApoB; and stronger effects in men, such as for cardiovascular diseases. Our findings underscore the need for nuanced, sex-specific policy related to BMI to address inequities in health.Funding:None.
Kinesin motor proteins facilitate microtubule-based transport by converting chemical energy into mechanical forces, but this activity is autoinhibited until cargo is loaded. Regulatory mechanisms underlying this autoinhibitory conformation are not well understood. Here, we show that a NEver in mitosis Kinase NEKL-3 directly phosphorylates a flexible elbow region between two coiled-coil domains connecting the motor head and tail of an intraflagellar transport kinesin, OSM-3. The phosphor-dead (PD) mutation, but not phosphor-mimic (PM) mutation, induces constitutive motility of OSM-3 in vitro. Using knock-in animals, we discovered that both PD and PM mutations shorten theC. eleganssensory cilia. The constitutively active OSM-3PD fails to enter cilia and abnormally accumulates in neurites, mimicking another hyperactive mutation, OSM-3G444E. Conversely, OSM-3PM enters cilia but moves at a reduced speed, indicating an inhibitory role of elbow phosphorylation in kinesin motility. These findings highlight the crucial role of elbow phosphorylation in regulating kinesin autoinhibition.
Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea that seriously threatens public health. The disruption of normal gut microbiota by the use of broad-spectrum antimicrobial agents enablesC. difficileto proliferate in the colon. The emergence and prevalence of hypervirulentC. difficilestrains result in increased morbidity, mortality, and high recurrence rates of CDI, thus creating a pressing need for novel therapeutics. The multi-domain toxins TcdA and TcdB are the primary determinants of CDI pathogenesis, rendering them ideal drug targets in the anti-virulence paradigm. In this study, we identified caffeic acid and its derivatives from natural compounds library as active inhibitors of TcdB via a cell-based high-throughput phenotypic screening. Further mechanistic investigations revealed that caffeic acid phenethyl ester (CAPE) could directly bind to TcdB, thus suppressing InsP6-induced autoproteolysis and inhibiting glucosyltransferase activity. CAPE treatment remarkably reduces the pathology of CDI in a murine infection model in terms of alleviated diarrhea symptoms, decreased bacterial colonization, and relieved histopathological lesions. Moreover, CAPE treatment ofC. difficile-challenged mice induces a remarkable increase in the diversity and composition of the gut microbiota and alterations of gut metabolites (e.g., adenosine, D-proline, and melatonin), which might partially contribute to the therapeutic outcomes of CAPE against CDI. Our results reveal the potential of CAPE as a therapeutic for the management of CDI, or CAPE might serve as a lead compound for the development of antivirulence drugs targeting TcdB.
Background:Trials of incretins are making it increasingly clear that body mass index (BMI) is linked to several diseases throughout life, but trials cannot easily provide a comprehensive assessment of the role of BMI in health-related attributes for men and women. To systematically investigate the role of BMI, we conducted a sex-specific Mendelian randomization-phenome-wide association study.Methods:We comprehensively examined the associations of genetically predicted BMI in women (n: 194,174) and men (n: 167,020) using health-related attributes from the UK Biobank with inverse variance weighting and sensitivity analysis.Results:BMI impacted 232 of 776 traits considered in women and 203 of 680 traits in men, after adjusting for false discovery; differences by sex were found for 105 traits, and 46 traits remained after adjusting for false discovery. BMI was more strongly positively associated with myocardial infarction, major coronary heart disease events, ischemic heart disease, and heart attack in men than women. BMI was more strongly positively associated with apolipoprotein B (ApoB) and diastolic blood pressure in women than men.Conclusions:Our study revealed that BMI might affect a wide range of health-related attributes and also highlights notable sex differences in its impact, including opposite associations for certain attributes, such as ApoB; and stronger effects in men, such as for cardiovascular diseases. Our findings underscore the need for nuanced, sex-specific policy related to BMI to address inequities in health.Funding:None.
Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individual’s age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength, and stimulus-reaction time. The model predicted a person’s age with best accuracy when it heavily weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated ‘biological’ age and chronological age (∆Age) appear to reflect an individual’s relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate ∆Age. Remarkably, the effect of each year of physiological ∆Age on Gompertz mortality risk was equivalent to that of one chronological year. A genome-wide association study (GWAS) of ∆Age and analysis of environmental factors associated with ∆Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a person’s biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.
The brain learns an internal model of the environment through sensory experiences, which is essential for high-level cognitive processes. Recent studies show that spontaneous activity reflects such a learned internal model. Although computational studies have proposed that Hebbian plasticity can learn the switching dynamics of replayed activities, it is still challenging to learn dynamic spontaneous activity that obeys the statistical properties of sensory experience. Here, we propose a pair of biologically plausible plasticity rules for excitatory and inhibitory synapses in a recurrent spiking neural network model to embed stochastic dynamics in spontaneous activity. The proposed synaptic plasticity rule for excitatory synapses seeks to minimize the discrepancy between stimulus-evoked and internally predicted activity, while inhibitory plasticity maintains the excitatory-inhibitory balance. We show that the spontaneous reactivation of cell assemblies follows the transition statistics of the model’s evoked dynamics. We also demonstrate that simulations of our model can replicate recent experimental results of spontaneous activity in songbirds, suggesting that the proposed plasticity rule might underlie the mechanism by which animals learn internal models of the environment.
Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individual’s age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength, and stimulus-reaction time. The model predicted a person’s age with best accuracy when it heavily weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated ‘biological’ age and chronological age (∆Age) appear to reflect an individual’s relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate ∆Age. Remarkably, the effect of each year of physiological ∆Age on Gompertz mortality risk was equivalent to that of one chronological year. A genome-wide association study (GWAS) of ∆Age and analysis of environmental factors associated with ∆Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a person’s biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.
Kinesin motor proteins facilitate microtubule-based transport by converting chemical energy into mechanical forces, but this activity is autoinhibited until cargo is loaded. Regulatory mechanisms underlying this autoinhibitory conformation are not well understood. Here, we show that a NEver in mitosis Kinase NEKL-3 directly phosphorylates a flexible elbow region between two coiled-coil domains connecting the motor head and tail of an intraflagellar transport kinesin, OSM-3. The phosphor-dead (PD) mutation, but not phosphor-mimic (PM) mutation, induces constitutive motility of OSM-3 in vitro. Using knock-in animals, we discovered that both PD and PM mutations shorten theC. eleganssensory cilia. The constitutively active OSM-3PD fails to enter cilia and abnormally accumulates in neurites, mimicking another hyperactive mutation, OSM-3G444E. Conversely, OSM-3PM enters cilia but moves at a reduced speed, indicating an inhibitory role of elbow phosphorylation in kinesin motility. These findings highlight the crucial role of elbow phosphorylation in regulating kinesin autoinhibition.
Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis.RUNX2has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis and apoptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferation in vitro and tumorigenesis in vivo in oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis and apoptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can upregulate RUNX2 isoform II to inhibit ferroptosis and apoptosis and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway.
Mapping the vascular organization of the brain is of great importance across various domains of basic neuroimaging research, diagnostic radiology, and neurology. However, the intricate task of precisely mapping vasculature across brain regions and cortical layers presents formidable challenges, resulting in a limited understanding of neurometabolic factors influencing the brain’s microvasculature. Addressing this gap, our study investigates whole-brain vascular volume using ferumoxytol-weighted laminar-resolution multi-echo gradient-echo imaging in macaque monkeys. We validate the results with published data for vascular densities and compare them with cytoarchitecture, neuron and synaptic densities. The ferumoxytol-induced change in transverse relaxation rate (ΔR2*), an indirect proxy measure of cerebral blood volume (CBV), was mapped onto 12 equivolumetric laminar cortical surfaces. Our findings reveal that CBV varies threefold across the brain, with the highest vascular volume observed in the inferior colliculus and lowest in the corpus callosum. In the cerebral cortex, CBV is notably high in early primary sensory areas and low in association areas responsible for higher cognitive functions. Classification of CBV into distinct groups unveils extensive replication of translaminar vascular network motifs, suggesting distinct computational energy supply requirements in areas with varying cytoarchitecture types. Regionally, baseline R2* and CBV exhibit positive correlations with neuron density and negative correlations with receptor densities. Adjusting image resolution based on the critical sampling frequency of penetrating cortical vessels allows us to delineate approximately 30% of the arterial–venous vessels. Collectively, these results mark significant methodological and conceptual advancements, contributing to the refinement of cerebrovascular MRI. Furthermore, our study establishes a linkage between neurometabolic factors and the vascular network architecture in the primate brain.
The brain learns an internal model of the environment through sensory experiences, which is essential for high-level cognitive processes. Recent studies show that spontaneous activity reflects such a learned internal model. Although computational studies have proposed that Hebbian plasticity can learn the switching dynamics of replayed activities, it is still challenging to learn dynamic spontaneous activity that obeys the statistical properties of sensory experience. Here, we propose a pair of biologically plausible plasticity rules for excitatory and inhibitory synapses in a recurrent spiking neural network model to embed stochastic dynamics in spontaneous activity. The proposed synaptic plasticity rule for excitatory synapses seeks to minimize the discrepancy between stimulus-evoked and internally predicted activity, while inhibitory plasticity maintains the excitatory-inhibitory balance. We show that the spontaneous reactivation of cell assemblies follows the transition statistics of the model’s evoked dynamics. We also demonstrate that simulations of our model can replicate recent experimental results of spontaneous activity in songbirds, suggesting that the proposed plasticity rule might underlie the mechanism by which animals learn internal models of the environment.
Mapping the vascular organization of the brain is of great importance across various domains of basic neuroimaging research, diagnostic radiology, and neurology. However, the intricate task of precisely mapping vasculature across brain regions and cortical layers presents formidable challenges, resulting in a limited understanding of neurometabolic factors influencing the brain’s microvasculature. Addressing this gap, our study investigates whole-brain vascular volume using ferumoxytol-weighted laminar-resolution multi-echo gradient-echo imaging in macaque monkeys. We validate the results with published data for vascular densities and compare them with cytoarchitecture, neuron and synaptic densities. The ferumoxytol-induced change in transverse relaxation rate (ΔR2*), an indirect proxy measure of cerebral blood volume (CBV), was mapped onto 12 equivolumetric laminar cortical surfaces. Our findings reveal that CBV varies threefold across the brain, with the highest vascular volume observed in the inferior colliculus and lowest in the corpus callosum. In the cerebral cortex, CBV is notably high in early primary sensory areas and low in association areas responsible for higher cognitive functions. Classification of CBV into distinct groups unveils extensive replication of translaminar vascular network motifs, suggesting distinct computational energy supply requirements in areas with varying cytoarchitecture types. Regionally, baseline R2* and CBV exhibit positive correlations with neuron density and negative correlations with receptor densities. Adjusting image resolution based on the critical sampling frequency of penetrating cortical vessels allows us to delineate approximately 30% of the arterial–venous vessels. Collectively, these results mark significant methodological and conceptual advancements, contributing to the refinement of cerebrovascular MRI. Furthermore, our study establishes a linkage between neurometabolic factors and the vascular network architecture in the primate brain.
Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis.RUNX2has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis and apoptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferation in vitro and tumorigenesis in vivo in oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis and apoptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can upregulate RUNX2 isoform II to inhibit ferroptosis and apoptosis and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway.
Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea that seriously threatens public health. The disruption of normal gut microbiota by the use of broad-spectrum antimicrobial agents enablesC. difficileto proliferate in the colon. The emergence and prevalence of hypervirulentC. difficilestrains result in increased morbidity, mortality, and high recurrence rates of CDI, thus creating a pressing need for novel therapeutics. The multi-domain toxins TcdA and TcdB are the primary determinants of CDI pathogenesis, rendering them ideal drug targets in the anti-virulence paradigm. In this study, we identified caffeic acid and its derivatives from natural compounds library as active inhibitors of TcdB via a cell-based high-throughput phenotypic screening. Further mechanistic investigations revealed that caffeic acid phenethyl ester (CAPE) could directly bind to TcdB, thus suppressing InsP6-induced autoproteolysis and inhibiting glucosyltransferase activity. CAPE treatment remarkably reduces the pathology of CDI in a murine infection model in terms of alleviated diarrhea symptoms, decreased bacterial colonization, and relieved histopathological lesions. Moreover, CAPE treatment ofC. difficile-challenged mice induces a remarkable increase in the diversity and composition of the gut microbiota and alterations of gut metabolites (e.g., adenosine, D-proline, and melatonin), which might partially contribute to the therapeutic outcomes of CAPE against CDI. Our results reveal the potential of CAPE as a therapeutic for the management of CDI, or CAPE might serve as a lead compound for the development of antivirulence drugs targeting TcdB.
Understanding developmental changes in neuronal lineages is crucial to elucidate how they assemble into functional neural networks. Studies investigating nervous system development in model systems have only focused on select regions of the CNS due to the limited availability of genetic drivers that target specific neuronal lineages throughout development and adult life. This has hindered our understanding of how distinct neuronal lineages interconnect to form neuronal circuits during development. Here, we present a split-GAL4 library composed of genetic driver lines, which we generated via editing the genomic locus of lineage-specific transcription factors and demonstrate that we can use this library to specifically target most individual neuronal hemilineages in theDrosophilaventral nerve cord (VNC) throughout development and into adulthood. Using these genetic driver lines, we found striking morphological changes in neuronal processes within a lineage during metamorphosis. We also demonstrated how neurochemical features of neuronal classes can be quickly assessed. Lastly, we documented behaviors elicited in response to optogenetic activation of individual neuronal lineages and generated a comprehensive lineage-behavior map of the entire fly VNC. Looking forward, this lineage-specific split-GAL4 driver library will provide the genetic tools needed to address the questions emerging from the analysis of the recent VNC connectome and transcriptome datasets.
Dynamic CpG methylation ‘barcodes’ were read from 15,000–21,000 single cells from three human male brains. To overcome sparse sequencing coverage, the barcode had ~31,000 rapidly fluctuating X-chromosome CpG sites (fCpGs), with at least 500 covered sites per cell and at least 30 common sites between cell pairs (average of ~48). Barcodes appear to start methylated and record mitotic ages because excitatory neurons and glial cells that emerge later in development were less methylated. Barcodes are different between most cells, with average pairwise differences (PWDs) of ~0.5 between cells. About 10 cell pairs per million were more closely related with PWDs <0.05. Barcodes appear to record ancestry and reconstruct trees where more related cells had similar phenotypes, albeit some pairs had phenotypic differences. Inhibitory neurons showed more evidence of tangential migration than excitatory neurons, with related cells in different cortical regions. fCpG barcodes become polymorphic during development and can distinguish between thousands of human cells.
Understanding developmental changes in neuronal lineages is crucial to elucidate how they assemble into functional neural networks. Studies investigating nervous system development in model systems have only focused on select regions of the CNS due to the limited availability of genetic drivers that target specific neuronal lineages throughout development and adult life. This has hindered our understanding of how distinct neuronal lineages interconnect to form neuronal circuits during development. Here, we present a split-GAL4 library composed of genetic driver lines, which we generated via editing the genomic locus of lineage-specific transcription factors and demonstrate that we can use this library to specifically target most individual neuronal hemilineages in theDrosophilaventral nerve cord (VNC) throughout development and into adulthood. Using these genetic driver lines, we found striking morphological changes in neuronal processes within a lineage during metamorphosis. We also demonstrated how neurochemical features of neuronal classes can be quickly assessed. Lastly, we documented behaviors elicited in response to optogenetic activation of individual neuronal lineages and generated a comprehensive lineage-behavior map of the entire fly VNC. Looking forward, this lineage-specific split-GAL4 driver library will provide the genetic tools needed to address the questions emerging from the analysis of the recent VNC connectome and transcriptome datasets.
During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner. Weak synapses are preferentially removed, but the mechanism linking neuronal activity to synapse removal is unclear. Here, we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 deficiency results in defects in synapse elimination driven by both spontaneous and experience-dependent neural activity. Notably, caspase-3 deficiency blocks activity-dependent synapse elimination, as evidenced by reduced engulfment of inactive synapses by microglia. Furthermore, in a mouse model of Alzheimer’s disease, caspase-3 deficiency protects against synapse loss induced by amyloid-β deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.
The myometrium plays a critical role during pregnancy as it is responsible for both the structural integrity of the uterus and force generation at term. Emerging studies in mice indicate a dynamic change of the myometrial epigenome and transcriptome during pregnancy to ready the contractile machinery for parturition. However, the regulatory systems underlying myometrial gene expression patterns throughout gestation remain largely unknown. Here, we investigated human term pregnant nonlabor myometrial biopsies for transcriptome, enhancer histone mark cistrome, and chromatin conformation pattern mapping. More than thirty thousand putative enhancers with H3K27ac and H3K4me1 double positive marks were identified in the myometrium. Enriched transcription factor binding motifs include known myometrial regulators AP-1, STAT, NFkB, and PGR among others. Putative myometrial super enhancers are mostly colocalized with progesterone receptor-occupying sites and preferentially associated with highly expressing genes, suggesting a conserved role of PGR in regulating the myometrial transcriptome between species. In human myometrial specimens, inferred PGR activities are positively correlated with phospholipase C like 2 (PLCL2) mRNA levels, supporting that PGR may act through this genomic region to promotePLCL2expression. PGR overexpression facilitatedPLCL2gene expression in myometrial cells. Using CRISPR activation, we assessed the functionality of a PGR putative enhancer 35 kilobases upstream of the contractile-restrictive genePLCL2. In summary, the results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women’s health research.
During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner. Weak synapses are preferentially removed, but the mechanism linking neuronal activity to synapse removal is unclear. Here, we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 deficiency results in defects in synapse elimination driven by both spontaneous and experience-dependent neural activity. Notably, caspase-3 deficiency blocks activity-dependent synapse elimination, as evidenced by reduced engulfment of inactive synapses by microglia. Furthermore, in a mouse model of Alzheimer’s disease, caspase-3 deficiency protects against synapse loss induced by amyloid-β deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.
Dynamic CpG methylation ‘barcodes’ were read from 15,000–21,000 single cells from three human male brains. To overcome sparse sequencing coverage, the barcode had ~31,000 rapidly fluctuating X-chromosome CpG sites (fCpGs), with at least 500 covered sites per cell and at least 30 common sites between cell pairs (average of ~48). Barcodes appear to start methylated and record mitotic ages because excitatory neurons and glial cells that emerge later in development were less methylated. Barcodes are different between most cells, with average pairwise differences (PWDs) of ~0.5 between cells. About 10 cell pairs per million were more closely related with PWDs <0.05. Barcodes appear to record ancestry and reconstruct trees where more related cells had similar phenotypes, albeit some pairs had phenotypic differences. Inhibitory neurons showed more evidence of tangential migration than excitatory neurons, with related cells in different cortical regions. fCpG barcodes become polymorphic during development and can distinguish between thousands of human cells.
The myometrium plays a critical role during pregnancy as it is responsible for both the structural integrity of the uterus and force generation at term. Emerging studies in mice indicate a dynamic change of the myometrial epigenome and transcriptome during pregnancy to ready the contractile machinery for parturition. However, the regulatory systems underlying myometrial gene expression patterns throughout gestation remain largely unknown. Here, we investigated human term pregnant nonlabor myometrial biopsies for transcriptome, enhancer histone mark cistrome, and chromatin conformation pattern mapping. More than thirty thousand putative enhancers with H3K27ac and H3K4me1 double positive marks were identified in the myometrium. Enriched transcription factor binding motifs include known myometrial regulators AP-1, STAT, NFkB, and PGR among others. Putative myometrial super enhancers are mostly colocalized with progesterone receptor-occupying sites and preferentially associated with highly expressing genes, suggesting a conserved role of PGR in regulating the myometrial transcriptome between species. In human myometrial specimens, inferred PGR activities are positively correlated with phospholipase C like 2 (PLCL2) mRNA levels, supporting that PGR may act through this genomic region to promotePLCL2expression. PGR overexpression facilitatedPLCL2gene expression in myometrial cells. Using CRISPR activation, we assessed the functionality of a PGR putative enhancer 35 kilobases upstream of the contractile-restrictive genePLCL2. In summary, the results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women’s health research.
Experiments in mice reveal how three rare mutations in a gene calledTRIOcan lead to different neurodevelopmental outcomes.
Background:This study investigated the presence of the healthy vaccinee effect—the imbalance in health status between vaccinated and unvaccinated individuals—in two rigorously conducted COVID-19 vaccine effectiveness studies involving primary series and booster vaccinations. It also examined the temporal patterns and variability of this effect across different subpopulations by analyzing the association between COVID-19 vaccination and non-COVID-19 mortality in Qatar.Methods:Two matched, retrospective cohort studies assessed the incidence of non-COVID-19 death in national cohorts of individuals with a primary series vaccination versus no vaccination (two-dose analysis), and individuals with three-dose (booster) vaccination versus primary series vaccination (three-dose analysis), from January 5, 2021, to April 9, 2024.Results:The adjusted hazard ratio (aHR) for non-COVID-19 death was 0.76 (95% CI: 0.64–0.90) in the two-dose analysis and 0.85 (95% CI: 0.67–1.07) in the three-dose analysis. In the first 6 months of follow-up in the two-dose analysis, the aHR was 0.35 (95% CI: 0.27–0.46); however, the combined analysis of all subsequent periods showed an aHR of 1.52 (95% CI: 1.19–1.94). In the first 6 months of follow-up in the three-dose analysis, the aHR was 0.31 (95% CI: 0.20–0.50); however, the combined analysis of all subsequent periods showed an aHR of 1.37 (95% CI: 1.02–1.85). The overall effectiveness of the primary series and third-dose vaccinations against severe, critical, or fatal COVID-19 was 95.9% (95% CI: 94.0–97.1) and 34.1% (95% CI: –46.4–76.7), respectively. Subgroup analyses showed that the healthy vaccinee effect is pronounced among those aged 50 years and older and among those more clinically vulnerable to severe COVID-19.Conclusions:A pronounced healthy vaccinee effect was observed during the first 6 months following vaccination, despite meticulous cohort matching. This effect may have stemmed from a lower likelihood of vaccination among seriously ill, end-of-life individuals, and less mobile elderly populations.Funding:Biomedical Research Program and the Biostatistics, Epidemiology, and Biomathematics Research Core, and Junior Faculty Transition to Independence Program, all at Weill Cornell Medicine-Qatar, Qatar University, Ministry of Public Health, Hamad Medical Corporation, Sidra Medicine, Qatar Genome Programme, Qatar University Biomedical Research Center, and L’Oréal-UNESCO For Women In Science Middle East Regional Young Talents Program.
Xist,a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However,Xist’s ability to diffuse under select circumstances has also been documented, leading us to suspect thatXistRNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate thatXistRNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status.Xistbinds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for humanXISTRNA. We find thatXistbinding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi,Xistbinding does not lead to full silencing and also does not spread beyond the target gene. Over-expressingXistin transgenic ES cells similarly leads to autosomal gene suppression, while deletingXist’s Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with theXistinhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal thatXisttargets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by a small molecule inhibitor.
Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis.Drosophilatracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the fibroblast growth factor mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here, we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.
Xist,a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However,Xist’s ability to diffuse under select circumstances has also been documented, leading us to suspect thatXistRNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate thatXistRNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status.Xistbinds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for humanXISTRNA. We find thatXistbinding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi,Xistbinding does not lead to full silencing and also does not spread beyond the target gene. Over-expressingXistin transgenic ES cells similarly leads to autosomal gene suppression, while deletingXist’s Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with theXistinhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal thatXisttargets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by a small molecule inhibitor.
Genetic variants inTRIOare associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD), and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ),and+/M2145T(bipolar disorder, BPD) – impacts mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that model clinical phenotypes in humans.Triovariants differentially impact head and brain size, with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but+/K1431Mmice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in+/K1431Mvariant cortex. Our work reveals that discrete NDD-associatedTriovariants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.
Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis.Drosophilatracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the fibroblast growth factor mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here, we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.
Genetic variants inTRIOare associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD), and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ),and+/M2145T(bipolar disorder, BPD) – impacts mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that model clinical phenotypes in humans.Triovariants differentially impact head and brain size, with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but+/K1431Mmice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in+/K1431Mvariant cortex. Our work reveals that discrete NDD-associatedTriovariants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.
The zona pellucida (ZP) is vital for species-specific fertilization as this barrier mediates sperm-oocyte binding. Here, we determined whether sperm from distant mammalian orders (Carnivora, Primates, and Rodentia) could penetrate bovine oocytes by examining the role of bovine oviductal fluid and species-specific oviductal glycoprotein (OVGP1 or oviductin) from bovine, murine, or human sources in modulating the species-specificity of bovine and murine oocytes. Sperm from all the species were found to penetrate intact bovine ovarian oocytes to form hybrid embryos. However, contact with oviductal fluid or bovine, murine, or human OVGP1, conferred the ZP species-specificity, allowing only the penetration of the corresponding sperm regardless of the ZP’s origin. Glycolytic and microstructural analyses revealed that OVGP1 covers the pores present in the ZP and that OVGP1 glycosylation determines sperm specificity. This suggests specific fertilization capacity is acquired in the oviduct through the ZP’s incorporation of specific oviductin.
The zona pellucida (ZP) is vital for species-specific fertilization as this barrier mediates sperm-oocyte binding. Here, we determined whether sperm from distant mammalian orders (Carnivora, Primates, and Rodentia) could penetrate bovine oocytes by examining the role of bovine oviductal fluid and species-specific oviductal glycoprotein (OVGP1 or oviductin) from bovine, murine, or human sources in modulating the species-specificity of bovine and murine oocytes. Sperm from all the species were found to penetrate intact bovine ovarian oocytes to form hybrid embryos. However, contact with oviductal fluid or bovine, murine, or human OVGP1, conferred the ZP species-specificity, allowing only the penetration of the corresponding sperm regardless of the ZP’s origin. Glycolytic and microstructural analyses revealed that OVGP1 covers the pores present in the ZP and that OVGP1 glycosylation determines sperm specificity. This suggests specific fertilization capacity is acquired in the oviduct through the ZP’s incorporation of specific oviductin.
The General Stress Response promotes survival of bacteria in adverse conditions, but how sensor proteins transduce species-specific signals to initiate the response is not known. The serine/threonine phosphatase RsbU initiates the General Stress Response inBacillus subtilisupon binding a partner protein (RsbT) that is released from sequestration by environmental stresses. We report that RsbT activates RsbU by inducing otherwise flexible linkers of RsbU to form a short coiled-coil that dimerizes and activates the phosphatase domains. Importantly, we present evidence that related coiled-coil linkers and phosphatase dimers transduce signals from diverse sensor domains to control the General Stress Response and other signaling across bacterial phyla. This coiled-coil linker transduction mechanism additionally suggests a resolution to the mystery of how shared sensory domains control serine/threonine phosphatases, diguanylate cyclases and histidine kinases. We propose that this provides bacteria with a modularly exchangeable toolkit for the evolution of diverse signaling pathways.
Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.
Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.
Protein abundance tends to be more evolutionarily conserved than mRNA levels both within and between species, yet the mechanisms underlying this phenomenon remain largely unknown. Upstream open reading frames (uORFs) are widespreadcis-regulatory elements in eukaryotic genomes that regulate translation, but it remains unclear whether and how uORFs contribute to stabilizing protein levels. In this study, we performed ribosome translation simulations on mRNA to quantitatively assess the extent to which uORF translation influences the translational variability of downstream coding sequences (CDSs) across varying contexts. Our simulations revealed that uORF translation dampens CDS translational variability, with buffering capacity increasing in proportion to uORF translation efficiency, length, and number. We then compared the translatomes at different developmental stages of twoDrosophilaspecies, demonstrating that uORFs buffer mRNA translation fluctuations during both evolution and development. Experimentally, deleting a uORF in thebicoid(bcd) gene—a prominent example of translational buffering—resulted in extensive changes in gene expression and phenotypes inDrosophila melanogaster. Additionally, we observed uORF-mediated buffering between primates and within human populations. Together, our results reveal a novel regulatory mechanism by which uORFs stabilize gene translation during development and across evolutionary time.
The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, the involvements of DA release, real-time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.
Protein abundance tends to be more evolutionarily conserved than mRNA levels both within and between species, yet the mechanisms underlying this phenomenon remain largely unknown. Upstream open reading frames (uORFs) are widespreadcis-regulatory elements in eukaryotic genomes that regulate translation, but it remains unclear whether and how uORFs contribute to stabilizing protein levels. In this study, we performed ribosome translation simulations on mRNA to quantitatively assess the extent to which uORF translation influences the translational variability of downstream coding sequences (CDSs) across varying contexts. Our simulations revealed that uORF translation dampens CDS translational variability, with buffering capacity increasing in proportion to uORF translation efficiency, length, and number. We then compared the translatomes at different developmental stages of twoDrosophilaspecies, demonstrating that uORFs buffer mRNA translation fluctuations during both evolution and development. Experimentally, deleting a uORF in thebicoid(bcd) gene—a prominent example of translational buffering—resulted in extensive changes in gene expression and phenotypes inDrosophila melanogaster. Additionally, we observed uORF-mediated buffering between primates and within human populations. Together, our results reveal a novel regulatory mechanism by which uORFs stabilize gene translation during development and across evolutionary time.
The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, the involvements of DA release, real-time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.
The General Stress Response promotes survival of bacteria in adverse conditions, but how sensor proteins transduce species-specific signals to initiate the response is not known. The serine/threonine phosphatase RsbU initiates the General Stress Response inBacillus subtilisupon binding a partner protein (RsbT) that is released from sequestration by environmental stresses. We report that RsbT activates RsbU by inducing otherwise flexible linkers of RsbU to form a short coiled-coil that dimerizes and activates the phosphatase domains. Importantly, we present evidence that related coiled-coil linkers and phosphatase dimers transduce signals from diverse sensor domains to control the General Stress Response and other signaling across bacterial phyla. This coiled-coil linker transduction mechanism additionally suggests a resolution to the mystery of how shared sensory domains control serine/threonine phosphatases, diguanylate cyclases and histidine kinases. We propose that this provides bacteria with a modularly exchangeable toolkit for the evolution of diverse signaling pathways.
We present a method for spatially resolving the electric field potential throughout the entire volume of the human brain from electroencephalography (EEG) data. The method isnota variation of the well-known ‘source reconstruction’ methods, but rather a direct solution to the EEG inverse problem based on our recently developed model for brain waves that demonstrates the inadequacy of the standard ‘quasi-static approximation’ that has fostered the belief that such a reconstruction is not physically possible. The method retains the high temporal/frequency resolution of EEG, yet has spatial resolution comparable to (or better than) functional MRI (fMRI), without its significant inherent limitations. The method is validated using simultaneous EEG/fMRI data in healthy subjects, intracranial EEG data in epilepsy patients, comparison with numerical simulations, and a direct comparison with standard state-of-the-art EEG analysis in a well-established attention paradigm. The method is then demonstrated on a very large cohort of subjects performing a standard gambling task designed to activate the brain’s ‘reward circuit’. The technique uses the output from standard extant EEG systems and thus has potential for immediate benefit to a broad range of important basic scientific and clinical questions concerning brain electrical activity. By offering an inexpensive and portable alternative to fMRI, it provides a realistic methodology to efficiently promote the democratization of medicine.
The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson’s disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable. We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. At the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients displaying brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition. In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Furthermore, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence.
Attention mechanisms guide visuomotor behavior by weighing physical salience and internal goals to prioritize stimuli as choices for action. Although less well studied, selection history, which reflects multiple facets of experience with recent events, is increasingly recognized as a distinct source of attentional bias. To examine how selection history impacts saccadic choices, we trained two macaque monkeys to perform an urgent version of an oddball search task in which a red target appeared among three green distracters or vice versa. By imposing urgency, performance could be tracked continuously as it transitioned from uninformed guesses to informed choices as a function of processing time. This, in turn, permitted assessment of attentional control as manifest in motor biases, processing speed, and asymptotic accuracy. Here, we found that the probability of making a correct choice was strongly modulated by the histories of preceding target locations and target colors. Crucially, although both effects were gated by success (or reward), their dynamics were clearly distinct: whereas location history promoted a motor bias, color history modulated perceptual sensitivity, and these influences acted independently. Thus, combined selection histories can give rise to enormous swings in visuomotor performance even in simple tasks with highly discriminable stimuli.
Attention mechanisms guide visuomotor behavior by weighing physical salience and internal goals to prioritize stimuli as choices for action. Although less well studied, selection history, which reflects multiple facets of experience with recent events, is increasingly recognized as a distinct source of attentional bias. To examine how selection history impacts saccadic choices, we trained two macaque monkeys to perform an urgent version of an oddball search task in which a red target appeared among three green distracters or vice versa. By imposing urgency, performance could be tracked continuously as it transitioned from uninformed guesses to informed choices as a function of processing time. This, in turn, permitted assessment of attentional control as manifest in motor biases, processing speed, and asymptotic accuracy. Here, we found that the probability of making a correct choice was strongly modulated by the histories of preceding target locations and target colors. Crucially, although both effects were gated by success (or reward), their dynamics were clearly distinct: whereas location history promoted a motor bias, color history modulated perceptual sensitivity, and these influences acted independently. Thus, combined selection histories can give rise to enormous swings in visuomotor performance even in simple tasks with highly discriminable stimuli.
Although hierarchy is commonly invoked in descriptions of motor cortical function, its presence and manifestation in firing patterns remain poorly resolved. Here, we use optogenetic inactivation to demonstrate that short-latency influence between forelimb premotor and primary motor cortices is asymmetric during reaching in mice, demonstrating a partial hierarchy between the endogenous activity in each region. Multi-region recordings revealed that some activity is captured by similar but delayed patterns where either region’s activity leads, with premotor activity leading more. Yet firing in each region is dominated by patterns shared between regions and is equally predictive of firing in the other region at the single-neuron level. In dual-region network models fit to data, regions differed in their dependence on across-region input, rather than the amount of such input they received. Our results indicate that motor cortical hierarchy, while present, may not be exposed when inferring interactions between populations from firing patterns alone.
The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson’s disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable. We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. At the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients displaying brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition. In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Furthermore, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence.
Oxidative phosphorylation has emerged as a critical therapeutic vulnerability ofM. tuberculosis(Mtb). However, it is unknown how intracellular bacterial pathogens such asMtbmaintain respiration during infection despite the chemical effectors of host immunity.Mtbsynthesizes diisonitrile lipopeptides that tightly chelate copper, but the role of these chalkophores in host-pathogen interactions is also unknown. We demonstrate thatM. tuberculosischalkophores maintain the function of the heme-copperbcc:aa3respiratory supercomplex under copper limitation. Chalkophore deficiency impairsMtbsurvival, respiration to oxygen, and ATP production under copper deprivation in culture, effects that are exacerbated by loss of the heme-dependent Cytochrome BD respiratory oxidase. Our genetic analyses indicate that the maintenance of respiration is the major cellular target of chalkophore-mediated copper acquisition.M. tuberculosislacking chalkophore biosynthesis is attenuated in mice, a phenotype that is also severely exacerbated by loss of the CytBD respiratory oxidase. We find that the host immune pressure that attenuates chalkophore-deficientMtbis independent of adaptive immunity and neutrophils. These data demonstrate that chalkophores counter host-inflicted copper deprivation and highlight a multilayered system by whichM. tuberculosismaintains respiration during infection.
Understanding the variability of the environment is essential to function in everyday life. The brain must hence take uncertainty into account when updating its internal model of the world. The basis for updating the model are prediction errors that arise from a difference between the current model and new sensory experiences. Although prediction error neurons have been identified in layer 2/3 of diverse brain areas, how uncertainty modulates these errors and hence learning is, however, unclear. Here, we use a normative approach to derive how uncertainty should modulate prediction errors and postulate that layer 2/3 neurons represent uncertainty-modulated prediction errors (UPE). We further hypothesise that the layer 2/3 circuit calculates the UPE through the subtractive and divisive inhibition by different inhibitory cell types. By implementing the calculation of UPEs in a microcircuit model, we show that different cell types can compute the means and variances of the stimulus distribution. With local activity-dependent plasticity rules, these computations can be learned context-dependently, and allow the prediction of upcoming stimuli and their distribution. Finally, the mechanism enables an organism to optimise its learning strategy via adaptive learning rates.
A classic problem in metabolism is that fast-proliferating cells use seemingly wasteful fermentation for energy biogenesis in the presence of sufficient oxygen. This counterintuitive phenomenon, known as overflow metabolism or the Warburg effect, is universal across various organisms. Despite extensive research, its origin and function remain unclear. Here, we show that overflow metabolism can be understood through growth optimization combined with cell heterogeneity. A model of optimal protein allocation, coupled with heterogeneity in enzyme catalytic rates among cells, quantitatively explains why and how cells choose between respiration and fermentation under different nutrient conditions. Our model quantitatively illustrates the growth rate dependence of fermentation flux and enzyme allocation under various perturbations and is fully validated by experimental results inEscherichia coli. Our work provides a quantitative explanation for the Crabtree effect in yeast and the Warburg effect in cancer cells and can be broadly used to address heterogeneity-related challenges in metabolism.
A classic problem in metabolism is that fast-proliferating cells use seemingly wasteful fermentation for energy biogenesis in the presence of sufficient oxygen. This counterintuitive phenomenon, known as overflow metabolism or the Warburg effect, is universal across various organisms. Despite extensive research, its origin and function remain unclear. Here, we show that overflow metabolism can be understood through growth optimization combined with cell heterogeneity. A model of optimal protein allocation, coupled with heterogeneity in enzyme catalytic rates among cells, quantitatively explains why and how cells choose between respiration and fermentation under different nutrient conditions. Our model quantitatively illustrates the growth rate dependence of fermentation flux and enzyme allocation under various perturbations and is fully validated by experimental results inEscherichia coli. Our work provides a quantitative explanation for the Crabtree effect in yeast and the Warburg effect in cancer cells and can be broadly used to address heterogeneity-related challenges in metabolism.
We present a method for spatially resolving the electric field potential throughout the entire volume of the human brain from electroencephalography (EEG) data. The method isnota variation of the well-known ‘source reconstruction’ methods, but rather a direct solution to the EEG inverse problem based on our recently developed model for brain waves that demonstrates the inadequacy of the standard ‘quasi-static approximation’ that has fostered the belief that such a reconstruction is not physically possible. The method retains the high temporal/frequency resolution of EEG, yet has spatial resolution comparable to (or better than) functional MRI (fMRI), without its significant inherent limitations. The method is validated using simultaneous EEG/fMRI data in healthy subjects, intracranial EEG data in epilepsy patients, comparison with numerical simulations, and a direct comparison with standard state-of-the-art EEG analysis in a well-established attention paradigm. The method is then demonstrated on a very large cohort of subjects performing a standard gambling task designed to activate the brain’s ‘reward circuit’. The technique uses the output from standard extant EEG systems and thus has potential for immediate benefit to a broad range of important basic scientific and clinical questions concerning brain electrical activity. By offering an inexpensive and portable alternative to fMRI, it provides a realistic methodology to efficiently promote the democratization of medicine.
Although hierarchy is commonly invoked in descriptions of motor cortical function, its presence and manifestation in firing patterns remain poorly resolved. Here, we use optogenetic inactivation to demonstrate that short-latency influence between forelimb premotor and primary motor cortices is asymmetric during reaching in mice, demonstrating a partial hierarchy between the endogenous activity in each region. Multi-region recordings revealed that some activity is captured by similar but delayed patterns where either region’s activity leads, with premotor activity leading more. Yet firing in each region is dominated by patterns shared between regions and is equally predictive of firing in the other region at the single-neuron level. In dual-region network models fit to data, regions differed in their dependence on across-region input, rather than the amount of such input they received. Our results indicate that motor cortical hierarchy, while present, may not be exposed when inferring interactions between populations from firing patterns alone.
Understanding the variability of the environment is essential to function in everyday life. The brain must hence take uncertainty into account when updating its internal model of the world. The basis for updating the model are prediction errors that arise from a difference between the current model and new sensory experiences. Although prediction error neurons have been identified in layer 2/3 of diverse brain areas, how uncertainty modulates these errors and hence learning is, however, unclear. Here, we use a normative approach to derive how uncertainty should modulate prediction errors and postulate that layer 2/3 neurons represent uncertainty-modulated prediction errors (UPE). We further hypothesise that the layer 2/3 circuit calculates the UPE through the subtractive and divisive inhibition by different inhibitory cell types. By implementing the calculation of UPEs in a microcircuit model, we show that different cell types can compute the means and variances of the stimulus distribution. With local activity-dependent plasticity rules, these computations can be learned context-dependently, and allow the prediction of upcoming stimuli and their distribution. Finally, the mechanism enables an organism to optimise its learning strategy via adaptive learning rates.
The successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit–host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than 400 topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.
The successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit–host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than 400 topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.
Oxidative phosphorylation has emerged as a critical therapeutic vulnerability ofM. tuberculosis(Mtb). However, it is unknown how intracellular bacterial pathogens such asMtbmaintain respiration during infection despite the chemical effectors of host immunity.Mtbsynthesizes diisonitrile lipopeptides that tightly chelate copper, but the role of these chalkophores in host-pathogen interactions is also unknown. We demonstrate thatM. tuberculosischalkophores maintain the function of the heme-copperbcc:aa3respiratory supercomplex under copper limitation. Chalkophore deficiency impairsMtbsurvival, respiration to oxygen, and ATP production under copper deprivation in culture, effects that are exacerbated by loss of the heme-dependent Cytochrome BD respiratory oxidase. Our genetic analyses indicate that the maintenance of respiration is the major cellular target of chalkophore-mediated copper acquisition.M. tuberculosislacking chalkophore biosynthesis is attenuated in mice, a phenotype that is also severely exacerbated by loss of the CytBD respiratory oxidase. We find that the host immune pressure that attenuates chalkophore-deficientMtbis independent of adaptive immunity and neutrophils. These data demonstrate that chalkophores counter host-inflicted copper deprivation and highlight a multilayered system by whichM. tuberculosismaintains respiration during infection.
Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.
Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.
The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimer’s disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty-related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics, and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.
The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimer’s disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty-related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics, and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.
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Targeted monotherapies for cancer often fail due to inherent or acquired drug resistance. By aiming at multiple targets simultaneously, drug combinations can produce synergistic interactions that increase drug effectiveness and reduce resistance. Computational models based on the integration of omics data have been used to identify synergistic combinations, but predicting drug synergy remains a challenge. Here, we introduce Drug synergy Interaction Prediction (DIPx), an algorithm for personalized prediction of drug synergy based on biologically motivated tumor- and drug-specific pathway activation scores (PASs). We trained and validated DIPx in the AstraZeneca-Sanger (AZS) DREAM Challenge human cell-line dataset using two separate test sets: Test Set 1 comprised the combinations already present in the training set, while Test Set 2 contained combinations absent from the training set, thus indicating the model’s ability to handle novel combinations. The Spearman’s correlation coefficients between predicted and observed drug synergy were 0.50 (95% CI: 0.47–0.53) in Test Set 1 and 0.26 (95% CI: 0.22–0.30) in Test Set 2, compared to 0.38 (95% CI: 0.34–0.42) and 0.18 (95% CI: 0.16–0.20), respectively, for the best performing method in the Challenge. We show evidence that higher synergy is associated with higher functional interaction between the drug targets, and this functional interaction information is captured by PAS. We illustrate the use of PAS to provide a potential biological explanation in terms of activated pathways that mediate the synergistic effects of combined drugs. In summary, DIPx can be a useful tool for personalized prediction of drug synergy and exploration of activated pathways related to the effects of combined drugs.
Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 × 10-6, OR = 0.437, SE = 0.182) in theHLA-DPB1gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.
Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 × 10-6, OR = 0.437, SE = 0.182) in theHLA-DPB1gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.
The interferon-induced GTPase GVIN1 prevents bacteria from spreading among cells by coating them and rendering them immobile.
Targeted monotherapies for cancer often fail due to inherent or acquired drug resistance. By aiming at multiple targets simultaneously, drug combinations can produce synergistic interactions that increase drug effectiveness and reduce resistance. Computational models based on the integration of omics data have been used to identify synergistic combinations, but predicting drug synergy remains a challenge. Here, we introduce Drug synergy Interaction Prediction (DIPx), an algorithm for personalized prediction of drug synergy based on biologically motivated tumor- and drug-specific pathway activation scores (PASs). We trained and validated DIPx in the AstraZeneca-Sanger (AZS) DREAM Challenge human cell-line dataset using two separate test sets: Test Set 1 comprised the combinations already present in the training set, while Test Set 2 contained combinations absent from the training set, thus indicating the model’s ability to handle novel combinations. The Spearman’s correlation coefficients between predicted and observed drug synergy were 0.50 (95% CI: 0.47–0.53) in Test Set 1 and 0.26 (95% CI: 0.22–0.30) in Test Set 2, compared to 0.38 (95% CI: 0.34–0.42) and 0.18 (95% CI: 0.16–0.20), respectively, for the best performing method in the Challenge. We show evidence that higher synergy is associated with higher functional interaction between the drug targets, and this functional interaction information is captured by PAS. We illustrate the use of PAS to provide a potential biological explanation in terms of activated pathways that mediate the synergistic effects of combined drugs. In summary, DIPx can be a useful tool for personalized prediction of drug synergy and exploration of activated pathways related to the effects of combined drugs.
The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, andTET2knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of theFBP1promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, andTET2knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of theFBP1promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
A fundamental challenge in neuroscience is understanding neural functioning and plasticity of the brain. The anterior temporal lobe (ATL) is a hub for semantic memory, which generates coherent conceptual representations. GABAergic inhibition plays a crucial role in shaping human cognition and plasticity, but it is unclear how this inhibition relates to human semantic memory and its plasticity. Here, we employed a combination of continuous theta burst stimulation (cTBS), MR spectroscopy and fMRI to investigate the role of GABA in semantic memory and its neuroplasticity. We found that inhibitory cTBS increased GABA concentrations in the ATL and reduced blood-oxygen level-dependent (BOLD) activation during semantic tasks. Crucially, changes in GABA were tightly linked to changes in regional activity, suggesting that GABA mediates cTBS-induced plasticity. Individuals with better semantic performance exhibited selective activity in the ATL, attributable to higher GABA levels, which can sharpen distributed semantic representations. Our results revealed a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic performance, thus offering an explanation for the individual differences in semantic memory function and neuromodulation outcomes. These findings offer a neurochemical explanation for individual variability in neuromodulation and provide insights for developing targeted interventions for semantic impairments.
A fundamental challenge in neuroscience is understanding neural functioning and plasticity of the brain. The anterior temporal lobe (ATL) is a hub for semantic memory, which generates coherent conceptual representations. GABAergic inhibition plays a crucial role in shaping human cognition and plasticity, but it is unclear how this inhibition relates to human semantic memory and its plasticity. Here, we employed a combination of continuous theta burst stimulation (cTBS), MR spectroscopy and fMRI to investigate the role of GABA in semantic memory and its neuroplasticity. We found that inhibitory cTBS increased GABA concentrations in the ATL and reduced blood-oxygen level-dependent (BOLD) activation during semantic tasks. Crucially, changes in GABA were tightly linked to changes in regional activity, suggesting that GABA mediates cTBS-induced plasticity. Individuals with better semantic performance exhibited selective activity in the ATL, attributable to higher GABA levels, which can sharpen distributed semantic representations. Our results revealed a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic performance, thus offering an explanation for the individual differences in semantic memory function and neuromodulation outcomes. These findings offer a neurochemical explanation for individual variability in neuromodulation and provide insights for developing targeted interventions for semantic impairments.
Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.
Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar (Melopsittacus undulatus) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.
Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: (1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs. non-specific mid-cervical expression), and (2) can this method produce a sustained increase in inspiratory tidal volume? Wild-type (C57Bl/6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild-type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive neuronal DREADD expression in the C4 ventral horns, targeting phrenic motoneurons. Diaphragm electromyograms (EMG) were recorded in isoflurane-anesthetized spontaneously breathing mice at 4–9 weeks post-AAV delivery. The DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in ChAT-Cre rats were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume during spontaneous breathing, assessed using whole-body plethysmography without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in tidal volume. Subsequently, phrenic nerve recordings performed under urethane anesthesia confirmed that J60 evoked a >200% increase in inspiratory output. We conclude that targeting mid-cervical spinal DREADD expression to the phrenic motoneuron pool enables ligand-induced, sustained increases in phrenic motor output and tidal volume. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.
Daptomycin is a potent lipopeptide antibiotic used in the treatment of life-threatening Gram-positive infections, but the molecular mechanism of its interaction with bacterial membrane remains unclear. Here, we show that this interaction is divided into two stages, of which the first is a fast and reversible binding of the drug to phospholipid membrane in milliseconds, and the second is a slow and irreversible insertion into membrane in minutes, only in the presence of the bacteria-specific lipid phosphatidylglycerol, to a saturating point where the ratio of the drug to phosphatidylglycerol is 1:2. Fluorescence-based titration showed that the antibiotic simultaneously binds two molecules of phosphatidylglycerol with a nanomolar binding affinity in the presence of calcium ion. The resulting stable complex is easily formed in a test tube and readily isolated from the membrane of drug-treated bacterial cells, strongly supporting a unique drug uptake mechanism in which daptomycin forms a stable multicomponent complex with calcium and phosphatidylglycerol. Revelation of this novel uptake mechanism provides fresh insights into the mode of action of daptomycin and paves the way to new strategies to attenuate resistance to the drug.
Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar (Melopsittacus undulatus) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.
Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.
The imprinted geneZDBF2is regulated through a unique mechanism involving a transient paternal transcript in early embryos, rather than persistent gametic DNA methylation. In humans and mice, this transcript—CMKLR2-AS(also known asGPR1-AS) or the long isoform ofZdbf2(Liz/Zdbf2linc/Platr12)—arises from the unmethylated paternal allele and initiates secondary epigenetic marks that maintainZDBF2expression. Here, we investigate the evolutionary origin of this mechanism, and show that the first exon of humanGPR1-ASoverlaps with a MER21C long terminal repeat (LTR), a retrotransposon subfamily specific to Boreoeutherian mammals. Comparative analyses revealed that this MER21C insertion occurred in the common ancestor of Euarchontoglires, including primates, rodents, and rabbits. Although not annotated, the first exon of mouseLizdisplays conserved features with the MER21C-overlapping exon in humans. In rabbit and nonhuman primate placentas,GPR1-ASorthologs with LTR-embedded first exons were also identified. In contrast, in non-Euarchontoglire mammals such as cow and tammar wallaby,ZDBF2is biallelically expressed, suggesting absence of imprinting. These findings suggest thatZDBF2imprinting emerged in Euarchontoglires via MER21C insertion. Together with our prior work on LTR-driven imprinting in oocytes, our findings demonstrate that post-fertilization activation of retrotransposons can also drive lineage-specific acquisition of imprinting.
Nervous necrosis virus typically enters host cells via endocytosis, but it can also enter via a process called macropinocytosis.
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AbstractThe development of novel anti-seizure drugs targeting novel mechanisms is crucial, especially for patients with intractable epilepsy. Previous studies using focal onset seizure rodent models have demonstrated that Icilin and WS-3, agonists of the transient receptor potential melastatin 8 (TRPM8) channel, suppress drug-induce epileptiform discharges (EDs) and seizures (ESs). In contrast, TRPM8 deficiency exacerbates EDs and ESs. This study investigated the mechanism underlying the anti-seizure effects of the TRPM8 agonist, WS-3, using a focal onset seizure mouse model. Mice were injected with WS-3 either before or after administering the seizure inducer, penicillin G potassium. EDs, ESs, and glutamate levels were subsequently evaluated. In wild-type (WT) mice, WS-3 injected after the seizure inducer reduced glutamate levels and ED power by 44% and 60%, respectively, with a positive correlation between WS-3 efficacy and these parameters. WS-3 injection before seizure induction suppressed the increase in glutamate levels and the development of ED and ES, with positive correlations observed among the three parameters. Conversely, TRPM8-knockout mice showed no anti-seizure effects from WS-3. TRPM8 deficiency led to a further increase in the glutamate levels, ED power, and ES severity after the seizure inducer injection. Additionally, TRPM8-deficient mice experienced EDs with fewer glutamate exposures and shortened latency to ED development following seizure induction. These findings suggest that TRPM8 agonists suppress the development of EDs and ESs by reduction of extracellular glutamate levels, indicating that TRPM8 channels may represent a promising treatment option for epilepsy.
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AbstractWe developed an approach to disrupt cocaine-seeking behaviors using mediated devaluation. Male rats underwent cocaine self-administration training in which active lever responses led to cocaine infusions and the presentation of a tone-light conditioned stimulus (CS). Subsequently, during mediated devaluation rats received non-contingent presentations of the cocaine-associated CS in a second distinct context, which led to the cue-evoked retrieval of associated memories. This was immediately followed by an intraperitoneal injection of lithium chloride (LiCl) and served to pair the memory of cocaine reward with gastric malaise. Consequently, this led to a substantial reduction in cocaine-seeking behavior during extinction training, relative to rats that received CS-saline or LiCl alone during mediated devaluation. Cue- and cocaine-evoked reinstatement testing indicated that the manipulations did not devalue the CS or the reinforcing properties of cocaine. A separate cohort of rats received a dual-viral chemogenetic strategy that permitted circuit-specific inactivation of midbrain ventral tegmental area (VTA) cells projecting to the nucleus accumbens (NAc). Inactivation of VTA→NAc circuitry during mediated devaluation prevented the subsequent reduction of cocaine-seeking behavior during extinction training. Overall, these findings suggest that intact mesolimbic signaling is required to enable disruptions in cocaine-seeking behavior following mediated devaluation.
AbstractThe role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [11C]CURB λk3, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [11C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [11C]CURB λk3were observed between MDD participants and controls (F1,27= 0.32;p= 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [11C]CURB λk3binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F1,11= 6.75;p= 0.02). Depressive severity and anxiety did not have a significant relationship to [11C]CURB λk3binding. The relationship of greater fronto-limbic [11C]CURB λk3to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.
AbstractPain syndromes include physical, sensory, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. Experimental induction of long-term inflammatory pain in rodents by hindpaw injection of complete Freund’s adjuvant (CFA) produces anhedonia and dysregulated naturalistic behaviors, similar to the effects of unregulated stress. We examined whether these similarities extend to changes in sleep and rhythms, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG in mice. Comparisons were made between groups that received injections at the onset of the light or dark phase. We found that CFA-induced inflammatory pain alters sleep architecture in both sexes; most notably, it increased sleep duration in the dark phase—when mice are normally more likely to be awake—while also increasing sleep bout length and reducing wake bout length. In contrast, during the light phase, it decreased sleep bout length, indicating fragmentation. Similarly, CFA-induced increases in REM and SWS duration and bouts were largest during the dark phase. Dark-phase effects were remarkably consistent regardless of whether the mice had been injected at darkness onset or 12 h earlier, whereas light-phase effects were more dependent on time since injection. Injections also produced non-specific alterations in circadian rhythmicity. Our findings indicate that inflammatory pain prominently increases sleep during normally active phases as well as transitions between sleep and wakefulness throughout the day. These effects align with clinical observations and establish a basis for mechanistic studies and use of these procedures to better predict outcomes in humans.
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AbstractAbnormal motivation for natural rewards is a hallmark of various psychiatric disorders, including behavioral addiction. The mesolimbic dopamine pathway has been identified as a critical modulator of motivated behavior primarily based on studies using food-reinforced operant tasks. However, the focus on food rewards in previous studies limits the generalizability of these findings to other natural rewards implicated in behavioral addiction. In this study, we investigated the reinforcing and high motivational properties of wheel running in rodents by developing a wheel running-reinforced operant conditioning procedure. This procedure allowed for the independent quantification of appetitive and consummatory behaviors as operant responses and running duration, respectively, facilitating an in-depth exploration of the role of dopamine signaling in the medial nucleus accumbens (mNAc) in wheel running motivation. The results indicated that the systemic inhibition of dopamine D1and D2receptors suppressed appetitive behavior, whereas inhibition of D1receptors reduced consummatory behavior. Similarly, inhibition of mNAc neural activity and blockade of D1and D2receptors within this region diminished appetitive behavior, with D1receptor inhibition uniquely impairing consummatory behavior. Fiber photometry recordings demonstrated that decreases in mNAc neural activity and increases in dopamine levels preceded appetitive behavior. Additionally, mNAc neural activity and dopamine levels were elevated following cues signaling the availability of wheel running. Furthermore, systemic D1receptor inhibition attenuated the reduction in mNAc neural activity observed during appetitive behavior. These findings suggest that increased dopamine release and the subsequent D1receptor-mediated suppression of mNAc neural activity underlie the motivated behavior for wheel running.
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AbstractNovel treatment evaluation for youth with alcohol use disorder (AUD) is needed. Cannabidiol (CBD), a constituent of theCannabis sativaplant, may be a promising candidate pharmacotherapy due to its potential therapeutic properties and preclinical research suggesting it decreases alcohol use. Due to limited data in humans, rigorous screening of the acute neural, psychophysiological, and alcohol-related effects of CBD is indicated to assess its viability as a potential treatment for youth AUD. Using a within-subjects, randomized, double-blind, placebo-controlled design, we tested acute multi-modal effects of CBD (600 mg) in non-treatment seeking youth with AUD (N= 36; ages 17–22; 69% female). Outcomes included (1) glutamate+glutamine (Glx) and GABA levels in the anterior cingulate cortex measured with proton magnetic resonance spectroscopy; (2) whole-brain and a priori region-of-interest neural alcohol cue-reactivity measured with functional MRI; (3) psychophysiological response to alcohol olfactory cues measured by self-reported acute alcohol craving, heart rate variability, and skin conductance; and (4) alcohol use. No CBD-associated adverse events were observed. There were no effects of acute CBD administration, compared to placebo, on any outcomes of interest. This is the first adequately powered medication screening study for the use of CBD in youth with AUD. We did not detect significant effects of CBD on neurometabolic, neurobehavioral, psychophysiological, or alcohol use outcomes in this sample. Future studies may benefit from chronic administration to better understand substance-related effects.Clinicaltrials.gov NCT05317546https://clinicaltrials.gov/study/NCT05317546
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AbstractWe have previously shown that neuropeptide Y (NPY) reduces social fear in an animal model that closely mimics the key behavioral symptoms of social anxiety disorder (SAD). Since NPY cannot yet be routinely administered to patients, we investigated the effects of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor approved for the treatment of type 2 diabetes mellitus, on social fear and comorbid depression in mice. In addition to its well-known effects on glucose metabolism, sitagliptin also prevents the degradation of NPY, thereby increasing its concentration in the blood and the brain. We show that sitagliptin administration via drinking water (50 and 100 mg/kg/day, for 4 weeks) not only reduced social fear but also prevented the onset of comorbid depressive-like behavior in outbred CD1 mice. A similar phenotype was observed in homozygous DPP4-deficient mice, emphasizing the role of DPP4 in regulating these behaviors. However, in NPY-deficient mice, sitagliptin showed reduced efficacy, suggesting that NPY plays an important role in mediating the effects of sitagliptin on social fear and comorbid depression. These findings have important clinical implications, indicating that early intervention with sitagliptin could be an effective strategy for treating SAD, alleviating both core symptoms and reducing the risk of developing comorbid mood disorders that often complicate treatment outcomes.
AbstractStress and traumatic experiences have significant and lasting effects on sensory systems. We recently identified unique expression of proteins associated with epidermal skin cells (keratinocytes) and mechanosensory Merkel cells (MC) in circulating extracellular vesicles from adult women who had experienced sexual trauma specifically during adolescence, biologically linking trauma exposure with a specific neuron-like skin cell. Here, we aimed to develop and validate a preclinical mouse model utilizing chemogenetic (DREADD Gq) activation of a population of MC. Using a reporter line, we confirmed the expected pattern of the Krt14 Cre in specific MC skin areas and that these tissues expressed relevant MC marker genes similarly between male and female mice. Chemogenetic stimulation of MC produced robust neuronal activation of the insular cortex (IC), a brain region relevant to somatosensory and valence integration. To determine if the mice could detect MC activation, home cage behaviors following CNO treatment significantly increased nest grooming time. Conditioned place preference further revealed an avoidance response following MC stimulation; an effect that was stronger in female mice. Finally, to connect back to our trauma question, we examined MC activation in fear conditioning and identified deficits in fear extinction. Overall, these studies validate utilization of this preclinical model in further investigating the mechanosensory system and its potential involvement in PTSD symptoms and therapeutic interventions. Ongoing studies will focus on critical developmental periods relevant to both MC development and sex differences associated with trauma vulnerability and potential sensory based therapeutic options for PTSD-related symptoms.
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AbstractCues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or ‘neuronal ensembles’ in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify ‘anti-craving’ relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of ‘originally’, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost – resulting in their persistent activation and non-cue selective activation or ‘excitatory overdrive’. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting ‘inhibitory underdrive’. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory ‘overdrive’ and inhibitory ‘underdrive’ likely underlies EE’s anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.
AbstractAntidepressant-induced apathy syndrome is reported in a high number of patients. It is characterised by loss of motivation for daily activities and emotional blunting. It has a negative impact on quality of life and treatment outcome, yet the changes in underlying neurobiology driving this syndrome remain unclear. To begin to address this, a comprehensive understanding of how different classes of antidepressant treatment impact on behaviours relevant to apathy is critical. Rodent motivation for reward is commonly assessed using effort-based operant conditioning paradigms such as the Effort for Reward task. However, motivation to perform spontaneous/innate behaviours may provide additional insight into changes in behaviour reflective of daily activities. We tested the acute and chronic effects of antidepressants on the Effort for Reward task, and the spontaneous/innate Effort-Based Forage task. Acute treatment revealed important divergence in drug effect between tasks, where selective serotonin reuptake inhibitor (SSRI)/serotonin and noradrenaline reuptake inhibitor (SNRI) treatment impaired foraging behaviour in the Effort Based Forage task, but enhanced high-effort, high-value reward responding in the Effort for Reward task. Treatment with a noradrenaline reuptake inhibitor (NRI) or multimodal agent impaired foraging behaviour but did not affect high reward responding in the Effort for Reward task. Conversely, chronic treatment with an SSRI but not SNRI enhanced motivated foraging behaviour but led to a general impairment in Effort for Reward task output. Together, these data demonstrate that SSRI treatment induces opposing effects on conditioned versus innate motivation which may have significant translational relevance when interpreting drug effect. Further, these behavioural effects differ depending on whether antidepressants are acutely or chronically administered.
Attention samples visual space sequentially to enhance behaviorally relevant sensory representations. While traditionally conceptualized as a static continuous spotlight, contemporary models of attention highlight its discrete nature. But which neural mechanisms govern the temporally precise allocation of attention? Periodic brain activity as exemplified by neuronal oscillations as well as aperiodic temporal structure in the form of intrinsic neural timescales have been proposed to orchestrate the attentional sampling process in space and time. However, both mechanisms have been largely studied in isolation. To date, it remains unclear whether periodic and aperiodic temporal structure reflect distinct neural mechanisms. Here, we combined computational simulations with a multimodal approach encompassing five experiments, and three different variants of classic spatial attention paradigms, to differentiate aperiodic from oscillatory-based sampling. Converging evidence across behavior as well as scalp and intracranial electroencephalography (EEG) revealed that periodic and aperiodic temporal regularities can theoretically and experimentally be distinguished. Our results extend the rhythmic sampling framework of attention by demonstrating that aperiodic neural timescales predict behavior in a spatially-, context-, and demand-dependent manner. Aperiodic timescales increased from sensory to association cortex, decreased during sensory processing or action execution, and were prolonged with increasing behavioral demands. These results reveal that multiple, concurrent temporal regularities govern attentional sampling.
Humans sometimes have an insight that leads to a sudden and drastic performance improvement on the task they are working on. The precise origins of such insights are unknown. Some evidence has shown that sleep facilitates insights, while other work has not found such a relationship. One recent suggestion that could explain this mixed evidence is that different sleep stages have differential effects on insight. In addition, computational work has suggested that neural variability and regularisation play a role in increasing the likelihood of insight. To investigate the link between insight and different sleep stages as well as regularisation, we conducted a preregistered study in which N=90 participants performed a perceptual insight task before and after a 20 minute daytime nap. Sleep EEG data showed that N2 sleep, but not N1 sleep, increases the likelihood of insight after a nap, suggesting a specific role of deeper sleep. Exploratory analyses of EEG power spectra showed that spectral slopes could predict insight beyond sleep stages, which is broadly in line with theoretical suggestions of a link between insight and regularisation. In combination, our findings point towards a role of N2 sleep and aperiodic, but not oscillatory, neural activity for insight.
[Fe-S] clusters are ancient and ubiquitous protein co-factors, which contributed to the emergence of life in an anoxic planet. We have recently identified two minimal [Fe-S] biogenesis systems, MIS and SMS, inferred to be ancestral systems dating back to the Last Universal Common Ancestor and which gave rise to the well-studied modern Iron-Sulfur Cluster (ISC), Nitrogen Fixation (NIF), and Sulfur Mobilization (SUF) machineries. The present study focuses on the ancestor SMS from the hyperthermophilic archaeonMethanocaldococcus jannaschii. Biochemical and structural studies showed that SMS is made of a SmsC2B2heterotetratmer wherein the SmsC subunit hosts both ATP and [Fe-S] cluster binding sites. Binding of ATP and assembly of [Fe-S] were found to be mutually exclusive allowing for a regulatory coupling between binding of both substrates. Mutagenesis and in vitro transfer experiments revealed the key role of SmsC-contained Cys residues in cluster assembly. Strikingly, the SMS system rescued a non-viableEscherichia colistrain lacking endogenous ISC and SUF systems grown under anoxic conditions, in the presence of Na2S, indicating that sulfide is a source of sulfur for SMS. In addition, we predict that most archaea SmsC proteins hold a similar C-terminal [Fe-S] cluster assembly site. Taking into account those unique structural and functional features, we propose a mechanistic model describing how SmsC2B2assembles and distributes [4Fe-4S] clusters. Altogether this study established SMS as a newbona fide[Fe-S] biogenesis system that operated in anaerobic prokaryotes prior to evolve to SUF after the Great Oxydation Event.
Innovations often shape the trajectory of macroevolution, yet their effects are usually considered independently, thus ignoring the functional and evolutionary interactions between them. Two innovations that have underpinned the ecological and evolutionary success of ray-finned fishes (Actinopterygii) are large teeth and highly protrusible jaws, which independently expanded the diversity of prey capture strategies. Here, we explore the functional relationship between these innovations across actinopterygians using high-speed videography and phylogenetic comparative methods. We find that these two innovations are functionally and evolutionarily incompatible because there is an overarching tradeoff between jaw protrusion and tooth size. Having large teeth decreases the kinematic diversity of prey capture by restricting species to overtake prey predominantly by swimming, while highly protrusible jaws are only found in species with small teeth. The space within tooth-bearing bones may impose this constraint, by limiting the maximum tooth size of species with gracile jaws adapted for high mobility and jaw protrusion. Nevertheless, some species break this constraint on tooth size through novel adaptations that accommodate exceptionally large teeth, unlocking new feeding modes which may have expanded the nature of aquatic feeding and influenced the ecosystems themselves. Although both high jaw protrusion and large teeth separately expanded prey capture strategies in fishes, they are generally not found in combination and are evolutionarily incompatible.
Viruses encounter a range of selective pressures, but inefficiencies during replication can be masked. To uncover factors that limit viral replication, we used forward genetics to enrich for a murine norovirus (MNV) mutant with faster replication. We sequentially harvested the earliest progeny in cultured cells and identified a single amino acid change in the viral NS3 protein, K40R, that was sufficient to enhance replication speed. We found that the NS3-K40R virus induced earlier cell death and viral egress compared with wild-type virus. Mechanistically, NS3-K40R protein disrupted membranes more efficiently than wild-type NS3 protein, potentially contributing to increased mitochondrial dysfunction and cell death. Immunodeficient mice infected with NS3-K40R virus had increased titers, suggesting that increasing egress did not reduce fitness in vivo. Overall, by using a forward genetic approach, we identified a previously unknown inefficiency in norovirus egress and provide new insights into selective pressures that influence viral replication and evolution.
The ‘sprawling-parasagittal’ postural transition is a key part of mammalian evolution, associated with sweeping reorganization of the postcranial skeleton in mammals compared to their forebears, the non-mammalian synapsids. However, disputes over forelimb function in fossil synapsids render the precise nature of the ‘sprawling-parasagittal’ transition controversial. We shed new light on the origins of mammalian posture, using evolutionary adaptive landscapes to integrate 3D humerus shape and functional performance data across a taxonomically comprehensive sample of fossil synapsids and extant comparators. We find that the earliest pelycosaur-grade synapsids had a unique mode of sprawling, intermediate between extant reptiles and monotremes. Subsequent evolution of synapsid humerus form and functional traits showed little evidence of a direct progression from sprawling pelycosaurs to parasagittal mammals. Instead, posture was evolutionarily labile, and the ecological diversification of successive synapsid radiations was accompanied by variation in humerus morphofunctional traits. Further, synapsids frequently evolve toward parasagittal postures, diverging from the reconstructed optimal evolutionary path; the optimal path only aligns with becoming increasingly mammalian in derived cynodonts. We find the earliest support for habitual parasagittal postures in stem therians, implying that synapsids evolved and radiated with distinct forelimb trait combinations for most of their recorded history.
Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate uniquein vitromodels to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.
Ovulation is a spatiotemporally coordinated process that involves several tightly controlled events, including oocyte meiotic maturation, cumulus expansion, follicle wall rupture and repair, and ovarian stroma remodeling. To date, no studies have detailed the precise window of ovulation at single-cell resolution. Here, we performed parallel single-cell RNA-seq and spatial transcriptomics on paired mouse ovaries across an ovulation time course to map the spatiotemporal profile of ovarian cell types. We show that major ovarian cell types exhibit time-dependent transcriptional states enriched for distinct functions and have specific localization profiles within the ovary. We also identified gene markers for ovulation-dependent cell states and validated these using orthogonal methods. Finally, we performed cell–cell interaction analyses to identify ligand-receptor pairs that may drive ovulation, revealing previously unappreciated interactions. Taken together, our data provides a rich and comprehensive resource of murine ovulation that can be mined for discovery by the scientific community.
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The ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and non-infectious granulomas and the foreign body response, but are also observed in the aging ovary. The function and consequence of ovarian MNGCs remain unknown as their biological activity is highly context-dependent, and their large size has limited their isolation and analysis through technologies such as single-cell RNA sequencing. In this study, we define ovarian MNGCs through a deep analysis of their presence across age and species using advanced imaging technologies as well as their unique transcriptome using laser capture microdissection. MNGCs form complex interconnected networks that increase with age in both mouse and nonhuman primate ovaries. MNGCs are characterized by highGpnmbexpression, a putative marker of ovarian and non-ovarian MNGCs. Pathway analysis highlighted functions in apoptotic cell clearance, lipid metabolism, proteolysis, immune processes, and increased oxidative phosphorylation and antioxidant activity. Thus, MNGCs have signatures related to degradative processes, immune function, and high metabolic activity. These processes were enriched in MNGCs compared to primary ovarian macrophages, suggesting discrete functionality. MNGCs express CD4 and colocalize with T-cells, which were enriched in regions of MNGCs, indicative of a close interaction between these immune cell types. These findings implicate MNGCs in modulation of the ovarian immune landscape during aging given their high penetrance and unique molecular signature that supports degradative and immune functions.
Intelligent behavior involves mentally arranging learned information in novel ways and is particularly well developed in humans. While nonhuman primates (NHP) will learn to arrange new items in serial order and re-arrange neighboring items within that order, it has remained contentious whether they are capable to re-assign items more flexibly to non-adjacent serial positions. Such mental re-indexing is facilitated by inferring the sequential structure of experiences as opposed to learning serial chains of item-item associations. Here, we tested the ability for flexible mental re-indexing in rhesus macaques. Subjects learned to choose five objects in a predetermined sequential order. A change of the background context indicated when the object order changed, probing the subjects to mentally re-arrange objects to non-adjacent positions of the learned serial structure. Subjects successfully used the context cue to pro-actively re-index items to new, non-adjacent positions. Mental re-indexing was more likely when the initial order had been learned at a higher level, improved with more experience of the re-indexing rule and correlated with working memory performance in a delayed match-to-sample task. These findings suggest that NHPs inferred the sequential structure of experiences beyond a chaining of item-item associations and mentally re-arrange items within that structure. The pattern of results indicates that NHPs form non-spatial cognitive maps of their experiences, which is a hallmark for flexible mental operations in many serially ordered behaviors including communication, counting or foraging.
Across saccades, neurons in retinotopically organized visual representations experience drastically different images, but visual percepts remain stable. Here we investigated whether such stability can be mediated, in part, via prediction-error signaling by neurons processing post-saccadic visual images. We specifically recorded from foveal superior colliculus (SC) neurons when a visual image only overlapped with their response fields (RF’s) after foveating saccades but not pre-saccadically. When we rapidly changed the target features intra-saccadically, the foveal neurons’ post-saccadic visual reafferent responses were elevated, even though the neurons did not directly sample the pre-saccadic extrafoveal target features. This effect did not occur in the absence of saccades, and it also scaled with the extent of the introduced intra-saccadic image feature discrepancies. These results suggest that foveal SC neurons may signal a trans-saccadic prediction error when the foveated image stimulating them is inconsistent with that expected from pre-saccadic extrafoveal representations, a potential perceptual stability mechanism.
Glycoprotein 2 (GP2) and Uromodulin (UMOD) are considered as paralogs that share high sequence similarity and have similar antibacterial functions. UMOD are abundant as filaments in the urinary tract, and a high-mannose N-glycosylation site located on the N-terminal region protruding from UMOD filament core (referred to as branch) acts as an adhesion antagonist against pathogenic bacterial infections. The antibacterial function of UMOD can be eliminated by proteases, as the UMOD branch is susceptible to proteolytic activity. GP2 is expressed in the pancreas and secreted into the digestive tract. Whether GP2 executes its function in filament form and how it remains functional in the protease-enriched digestive tract is unclear. In this study, we extract GP2 filaments from surgically excised human pancreas and determined their cryo-EM structure. Our structure analysis unveiled that GP2 forms filaments with its ZP modules, composing the ZPN and ZPC domains along with a linker that connects these two domains. The N-terminal region (branch) of GP2 does not constitute the filament core and appears flexible in the cryo-EM structure. Our biochemical experiments suggested that although the GP2 branch is also protease-susceptible, additional high-mannose N-glycans were identified on the protease-resistant GP2 filament core. Consequently, the branch-free GP2 filaments retain their binding ability to the bacterial adhesin FimH, ensuring GP2’s antibacterial function unaffected in the proteolytic environment. Our study provides the first experimental evidence of GP2 filament formation and reveals the molecular mechanisms underlying GP2’s adaptation to a different environment compared to UMOD.
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T stem cell-like memory cells (TSCMcells) are considered to be essential for the maintenance of immune memory. The TSCMpopulation has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human TSCMpopulation consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-termin vivolabelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profilesex vivo, different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi TSCMincreases with age. Most importantly, CD95hi and CD95int TSCMcells also have very different dynamicsin vivowith CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int TSCM. While both TSCMsubpopulations exhibit considerable multipotency, no single population of TSCMcells has both the properties of self-renewal and clonal longevity. Instead, the “stemness” of the TSCMpopulation is generated by the complementary dynamic properties of the two subpopulations: CD95int TSCMwhich have the property of clonal longevity and CD95hi TSCMwhich have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.
Predictive coding posits the brain predicts incoming sensory information and signals a positive prediction error when the actual input exceeds what was predicted, and a negative prediction error when it falls short of the prediction. It is theorized that specific neurons encode the negative prediction error, distinct from those for the positive prediction error, and are linked to responses to omitted expected inputs. However, what information is actually encoded by omission responses remains unclear. This information is essential to confirm their role as negative prediction errors. Here, we record single-unit activity in the rat auditory cortex during an omission paradigm where tone probabilities are manipulated to vary the prediction content. We identify neurons that robustly respond to omissions, with responses that increase with evidence accumulation and directly correlate with tone predictability—key characteristics suggesting their role as negative prediction-error neurons. Interestingly, these neurons showed selective omission responses but broad tone responses, revealing an asymmetry in error signaling. To capture this asymmetry, we propose a circuit model composed of laterally interconnected prediction-error neurons that qualitatively reproduce the observed asymmetry. Furthermore, we demonstrate that these lateral connections enhance the precision and efficiency of prediction encoding across receptive fields, and that their validity is supported by the free energy principle.
The evolution of sexual secondary characteristics necessitates regulatory factors that confer sexual identity to differentiating tissues and cells. InColias eurythemebutterflies, males exhibit two specialized wing scale types—ultraviolet-iridescent (UVI) and spatulate scales—which are absent in females and likely integral to male courtship behavior. This study investigates the regulatory mechanisms and single-nucleus transcriptomics underlying these two sexually dimorphic cell types during wing development. We show thatDoublesex(Dsx) expression is itself dimorphic and required to repress the UVI cell state in females, while unexpectedly, UVI activation in males is independent fromDsx. In the melanic marginal band,Dsxis required in each sex to enforce the presence of spatulate scales in males, and their absence in females. Single-nucleus RNAseq reveals that UVI and spatulate scale cell precursors each show distinctive gene expression profiles at 40% of pupal development, with marker genes that include regulators of transcription, cell signaling, cytoskeletal patterning, and chitin secretion. Both male-specific cell types share a low expression of theBric-a-brac(Bab) transcription factor, a key repressor of the UVI fate. Bab ChIP-seq profiling suggests that Bab binds thecis-regulatory regions of gene markers associated to UVI fate, including potential effector genes involved in the regulation of cytoskeletal processes and chitin secretion, and loci showing signatures of recent selective sweeps in a UVI-polymorphic population. These findings open new avenues for exploring wing patterning and scale development, shedding light on the mechanisms driving the specification of sex-specific cell states and the differentiation of specialized cell ultrastructures.
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Successful initiation of animal development requires activation of the egg immediately prior to fusion of gamete pronuclei. In all taxa, this is initiated by waves of calcium transients which transverse across the egg. Calcium waves also occur at cleavage furrows during later blastula cytokinesis. Calcium is released from the endoplasmic reticulum through activation of inositol-1,4,5-trisphosphate (IP3) receptors. Only a subset of the mechanisms employed to generate IP3during vertebrate egg activation are defined, with strong evidence that other critical mechanisms exist. Serine proteases have been long implicated in egg activation and fertilization. Here, we report that treatment of zebrafish eggs with serine protease inhibitors leads to defective calcium wave propagation and failed egg activation. We further show that mutation of zebrafish Protease-activated receptor 2a (Par2a) also results in severe disruption of egg activation, leading to failed chorion elevation and ooplasmic segregation. Milderpar2amutants progress further, but then show abnormal blastomere cleavage. We observed thatpar2amutants show decreased amplitude and duration of calcium transients. Restoring Ca++or direct injection of IP3ligand rescues egg activation aborted by either serine protease inhibitor treatment or by mutation of Par2a. We thus show that serine protease activity is a critical regulator of IP3and subsequent calcium wave amplification during zebrafish egg activation, and link this to intracellular calcium release via the protease receptor, Par2a. This constitutes a novel signaling pathway critical for successful fertilization.
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The dynamic fluctuations in the amplitude of sound, known as sound envelopes, are ubiquitous in natural sounds and convey information critical for the recognition of speech, and of sounds generally. We are perceptually most sensitive to slow modulations which are most common. However, previous studies of envelope coding in the brainstem found an under-representation of these slow, low-frequency, modulations. Specifically, the synchronization of spike times to the envelope was enhanced in some neuron types, forming channels specialized for envelope processing but tuned to a restricted range of fast, high-frequency, envelopes (200–500 Hz). Here, we show using a historical dataset from cats that previous analyses, which made strong assumptions about the neural code, underestimated the encoding of low-frequency envelopes. While some neurons encode envelope better than others, most encode a wide range of envelope frequencies, and represent slower envelope fluctuations most accurately in their precise patterns of spike times. Identification of envelope frequency from spike-timing was linked to reliability, and to the way that dynamics of spiking interacted with the time-varying envelope. In some of the best-performing neurons, temporally complex “mode-locked” spike patterns served to enhance envelope coding. A second long-standing contradiction was that neural envelope coding is degraded at high sound levels, whilst the perception of envelope is robust at a wide range of sound levels. We find that spike-time encoding of envelope shape becomes level-robust for small populations of neurons. These findings argue against feature-specific coding of envelopes in the brainstem, and for a distributed population spike-time code for which synchrony to the envelope is an incomplete description. This code is accurate for slow fluctuations and robust across sound level. Thus, precise spike-timing information in the brainstem is after-all aligned with the needs of communication and the perception of environmental sounds.
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Understanding synaptic dynamics during the sleep–wake cycle in the cortex is crucial yet remains controversial. The synaptic homeostasis hypothesis (SHY) suggests synaptic depression during non-rapid eye movement (NREM) sleep, while other studies report synaptic potentiation or synaptic changes during NREM sleep depending on activities in wakefulness. To find boundary conditions between these contradictory observations, we focused on learning rules and firing patterns that contribute to the synaptic dynamics. Using computational models considering mammalian cortical neurons, we found that under Hebbian and spike-timing dependent plasticity (STDP), wake-like firing patterns decrease synaptic weights, while sleep-like patterns strengthen synaptic weights. We refer to this tendency as Wake Inhibition and Sleep Excitation (WISE). Conversely, under Anti-Hebbian and Anti-STDP, synaptic depression during NREM sleep was observed, aligning with the conventional synaptic homeostasis hypothesis. Moreover, synaptic changes depended on firing rate differences between NREM sleep and wakefulness. We provide a unified framework that could explain synaptic homeodynamics under the sleep–wake cycle.
Bacteria produce a plethora of natural products that are in clinical, agricultural and biotechnological use. Genome mining has uncovered millions of biosynthetic gene clusters (BGCs) that encode their biosynthesis, the vast majority of them lacking a clear product or function. Thus, a major challenge is to predict the bioactivities of the molecules these BGCs specify, and how to elicit their expression. Here, we present an innovative strategy whereby we harness the power of regulatory networks combined with global gene expression patterns to predict BGC functions. Bioinformatic analysis of all genes predicted to be controlled by the iron master regulator DmdR1 combined with co-expression data, led to identification of the novel operondesJGHthat plays a key role in the biosynthesis of the iron overload drug desferrioxamine (DFO) B inStreptomyces coelicolor. Deletion of eitherdesGordesHstrongly reduces the biosynthesis of DFO B, while that of DFO E is enhanced. DesJGH most likely act by changing the balance between the DFO precursors. Our work shows the power of harnessing regulation-based genome mining to functionally prioritize BGCs, accelerating the discovery of novel bioactive molecules.
Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is epistatic over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, supported by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells.
Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, most of these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased toward the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published functional screens and proteomics data to reveal (i) common pathways that were identified in all OMICs datasets—including regulation of Wnt signaling and gap junctions, (ii) pathways uniquely identified in this screen—including NADH oxidation, or (iii) pathways supported by this screen and proteomics data but not published functional screens—including arachionate production and MAPK signaling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 32 proteins that were determined to impact viral replication and 27 impacting late stages of infection, respectively. Additionally, a subset of proteins was tested across other coronaviruses revealing a subset of proviral factors that were conserved across pandemic SARS-CoV-2, epidemic SARS-CoV-1 and MERS-CoV, and the seasonal coronavirus OC43-CoV. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus–host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.
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Migraine aura – manifesting as transient, neurological disturbances – presents a complex and unresolved relationship with migraine headache. Cortical spreading depolarization (SD), recognized as the mechanism underlying aura symptoms, has been shown to trigger head pain through activation of trigeminal nociceptors in animal models. However, recent clinical data challenge the notion that aura causes migraine headache in patients. In this Essay, we critically examine the pathophysiology of migraine aura and migraine headache, exploring evidence from clinical observations, (genetic) mouse models, and pharmacological studies. We also discuss the role of SD, the trigeminovascular system, and the impact of pharmacological agents that both trigger and treat migraine attacks. Our essay highlights the complexities and conflicting data surrounding the interplay between aura and headache, emphasizing the need for further research to unravel this mystery and improve therapeutic strategies for individuals with migraine.
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Presynaptic scaffold proteins, including liprin-α, RIM, and ELKS, are pivotal to the assembly of the active zone and regulating the coupling of calcium signals and neurotransmitter release, yet the underlying mechanism remains poorly understood. Here, we determined the crystal structure of the liprin-α2/RIM1 complex, revealing a multifaceted intermolecular interaction that drives the liprin-α/RIM assembly. Neurodevelopmental disease-associated mutations block the formation of the complex. Disrupting this interaction in cultured human neurons impairs synaptic transmission and reduces the readily releasable pool of synaptic vesicles. Super-resolution imaging analysis supports a role for liprin-α in recruiting RIM1 to the active zone, presumably by promoting the liquid–liquid phase separation (LLPS) of RIM1. Strikingly, the liprin-α/RIM interaction modulates the competitive distribution of ELKS1 and voltage-gated Ca2+channels (VGCCs) in RIM1 condensates. Disrupting the liprin-α/RIM interaction significantly decreased VGCC accumulation in the condensed phase and rendered release more sensitive to the slow calcium buffer EGTA, suggesting an increased physical distance between VGCC and vesicular calcium sensors. Together, our findings provide a plausible mechanism of the liprin-α/RIM complex in regulating the coupling of calcium channels and primed synaptic vesicles via LLPS for efficient synaptic transmission and uncover the pathological implication of liprin-α mutations in neurodevelopmental disorders.
Genes do not act in isolation, and the effects of a specific variant at one locus can often be greatly modified by polymorphic variants at other loci. A good example isFLOWERING LOCUS C(FLC), which has been inferred to explain much of the flowering time variation inArabidopsis thaliana. We use a set of 62flcspecies-wide mutants to document pleiotropic, genotype-dependent effects forFLCon flowering as well as several other traits. Time to flowering was greatly reduced in all mutants, with the remaining variation explained mainly by allelic variation at theFLCtargetFT. Analysis ofFTsequence variation suggested that extremely early combinations ofFLCandFTalleles should exist in the wild, which we confirmed by targeted collections. Our study provides a proof of concept on how pan-genetic analysis of hub genes can reveal the true extent of genetic networks in a species.
tRNA halves are among the most abundant short non-coding RNAs in the cellular transcriptome. Here we report that in androgen receptor-positive LNCaP prostate cancer cells, the hormone-dependent 5′-tRNALysCUUhalf promoted cell proliferation by facilitating cell cycle progression. Global mRNA profiling upon the 5′-tRNALysCUUhalf depletion revealed that the mRNA of p21, a negative regulator of the cell cycle, is post-transcriptionally destabilized via a 5′-tRNALysCUUhalf-driven mechanism. YBX1, identified as a protein interacting with 5′-tRNALysCUUhalf in the cytosol, was shown to stabilize p21 mRNA. Specific sequences resembling the 5′-tRNALysCUUhalf, located in the 3′-UTR of p21 mRNA and termed LL588, were identified as the binding site for YBX1 and are required for p21 mRNA stability. In vitro binding assays demonstrated that the 5′-tRNALysCUUhalf is capable of displacing YBX1 from LL588. Collectively, our findings suggest that the 5′-tRNALysCUUhalf directly binds to and displaces YBX1 from p21 mRNA, leading to the destabilization of p21 mRNA and the promotion of cell cycle progression in hormone-dependent cancers. Our study illuminates the role of tRNA halves in regulating mRNA stability and suggests that this may be part of broader regulatory networks affecting mRNA levels, orchestrated by various tRNA halves and their interacting proteins.
Neural tracking (entrainment) of auditory rhythms enhances perception. We previously demonstrated that transcranial alternating current stimulation (tACS) can enhance or suppress entrainment to rhythmic auditory stimuli, depending on the timing between the electrical and auditory signals, although tACS effects are primarily modulatory. This study further investigated entrainment to tACS and auditory rhythms when the electrical and auditory signals were presented together (Experiment 1,N= 34) or independently (Experiment 2,N= 24; Experiment 3,N= 12). We hypothesized that tACS effects would be more pronounced when the auditory rhythm was made less perceptually salient to reduce the competition with the electrical rhythm. Participants detected silent gaps in modulated or unmodulated noise stimuli. In Experiment 1, auditory stimuli predominated in entraining behavior. While behavioral entrainment to sound rhythms was affected by the modulation depth of the auditory stimulus, entrainment to tACS was not. In Experiment 2, with no rhythmic information from the sound, 17 of 24 participants showed significant behavioral entrainment to tACS, although the most effective tACS frequency varied across participants. An oscillator model with a free parameter for the individual resonance frequency produced profiles similar to those we observed behaviorally. In Experiment 3, both neural and behavioral entrainment to rhythmic sounds were affected by the auditory stimulus frequency, but again the most effective entraining frequency varied across participants. Our findings suggest that tACS effects depend on the individual’s preferred frequency when there is no competition with sensory stimuli, emphasizing the importance of targeting individual frequencies in tACS experiments. When both sensory and electrical stimuli are rhythmic and compete, sensory stimuli prevail, indicating the superiority of sensory stimulation in modulating behavior.
Generalization from past experience is an important feature of intelligent systems. When faced with a new task, one efficient computational approach is to evaluate solutions to earlier tasks as candidates for reuse. Consistent with this idea, we found that human participants (n= 38) learned optimal solutions to a set of training tasks and generalized them to novel test tasks in a reward-selective manner. This behavior was consistent with a computational process based on the successor representation known as successor features and generalized policy improvement (SF&GPI). Neither model-free perseveration or model-based control using a complete model of the environment could explain choice behavior. Decoding from functional magnetic resonance imaging data revealed that solutions from the SF&GPI algorithm were activated on test tasks in visual and prefrontal cortex. This activation had a functional connection to behavior in that stronger activation of SF&GPI solutions in visual areas was associated with increased behavioral reuse. These findings point to a possible neural implementation of an adaptive algorithm for generalization across tasks.
Body ownership disorders can be triggered by disease or body damage. Methods to probe limb embodiment are required to address those disorders. This includes the development of neuroprostheses that better integrate into the body scheme of the user. To this end, the “rubber hand illusion” protocol is a key behavioral method to probe the powerful embodiment that can be triggered by congruent somatosensory and visual inputs from the limb. So far, the neurophysiology of limb embodiment remains poorly known, in part because translating the rubber hand illusion to animal models such as the mouse remains challenging. Yet, mapping out the brain circuits of embodiment thanks to the use of genetic and optogenetic research tools would allow to propose novel embodiment restoration strategies. Here, we show that the rubber hand illusion described in humans can be translated to the mouse forelimb model using an automated, videography-based procedure. We exposed head-fixed mice to a visible, static 3D-printed replica of the right forelimb, while their own forelimb was hidden from their sight. We synchronously brushed their hidden forelimb and the replica. Following these visuo-tactile associations, the replica was visually threatened, and we probed the reaction of the mice using automated tracking of pupils and facial expression. The mice focused significantly more of their gaze toward the threatened forelimb replica after receiving synchronous tactile and visual information compared to asynchronous. More generally, across test and control conditions, the mouse pupillary response was consistent with the human overt response to the rubber hand illusion. Thus, our results show that mice exhibit quantifiable behavioral markers of the embodiment of an artificial forelimb.
Indisulam, a sulfonamide-based compound, is employed as a second-line therapy for NSCLC due to its anti-tumor activity. However, its clinical efficacy is hindered by acquired resistance, the molecular basis of which remains poorly understood. Here, we demonstrate that hypermethylation of RNA-binding protein 39 (RBM39), a specific target of Indisulam, is closely associated with Indisulam resistance. PRMT6 methylates RBM39 at R92. This methylation inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 protein levels, promotes alternative splicing and expression of proto-oncogenes, and ultimately leads to malignant proliferation and metastasis of NSCLC cells and tumor growth in xenograft mouse models. Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC.
Inhaled anesthetics were first introduced into clinical use in the 1840s. Molecular and transgenic animal studies indicate that inhaled anesthetics act through several ion channels, including γ-aminobutyric acid type A receptors (GABAARs) and two-pore domain K+(K2P) channels, but other targets may mediate anesthetic effects. Mutations in the type 1 ryanodine receptor (RyR1), which is a calcium release channel on the endoplasmic reticulum membrane, are relevant to malignant hyperthermia, a condition that can be induced by inhaled anesthetics. However, it was previously uncertain whether inhaled anesthetics directly interact with RyR1. In our study, we demonstrated that isoflurane and other inhaled anesthetics activate wild-type RyR1. By employing systematic mutagenesis, we discovered that altering just one amino acid residue negates the response to isoflurane, thus helping us to pinpoint the potential binding site. Knock-in mice engineered to express a mutant form of RyR1 that is insensitive to isoflurane exhibited resistance to the loss of righting reflex (LORR) when exposed to isoflurane anesthesia. This observation suggests a connection between RyR1 activation and the anesthetic effects in vivo. Moreover, it was shown that RyR1 is involved in the neuronal response to isoflurane. Additionally, administering new RyR1 agonists, which share the same binding site as isoflurane, resulted in a sedation-like state in mice. We propose that isoflurane directly activates RyR1, and this activation is pertinent to its anesthetic/sedative effects.
A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, the sound of an approaching vehicle signals when it is safe to cross the street; distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in predictive licking for reward. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impaired animals’ ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.
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AbstractA variety of biomarkers other than degree of neurovascular compression have been used to estimate the likelihood of long-term pain-freedom after microvascular decompression (MVD). In this study, we report the prognostic implications of microstructural changes found in patients with idiopathic trigeminal neuralgia (iTN) with an arterial contactwithoutmorphological changes. Patients 18 years or older who underwent MVD as their initial surgical procedure for iTN witharterial contact without morphological changesbetween March 2013 and December 2021 were analyzed. Mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy (MD, RD, AD, and FA) were extracted from the cisternal segment of the trigeminal nerve immediately adjacent to the root entry point. Metrics were compared between symptomatic and asymptomatic trigeminal nerves. Metrics from the symptomatic trigeminal nerve were compared between responders and nonresponders to MVD. To avoid false discovery of a significantP-value, we used the Bonferroni correction method. A statistical significance criterion of q < 0.05 was used. When comparing the symptomatic trigeminal nerve with the asymptomatic trigeminal nerve, the MD was significantly increased on the symptomatic side (q = 0.00047), the RD was significantly increased on the symptomatic side (q = 0.0000066), and the FA was significantly decreased on the symptomatic side (q = 0.0000054). Fractional anisotropy was significantly decreased in nonresponders (q = 0.0056). Fractional anisotropy has potential to preoperatively identify patients with iTN with arterial contact without morphological changes that will respond to MVD. This study identifies a subset of patients with iTN who are not truly “idiopathic.”
AbstractAs individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by “inflammaging,” a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link between inflammaging and age-related development of pain is crucial for identifying novel therapeutic targets. We hypothesized that the circulatory milieu plays a role in regulating pain and that inflammaging contributes to changes in pain behavior with age. To test these hypotheses, we monitored nociception and postsurgical pain in male and female mice aged 3 and 24 months and analyzed their serum proteome, including cytokine/chemokine profiles. Our results demonstrated that compared with young mice, aging mice were hyposensitive to mechanical stimulation, yet their pain response to incision was aggravated and prolonged. Serum proteomic analysis revealed sex-specific inflammaging patterns. To explore the link between inflammaging and age-related alteration in pain behavior, we applied a rejuvenation strategy by transferring serum from 3-month-old mice to 19- to 21-month-old mice. Young serum normalized mechanical sensitivity in aged mice, alleviated postsurgical mechanical pain, and promoted recovery. Alongside the improvements in pain behavior phenotype, young serum recalibrated the aging serum profile. It reduced age-associated increases of cytokine/chemokine levels in male mice and rescued age-related, female-selective downregulation of inflammatory pathways such as liver X receptor/retinoid X receptor activation, D24-dehydrocholesterol reductase, and complement signaling. Our findings suggest that the circulatory environment, notably inflammaging, plays a significant role in altered pain behavior of aging mice. The sex-specific signature of age-dependent systemic inflammation highlights the importance of investigating inflammaging through the lens of sexual dimorphism.
AbstractResearch on social disparities in pain and pain treatment has grown substantially in recent decades, as reflected in a growing number of review articles on these topics. This scoping review of reviews provides a macrolevel overview of scholarship in this area by examining what specific topics and findings have been presented in published reviews. We searched CINAHL, Cochrane Database of Systematic Reviews, Embase, PsycINFO, PubMed, and Web of Science for English-language, peer-reviewed review articles, qualitative or quantitative, that aimed to characterize or explain pain-related differences or inequities across social groups. Of 4432 unique records screened, 397 articles, published over a 56-year period, were included. For each, we documented (1) axes of social difference studied (eg, sex/gender, race/ethnicity), (2) pain-related outcomes (eg, chronic pain prevalence), (3) broad findings, (4) types of mechanisms proposed, and (5) policy or practice recommendations. Findings reveal a sharp increase in the number of published review articles on pain-related disparities since approximately the year 2000. The most commonly studied social dimension was sex/gender, followed by race/ethnicity and age. Studies examining disparities by socioeconomic status, geography, or other categories were rarer. While most findings showed disadvantaged social groups to have worse pain outcomes, there were intriguing exceptions. Biological, psychological, and sociocultural mechanisms were considered much more frequently than sociostructural (macrolevel) ones. Policy/practice recommendations were typically individual-level behavioral suggestions for providers or patients. We identify high-priority areas for future research, including greater attention to lower-income countries, chronic pain prevention, and macrolevel drivers of pain disparities.
AbstractThe inclusion of diverse populations in pain research is crucial to obtaining a complete understanding of how the biopsychosocial experience of pain is seen through the lens of different populations. Traditionally, individuals who identify as Black/African American or Hispanic/Latino have not participated in early phase clinical trials, and as a result, their unique perspectives of the management of pain have not been included in study results. In this qualitative research study, we sought to uncover barriers that prevent diverse populations from participating in pain treatment clinical trials. Partnering with a community organization, we used a semistructured interview to conduct nine focus groups among underrepresented populations to obtain these perspectives. A total of 54 patients with ages ranging from 23 to 77 years old were recruited for this study. Of the patients recruited for the study, 74% identified as non-Hispanic Black, and 24% identified as Hispanic/Latino. Results were recorded, transcribed, and analyzed for thematic saturation using inductive qualitative content analysis. Results uncovered an array of different perspectives including the recognition of historical wrongs that lead to mistrust of the research and healthcare systems. However, other perspectives include recognition that the location of study sites, time required for participation, and overall accessibility of the study play a significant role in an individual's willingness to participate.
AbstractThis cross-sectional retrospective study evaluated the diagnostic accuracy of cold detection thresholds (CDT) and warm detection thresholds (WDT), measured by quantitative sensory testing, for detecting small fiber impairment in polyneuropathy and diagnosing small fiber neuropathy (SFN). A total of 384 individuals with distally distributed sensory disturbances were included. Using ACTTION criteria, 138 patients with polyneuropathy were identified. Among them, 36 were diagnosed with SFN, 91 with mixed fiber polyneuropathy, and 11 with pure large fiber polyneuropathy. First, we assessed CDT and WDT accuracy, both individually and combined (ie, an abnormal value in either CDT or WDT), in detecting small fiber impairment in polyneuropathy. Next, we calculated CDT and WDT diagnostic accuracy for SFN, both alone and combined, and evaluated their accuracy when integrated with small fiber–related clinical abnormalities. Isolated abnormalities in CDT or WDT showed relatively low diagnostic accuracy. However, combined abnormalities achieved a sensitivity of 69% and specificity of 70% for detecting small fiber impairment in distal symmetric polyneuropathy. For SFN diagnosis, combining CDT and WDT yielded 78% sensitivity, 70% specificity, and a 94% negative predictive value. These metrics improved to 78% sensitivity and 100% specificity when CDT or WDT were integrated with small-fiber-related clinical abnormalities. Although individual CDT and WDT assessments offer limited diagnostic accuracy, their combination provides a practical, noninvasive approach for screening small fiber impairment in distal symmetric polyneuropathy and diagnosing SFN. This strategy may reduce the need for more invasive and less cost-effective procedures, like skin biopsy.
AbstractOffset analgesia reflects time-dependent, central nervous system pain inhibition and refers to a dramatic drop in pain intensity after an offset of noxious stimulus intensity. Neuropathic and nociplastic pain conditions with strong central nervous system pathophysiologic mechanisms show deficits in offset analgesia. Whether offset analgesia is altered in more peripherally driven chronic nociceptive pain was unknown. Therefore, the primary goal of the current study was to determine whether chronic nociceptive pain is associated with changes in offset analgesia. We measured offset analgesia and sensory function using quantitative sensory tests, patient-reported pain and function, and walking and stair climbing performance using standardized tasks in knee osteoarthritis patients with equivalent joint degeneration but Moderate-to-Severe (n = 36) or Mild pain intensity (n = 36) and Pain-free controls without knee osteoarthritis (n = 30) matching for age, gender, and body mass index. Offset analgesia was significantly reduced in knee osteoarthritis groups compared with the Pain-free controls, with deficits occurring at both the nonpainful forearm and painful knee and in both genders. Greater deficits in offset analgesia were associated with more impairment in walking and stair climbing. Onset hyperalgesia, a novel measure of time-dependent pain facilitation, was reduced in women with Mild knee pain but not in men. These results suggest that deficits in temporal pain inhibition and gender-specific changes in temporal pain facilitation may contribute to pain and functional impairment in knee osteoarthritis, supporting further study of central pain modulation as a clinically relevant mechanism of chronic nociceptive pain.
AbstractTraumatic stress exposures (TSEs) are common in life. Although most individuals recover after a TSE, a substantial subset develop adverse post-traumatic neuropsychiatric sequelae such as chronic post-traumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the Advancing Understanding of RecOvery afteR traumA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding, combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In Advancing Understanding of RecOvery afteR traumA study participants (n = 2480), using multinomial logistic regression modeling of 4 identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (odds ratio [OR] = 1.047,P< 0.001), the moderate pain class (OR = 1.031,P< 0.001), and the moderate recovery pain class (OR = 1.018,P= 0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison with SPS alone, neonatal limited bedding combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197) = 3.22,P< 0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP.
AbstractPain is multidimensional, including sensory-discriminative, affective-motivational, and cognitive-evaluative components. Although the concept of pain is learned through life, it is not known when and how the brain networks that are required to encode these different dimensions of pain develop. Using the 2 largest available databases of brain magnetic resonance images—the developing Human Connectome Project and the Human Connectome Project—we have mapped the development of the pain connectome—the neural network required for pain perception—in infants from 26 to 42 weeks of postmenstrual age (PMA, n = 372), compared with adults (n = 98). Partial correlation analysis of resting BOLD signal between pairwise combinations of 12 pain-related brain regions showed that overall functional connectivity is significantly weaker before 32 weeks PMA compared with adults. However, over the following weeks, significantly different developmental trajectories emerge across pain connectome subnetworks. The first subnetwork to reach adult levels in strength and proportion of connections is the sensory-discriminative subnetwork (34-36 weeks PMA), followed by the affective-motivational subnetwork (36-38 weeks PMA), while the cognitive-evaluative subnetwork has still not reached adult levels at term. This study reveals a previously unknown pattern of early development of the infrastructure necessary to encode different components of pain experience. Newborn neural pathways required for mature pain processing in the brain are incomplete in newborns compared with adults, particularly regarding the emotional and evaluative aspects of pain. The rapid age-related changes suggest that pain processing, and consequently pain experience, changes rapidly over this developmental period and unlikely to be the same as in adults, even at term.
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AbstractChronic musculoskeletal pain (CMP) is the most prevalent form of chronic pain. A subgroup of patients with CMP shows altered pain processing, including impaired endogenous pain modulation, as evaluated by experimental pain measures. One hypothesis is that genetic and/or epigenetic variants may contribute to individual differences in outcomes of dynamic experimental pain assessment. Therefore, a systematic review was performed to comprehensively summarize the current evidence regarding genetic and epigenetic influences on dynamic experimental pain measures in adults with and without CMP. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four electronic databases were searched to identify relevant studies. Risk of bias and quality of evidence were assessed using the Newcastle Ottawa Scale and the Grading of Recommendations, Assessment, Development, and Evaluation approach, respectively. A total of 24 articles were included, accounting for 34 different regions of interest. Low-quality evidence indicated no association between the rs4680 single-nucleotide polymorphism (SNP) of theCOMTgene or the serotonin-transporter-linked polymorphic region SNP of theSLC6Agene and conditioned pain modulation in healthy volunteers or in patients with CMP. In addition, low-quality evidence was found for the lack of an association between the rs1799971 SNP of theOPRM1gene and conditioned pain modulation in healthy volunteers. Other genetic and epigenetic variants provided limited or conflicting evidence. For now, it seems that dynamic experimental pain measurements are robust to genetic and epigenetic variations. However, more reproducible research is warranted to better understand whether or not and how genetic and epigenetic variations influence (altered) pain processing, which is crucial for advancing both preventive and therapeutic strategies in CMP populations.
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AbstractCoronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global health crisis, with many patients experiencing not only acute neurological and sensory symptoms but also persistent sensory abnormalities, commonly referred to as long COVID sequelae. The mechanisms underlying somatosensory abnormalities induced by SARS-CoV-2 remain largely unclear. In this study, we investigate the role of the SARS-CoV-2 nucleocapsid (N) protein in pain regulation. Our data show that SARS-CoV-2 N protein exacerbates pathological pain in mouse models of bone cancer, chemotherapy, neuropathic, and inflammatory, and promotes the chronification of acute inflammatory pain. We also identify a potential interaction between the N protein and Nav1.7 in dorsal root ganglion neurons from mice, monkeys, and humans. Furthermore, the N protein significantly increases Nav1.7 currents in dorsal root ganglion neurons from both mice and monkeys by delaying Nav1.7 inactivation without altering its expression or membrane trafficking. This modulation of Nav1.7 function by the N protein not only intensifies pain hypersensitivity but also prolongs the duration of pain, potentially facilitating the transition from acute to chronic pain. Our findings underscore the importance of vigilant management of SARS-CoV-2 infection in patients with pathological pain and suggest potential therapeutic targets for mitigating COVID-19–related pain.
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AbstractMaintaining a dynamic balance among various life-history traits is crucial for survival in a warming world, yet the underlying mechanisms remain enigmatic. In this study, we employed the western clawed frog (Xenopus tropicalis) as a model and conducted a long-tern experiment from zygotes to adult stage. We find that even within the previously considered normal temperature range, a 5 °C increase in ambient temperature can establish a new metabolic state, resulting in elevated oxidative stress and a shift in energy allocation towards immune defense at the expense of sexual development. This conceptual framework of temperature-dependent trade-off strategy suggests that, while some studies observed that warm temperature reduces the risk of infection, it is important to note that this change may present challenges in the form of accelerated aging and reduced fertility, especially in ectotherms. These results not only indicate a far more complex adaptive response to future climate change than previously anticipated, but also provide a concise method for constructing animal models to explore diseases related to homeostatic disorders.
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AbstractCross-ecosystem subsidies influence the structure and dynamics of recipient ecosystems and can be sensitive to disturbance. Primary production exported from marine to shoreline ecosystems is among the largest known cross-ecosystem subsidies. However, the spatial scales at which this important connection is manifested are largely unquantified. We used local and regional observations of nearshore kelp canopy biomass and beach kelp wrack inputs to evaluate the scales at which connectivity between kelp forests and beaches is maximized. Regardless of the spatial and temporal scales considered, connectivity was highly local (<10 km) and strongest in winter. Kelp canopy biomass was the primary driver of wrack subsidies, but recipient ecosystem attributes, particularly beach width and orientation, were also important. These drivers of connectivity highlight that disturbance to either ecosystem will have large implications for beach ecosystem productivity. Spatial connectivity can regulate recovery from disturbances such that ecosystem connections must be considered in conservation efforts.
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AbstractCRISPR-Cas diagnostics are revolutionizing point-of-care molecular testing due to the programmability, simplicity, and sensitivity of Cas systems withtrans-cleavage activity. CRISPR-Cas12 assays are promising for detecting single nucleotide polymorphisms (SNPs). However, reports vary widely describing Cas12 SNP sensitivity, and an underlying mechanism is lacking. We systematically varied crRNA length and valency to investigate the role of crRNA architectures on Cas12 biosensing in the context of speed-of-detection, sensitivity, and selectivity. Our results demonstrate that crRNAs complementary to 20 base pairs of the target DNA is optimal for rapid and sensitive detection, while a complementary length of 15 base pairs is ideal for robust SNP detection. Additionally, we uncovered a unique periodicity in SNP sensitivity based on nucleotide position and developed a structural model explaining what drives Cas12 SNP sensitivity. Lastly, we showed that bivalent CRISPR-Cas sensors have synergistic and enhanced activity that is distance dependent.
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AbstractThree dimensional immunohistochemistry (3D-IHC), immunolabeling of 3D tissues, reveals the spatial organization of molecular and cellular assemblies in the context of the tissue architecture. Deep and rapid penetration of antibodies into 3D tissues and highly sensitive detection are critical for high-throughput imaging analysis of immunolabeled 3D tissues. Here, we report a nanobody (nAb)-based 3D-IHC, POD-nAb/FT-GO 3D-IHC, for high-speed and high-sensitive detection of targets within 3D tissues. Peroxidase-fused nAbs (POD-nAbs) enhanced immunolabeling depth and allowed for highly sensitive detection by combined with a fluorescent tyramide signal amplification system, Fluorochromized Tyramide-Glucose Oxidase (FT-GO). Multiplex labeling was implemented to the 3D-IHC by quenching POD with sodium azide. Using the 3D-IHC technique, we successfully visualized somata and processes of neuronal and glial cells in millimeter-thick mouse brain tissues within three days. Given its high-speed and high-sensitive detection, our 3D-IHC protocol, POD-nAb/FT-GO 3D-IHC, would provide a useful platform for histochemical analysis in 3D tissues.
AbstractQuenchbodies, antibodies labelled with fluorophores that increase in intensity upon antigen binding, offer great promise for biosensor development. Nanobody-based quenchbodies are particularly attractive due to their small size, ease of expression, high stability, rapid evolvability, and amenability to protein engineering. However, existing designs for protein detection show limited dynamic range, with fluorescence increases of only 1.1–1.4 fold. Here we identify the tryptophan residues in the nanobody complementarity-determining regions (CDRs) that are critical to quenchbody performance. Using a combination of rational design and molecular dynamics simulations, we developed an optimised nanobody scaffold with tryptophans introduced at key positions. We used this scaffold in an in vitro directed-evolution screen against human inflammatory cytokine interleukin-6 (IL-6). This yielded quenchbodies with 1.5–2.4-fold fluorescence increases, enabling IL-6 detection down to 1–2 nM. Our scaffold provides a valuable platform for developing biosensors for diverse protein targets, with applications in research, diagnostics, and environmental monitoring.
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AbstractBrassicales plants defend themselves with glucosinolates that, upon herbivory, are hydrolyzed into toxic isothiocyanates (ITCs) and other derivatives. The side chain diversity of glucosinolates results in a range of structurally distinct products, but how this chemical variation affects herbivores and their detoxification responses remains incompletely understood. Here, we show the effects of ITC hydrolysis products with various side chains onSpodoptera littoralislarvae and their detoxification system. ITCs inhibit larval growth to varying degrees, depending on the chemical nature of their side chain. The larvae metabolize ITCs by conjugating them to glutathione in the mercapturic acid pathway and to lysine forming an amine conjugate. Over half of the 34S. littoralisglutathione-S-transferases (GSTs), tested as His-tagged derivatives, actively conjugate ITCs, with most catalyzing reactions with multiple substrates. Larval performance on various ITC-containing diets correlates positively with GST activity, highlighting this detoxification system’s role in supporting growth on glucosinolate-containing plants. The propensity of multiple GSTs to react with an individual ITC and the wide expression of GST-encoding genes across larval organs likely promote the ability of this generalist herbivore to thrive on glucosinolate-defended Brassicales plants. These findings provide insight into herbivore adaptation and may inform future research on plant–insect interactions.
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AbstractVDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid–protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
AbstractOptic flow, the retinal pattern of motion experienced during self-motion, contains information about one’s direction of heading. The global pattern due to self-motion is locally confounded when moving objects are present, and the flow is the sum of components due to the different causal sources. Nonetheless, humans can accurately retrieve information from such flow, including the direction of heading and the scene-relative motion of an object. Flow parsing is a process speculated to allow the brain’s sensitivity to optic flow to separate the causal sources of retinal motion in information due to self-motion and information due to object motion. In a computational model that retrieves object and self-motion information from optic flow, we implemented flow parsing based on heading likelihood maps, whose distributions indicate the consistency of parts of the flow with self-motion. This allows for concurrent estimation of heading, detecting and localizing a moving object, and estimating its scene-relative motion. We developed a paradigm that allows the model to perform all these estimations while systematically varying the object’s contribution to the flow field. Simulations of that paradigm show that the model replicates many aspects of human performance, including the dependence of heading estimation on object speed and direction.
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AbstractThree-dimensional multiplexed fluorescence imaging is an indispensable technique in neuroscience. For two-dimensional multiplexed imaging, cyclic immunofluorescence, which involves repeating staining, imaging, and signal removal over multiple cycles, has been widely used. However, the application of cyclic immunofluorescence to three dimensions poses challenges, as a single staining process can take more than 12 hours for thick specimens, and repeating this process for multiple cycles can be prohibitively long. Here, we propose SEPARATE (Spatial Expression PAttern-guided paiRing And unmixing of proTEins), a method that reduces the number of cycles by half by imaging two proteins using a single fluorophore. This is achieved by labeling two proteins with the same fluorophores and unmixing their signals based on their three-dimensional spatial expression patterns, using a neural network. We employ a feature extraction network to quantify the spatial distinction between proteins, with these quantified values, termed feature-based distances, used to identify protein pairs. We then validate the feature extraction network with ten proteins, showing a high correlation between spatial pattern distinction and signal unmixing performance. We finally demonstrate the volumetric multiplexed imaging of six proteins using three fluorophores, pairing them based on feature-based distances and unmixing their signals through protein separation networks.
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AbstractLittle is known about host-gut microbiome interactions within natural populations at the intestinal mucosa, the primary interface. We investigate associations between the intestinal microbiome and mucosal immune measures while controlling for host, social and ecological factors in 199 samples of 158 wild spotted hyenas (Crocuta crocuta) in the Serengeti National Park, Tanzania. We profile the microbiome composition using a multi-amplicon approach and measure faecal immunoglobulin A and mucin. Probabilistic models indicate that both immune measures predicted microbiome similarity among individuals in an age-dependent manner. These associations are the strongest within bacteria, intermediate within parasites, and weakest within fungi communities. Machine learning models accurately predicted both immune measures and identify the taxa driving these associations: symbiotic bacteria reported in humans and laboratory mice, unclassified bacteria, parasitic hookworms and fungi. These findings improve our understanding of the gut microbiome, its drivers, and interactions in wild populations under natural selection.
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AbstractIgGs have become successful drug scaffolds by combining specific target binding with the ability to induce cellular cytotoxicity. Furthermore, IgGs possess unusually long half-lives in the blood (2-3 weeks). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with the FcRn-receptor whereby IgGs are recycled. No high-resolution structure of FcRn in complex with a full-length IgG is available, and the interaction was long thought to be mediated solely via the IgG-Fc. However, some IgGs with identical Fc-parts, but different Fab-domains, exhibit different half-lives, suggesting involvement of the Fab-domains in FcRn binding. Here, we employ structural mass spectrometry (HDX-MS and XL-MS) to explore the interaction of full-length IgGs with FcRn. HDX-MS and XL-MS experiments confirm an interaction between FcRn and the Fc-region of IgGs, through three cross-links between FcRn and the IgG-Fc-domain and a reduction in HDX in both the receptor and the Fc-region upon complex formation. However, FcRn-induced changes in HDX are also observed in the Fab-domains, supported by cross-links between the Fab-domains and the α3-domain of FcRn. Our results thus provide direct evidence for an IgG Fab-FcRn interaction. We envision that these results could advance the engineering of IgG-antibodies with tailored pharmacokinetics and enhanced efficacy.
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AbstractDue to the low disease prevalence, transcriptomic studies of neurodevelopmental disorders (NDDs) often face limited statistical power, constraining the depth of insights they can provide. To tackle this limitation, we integrated 151 human RNA sequencing datasets from 115 independent studies, and characterized the common and distinct molecular pathways of NDDs and their neurological phenotypes. In addition to revealing an aberrant expression profile of imprinted genes, our analysis identified transcriptomic changes in inflammatory, translational, mitochondrial, and synaptic processes across the different NDDs. We further highlight disorder-associated alterations, including upregulation ofITGB4across Rett syndrome datasets. Moreover, gene expression changes inLHX1/5-mediated cerebellar Purkinje cell layer formation were found to be specific to seizure-associated NDDs. We combined the datasets into a publicly accessible NDD transcriptomic atlas:https://SyNUM.shinyapps.io/NDD-transcriptomic-atlas/. Together, our findings provide fundamental insights into the molecular pathophysiology of NDDs and highlight genes and pathways with aberrant transcriptomic profiles. This knowledge can guide future therapeutic development and precision medicine approaches.
AbstractCocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven in part by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations─or ensembles─across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse.
AbstractMatrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, and integrate multi-omics with imaging and biochemical assays to investigate the molecular mechanisms. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimulus. We also identify activation of p-JUN in response to the stiff matrix and promoting phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness may be responsible for various fibrotic diseases and provide insight into intervening approaches.
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AbstractDevelopmental processes underlying the characteristic segmented body plans in arthropods vary widely. WhileDrosophilais well-studied, few other arthropod species offer platforms for comparable genomics at single-cell resolution. Here, we present high-quality quantitative data from single-nucleus RNA sequencing of spiderParasteatoda tepidariorumembryos at late stage 5 and stage 7, a critical period of emergence of segmental units along the anterior–posterior (AP) axis. Clustering analysis of the stage-7 dataset reconstructs an axial alignment of ectoderm cells, reflecting the differing cell states along the segmenting AP axis. This enables us to obtain genome-wide quantitative gene expression profiles along the reconstructed axis, which were used for unbiased and thorough molecular investigation of pattern elements employing statistical methods. Comprehensive gene-to-gene correlation analyses suggest distinct gene-regulatory interactions in different regions along the reconstructed axis. This study lays the foundation for exploring the origins of developmental diversity in the arthropod body plan.
AbstractHeterogeneity among somatosensory neurons is necessary for internal and external sensation. Precise patterns of gene transcription orchestrated through enhancer activation maintain heterogeneity. Thus, high-resolution cell type classification, chromatin accessibility and its relation to enhancer activation can explain the governing principles for sensory neuron heterogeneity. Here, we present an integrated atlas from published high-quality scRNA-seq datasets and resequencing the dorsal root ganglion, including over 44,000 neurons. MERSCOPE spatial transcriptomics confirms cell types in situ, including previously unrecognized neuronal types, and a spatial zonation of both neurons and non-neuronal cells. We present a cell type specific open chromatin atlas revealing enhancer driven regulons and gene-regulatory networks organized into co-regulated gene-programs that together define sensory neuron diversity. Cell type complexity is shown to be generated by layered co-regulated transcriptional modules representing shared functions across different scales of the neuronal type hierarchy with cell type specific contribution as the exception.
AbstractVisual attention paradigms have revealed that neural excitability in higher-order visual areas is modulated according to a priority map guiding attention towards task-relevant locations. Neural activity in early visual regions, however, has been argued to be modulated based on bottom-up salience. Here, we combined Magnetoencephalography (MEG) and Rapid Invisible Frequency Tagging (RIFT) in a classic visual search paradigm to study feature-guidance in early human visual cortex. Our results demonstrate evidence for both target boosting and distractor suppression when the participants were informed about the task-relevant and -irrelevant colour (guided search) compared to when they were not (unguided search). These results conceptually replicated using both a magnitude-squared coherence approach and a General Linear Model based on a single-trial measure of the RIFT response. The present findings reveal that feature-guidance in visual search affects neuronal excitability as early as primary visual cortex, possibly contributing to a priority-map-based mechanism.
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AbstractA diverse subset of cyanobacteria can transiently modify their photosynthetic machinery during far-red light photoacclimation to drive photosynthesis with less energetic photons (700 nm–800 nm). To achieve this, all the main light-driven components of the photosynthetic apparatus, including their allophycocyanin antenna, are replaced with red-shifted paralogues. Recent studies based on the structure of an incomplete complex provided some insights into the tuning of the far-red phycobiliproteins. Here, we solved the structure of the intact bicylindrical allophycocyanin complex from the cyanobacteriumChroococcidiopsis thermalisPCC 7203 at a resolution of 2.51 Å determined by Cryo-electron microscopy single particle analysis. A comparison between conserved structural features in far-red and white light allophycocyanin cores provides insight on the evolutionary adaptations needed to optimize excitation energy transfer in the far-red light adapted photosynthetic apparatus. The reduction in antenna size in far-red photosynthesis suggests a need to optimize membrane packing to increase the number of photosystems and tune the ratio between chlorophyllfmolecules and bilin pigments, while the wider spread in the absorption range of the bilins suggests faster and more efficient excitation energy transfer to far-red Photosystem II by limiting backflow of excitation from the reaction centres to the far-red bilin pigments.
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AbstractKlebsiella pneumoniaeis the leading cause of neonatal sepsis, strongly associated to antimicrobial resistance, with no vaccine available. K-antigens (KAg) have been identified as potential targets, but their diversity makes vaccine development challenging. Alternatively, the use of subcapsular O-antigens (OAg) raises questions about antibodies accessibility. We characterized clinical isolates from the BARNARDS study, designed to identify the burden of neonatal sepsis in low-middle income countries. Genomic prediction was verified through structural analysis of polysaccharides. Antibodies generated against common KAg and OAg bound all homologous organisms, regardless of specific polysaccharide structural features. Interestingly, anti-KAg antibodies exhibited bactericidal activity against a comparable number of isolates as anti-OAg antibodies. There was no association between polysaccharide characteristics andK. pneumoniaesusceptibility to killing. Antibody cross-reactivity among different KAg was observed, together with extensive cross-reactivity among OAg antibodies. This study aids in defining an optimal vaccine composition to prevent neonatal sepsis caused byK. pneumoniae.
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AbstractWorking memory allows temporary storage and manipulation of information during cognitive tasks. While the primate lateral prefrontal cortex (PFC) is involved in working memory, little is known about neuronal activity during memory updating. We trained macaque monkeys on an oculomotor n-back task, requiring them to remember locations of sequentially presented visual stimuli and generate a saccade to the location of the most recent or previous stimulus based on task rules. Many PFC neurons showed transient activity when a memory of a particular stimulus location was no longer needed, whereas others showed sustained activity for remembered locations. Decoding analysis successfully predicted future target selection based on the task rule from neuronal activity, indicating that these neuronal populations contain sufficient information to guide behavior. Furthermore, electrical stimulation at recording sites erased specific spatial memories, demonstrating a causal role of prefrontal neurons in maintaining and updating short-term memory.
AbstracttRNA undergoes various post-transcriptional modifications in the anticodon loop. FTSJ1, a protein conserved among most eukaryotes, mediates 2’-O-methylations at position 32 (Nm32) or position 34 (Nm34), complexed with THADA or WDR6, respectively. These methylations are crucial for accurate translation and cellular growth. FTSJ1 mutations are associated with non-syndromic X-linked intellectual disability. Although the structure of the FTSJ1-WDR6 complex in yeast has been solved, the structural details of the FTSJ1-THADA complex formation and substrate recognition remain unclear. Herein, using cryo-electron microscopy, we solve the high-resolution structure of FTSJ1-THADA with or without a tRNA substrate. FTSJ1 binds to THADA via its C-terminal region, with a unique interaction mode distinct from the FTSJ1-WDR6 complex. The tRNA substrate is anchored inside THADA, and key THADA residues for THADA-tRNA interaction are identified via structural and biochemical analyses. These findings demonstrate how FTSJ1 and THADA form a complex to mediate Nm32 modification in various tRNAs.
AbstractAI image processing techniques hold promise for clinical applications by enabling analysis of complex status information from cells. Importantly, real-time brightfield imaging has advantages of informativeness, non-destructive nature, and low cost over fluorescence imaging. Currently, human liver organoids (HLOs) offer an alternative to animal models due to their excellent physiological recapitulation including basic functions and drug metabolism. Here we show a drug-induced liver injury (DILI) level prediction model using HLO brightfield images (DILITracer) considering that DILI is the major causes of drug withdrawals. Specifically, we utilize BEiT-V2 model, pretrained on 700,000 cell images, to enhance 3D feature extraction. A total of 30 compounds from FDA DILIrank are selected (classified into Most-, Less-, and No-DILI) to activate HLOs and corresponding brightfield images are collected at different time series and z-axis. Our computer vision model based on image-spatial-temporal coding layer excavates fully spatiotemporal information of continuously captured images, links HLO morphology with DILI severity, and final output DILI level of compounds. DILITracer achieves an overall accuracy of 82.34%. To our knowledge, this is the first model to output ternary classification of hepatotoxicity. Overall, DILITracer, using clinical data as an endpoint categorization label, offers a rapid and effective approach for screening hepatotoxic compounds.
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AbstractBrain activity emerges in a dynamic landscape of regional increases and decreases that span the cortex. Increases in activity during a cognitive task are often assumed to reflect the processing of task-relevant information, while reductions can be interpreted as suppression of irrelevant activity to facilitate task goals. Here, we explore the relationship between task-induced increases and decreases in activity from a geometric perspective. Using a technique known as kriging, developed in earth sciences, we examined whether the spatial organisation of brain regions showing positive activity could be predicted based on the spatial layout of regions showing activity decreases (and vice versa). Consistent with this hypothesis we established the spatial distribution of regions showing reductions in activity could predict (i) regions showing task-relevant increases in activity in both groups of humans and single individuals; (ii) patterns of neural activity captured by calcium imaging in mice; and, (iii) showed a high degree of generalisability across task contexts. Our analysis, therefore, establishes that antagonistic relationships between brain regions are topographically determined, a spatial analog for the well documented anti-correlation between brain systems over time.
AbstractMRG15, a chromatin remodeling protein, plays a pivotal role in cellular senescence and proliferation. However, the precise roles and mechanisms of MRG15 in aging regulation remain unclear. Our research elucidates the distinct functions of MRG15’s splice variants in aging. We find that MRG15L, contrary to the previously assumed MRG15S, accumulates with advancing age. Using histone peptide binding assays and protein interaction analysis, we demonstrate that MRG15L exhibits reduced affinity for histone H4 acetylation sites, thereby weakening CDK1 regulation, leading to G2/M phase arrest and promoting cellular senescence. During postnatal cardiac development, MRG15L expression increases and is linked to reduced regenerative capacity. Moreover, targeted knockout of MRG15L in mice enhances cardiac repair and regeneration following myocardial ischemia-reperfusion injury. These findings highlight MRG15L as a promising therapeutic target for age-related diseases, revealing its critical role in modulating aging pathways through alternative splicing.
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AbstractEpigenetic mapping studies across individuals have identified many positions of epigenetic variation across the human genome. However the relationships between these positions, and in particular global patterns that recur in many regions of the genome, remains understudied. In this study, we use a stacked chromatin state model to systematically learn global patterns of epigenetic variation across individuals and annotate the human genome based on them. We apply this framework to histone modification data across individuals in lymphoblastoid cell lines and across autism spectrum disorder cases and controls in prefrontal cortex tissue. We find that global patterns are correlated across multiple histone modifications and with gene expression. We use the global patterns as a framework to predict trans-regulators and study a complex disorder. The frameworks for identifying and analyzing global patterns of epigenetic variation are general and we expect will be useful in other systems.
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AbstractAlthough long considered safe, recent data have shown that emulsifiers such as polysorbates promoted intestinal inflammation and were associated with increased risks of developing chronic pathologies. We evaluated the potential of plant-based emulsifiers (pea protein isolate, PPI, and corn arabinoxylans, CAX) as alternatives to Polysorbate 80 (Tween 80, T80). Combining PPI and CAX led to a similar vitamin D3bioavailability to T80 in vitro and in vivo in mice. We then exposed female and male mice to dietary doses of emulsifiers in oil-in-water emulsions (180 mg/kg/day for T80, 5 days/week) for 11 weeks. Conversely to previous studies conducted with higher doses of emulsifiers, T80, PPI, and PPI + CAX groups were similar to the control group (oil alone) in terms of physiological characteristics and inflammation biomarkers. However, LPS-specific serum IgG levels were reduced in the PPI (−31.05%, p = 0.0006) and PPI + CAX (−34.66%, p = 0.0001) groups compared to the T80 group at the end of the intervention. Exposure to T80, but not to PPI or PPI + CAX, reduced the distance between bacteria and the jejunal epithelium (−60.67%, p = 0.0779) and significantly increased Firmicutes_D phylla in male mice. Overall, we showed that a combination of pea protein and arabinoxylans appears as a sustainable alternative to polysorbates for vitamin D3delivery.
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AbstractImmature great apes learn how to build their nests over multiple years, yet how they do so has remained largely unclear. We investigated the detailed role of social learning in the acquisition of nest-building skills in wild Sumatran orangutans (Pongo abelii) using data on nest-building, nest practice, and nest peering behaviour from 44 individuals, collected over 17 years. We found that nest peering (but not being close to a nesting individual without peering) is associated with a significant increase in nest practice and is primarily directed at multi-step nest elements. Dependent immatures mostly peer at their mothers and use nest tree species in common with her, independent immatures peer at a larger range of individuals and use nest tree species in common with them. Our results suggest that orangutans acquire their nest-building skills through observational social learning, selective attention to “know-how” and the transmission of “know-what” information.
AbstractPredicting prokaryotic phenotypes—observable traits that govern functionality, adaptability, and interactions—holds significant potential for fields such as biotechnology, environmental sciences, and evolutionary biology. In this study, we leverage machine learning to explore the relationship between prokaryotic genotypes and phenotypes. Utilizing the highly standardized datasets in the BacDivedatabase, we model eight physiological properties based on protein family inventories, evaluate model performance using multiple metrics, and examine the biological implications of our predictions. The high confidence values achieved underscore the importance of data quality and quantity for reliably inferring bacterial phenotypes. Our approach generates 50,396 completely new datapoints for 15,938 strains, now openly available in the BacDivedatabase, thereby enriching existing phenotypic resources and enabling further research. The open-source software we provide can be readily applied to other datasets, such as those from metagenomic studies, and to various applications, including assessing the potential of soil bacteria for bioremediation.
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AbstractIncreasing evidence suggests vaginal dysbiosis is associated with persistent high-risk human papillomavirus (hrHPV) infection and cervical intraepithelial neoplasia (CIN) development. In this pilot longitudinal study, we investigate the potential of vaginal microbiome biomarkers to predict CIN3 development in hrHPV-positive (hrHPV+) women of reproductive age and assess loop electrosurgical excision procedure (LEEP) outcomes.Fifty-nine non-menopausal women 20–53 years old, with normal cytology, were selected from the ARTISTIC trial and followed up twice over six years. Vaginal microbiome was analysed by 16S rRNA sequencing. HrHPV+ women with CIN3 showed a significant overrepresentation ofSneathia amnii,Megasphaera genomosp., Peptostreptococcus anaerobius and Achromobacter spanius(p< 0.05). Successfully LEEP-treated hrHPV-negative women exhibited increasedLactobacillusspecies, especiallyLactobacillus gasseri. Additionally,Lactobacillus helveticus,suntoryeusandvaginalisshowed a potential protective role against CIN3 development.These unique microbial biomarkers associated with CIN3 development and recovery following LEEP treatment bring new insights into the vaginal microbiome’s role on disease progression.
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AbstractMemory consolidation is highly influenced by ongoing experiences. Here, we explore the temporal rules that determine whether events are cooperatively associated or competitively separated. We show that neutral events are associated with fearful events if they occur within less than 30 min. In some individuals, memory association can lead to a competitive suppression of the fearful response by the neutral event. Activation of the thalamic MGm inputs to the lateral amygdala, results in an increase in memory association, whereas manipulation of the cortical inputs have no effect. Introducing a third event leads to competition depending on the temporal relationship between the initial association and the competitive event. Our results show a critical temporal rule of memory association, modulated by thalamic activity that shapes fear memory consolidation.
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AbstractConvulsive seizure behaviors are a hallmark feature of epilepsy, but automated detection of these events in freely moving animals is difficult. Here, we employed a high-resolution multi-camera array microscope with high-speed video acquisition and custom supervised machine learning (ML) for automated detection of larval zebrafish between 3- and 7-days post-fertilization (dpf). We assessed data from over 2700 zebrafish either exposed to a chemoconvulsant (pentylenetetrazole, PTZ) or genetic zebrafish lines representing Developmental Epileptic Encephalopathy (DEE) syndromes. Using eight-point skeletal body pose estimation for tracking individual larvae arrayed in a 96-well format, we report reliable, quantitative and age-dependent changes in maximum swim speed, as well as eye-, head- and tail- angle kinematics. Finally, we employed an ML-based algorithm to automatically identify normal and abnormal behaviors in an unbiased manner. Our results offer a robust framework for automated detection of zebrafish seizure-associated behaviors.
AbstractGreen macroalgae within the order Bryopsidales lack the fundamental photoprotective mechanisms of green algae, the xanthophyll cycle and energy-dependent dissipation of excess light. Here, by measuring chlorophyll fluorescence at 77 K after specific light treatments, we show that Bryopsidales algae also lack state transitions, another ubiquitous photoprotection mechanism present in other green algae. Certain Sacoglossa sea slugs can feed on Ulvophyceae algae, including some Bryopsidales, and steal chloroplasts – kleptoplasts – that remain functional inside the animal cells for months without the support of the algal nucleus. Our data reveal that the state transition capacity is not retained in the kleptoplasts of the sea slugs, and we provide evidence that the loss is caused by structural changes during their incorporation by the animals. Enforced chloroplast sphericity was observed in all studied kleptoplastic associations, and we propose that it is a fundamental property supporting long-term retention of kleptoplasts in photosynthetic sea slugs.
AbstractColorectal cancers (CRCs) present across a range of differentiation grades, which impact patient outcome and management; however, the molecular features and drivers of differentiation status are not fully understood. To address this, 84 commonly used human CRC cell lines were grown as xenografts in mice, revealing models of low-grade (LG) and high-grade (HG) CRC. Transcriptional profiling revealed coordinate downregulation of multiple transcription factors involved in intestinal development and differentiation, markers of colonic lineage-specific differentiation, and effectors of normal functions of the colonic epithelium in HG tumours. Mechanistically, multiple genes suppressed in HG tumours harboured promoter methylation, indicative of stable epigenetic silencing. Furthermore, markers of LGR5+ colon stem cells were suppressed in HG tumours, while markers of cell proliferation, fetal-like intestinal stem cells, and non-canonical cell types including mesenchymal cells were increased. These changes manifested in HG cell line displaying increased proliferation, migration and metastatic capacity. Importantly, CRC cell line-derived transcriptional profiles of differentiation grade were reflected in LG and HG patient-derived tumour organoids and primary CRCs, revealing cell lines accurately model differentiation grade. The models and tumour differentiation-related properties identified herein may inform new approaches for tailored CRC treatments based on tumour grade.
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AbstractKcnq channels are low-threshold voltage-dependent K+channels that generate M-currents, which regulate the peri-threshold membrane potential. Kcnq channels reportedly participate in band-pass frequency responses (i.e., resonance), but it remains largely unclear how they contribute to generating resonance. We examined resonance in HEK293 cells expressingmouse Kcnq2andKcnq3(Kcnq2/3) using whole-cell recording.Kcnq2/3-expressing cells generated resonance-like frequency-dependent responses. Kcnh7 channels displayed a rapid opposing conductance change followed by slow activation in response to a depolarizing voltage step, properties thought to be necessary for inductor-like activity. However, Kcnq2/3 channels exhibited only slow activation. The lack of an opposing conductance change was caused by the absence of rapid Kcnq2/3 channel inactivation. These data suggest that core ion channel characteristics that cause resonance-like frequency responses are not uniform among ion channels. The opposing conductance change is not necessary for resonance-like frequency responses but is crucial for fine frequency tuning and oscillation.
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AbstractIn almost all respiratory organisms, organic substrates are degraded via catabolic processes to the central metabolite acetyl-CoA which is then oxidized to CO2for energy metabolism or used as a building block for anabolism. Most microorganisms have either the closed tricarboxylic acid cycle or the complete Wood-Ljungdahl-pathway for acetyl-CoA oxidation, but the sulfate-reducing, naphthalene-degrading culture N47 possesses both completely. Combining13C- labeled substrates and mass-specific GC-MS analysis of amino acids and fatty acids with enzyme activity assays suggests that N47 has a chemoorganoautotrophic metabolism degrading complex organic substrates such as naphthalene. Surprisingly, however, the biomass is mainly produced from acetyl-CoA generated de novo via CO2-fixation. This metabolism probably requires both a complete Wood-Ljungdahl pathway for acetyl-CoA oxidation and a reverse tricarboxylic acid cycle for CO2fixation. Based on genome analysis, this chemoorganoautotrophic metabolism seems to also occur in other sulfate-reducers and anaerobic ammonium-oxidizers.
AbstractPeach (Prunus persica), a model species in the Rosaceae family and a globally significant temperate fruit, requires advanced genotyping tools to accelerate genomics-assisted breeding. To address this need, we developed the PeachSNP170K array and genotyped 489 peach accessions, generating a high-resolution SNP-based kinship framework that surpasses the limitations of traditional pedigree analysis. This approach enabled the identification of genomic regions underlying key phenotypic variations. Genome-wide association studies (GWAS) uncovered 1202 SNPs linked to sugar and acid content, as well as flowering time, including identified loci associated with citrate content and flowering time. Notably, we identifiedPpNHX1(sodium/proton antiporter 1) within a citrate-associated locus, which influences citrate accumulation in peach fruit. Additionally, haplotype analysis revealed a highly selected haplotype, Hap3, within a major flowering-time locus, contributing to low-latitude adaptation. These findings establish the PeachSNP170K array as a powerful tool for high-throughput genomic analysis, providing valuable resources for peach research and breeding.
AbstractThe nature and distribution of the synaptic changes that underlie memory are not well understood. Here we examine the synaptic plasticity behind context fear conditioning in male and female mice and find that new learning produces synaptic potentiation specifically onto engram neurons in the basolateral amygdala. This potentiation lasts at least 7 days, is reversed by extinction, and its disruption impairs memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles, or biochemical induction of synaptic potentiation in US-responsive neurons alone, is sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons underlies memory formation and is necessary and sufficient to establish context fear associations.
AbstractWe investigated Transglutaminase 2 (TGM2) in high fat diet (HFD) obese mice, finding upregulated TGM2+ adipose tissue macrophages (ATMs) in HFD epididymal white adipose tissue (eWAT) compared to chow diet (CD) eWAT. UsingTgm2CRISPR silencing, we examined TGM2 modulation of inflammation in vitro within bone marrow-derived macrophages (BMMs), as well as in co-cultured eWAT stromal vascular fraction (SVF) cells. Tgm2 silencing in BMMs led to increased pro-inflammation, compared to control. In contrast, in vitro exposure of eWAT SVF to recombinant TGM2 increased anti-inflammatory IL-10 secretion. However, IL-10 was not induced by recombinant TGM2 in CD activated CD4 + T cells, or in HFD-derived SVF CD4 + T cells. In vivoTgm2silencing in CD11b+ cells in HFD mice resulted in pro-inflammation in eWAT and serum, and increased adiposity and insulin resistance, suggesting that TGM2 + ATMs possess an anti-inflammatory role in obesity that is insufficient to reverse obesity-induced inflammation.
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AbstractMonoallelic gene expression is a pivotal phenomenon in developmental biology, notably through the influence of imprinted genes. Our model predicts that monoallelic expression generates expression variability, which we assess by measuring genetic noise and entropy within Shannon’s information theory framework. Analyzing single-cell allele-specific expression across human and mouse datasets, we consistently observe increased expression variability due to monoallelic expression, affecting both imprinted and co-expressed non-imprinted genes. Moreover, we find decreasing variability in developing neurons and increasing variability in glial cells. The discovery of distinct noise patterns in over 80% of analyzed genes between glial and neuronal populations highlights the importance of differential noise in neurodevelopmental processes. Given the critical role of imprinted genes in biological processes such as growth and brain development, disruptions in their expression might contribute to various disorders. Understanding the stochastic nature of monoallelic expression and its genome-wide impact offers new insights into the mechanisms underlying these pathologies.
AbstractLysine propionylation modification (Kpr) plays an important role in the pathogenesis of several cardiovascular diseases, but the role of Kpr in postoperative atrial fibrillation (POAF) is unclear. Here, we established an atlas of proteomics and propionylation proteomics in the atrial appendage tissues from 28 CABG patients, exploring the role of Kpr proteins in the occurrence of POAF. The Kpr of ALDH6A1 was most significantly increased on Lys113 (2.25 folds). The activity of ALDH6A1 increased due to higher binding energy of propionylated ALDH6A1 and NAD+, causing an increase in NADH levels in cells and triggering abnormal energy metabolism. Furthermore, the increase in NADH levels triggered the accumulation of reactive oxygen species, which may cause oxidative stress, resulting in the development of AF. This study reveals the important role of ALDH6A1-NADH pathway in POAF, and provides new insights for exploring the pathogenesis of POAF in CABG.
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AbstractIntelligence is a broad mental capability influencing human performance across tasks. Individual differences in intelligence have been linked to characteristics of structural and functional brain networks. Here, we consider their alignment, the structural-functional brain network coupling (SC-FC coupling) during resting state and during active cognition, to predict general intelligence. Using diffusion-weighted and functional magnetic resonance imaging data from 764 participants of the Human Connectome Project (replication:N1= 126,N2= 180), we model SC-FC coupling with similarity and communication measures that capture functional interactions unfolding on top of structural brain networks. By accounting for variations in brain region-specific neural signaling strategies, we show that individual differences in SC-FC coupling patterns predict individual intelligence scores. Most robust predictions result from cognitively demanding tasks and task combinations. Our study suggests the existence of an intrinsic SC-FC coupling organization enabling fine-drawn intelligence-relevant adaptations that support efficient information processing by facilitating brain region-specific adjustment to external task demands.
AbstractMarine mammals host a diverse array of parasites engaged in a continuous evolutionary arms race. However, our understanding of the biology of parasitic insects associated with marine mammals, particularly their adaptations to challenging marine environments, remains limited. The seal louse,Echinophthirius horridus, which infests true seals, is one of thirteen insect species capable of enduring prolonged dives in open seas. This ectoparasite has evolved several adaptations to withstand extreme conditions, such as low oxygen levels (hypoxia), temperature fluctuations, hydrostatic pressure, and strong drag forces during dives. To prevent drowning during their host’s 20–35 min dives, seal lice have developed specialized respiratory mechanisms that allow them to survive in oxygen-poor waters and at depths up to 600 m. Advanced imaging techniques, including CLSM, SEM, synchrotronX-ray microtomography, and histological sectioning and 3D-reconstruction, have revealed a specialized spiracle closing apparatus for storing oxygen in their tracheal system. Furthermore, our buoyancy experiments showed that the lice consume oxygen under water and, with morphological data, provide what is to our knowledge the first direct evidence against plastron presence. These findings enhance our understanding of the physical adaptations of lice and their survival in extreme ecological conditions, contributing to broader ecological and evolutionary theories.
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AbstractOptical pooled screening is an important tool to study dynamic phenotypes for libraries of genetically engineered cells. However, the desired engineering often requires that the barcodes used for in situ genotyping are expressed from the chromosome. This has not previously been achieved in bacteria. Here we describe a method for in situ genotyping of libraries with genomic barcodes inEscherichia coli. The method is applied to measure the intracellular maturation time of 84 red fluorescent proteins.
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AbstractDecreased renal uric acid excretion is a major contributor to hyperuricemia (HUA), but its underlying mechanism remains unclear. Here, we identify cathepsin B (CTSB) as a key regulator of urate handling in HUA. Urinary CTSB levels were elevated in HUA patients, and renal CTSB expression was increased in HUA mice. In CTSBtecKOmice, the expression of reabsorptive urate transporters URAT1 and GLUT9 was decreased, while the secretory transporter ABCG2 was upregulated, leading to enhanced renal uric acid excretion and reduced serum uric acid (SUA). CTSB deficiency also reduced serum IL-1β, IL-6, and TNF-α levels. In vitro and transcriptomic analyses revealed that CTSB inhibition suppressed glycolysis—marked by reduced HK2 and PKM2 expression—downregulated URAT1 and GLUT9, and upregulated ABCG2. Conversely, CTSB overexpression enhanced glycolysis and reversed these effects. These findings suggest that CTSB promotes urate retention via glycolysis and may serve as a novel target for HUA treatment.
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ABSTRACTTrifluoperazine (TFP), a known inhibitor of Ca2+‐bound calmodulin (Ca2+/CaM), has been reported to elevate cytosolic Ca2+levels by disinhibiting inositol 1,4,5‐triphosphate receptor 2 (IP3R2), thereby suppressing glioblastoma invasion and inducing apoptosis. Interestingly, TFP induces a sustained Ca2+plateau, sensitive to extracellular Ca2+, suggesting involvement of Ca2+entry such as store‐operated calcium entry (SOCE). However, the underlying molecular mechanism remains elusive. Here, we report that TFP induces sustained Ca2+signals by blocking the Ca2+/CaM‐dependent desensitization of SOCE channels in cortical astrocyte cultures. TFP induces a prolonged Ca2+response, with distinct kinetics compared to other Ca2+modulators such as TFLLR‐NH2(a Gαq‐coupled GPCR agonist) and thapsigargin (a sacro/endoplasmic reticulum Ca2+‐ATPase inhibitor). Under extracellular Ca2+‐free conditions, Ca2+levels increase without reaching a plateau, suggesting that the sustained Ca2+signal relies on Ca2+influx. Pharmacological analysis shows that sustained Ca2+signals by TFP are CaM‐dependent. Gene silencing targeting STIM1 and Orai1–3 confirmed their essential roles in the sustained response. We find that TFP effectively “locks open” SOCE channels by inhibiting their desensitization, maintaining SOCE activity. This effect is also observed in ex vivo hippocampal dentate gyrus astrocytes. Structural modeling supports a mechanism in which TFP disrupts the interaction between Ca2+/CaM and the SOAR domain of STIM1. Together, these findings indicate that TFP elevates cytosolic Ca2+levels by maintaining SOCE activation, offering novel insights into the molecular actions of this drug. TFP can be a pharmacological tool for SOCE research as it locks SOCE channels open.
ABSTRACTOligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS) are capable of proliferating, migrating, and differentiating into oligodendrocytes. OPCs are crucial for the myelination of axons during development and remyelination after injury in adulthood. OPCs also play important roles in promoting angiogenesis, neurotrophy, and immunomodulation, which makes them a relevant element of regenerative approaches for many CNS diseases, especially demyelinating ones. OPC migration is important during neurodevelopment and regeneration, and as such is regulated by a multitude of intracellular and extracellular factors. Identifying these factors will facilitate the optimized regulation of OPC migration and thus enhance therapeutic effects. This field is a current research hotspot, and new findings are constantly emerging. Here, we comprehensively review research progress on the regulatory factors that control OPC migration.
ABSTRACTSpinal cord injury (SCI) results in significant disruption of nerve fibers responsible for transmitting signals between the brain and body, often leading to partial or complete motor, sensory, and autonomic dysfunction below the injury site. Astrocytes are an important component in scar formation, crucial for suppression of injury propagation, effective wound healing, and the regulation of neuronal plasticity. Here, we identify the role of the actin‐binding protein Drebrin (DBN) in reactive astrogliosis following SCI. SCI induces the upregulation of DBN in astrocytes, which controls immediate injury containment but also the long‐term preservation of tissue integrity and healing in the spinal cord. DBN knockout results in enlarged spinal cord lesions, increased immune cell infiltration, and neurodegeneration. Mechanistically, DBN loss disrupts the polarization of scar border‐forming astrocytes, leading to impaired encapsulation of the injury. In summary, DBN serves as a pivotal regulator of SCI outcome by modulating astrocytic polarity, which is essential for establishing a protective barrier confining the lesion site.
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Azurin is a copper-containing redox protein naturally produced by Pseudomonas aeruginosa, which has shown promising activity against human cancer cells by inducing apoptosis. The present study describes the design of a recombinant vector, pT7-MAT-Tag-2-Azu, for azurin production in E. coli cells. The cytotoxic effects of purified azurin were tested on three breast cancer cell lines (MCF-7, MDA-MB-231, and HCC38) and a normal breast epithelial cell line (MCF10A) using the MTT assay. The results showed cytotoxicity against cancer cell lines with minimal effects on normal cells. Further analysis showed that azurin induced apoptosis through mitochondrial pathways, as evidenced by increased expression of apoptosis-related genes (Bax, TP53, Apaf-1, caspase-3, -8, -9) and their corresponding proteins, elevated levels of reactive oxygen species (ROS), and DNA damage, mitochondrial membrane potential (MMP), or brine shrimp lethality assay. Furthermore, in silico molecular docking, simulations predicted a stable, electrostatically driven interaction between azurin and the p53 protein, providing a structural basis for its mechanism of action. These findings suggest that recombinant azurin may serve as a potential therapeutic agent for breast cancer after further multifaceted research.
Triple-negative breast cancer (TNBC) poses significant challenges due to its high aggressiveness, poor prognosis, and the lack of effective targeted therapies. Paclitaxel (PTX) is a chemotherapeutic agent commonly used in the treatment of TNBC; however, its efficacy is often compromised by drug resistance mediated by autophagy. This study investigated the synergistic effects of the autophagy inhibitor 3-methyladenine (3-MA) and PTX in a TNBC nude mouse model. Monitoring tumor volume and employing HE staining, immunofluorescence, and transmission electron microscopy revealed that PTX monotherapy induced tumor autophagy, characterized by the accumulation of LC3B/VPS34 proteins and an increase in autophagosomes. However, the co-administration of 3-MA reversed this process, significantly decreasing the tumor growth rate. Immunofluorescence and qPCR demonstrated that the combination group had fewer Ki-67-positive cells and more Caspase-3-positive cells, along with upregulated expression of autophagy-related genes and Caspase-family apoptosis genes. Consequently, this study suggests that inhibiting autophagy with 3-MA disrupts the autophagy-mediated protective mechanism of tumor cells, promoting the activation of apoptotic signals and enhancing the antitumor activity of PTX. These findings may offer new molecular mechanistic insights and potential therapeutic strategies for overcoming PTX resistance in TNBC.
Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N5,N3-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC50 to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors.
Placenta accreta spectrum (PAS) and placenta previa (PP) are severe obstetric disorders associated with high maternal and perinatal morbidity. Early diagnosis of both conditions remains challenging, particularly in cases with subtle imaging findings. This study was aimed to evaluate the diagnostic value of first-trimester maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (β-hCG) in predicting PAS and PP. In this retrospective case–control study, a total of 100 pregnant women were included: 36 with PAS, 32 with PP, and 32 healthy controls. Serum levels were measured at 11–136 weeks of gestation. Both biomarkers were significantly altered in pathological groups compared to controls: PAPP-A was lower in PP (3.04 [1.42–4.52] IU/L) and PAS (3.63 [2.51–5.39] IU/L) vs. controls (5.34 [3.72–8.41] IU/L; p < 0.001), while β-hCG was higher in PP (45.4 [40.1–54.9] IU/L) and PAS (51.4 [32.3–74.8] IU/L) vs. controls (33.5 [22.7–54.1] IU/L; p = 0.044 and p < 0.001, respectively). ROC analysis demonstrated that combined biomarker modeling improved diagnostic accuracy over single-marker use, with AUCs reaching 0.85 (sensitivity 85.2%, specificity 72%) for PAS and 0.88 (sensitivity 100%, specificity 72%) for PP. These findings support the integration of biochemical screening into first-trimester risk assessment protocols. Incorporating maternal serum biomarkers may enhance early identification of high-risk pregnancies, allow timely referral to specialized care, and reduce adverse outcomes. Further prospective studies are warranted to validate the utility of this dual-marker approach across diverse populations and clinical settings.
The Dof (DNA-binding with one finger) domain protein family is a plant-specific zinc finger transcription factor family that plays a role in various biological processes in plants. However, research on Dof transcription factors in soybean (Glycine max) remains limited. In this study, we identified 79 putative soybean Dof genes, which are distributed across the entire genome. A comparative phylogenetic analysis of the Dof gene family in soybean, Arabidopsis, rice, maize, and Medicago revealed five major groups. The synteny relationship analysis showed a large number of gene duplication events in soybean. Twelve cis-acting elements were detected in the promoter region of the Dof gene, including five hormone response elements and several environmental response elements. Expression pattern analysis indicated that most Gmdof genes exhibited specific expression patterns. Nine genes in group V, which exhibited higher expression in the root, were identified as significantly responsive to salt stress through qRT-PCR. The possible biological functions of several Gmdof genes were discussed, including Gmdof11.2, Gmdof2.1, and Gmdof16.2. In summary, this study integrated phylogenetic analysis with genome-wide expression profiling to provide valuable information for understanding the functional characteristics of Dof genes in soybean.
Monomeric C-reactive protein (mCRP), derived from the dissociation of the native pentameric CRP (pCRP), has been implicated in the pathophysiology of various neurological conditions, particularly intracerebral hemorrhage (ICH) and neurodegenerative diseases. mCRP accumulates in the brain after hemorrhagic stroke, contributing to the formation of the metabolic penumbra and promoting inflammation. Recent studies have linked mCRP to the activation of microglia, endothelial cells, and complement pathways, which collectively intensify neuroinflammation and disrupt tissue repair mechanisms. Additionally, mCRP is associated with cognitive decline, particularly in ICH survivors, by promoting microvascular damage, neurodegeneration, and vascular instability. The presence of mCRP in distant regions of the brain, including the hypothalamus, suggests its potential role in spreading inflammation and exacerbating long-term neurological damage. This review synthesizes findings on the pathogenic role of mCRP in stroke and neurodegeneration, proposing that mCRP could serve as both a biomarker and a therapeutic target for improving outcomes in stroke patients. Emerging immunopharmacological strategies are being actively pursued to mitigate the pathogenic activity of mCRP, a potent pro-inflammatory effector implicated in a variety of immune-mediated and neuroinflammatory conditions. These approaches encompass the inhibition of native pentameric CRP dissociation into its monomeric isoform, the disruption of mCRP’s high-affinity interactions with lipid rafts and cell surface receptors involved in innate immune activation, and the enhancement of its clearance through mechanisms such as solubilization, opsonin-mediated tagging, and phagocytic engagement. Targeting these immunoregulatory pathways offers a compelling therapeutic framework for attenuating mCRP-driven inflammatory cascades in both systemic and CNS-specific pathologies.
Estrogens are potent hormones involved in numerous physiological and pathological processes. Their typically low concentrations in biological samples necessitate highly sensitive analytical methods for accurate quantification. This study presents a high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method for quantifying estradiol and its metabolites in blood serum and saliva. Analytes were extracted using solid-phase microextraction with a divinylbenzene sorbent and methanol as the desorption agent. FLD was performed after the derivatization of the analytes with dansyl chloride. Separation was achieved on a Poroshell 120 EC-C18 column (2.1 × 100 mm, 2.7 µm) at 50 °C using water with 0.1% formic acid and methanol as the mobile phase at 0.5 mL/min. A gradient elution increased the methanol concentration from 76% to 100% over 0–8 min, then it returned to 76% at 8.1 min and was held until 11 min had passed. Detection was at λEX 350 nm and λEM 530 nm. Good linearity was observed for estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol (10–300 ng/mL; R2 = 0.9893–0.9995). The LOQ for all analytes was 10 ng/mL. Solid-phase microextraction (SPME) offered advantages over liquid–liquid extraction. The method is suitable for quantifying estrogens in the 10 ng/mL–1 µg/mL range.
Colorectal cancer (CRC) remains one of the most prevalent malignancies of the gastrointestinal tract worldwide, with chronic inflammation recognized as a key factor in its progression. Among pro-inflammatory cytokines, interleukin 8 (IL-8) plays a pivotal role in promoting angiogenesis, tumor cell migration, and metastasis. Elevated IL-8 expression is frequently associated with advanced CRC stages. This study investigated the effects of betulin and its semi-synthetic derivatives, EB5 and ECH147, on IL-8 expression in CRC cell lines characterized by differing malignancy grades. IL-8 transcript and protein levels were quantified using real-time RT-qPCR and a proximity ligation assay, respectively, following compound exposure at 2, 8, and 24 h. Basal IL-8 levels were significantly higher in low-grade CRC cell lines. Among the compounds tested, ECH147 exerted the most pronounced, time-dependent inhibitory effect on CXCL8 expression. Furthermore, molecular docking analyses revealed that ECH147 exhibits stronger binding affinity toward the IL-8 protein compared to conventional chemotherapeutics. These findings suggest that the modification of the betulin structure via the incorporation of a propynoyl moiety enhances both its molecular interaction with CXCL8 and its anti-inflammatory potential. ECH147 and EB5 thus emerge as promising candidates for further development as immunomodulatory agents targeting the IL-8-associated pathway in CRC.
Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurosteroids, including allopregnanolone (ALLO), play critical roles in modulating neuronal activity in the brain. Levels of these compounds dynamically fluctuate in response to physiological and environmental conditions, particularly stress, suggesting complex regulatory interactions. This study aimed to explore the effects of acute stress and ALLO (individually and combined) on hippocampal expression of BDNF, its TrkB receptor, and other neurotrophins in sheep, a translational large animal model. Adult, luteal-phase sheep (n = 24), implanted with a guide cannula into the third brain ventricle, were divided into four experimental groups: (i) 3 days of Ringer–Locke solution (RL) infusion as the control; (ii) 3 days of RL infusion with 4 h acute stress on day three; (iii) 3 days of ALLO infusion (4 × 15 µg/60 µL/30 min) with 4 h acute stress on day three; and (iv) 3 days of ALLO infusion alone (n = 6 per group). Both acute stress and ALLO alone significantly reduced BDNF concentration and BDNF transcript abundance in the hippocampal CA1 and CA3 fields compared to the control group. The combined application of both stress and ALLO resulted in decreased levels of these parameters, except for BDNF concentration in the CA3 region. Additionally, TrkB mRNA expression in both hippocampal fields was significantly reduced in all treatment groups. Changes in mRNA levels for other neurotrophins, including nerve growth factor (NGF) and neurotrophin 3 (NT3) and 4 (NT4), varied under experimental conditions. While an inhibitory effect was predominant, NGF expression in the CA1 region remained unaffected by stress or ALLO. Interestingly, stress alone induced a significant increase in NT4 mRNA expression in the CA3 field compared to the control. In conclusion, the study demonstrated that a 4 h acute stress exposure inhibited the synthesis of BDNF, TrkB, and several other neurotrophins in the sheep hippocampus. Furthermore, ALLO, whose increased levels are highly correlated with the initial stress response, may serve as a mediator of this stress effect, temporarily preventing over-stimulation of hippocampal BDNF release and signaling.
Poplar leaves (Populi folium) are a herbal remedy traditionally used for the treatment of rheumatic diseases and prostate inflammation. The aim of our study was a comprehensive identification of secondary metabolites occurring in the leaves of Populus alba, Populus × candicans, and Populus nigra, in order to search for a source of raw plant material rich in active compounds. Total salicylate (TSC), flavonoid (TFC), and phenolic compound (TPC) contents were determined, and the antioxidant potential was assessed using DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2′-azino-bis(3-ethylbenzothiazoline- 6-sulfonic acid) diammonium salt), and FRAP (ferric reducing antioxidant power) assays as well as 2D-TLC (two-dimensional thin layer chromatography) bioautography using DPPH, riboflavin-light-NBT (nitro blue tetrazolium chloride), and xanthine oxidase inhibition tests. Secondary metabolites present in the analyzed poplar leaves were identified under the developed HPLC-DAD-ESI/MS (high performance liquid chromatography with photodiode array detection and electrospray ionization mass spectrometric detection analysis conditions and using the 2D-TLC method. Among the 80 identified compounds, 13 were shown for the first time in the genus Populus. The most diverse and similar set of flavonoids characterized the leaves of P. × candicans and P. nigra, while numerous salicylic compounds were present in the leaves of P. alba and P. × candicans. All analyzed leaves are a rich source of phenolic compounds. The highest flavonoid content was found in the leaves of P. × candicans and P. nigra, while the leaves of P. alba were characterized by the highest content of salicylates. All examined poplar leaves demonstrated antioxidant potential in all the assays used, which decreased in the following order: P. nigra, P. × candicans, P. alba.
Abnormal expressions and genetic mutations of EGFR are broadly involved in the progression of many human solid tumors, which has led to the development of small molecule inhibitors (TKIs). However, patients’ tumors usually develop resistance to targeted therapeutic TKIs after a period of treatment, mostly due to secondary mutations in EGFR. To date, three major and prevalent point mutations in EGFR, including L858R, T790M, and C797S, impact the use of TKIs in non-small cell lung cancer patients. Although at least four generations of TKIs have been designed and developed by targeting these mutations, how each mono, dual, or triple variant responds to clinical TKIs remains largely undeciphered. To fill this gap, we constructed a series of EGFR mutants and assessed their responses to clinical TKIs in vitro. The first-generation TKI, erlotinib, completely blocked the autophosphorylation of WT, L858R, C797S, and C797S/L858R, but only partially, if at all, in EGFR containing the T790M mutation alone or in combination. The third generation, osimertinib, completely abolished the autophosphorylation of WT, T790M, L858R, and T790M/L858R. It also significantly inhibited C797S and C790S/L858R, but had no effect on T790M/C797S or T790M/C797S/L858R. EAI045, as the fourth-generation TKI, almost completely inhibited WT and all mutants in complete growth media, but EGF-mediated phosphorylation of WT, C797S, and C797S/L858R were only partially inhibited in quiescence media, while the other mutants were fully inhibited. Furthermore, the abolishment of the enhanced tolerance to Dox in cells transiently expressing T790M/L858R and T790M/C797S/L858R by EAI045 suggests that their enhanced autophosphorylation is involved in their resistant ability. These findings provide some insights into how patients carrying typical mutations should be correctly and efficiently treated and why patients present side effects (because of non-specific inhibitory effects on cells without EGFR mutations).
Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes.
Melanoma is the most aggressive form of skin cancer, and despite significant therapeutic advances over the past decade, a substantial number of patients still progress to a fatal outcome. The initiation and progression of melanoma are strongly influenced by interactions between melanoma cells and other components of the tumor microenvironment (TME). In this review, we focus on the interplay between fibroblasts resident in the tumor microenvironment and tumor cells. In particular, we examine the molecular mechanisms through which melanoma cells induce the transformation of resident fibroblasts into their active form, known as cancer-associated fibroblasts (CAFs). We also explore the role of CAFs in shaping the melanoma microenvironment (MME) and in organizing the pre-metastatic niche, a specialized microenvironment that forms in distant organs or tissues to support the survival and expansion of metastatic melanoma cells. Finally, we discuss emerging therapeutic strategies aimed at disrupting the interactions between CAFs, melanoma cells, and other components of the tumor microenvironment to improve treatment outcomes.
Dengue virus (DENV) remains a critical global health challenge, with no approved antiviral treatments currently available. The growing prevalence of DENV infections highlights the urgent need for effective therapeutics. Antiviral peptides (AVPs) have gained significant attention due to their potential to inhibit viral replication. However, traditional drug discovery methods are often time-consuming and resource-intensive. Advances in artificial intelligence, particularly deep generative models (DGMs), offer a promising approach to accelerating AVP discovery. This report provides a comprehensive assessment of the role of DGMs in identifying novel AVPs for DENV. It presents an extensive survey of existing antimicrobial and AVP datasets, peptide sequence feature representations, and the integration of DGMs into computational peptide design. Additionally, in vitro and in silico screening data from previous studies highlight the therapeutic potential of AVPs against DENV. Variational autoencoders and generative adversarial networks have been extensively documented in the literature for their applications in AVP generation. These models have demonstrated a remarkable capacity to generate diverse and structurally viable compounds, significantly expanding the repertoire of potential antiviral candidates. Additionally, this report assesses both the strengths and limitations of DGMs, providing valuable insights for guiding future research directions. As a data-driven and scalable framework, DGMs offer a promising avenue for the rational design of potent AVPs targeting DENV and other emerging viral pathogens, contributing to the advancement of next-generation therapeutic strategies.
The tumor suppressor p16INK4a, encoded by CDKN2A, is frequently inactivated in cancer through genetic or epigenetic mechanisms. While promoter hypermethylation is the most common epigenetic cause, aberrant methylation of CDKN2A exon 2 has also been associated with various tumor types. However, analyzing DNA methylation of exon 2 is challenging due to its high sequence similarity with CDKN2B. We developed a pyrosequencing assay to analyze CpGs in CDKN2A exon 2, which was previously found to be hypermethylated in breast cancer. Our novel primer set enabled co-amplification of the homologous regions in CDKN2A, including CpGs 1–24, and CDKN2B CpGs 1–23. By quantifying the proportion of CDKN2A, we could accurately determine methylation levels for CpGs in CDKN2A exon 2. This method was applied to patient-derived glioma cells and commercial breast cancer cell lines. To reveal the role of exon 2 methylation in gene regulation, we additionally examined CDKN2AINK4a promoter methylation and expression at both mRNA and protein levels in breast cancer cell lines. We observed a range of (epi)genetic alterations, including homozygous deletions, transcript-specific expression, and exon 2 skipping. Our findings indicate that both promoter and exon 2 methylation contribute to regulation of CDKN2A expression. This novel method provides a valuable tool for future studies seeking a deeper understanding of CDKN2A regulation in cancer.
Spatial transcriptomics is an emerging technology that maps gene expression within tissue architecture. Its expanding use in medicine and veterinary science supports research, precision diagnostics, biomarker discovery, and development of targeted treatment strategies. While spatial transcriptomics applications in human health are well-documented with significant publication diversity and volume, published applications in veterinary medicine remain limited. A comprehensive search of PubMed was conducted, focusing on studies published from 2016 to early 2025 that employed spatial transcriptomics in the context of disease research, diagnosis, or treatment in human or animal health. The review followed the Arksey and O’Malley framework and adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. A total of 1398 studies met the inclusion criteria. The studies highlighted emerging trends of comparative research with animal model use for human health research. Commonly used spatial transcriptomics platforms included 10× Visium, Slide-seq, Nanostring (GeoMx, CosMX), and multiplexed error-robust fluorescence in situ hybridization (MERFISH). Key gaps in publications include limited veterinary representation, interspecies comparisons, standardized methods, public data use, and therapeutic studies, alongside biases in disease, species, organ, and geography. This review presents the current landscape of spatial transcriptomics publications for human and animal research and medicine, providing comprehensive data and highlighting underrepresented research areas and gaps for future consideration.
Skin aging is a multi-factorial process characterized by the progressive deterioration of biomechanical properties and cellular functionality. One such factor is the formation of advanced glycation end products (AGEs), which are known to have detrimental effects on the skin, including stiffening of the extracellular matrix (ECM) and reduction of cellular proliferation. AGEs accumulate because of sugar metabolism dysfunction; however, the direct impact of elevated sugar levels on cellular physiology requires further investigation. Here, we elucidated the effects of elevated fructose levels on skin cell function using in vitro models and hypothesized that high fructose levels adversely impact cell function. By fluorescence microscopy, we observed that high fructose induced different cellularity, cell morphology, and stress fiber appearance than the controls. Skin cells exposed to high fructose levels showed impaired growth and delayed closure in an artificial wound model. Mechanistically, high fructose conditions induce inflammatory cytokines and activate the NFκB pathway. Furthermore, we observed for the first time an increase in the senescence markers p16, p21, and p53 in response to high fructose levels. Taken together, we show that high fructose levels affect many critical skin functions that contribute to the aging process and recapitulate several aspects of aging related to AGEs.
Glioblastoma is the most prevalent and aggressive form of brain malignancy. Actual treatments face several challenges due to its high aggressiveness and poor prognosis. The chemotherapeutic agent temozolomide (TMZ) has limited therapeutic efficacy, and mutations in the tumour protein p53 gene (TP53) have been associated with treatment resistance. Thus, this study aimed to explore an innovative therapeutic strategy to enhance treatment efficacy of GBM. Previously, our team had developed a WRAP5 cell-penetrating peptide (CPP) functionalized with a transferrin receptor ligand (Tf) for the targeted delivery of TMZ and a p53-encoding plasmid to glioma cells. Our research had elucidated the circadian oscillations of the clock genes in the U87 glioma cells by employing two different computational models and observed that T16 and T8 time points revealed the highest circadian activity for Bmal1 and Per2 genes, respectively. Similar analysis was conducted for the transferrin receptor, which revealed that T7 and T8 were the key time points for its expression. A confocal microscopy study indicated the highest intracellular uptake of complexes and p53 mRNA expression at T8, the time point with the highest Per2 and transferrin receptor expression. Following mRNA analysis, the evaluation of p53 levels confirmed transcriptional changes at the protein level, and that T16 appears to be a favourable time point for enhancing therapeutic efficacy in U87 glioblastoma cells. These findings suggested that synchronizing the complexes’ administration with the biological clock of GBM cells may significantly improve glioblastoma therapeutics.
Type II testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men and are classified into seminomas and non-seminomatous subtypes. Seminomas are known for their highly pro-inflammatory tumor microenvironment (TME) with abundant immune cell infiltration. While previous work has demonstrated that the seminoma-derived cell line TCam-2 induces immune cell activation in co-culture and undergoes phenotypic changes itself, the underlying mechanisms remained unclear. To explore the role of direct cell–cell interaction and the effects mediated by soluble mediators such as cytokines, we conducted co-culture experiments of TCam-2 cells with purified human T cells or monocytes, including Transwell assays and treatments with IL-6, TNFα, or their respective blocking antibodies Tocilizumab and Adalimumab. In this way, we found that immune cell activation, indicated by enhanced secretion of pro-inflammatory cytokines and an upregulation of activation markers, strongly depended on direct physical contact between both cell types. Nonetheless, we also unveiled the role of soluble mediators in both immune cell activation and promoting a shift in TCam-2 cells from a seminoma-like phenotype to a more dedifferentiated phenotype, suggesting that cytokines critically shape the TME. These observations highlight the complexity of tumor–immune interactions in the seminoma microenvironment, offering new insight into immune-driven dynamics in TGCTs.
Currently, there is no standard treatment for renal cell carcinoma (RCC) that is free of side effects and resistance. Additionally, limited information exists on how curcumin affects the gene expression profiles of patients with translocation renal cell carcinoma (tRCC) and papillary renal cell carcinoma (pRCC). The pathways responsible for metastasis in tRCC are still not well understood, and there is no established treatment or reliable biomarker to predict outcomes for metastatic tRCC. Primary clinical data from patients were retrieved from the TCGA database and analyzed using cBioPortal, stitch, string, R and Python. Various analyses were performed, including differential gene expression, protein-protein interaction (PPI) network analysis, drug-targeted gene analysis, gene ontology (GO), enrichment analyses, and systematic searches to assess the impact of curcumin on the transcriptomic profiles of tRCC, pRCC, and clear cell renal cell carcinoma (ccRCC). No significant impact of sensitive genes on survival in KIRC and KIRP was found, though a trend suggested they may delay disease progression. The combination of curcumin with sunitinib showed promise in overcoming drug resistance in ccRCC by inducing ferroptosis, reducing iron, and increasing ADAMTS18 expression. This study, leveraging data from the TCGA database and other databases explored the impact of curcumin on transcriptomic profiles in tRCC, pRCC, and clear cell RCC (ccRCC). Gene analysis revealed immune and metabolic differences, with KIRC showing a stronger immune response. This study is the first to propose that future research into the miR-148/ADAMTS18 genes and the ferroptosis pathway in tRCC and pRCC could lead to the development of new therapies and the identification of novel therapeutic targets, potentially overcoming drug resistance and metastasis.
Age-related macular degeneration (AMD) is a progressive retinal disorder and a leading cause of irreversible blindness among elderly individuals, impacting millions of people globally. This review synthesizes the current understanding of the cellular and molecular signaling mechanisms driving AMD, with a focus on the distinct pathophysiological features of dry and wet AMD subtypes. Key mechanisms include oxidative stress, inflammation, lipid metabolism dysregulation, and immune dysregulation, all of which converge on the retinal pigment epithelium (RPE) as a central player in disease initiation and progression. In dry AMD, oxidative damage, mitochondrial dysfunction, and lipofuscin accumulation impair RPE function, contributing to drusen formation and geographic atrophy. In wet AMD, vascular endothelial growth factor-mediated angiogenesis, coupled with inflammation and endothelial metabolic reprogramming, drives choroidal neovascularization. This article integrates findings from multiomics approaches and highlights the potential of artificial intelligence in elucidating AMD pathogenesis and advancing personalized therapies. Future research directions emphasize targeting these molecular pathways to develop innovative treatments, offering hope for improved management of this debilitating condition.
Thermokinetic characterization of amorphous carbamazepine was performed utilizing non-isothermal differential scanning calorimetry (DSC) and thermogravimetry (TGA). Structural relaxation of the amorphous matrix was described in terms of the Tool–Narayanaswamy–Moynihan model with the following parameters: Δh* ≈ 200–300 kJ·mol−1, β = 0.57, x = 0.44. The crystallization of the amorphous phase was modeled using complex Šesták–Berggren kinetics, which incorporates temperature-dependent activation energy and degree of autocatalysis. The activation energy of the crystal growth was determined to be >320 kJ·mol−1 at the glass transition temperature (Tg). Owing to such a high value, the amorphous carbamazepine is stable at Tg, allowing for extensive processing of the amorphous phase (e.g., self-healing of the quench-induced mechanical defects or internal stress). A discussion was conducted regarding the converse relation between the activation energies of relaxation and crystal growth, which is possibly responsible for the absence of sub-Tg crystal growth modes. The high-temperature thermal decomposition of carbamazepine proceeds via multistep kinetics, identically in both an inert and an oxidizing atmosphere. A complex reaction mechanism, consisting of a series of consecutive and competing reactions, was proposed to explain the second decomposition step, which exhibited a temporary mass increase. Whereas a negligible degree of carbamazepine degradation was predicted for the temperature characteristic of the pharmaceutical hot-melt extrusion (~150 °C), the degradation risk during the pharmaceutical 3D printing was calculated to be considerably higher (1–2% mass loss at temperatures 190–200 °C).
Plant-derived polyphenols have become a subject of scientific interest in recent decades due to their widespread occurrence in dietary sources and multi-faceted biological activity, with many of these compounds being recognized as antioxidants and anti-inflammatory agents. Several of these chemicals have, moreover, attracted further interest as their anti-tumoral capabilities were discovered, promising potential implementation in the treatment of proliferative diseases, including various cancers. Malignancies of the central nervous system, the most prevalent of which are glioblastomas, are noted for their aggressiveness, dismal prognosis and low survival rates. This review focuses on two polyphenols with the most expansive body of research on this topic, namely resveratrol and curcumin. It covers recent developments in the research, including in vitro findings, animal model studies and clinical trials on these compounds’ effects on the growth and progression of glial tumors of the central nervous system. Its aim is to present the latest findings on the subject of the mechanisms of action of these phytochemicals and their synergistic activity with conventional therapies, as well as strategies to improve their efficacy for future therapeutic applications.
Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell dyscrasia. According to revised diagnostic criteria, pPCL is defined by the presence of ≥5% circulating plasma cells (CPCs) in the peripheral blood of patients with newly diagnosed multiple myeloma (NDMM). pPCL is characterized by a distinct cytogenetic profile, including frequent t(11;14), MAF/MAB translocations, 1q gain, and del(17p). While t(11;14) is generally associated with a favorable prognosis, the coexistence of multiple high-risk cytogenetic abnormalities is linked to poorer outcomes. Tandem autologous hematopoietic stem cell transplantation and novel anti-myeloma agents have improved survival in some patients; however, overall prognosis remains poor, particularly in those ineligible for transplantation. Venetoclax and emerging immunotherapies, such as CAR-T cells and bispecific antibodies, show promise and merit clinical trials focused on pPCL-enriched cohorts. Additionally, recent findings associating even minimal CPCs with adverse outcomes in NDMM support broader inclusion criteria in future trials. A deeper understanding of pPCL’s molecular pathology is critical for the development of effective targeted therapies. This article reviews recent advances in the molecular understanding of and treatment strategies for pPCL.
In recent years, as gene therapy technology has rapidly developed, there has been growing concern that it could be misused by athletes as a means of doping. However, current testing methods for gene doping have a range of limitations and require further improvement. Furthermore, significant progress has been made in the fields of blood storage, next-generation sequencing (NGS), and LabDroid (experimental robots). Against this background, this study was implemented to develop a test method for gene doping using dried blood spot (DBS), NGS, and the LabDroid ”Maholo”. As a first step, recombinant adeno-associated virus containing the human erythropoietin gene (hEPO) was injected into mice to establish a gene doping model. Subsequently, DBS was created using whole blood. Maholo was used to extract DNA from the DBS and to create DNA libraries for NGS. NGS in combination with bioinformatic analysis clearly identified DNA fragments that provided definitive evidence of gene doping in the mouse model, which were absent in the control mouse. To the best of our knowledge, this is the first attempt to use a biological model of hEPO gene doping in conjunction with Maholo, NGS, and DBS. This method should facilitate the further development of gene doping tests.
Ulva prolifera (Chlorophyta), a pivotal species in green tide generation, is particularly vulnerable to abiotic stressors, including variations in temperature and light intensity, requiring specific regulatory frameworks for survival. Epigenetic modification is recognized as a molecular mechanism contributing to the flexible adaptability to environmental alterations. In this study, using DNA methylation pattern analysis, we investigated abiotic stress responsive methylation events, as well as gene and pathway expression patterns, in green macroalgae U. prolifera cultured under elevated temperature–light stress (30 °C and 300 µmol photons m−2 s−1) and identified a negative correlation between CG methylation and gene expression patterns which indicated that abiotic stress caused CG demethylation and afterwards provoked the transcription response. CHG and CHH methylation exhibited an increased mutability and were preeminently found in transposable elements and intergenic regions, possibly contributing to genetic stability by restricting transposon activity. Furthermore, a rapid regeneration through spore ejection and the formation of new thalli was observed, which emphasized its tenacity capacity for stress memory. Our study also revealed an upregulation of genes associated with the glycolysis pathway and highlighted the critical roles of hexokinase, 6-phosphofructokinase-1, and fructose-6-phosphate in triggering glycolysis as a significant stress-adaptive pathway. Overall, these findings suggested that DNA methylation functions as a potential regulatory mechanism, maintaining environmental adaptability, genomic integrity, and underpinning regenerative capacity in U. prolifera. The findings elucidated the molecular resilience of U. prolifera, highlighting its feasibility for sustainable development and biotechnological applications.
Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that are multifactorial in nature. The pathophysiology involves interactions between the host immune system and environmental factors, including the gut microbiota, in genetically predisposed individuals. Advances in understanding these interactions have led to the development of novel therapeutic targets, ranging from anti-TNFα to more recent anti-interleukin 23 treatments. However, some patients still experience resistance to these therapies. Monogenic intestinal diseases (MIDs), which present with more severe symptoms than IBD and typically begin early in life, result from significant disruptions of intestinal homeostasis. MIDs are driven by mutations in a single gene, offering a unique opportunity to explore the mechanisms underlying intestinal homeostasis in health. In this review, we provide a comprehensive overview of the mechanisms of intestinal homeostasis by examining the cellular and molecular features of IBD and MID pathophysiologies.
Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC50 values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells.
The rising prevalence of antibiotic-resistant bacteria demands exploration of alternative antimicrobials. Antimicrobial peptides (AMPs) are a promising group of compounds naturally produced by microorganisms and could serve as potent agents against resistant pathogens. In this study, we evaluated the antimicrobial potential of the cell-free supernatant obtained from Pedobacter silvilitoris—a bacterium originally isolated from decomposing wood—and performed comprehensive genomic screening to uncover novel AMP-encoding genes. The supernatant showed strong inhibitory effects against a diverse selection of pathogens. Scanning electron microscopy (SEM) revealed extensive membrane damage, including pore formation in target bacterial cells, suggesting AMP-mediated activity. A genomic analysis identified 11 candidate AMP genes, named PS_AMP1 to PS_AMP11, based on the significant sequence similarity with known AMPs. Transcriptomic profiling further indicated that several candidates are expressed differentially between the logarithmic and stationary growth phases. Functional assays via gene cloning and peptide synthesis confirmed antimicrobial activity against both Gram-stain-negative and Gram-stain-positive bacteria, with PS_AMP11 emerging as the most effective candidate. Our findings demonstrate that AMPs derived from P. silvilitoris hold substantial promise as alternative antimicrobial agents. Nonetheless, additional structural optimizations may be necessary to fine-tune specificity and to reduce potential host toxicity before clinical deployment.
To advance our understanding of multiple sclerosis (MS), accurate identification of protein expression profiles as biomarkers for MS in cerebrospinal fluid (CSF) is critical. However, proteomic studies investigating MS have yielded inconsistent findings due to variability in sample sizes, diagnostic criteria, and data processing methods. We aimed to tackle these challenges by performing a thorough meta-analysis of proteomics datasets sourced from multiple independent studies. We conducted a thorough database search to gather all relevant studies using appropriate keywords. We screened articles using defined inclusion and exclusion criteria, and finally, six studies were included. We retrieved and combined data from five CSF datasets for discovery and two additional datasets for validation in 368 MS patients and controls. After data preprocessing, we calculated Z-scores for all datasets and for the integrated dataset. We used logistic regression models using training and validation datasets. We identified 11 differentially expressed proteins in the integrated dataset, revealing significant alterations in key pathways involved in immune response, neuroinflammation, and synaptic function. Notably, IGKC exhibited strong diagnostic potential, with an AUROC of 0.81. These findings highlight the value of re-analysing publicly available proteomics data to develop robust biomarker panels for MS diagnosis.
Alkaline phosphatase (ALP) deficiency has been linked to reduced physical performance, as seen in hypophosphatasia (HPP). However, its potential role in muscle function has not been fully explored. This was a cross-sectional study in 34 HPP adults and 34 matched healthy controls. Muscle strength was assessed using handgrip strength (HGS), considering values below the 10th percentile of the Spanish population as low strength. Muscle mass was evaluated using dual-energy X-ray absorptiometry and morphometric ultrasound. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and total hip. The prevalence of low muscle strength was significantly higher in the HPP group compared to controls (30% vs. 6%; p = 0.009), with decreased HGS in the HPP group (p = 0.039). Positive associations were observed between ALP and femoral neck BMD, leg circumference, and fat-free mass and an inverse association with tricipital skinfold. Subjects with serum ALP activity below the sex-adjusted median had a significantly higher risk of low muscle strength independently of HPP diagnosis. ALP remained independently associated with HGS (p = 0.005), and a predictive model using ALP values showed strong capability to predict low-muscle-strength risk. Based on these results, we conclude circulating ALP levels are independently associated with muscle strength and may represent a useful biomarker for the early detection of muscle dysfunction. Future longitudinal or interventional studies are needed to assess whether ALP plays a causal role in muscle strength.
Preeclampsia, one of the leading causes of maternal and fetal morbidity and mortality, affects approximately 3–5% of pregnancies worldwide. However, its etiology remains poorly understood. The aim of this study was to identify molecular markers of preeclampsia. Protein concentrations in blood and urine were determined using the Bio-Plex Kidney Toxicity 1 assay Bio-Rad, Hercules, CA, USA followed by magnetic separation and flow cytometry. This study included 51 patients with preeclampsia and 25 healthy pregnant women. The results revealed that five out of the six serum biomarkers of kidney injury were elevated in the preeclampsia group compared to the control group (calbindin 1, clusterin, glutathione transferase pi (GSTP1), monocyte chemotactic protein 1 (MCP-1), and kidney injury molecule type 1 (KIM-1)). Additionally, the serum concentrations of calbindin 1, clusterin, GSTP1, and KIM-1 were significantly higher in both early-onset and late-onset preeclampsia compared to the control group. The analysis of urinary proteins showed that only the KIM-1 concentration was elevated in late-onset preeclampsia compared to the control group. These findings suggest that the calbindin 1, clusterin, GSTP1, KIM-1, and MCP-1 concentrations in maternal plasma could serve as potential biomarkers for monitoring kidney injury in preeclamptic women. This study provides a foundation for future research to explore novel biomarkers of preeclampsia and renal injury in pregnant women.
Delta-9-tetrahydrocannabinol (THC) is a psychoactive element of Cannabis sativa and affects the human cannabinoid system through its receptors, CB1R and CB2R. CB1R was found in several brain areas, including the hippocampal formation (HF), and it is responsible for most THC side effects. We investigated THC’s effects in the HF of female Wistar rats to assess changes in its neurotransmission. Female Wister rats (n = 20) were gonadectomized under anesthesia at 8 weeks old. Afterwards, they received estradiol benzoate (EB) and/or THC. Immunohistochemistry was performed to assess the expression of the cholinergic receptor alpha 7 subunit (CHRNA7), the vesicular acetylcholine transporter (VAChT), the vesicular glutamate transporter (VGLUT), the gamma-aminobutyric acid type A receptor (GABRA), the CB1 receptor, and estradiol receptor alpha (EBα). In the HF, the expression of CHRNA7 was increased by EB and by THC in the Oil groups but decreased by THC in the EB groups. The same is true for VGLUT expression in the DG and hilum and for GABRA expression in the hilum. The expression of VAChT and CB1 is reduced by EB, while the concomitant administration of THC increases it. GAD expression is reduced by EB administration in CA1, CA3, and DG. Our results may help with decision-making regarding the prescription of low doses of THC as a therapeutical approach.
The development of orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a promising therapeutic avenue for the treatment of type 2 diabetes mellitus (T2DM) and obesity. An extensive in silico approach combining structure-based drug design and ligand-based strategies together with pharmacokinetic properties and drug-likeness predictions is implemented to identify novel non-peptidic GLP-1RAs from the COCONUT and Marine Natural Products (CMNPD) libraries. More than 700,000 compounds were screened by shape-based similarity filtering in combination with precision docking against the orthosteric site of the GLP-1 receptor (PDB ID: 6X1A). The docked candidates were further assessed with the molecular mechanics MM-GBSA tool to check the binding affinities; the final list of candidates was validated by running a 500 ns long MD simulation. Twenty final hits were identified, ten from each database. The hits contained compounds with reported antidiabetic effects but with no evidence of GLP-1 agonist activity, including hits 1, 6, 7, and 10. These findings proposed a novel mechanism for these hits through GLP-1 activity and positioned the other hits as potential promising scaffolds. Among the studied compounds—especially hits 1, 5, and 9—possessed strong and stable interactions with critical amino acid residues such as TRP-203, PHE-381, and GLN-221 at the active site of the 6X1A-substrate along with favorable pharmacokinetic profiles. Moreover, the RMSF and RMSD plots further suggested the possibility of stable interactions. Specifically, hit 9 possessed the best docking score with a ΔG_bind value of −102.78 kcal/mol, surpassing even the control compound in binding affinity. The ADMET profiling also showed desirable drug-likeness and pharmacokinetic characteristics for hit 9. The pipeline of computational integration underscores the potential of non-peptidic alternatives in natural product libraries to pursue GLP-1-mediated metabolic therapy into advanced preclinical validation.
Hypertensive disorders of pregnancy are associated with a higher risk of later cardiovascular disease, but the mechanistic links are unknown. We recruited two groups of women, one during pregnancy and another at least two years after delivery, including both cases (with a hypertensive disorder of pregnancy) and controls (with a normotensive pregnancy). We measured metabolites using liquid chromatography–mass spectroscopy and applied machine learning to identify metabolomic signatures at three time points: antepartum, postpartum, and mid-life. The mean ages of the pregnancy cohort (58 cases, 46 controls) and the mid-life group (71 cases, 74 controls) were 33.8 and 40.8 years, respectively. The levels of 157 metabolites differed significantly between the cases and the controls antepartum, including 19 acylcarnitines, 12 gonadal steroids, 11 glycerophospholipids, nine fatty acids, six vitamin D metabolites, and four corticosteroids. The machine learning model developed using all antepartum metabolite levels discriminated well between the cases and the controls antepartum (c-index = 0.96), postpartum (c-index = 0.63), and in mid-life (c-index = 0.60). Levels of 10,20-dihydroxyeicosanoic acid best distinguished the cases from the controls both antepartum and postpartum. These data suggest that the pattern of differences in metabolites found antepartum continues to distinguish women who had a hypertensive disorder of pregnancy from women with a normotensive pregnancy for years after delivery.
The diversity of structural types of carrageenans (CRGs)—sulfated polysaccharides of red algae—determines their different biological activities. The different types of CRGs (kappa, lambda, kappa/beta-CRGs) were isolated from the red algae of the Pacific coast. Molecular docking was performed to determine potential interactions of CRGs with the receptor-binding domain (RBD) of SARS-CoV-2 and its cellular receptor—angiotensin—converting enzyme type 2 (ACE2). CRGs interacted with ACE2 and RBD via hydrogen bonding and ionic interactions. The strongest binding affinity of CRGs and ACE2 was observed for kappa-CRG. Molecular docking was confirmed by results studying the effects of CRGs against SARS-CoV-2 in vitro. The ability of CRGs, as well as the complex CRG with sea urchin echinochrome (Ech), to inhibit SARS-CoV-2 replication in Vero E6 cells was studied using cytopathic effect (CPE) inhibition and RT-PCR assays. The simultaneous treatment of cells with CRGs and the virus revealed that kappa-CRG exhibited the most significant antiviral effect among all the polysaccharides, with a selective index (SI) of 33. The kappa-CRG/Ech complex exhibited the highest virucidal effect on SARS-CoV-2 particles with an SI above 70 (more than two times higher than that of CRG and Ech) and reduced viral RNA levels by 45% (IC = 45%). Our results illustrate that CRGs and kappa-CRG/Ech complex can act as protective agents against SARS-CoV-2.
Pre-metastatic niche (PMN) formation is a critical step in metastatic progression. However, the biological effects of subtherapeutic doses of ionizing radiation (SDIRs) following radiotherapy on this process remain unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIRs (3 × 0.3 Gy) on lung PMN development and metastasis upon SDIR exposure on days 8–10 post-tumor injection, followed by mastectomy and analyzed on day 24. SDIRs significantly increased the total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, the SDIR acted as an early catalyst for niche priming, upregulating Bv8 expression, enhancing neutrophil recruitment, and increasing MMP9, S100A8, and Il6 production in the PMN by day 11. Moreover, SDIR drives metastasis through distinct mechanisms. Proteomic analysis revealed SDIR-driven metabolic reprogramming, with a shift away from fatty acid metabolism toward glycolysis and lipid accumulation within the PMN. This shift contributes to extracellular matrix (ECM) remodeling, immune modulation, and the upregulation of adhesion-related pathways, shaping a microenvironment that accelerates metastatic outgrowth. By reprogramming the pre-metastatic lung, the SDIR highlights the need to integrate organ-specific radiation exposure into metastasis models. Metabolic and immune-stromal pathways emerge as potential therapeutic targets, underscoring the importance of refining radiotherapy strategies to mitigate unintended pro-metastatic effects.
Atopic dermatitis (AD) is a chronic inflammatory skin disease marked by impaired barrier function and immune dysregulation. This study explores transcriptomic differences between lesional (IL) and perilesional (PL) skin in patients with AD, focusing on barrier-related and vitamin D-associated pathways. RNA sequencing was performed on matched IL and PL biopsies from 21 adults with moderate-to-severe AD. Differential gene expression, pathway enrichment, and correlation analysis with clinical variables were assessed. A total of 8817 genes were differentially expressed in IL versus PL skin (padj < 0.05). Among genes with the highest level of dysregulation, strong upregulation was observed for inflammatory mediators (IL-19, IL-8, CXCL6), and epidermal remodeling and barrier-disrupting genes (MMP1, GJB2). The vitamin D pathway genes CYP27B1 and CYP24A1 were also significantly upregulated. In contrast, key barrier-related genes such as FLG2 and CGNL1 were markedly downregulated. While some patterns in gene expression showed subgroup-specific trends, no independent clinical predictors emerged in multivariate models. Reactome pathway analysis revealed the enrichment of pathways involved in keratinization, cornified envelope formation, IL-4/IL-13 signaling, chemokine activity, and antimicrobial responses, highlighting coordinated structural and immunologic dysregulation in lesional skin. Lesional skin in AD displays a distinct transcriptomic profile marked by barrier impairment, heightened inflammatory signaling, and activation of vitamin D-related pathways. These findings provide the first RNA-seq-based comparison of IL and adjacent PL skin in AD. We identify subclinical activation in PL skin and vitamin D pathway upregulation with disrupted gene coordination in lesions. These findings enhance our understanding of the molecular mechanisms underlying inflammation in AD.
Narenga porphyrocoma (Hance) Bor is a close relative of sugarcane, with traits such as drought resistance, robustness, early maturity, and disease resistance. In this study, we report the first genome assembly of N. porphyrocoma (Hance) Bor GXN1, a diploid species with a chromosomal count of 2n = 30. We assembled the genome into 15 pseudochromosomes with an N50 of 128.80 Mp, achieving a high level of completeness (99.0%) using benchmarking universal single-copy orthologs (BUSCO) assessment. The genome was approximately 1.8 Gb. Our analysis identified a substantial proportion of repetitive sequences, primarily long terminal repeats (LTRs), contributing to 69.12% of the genome. In total, 70,680 protein-coding genes were predicted and annotated, focusing on genes related to drought resistance. Transcriptome analysis under drought stress revealed the key gene families involved in plant physiological rhythms and hormone signal transduction, including aquaporins, late embryogenesis abundant proteins, and heat shock proteins. This research reveals the genome of the diploid wild sugarcane relative N. porphyrocoma (Hance) Bor, encouraging future studies on gene function, genome evolution, and genetic improvement of sugarcane.
Immuno-oncology has rapidly evolved into a cornerstone of modern cancer therapy, offering promising avenues for durable responses and personalized treatment strategies. This narrative review provides a thorough overview of the mechanisms underlying tumor–immune system interactions and the therapeutic innovations emerging from this knowledge. Central to this discussion is the tumor microenvironment (TME), a complex ecosystem of immune and stromal cells that supports tumor growth and shapes therapeutic outcomes. Key cellular and molecular factors within the TME are examined, along with diverse immune escape strategies. We further analyze the landscape of immunotherapeutic approaches, including immune checkpoint inhibitors, cancer vaccines, adoptive cell therapies such as CAR-T cells, and cytokine-based interventions. This review also addresses the increasing importance of predictive biomarkers in immuno-oncology, particularly in patient stratification, monitoring resistance, and managing immunotherapy-related toxicity. Finally, we explore the emerging role of the microbiome as a modulator of immunotherapy efficacy, shedding light on host–microbe–immune interactions that may influence clinical outcomes. By integrating current biological insights with therapeutic innovation, this review outlines the challenges and opportunities ahead in immuno-oncology and emphasizes the need for translational research and cross-disciplinary collaboration to optimize cancer immunotherapy in the era of precision medicine.
Arbuscular mycorrhizae fungi (AMF) plays an important role in plants’ response to environmental stress, and the main environmental stress encountered in grape production is high temperature stress. This study aims to inoculate Funneliformis mosseae (A type of AMF) on grapes and investigate their tolerance to high temperature stress after inoculation. The results showed that AMF could infect grape roots, and the mycorrhizal infection rate was 20.78%. After inoculation with AMF, the growth of grape plants was significantly better than that in the non-inoculation group. Compared with the uninoculated group, the net photosynthetic rate, transpiration rate and stomatal conductance were higher in the AMF group, and the intercellular CO2 concentration was lower. After high temperature treatment, there was no significant difference in the content of hydrogen peroxide (H2O2) in grape leaves between the two experimental groups at each time, and the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and other enzymes showed great differences, especially after high temperature treatment for 6 h. The activities of SOD, POD and CAT in AMF group were significantly higher than those in uninoculated group. The content of malondialdehyde (MDA) in grape leaves of the two experimental groups had no significant difference between 0 h and 3 h after high temperature treatment, and the MDA content in the AMF group was significantly lower than that in the uninoculated group after 6 h of high temperature treatment. The contents of soluble sugar and soluble protein in the AMF group were higher than those in the uninoculated group at all time periods, especially after 6 h of high temperature treatment. In addition, we found that VvHSP70, VvHSP17.9, VvGLOS1, VvHSFA2 genes all responded to high temperature stress, but there was no significant difference between the AMF group and the uninoculated group. It can be seen from the above that AMF can significantly enhance the adaptability of grape plants to high temperature stress by improving photosynthetic efficiency, antioxidant enzyme activity, soluble sugar and soluble protein content, and reduce Malondialdehyde (MDA) content, which provides guidance and theoretical basis for grape production.
Acinetobacter baumannii is an opportunistic pathogen and a major cause of nosocomial infections worldwide. This study aimed to isolate and characterize phages with lytic activity against multidrug-resistant A. baumannii strains to enable antibacterial alternatives. Eight phages (AKO8a, PS118, B612, MCR, IDQ7, 89P13, CRL20, and CIM23) were isolated and subjected to genomic, phylogenetic, and functional analyses. Antibacterial activity was assessed in vitro against A. baumannii strain AbAK04 by measuring optical density over 17 h at multiplicities of infection (MOIs) of 0.1, 1, and 10, using a repeated-measures design with time as a crossed factor and MOI as a nested factor. Tukey’s post-hoc test identified significant bacterial growth reductions of 57–72% (p < 0.001). Specifically, phages PS118 and 89P13 reduced growth by 71% at MOI 10; CIM23, B612, and CRL20 achieved 68% reduction at MOI 1; and MCR reduced growth by 64% at MOIs 0.1 and 1. Notably, lytic phage MCR encodes a glycosyl hydrolase family 58 (GH58) enzyme, potentially contributing to its antibacterial activity. Genomic analyses confirmed absence of virulence and antibiotic resistance genes, with all phages classified as novel species within the Kagunavirus genus. These findings support the use of these phages as promising candidates for in vivo evaluation.
T-cadherin (CDH13) is an atypical, glycosyl-phosphatidylinositol-anchored cadherin with functions ranging from axon guidance and vascular patterning to adipokine signaling and cell-fate specification. Originally identified as a homophilic cue for migrating neural crest cells, projecting axons, and growing blood vessels, it later emerged as a dual metabolic receptor for cardioprotective high-molecular-weight adiponectin and atherogenic low-density lipoproteins. We recently showed that mesenchymal stem/stromal cells lacking T-cadherin are predisposed to adipogenesis, underscoring its role in lineage choice. Emerging evidence indicates that CDH13 expression and function are fine-tuned by non-coding RNAs (ncRNAs). MiR-199b-5p, miR-377-3p, miR-23a/27a/24-2, and the miR-142 family directly bind CDH13 3′-UTR or its epigenetic regulators, affecting transcription or accelerating decay. Long non-coding RNAs (lncRNAs), including antisense transcripts CDH13-AS1/AS2, brain-restricted FEDORA, and context-dependent LINC00707 and UPAT, either sponge these miRNAs or recruit DNMT/TET enzymes to the CDH13 promoter. Circular RNAs (circRNAs), i.e.circCDH13 and circ_0000119, can add a third level of complexity by sequestering miRNA repressors or boosting DNMT1. Collectively, this ncRNA circuitry regulates T-cadherin across cardiovascular, metabolic, oncogenic, and neurodegenerative conditions. This review integrates both experimentally validated data and in silico predictions to map the ncRNA-CDH13 crosstalk between health and disease, opening new avenues for biomarker discovery and RNA-based therapeutics.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has been consistently linked to increased risk of cardiovascular disease (CVD). HDL lipoproteins may serve as a possible link in this association through their hepatic synthesis and atheroprotective properties. Serum samples were collected from 51 MASLD patients (diagnosed by abdominal ultrasound), 40 with coronary artery disease, and 50 healthy controls. HDL lipid profiles were investigated by proton nuclear magnetic resonance (1H NMR) spectroscopy. Patients with MASLD exhibit an increased percentage of lysophosphatidylcholine and sphingolipid content, mainly due to increased ceramides, and a reduced percentage of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol compared to controls. The % content of total and individual polyunsaturated fatty acids including linoleic, docosahexaenoic, eicosapentaenoic, and arachidonic acid was found to be reduced in patients with MASLD, while saturated fatty acid content was increased compared to the control group. These alterations in fatty acid composition were observed also in CAD patients compared to controls but were more pronounced in CAD patients. Compared to CAD patients, those with MASLD showed an increased content of sphingolipids, ceramides, and glycerolipids and a reduced content of phosphatidylinositol. Changes observed in the lipid composition of HDL lipoproteins in MASLD patients may impair the protective properties of HDL particles, contributing to increased CVD risk.
A series of new isatin hydrazones bearing phosphorus-containing moiety was synthesized through a simple, high-yield and easy work-up reaction of phosphine oxide (Phosenazide) or phosphinate (2-chloroethyl (4-(dimethylamino)phenyl)(2-hydrazinyl-2-oxoethyl)phosphinate, CAPAH) hydrazides with aryl-substituted isatins. The 31P NMR technique showed that, in most cases, out of 12 examples in solution, the ratio of the two spatial isomers varied from 1:1 to 1:3. Quantum chemical calculations confirmed the predominance of Z,syn form both in the gas phase and in solution. According to X-ray analysis data in crystals, they exist only in Z,syn form too. Most of the phosphine oxide derivatives and 5-methoxy- and 5-bromoaryl phosphinate analogs exhibit anti-aggregant activity at the level of acetylsalicylic acid but inhibit platelet activation processes more effectively. The 5-chloro type phosphinate derivative exhibits anti-aggregant properties more effectively than acetylsalicylic acid under the conditions of the tissue factor (TF)-activated thromboelastography (TEG) model, the ex vivo thrombosis model. Thus, all the obtained results can become the basis for future pharmaceutical developments to create effective anti-aggregation drugs with broad antithrombotic potential.
CD38, a nicotinamide adenine dinucleotide (NAD+) glycohydrolase, increases in old murine macrophages after infection compared to young controls. We aimed to determine whether the increase in CD38 in old murine macrophages after infection is directly associated with enhanced inflammation induced by the oral pathogens Aggregatibacter actinomycetemcomitans (Aa) or Porphyromonas gingivalis (Pg) when compared to young controls. Additionally, we determined the effects of a specific CD38 inhibitor (78c) on CD38, NAD+, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α expressions, and anti-oxidative responses in old murine macrophages induced by oral pathogens. Old and young murine macrophages were either uninfected or infected with the oral pathogens Aa or Pg for 1 to 24 h. Protein levels of CD38 and protein kinases, including nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs), NAD+, and inflammatory cytokine (IL-1β, IL-6, TNF-α) levels were evaluated. Additionally, old murine macrophages were treated with a vehicle or a CD38 inhibitor (78c) and cells were either uninfected or infected with Aa or Pg. CD38, NAD+, cytokine (IL-1β, IL-6, TNF-α) levels, reactive oxygen species (ROS), NAPDH oxidase 1 (Nox1), and anti-oxidative enzymes, including superoxide dismutase1 (Sod1), glutathione peroxidase 4 (Gpx4), Peroxiredoxin 1 (Prdx1), thioredoxin reductase 1 (Txnrd1), and catalase (Cat), were evaluated. The results showed that old murine macrophages significantly enhanced CD38 and reduced NAD+ levels 24 h after Aa or Pg infection compared to young controls. This enhanced CD38 in old murine macrophages was not directly correlated with the activation of protein kinases (NF-κB, PI3K, and MAPKs), nor the (IL-1β, IL-6, TNF-α) levels in macrophages. The inhibition of CD38 by 78c reduced CD38, enhanced NAD+ levels, attenuated IL-1β, IL-6 and TNF-α pro-inflammatory cytokine levels, reduced ROS and Nox1 expressions, and enhanced expressions of Sod1, Gpx4, Prdx1, Txnrd1, and Cat in old murine macrophages infected with Aa or Pg. These results suggest that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat aging-associated periodontitis.
Melatonin (MT) has been reported to alleviate chilling injury (CI) in postharvest tomato fruit during low-temperature storage. In the present study, the DNA methylation profile changes in the CpG islands of ethylene signaling genes regulated by MT in postharvest tomato fruit during low-temperature storage were detected. The MT treatment increased the content of total soluble solids (TSS) and enhanced the ethylene production of tomato fruit. Moreover, it decreased titratable acidity (TA) content, inhibited the activity of polygalacturonase (PG), and kept the firmness of tomato fruit under low-temperature storage. In the MT-treated tomato fruit, significant changes in DNA methylation of CpG island of SlACS10, LeCTR1, LeEIN3, SlERF-A1, and LeERT10 genes were induced; the expression of LeCTR1 was inhibited; and the expression of SlACS10, LeEIN3, and SlERF-A1 genes was increased, by which the ethylene signaling might be influenced and the CI was alleviated. The present results provide evidence that the CI of postharvest tomato fruit alleviated by MT might be related to the changes in DNA methylation of ethylene-signaling genes.
A growing global trend of adult obesity and the increasing prevalence of overweight/obesity in children indicate a higher risk in the future of adult diseases related to obesity. Current anti-obesity medications regulate appetite and metabolism by acting either in peripheral tissues or in the central nervous system. On the other hand, subsequent weight regain is a typical response to weight loss methods, and there is little evidence that current anti-obesity medications can help maintain long-term weight loss without causing a range of undesirable side effects. The combination of anti-obesity drugs targets multiple molecular pathways and structures in the central nervous system that are involved in weight regulation. This systematic review involves trials performed in pediatric populations, published up to 2025 and systematically searched on the ClinicalTrials.gov database, using “Glucagon like peptide-1 analog, Glucagon like peptide-1 receptor agonists” as the criterion for the “Intervention/treatment” category. We evaluated the entero-insular axis in pediatric patients with obesity, along with the mechanisms of action and therapeutic potential of the Glucagon like peptide-1receptor agonists. We analyzed incretin hormones and summarized the drugs approved by the Food and Drug Administration. Our objective is to identify new treatment strategies as we improve our understanding of the pathophysiology of obesity and the incretin axis.
Recent diagnostic advances reveal that lymphatic disease in Noonan syndrome (NS) and other NS-like RASopathies often stems from central conducting lymphatic anomalies (CCLAs). The RAS/MAPK-ERK pathway plays a central role in lymphangiogenesis. Targeting this pathway with MEK-inhibitor trametinib has emerged as a promising therapeutic strategy for managing CCLAs in patients with NS-like RASopathies. This case series assessed the clinical outcomes of trametinib therapy in eight patients with NS-like RASopathies and CCLA, each offering unique insights into the therapeutic efficacy of MEK inhibition. In infants, a lower dose of 0.01 mg/kg/day and earlier discontinuation of trametinib therapy effectively alleviated the symptoms of congenital chylothorax and rescued the lymphatic phenotype, compared to similar published cases. Moreover, four patients aged >11 y showed a slower response and did not achieve complete symptomatic recovery. In conclusion, it is advised to consider trametinib therapy for patients with severe, therapy-refractory CCLA in patients with NS-like RASopathies. However, individual responses to trametinib therapy may vary, with some patients demonstrating more favorable outcomes than others. Further investigation into potential enhancers and suppressors of the lymphatic phenotype is necessary for more accurate treatment predictions. While these factors are likely genetic, we cannot rule out other intrinsic or physiological factors.
From a previously performed proteomics screen, GPP130, or Golgi phosphoprotein of 130 kDa, was identified as a potential substrate of the proprotein convertase 7 (PC7; PCSK7). GPP130 is a type-II transmembrane protein with a luminal domain containing endosomal and Golgi-retrieval determinants, enabling a unique trafficking route. Most of the previous work on GPP130 relates to its binding and retrograde trafficking of the Shiga toxin. However, its cellular biology and its biochemical characterization remain understudied. Recently, GPP130 was reported to be implicated in cell cycle progression and cell proliferation in head and neck cancer cells. This led us to analyze the cBioPortal for Cancer Genomics, revealing that the GPP130/GOLIM4 gene is amplified in many cancers, including lung, ovarian, and cervical. This observation led us to use the A549 lung cancer cell line to investigate the growth-regulating roles of endogenous and overexpressed GPP130 and to analyze the impact of its cleavage/shedding by PC7 and/or Furin on cellular growth. Our cell-based assays suggest that GPP130 is a novel pro-protein convertase substrate that increases cell proliferation in A549, SKOV3, and HeLa cells, and that the latter activity is enhanced following its cleavage by PC7 and/or Furin into a membrane-bound N-terminal product and secreted C-terminal fragments. This novel work sheds light on the cell biology of the poorly characterized GPP130, its proliferative activity, and modulation upon its shedding by PC7 and Furin in lung cancer progression.
Mature dendritic cells (DCs) are known to activate effector immune responses, whereas steady state immature DCs can induce tolerance. Several studies have targeted immature murine quiescent DCs in vivo with antigen, including donor alloantigens, for the induction of tolerance. Receptors expressed by specific DC subsets have been also targeted with antibodies linked with antigens to induce tolerance; for instance, in vivo targeting of the DCIR2+ DC subset with donor alloantigen resulted in long-term survival of heart and skin transplants. DCs also express sialic acid immunoglobulin-like lectin (Siglec) receptors, and these have been successfully targeted with myelin oligiodendrocyte glycoprotein (MOG) antigen to induce tolerance in experimental autoimmune encephalomyelitis (EAE). We investigated, in a mismatched model of skin transplant (B6Kd into B6 recipient mice), whether targeting a sialylated alloantigen Kd (Sia-Kd) to Siglecs on recipient DCs promoted transplant survival. The injection of α2,3 Sia-Kd into B6 recipient mice prior to B6Kd skin transplantation, by binding to Batf3 dependent DCs, resulted in prolonged skin graft survival and an increase in CD4+CD62L+Foxp3+ Tregs. Targeting Siglecs on DC subsets in vivo represents a novel way of improving transplant survival.
Fragile X syndrome is characterized by the diminished expression of the fragile X messenger ribonucleoprotein (FMRP), a ubiquitously expressed RNA binding protein with numerous functions in cells. Our prior work found significant differences in physiological and behavioral outcomes as a function of FMRP levels and in response to diet in mice. Here, we assess protein biomarker levels as a function of FMRP levels, sex and matched casein and soy protein isolate-based purified ingredient diets in Fmr1KO and littermate mice. Brain regions (cortex, hippocampus, and hypothalamus) and blood plasma were analyzed by RayBiotech’s Quantibody® Mouse Cytokine Antibody Array 640 to quantitate the expression of 640 proteins. The main findings were the identification of numerous proteins that were differentially expressed in response to diet, sex and/or genotype. Of note, prolactin (PRL) levels in blood plasma were significantly elevated in Fmr1KO female mice as a function of genotype and sex selectively with the AIN-93G/casein diet. Also, using a moderately stringent significance cutoff, growth differentiation factor 9 (GDF-9) in plasma from mice fed AIN-93G/soy was the only protein studied by Quantibody arrays that was differentially expressed between WT and Fmr1KO male mice. When comparing the results from a pelleted infant formula study with AIN-93G-based diets, insulin-like growth factor binding protein 5 (IGFBP5) in plasma was the only protein differentially expressed as a function of soy in the diet. There was no overlap in statistically significant results when comparing tissue analyzed by mass spectrometry versus Quantibody arrays from mice maintained on AIN-93G-based diets. In conclusion, gene–diet interactions affect protein expression in Fmr1KO and littermate mice and need to be considered in study design.
Mesenchymal stem cell-derived exosomes (MSC-Exos) play a key role in tissue repair, immune regulation, and cancer biology. Due to limitations in MSC expansion and source variability, interest has shifted to induced pluripotent stem cell-derived MSCs (iMSCs) as a promising alternative. This study compares effects of exosomes derived from iMSCs (iMSC-Exos) and Wharton’s jelly MSCs (WJMSC-Exos) on MCF7 and A549 cancer cells. Both types of exosomes reduced MCF7 proliferation and induced a senescence-like state, rather than apoptosis, although the antiproliferative effect was transient in A549 cells. Notably, WJMSC-Exos promoted migration in both MCF7 and A549, whereas iMSC-Exos did not exhibit this effect. Overall, WJMSC-Exos had a more robust impact on cancer cell proliferation and migration. These findings highlight the diverse effects of exosomes on cancer and the development of a senescence-like state as an important response to Exos exposure. Moreover, these findings invite for more careful evaluation of the therapeutic role of iMSC-derived Exos.
Bovine alphaherpesvirus 1 (BoAHV-1) is a promising oncolytic virus that can infect the human lung carcinoma cell line A549. In an effort to adapt the virus to grow more rapidly in these cells through the serial passaging of viral progeny, we were unsuccessful. Here, we found that extracellular vesicles (EVs) secreted by BoAHV-1-infected A549 cells (referred to as EDVs) contain 59 viral proteins, including both viral structure proteins (such as gC and gD) and viral regulatory proteins (such as bICP4 and bICP22), as identified via a proteomic analysis. These EDVs can bind to and enter target cells, inhibit viral particles binding to cells, and stimulate the production of IFN-α and IFN-β in A549 cells. When EDVs are inoculated into rabbits via either the conjunctival sacs or intravenously, they can be readily detected in neurons within the trigeminal ganglia (TG), where they reduce viral replication and promote the transcription of IFN-γ. Furthermore, incorporation of the known anti-herpesvirus drug Acyclovir (ACY) into the EDVs leads to synergistically enhanced antiviral efficacy. Collectively, the EDVs exhibit antiviral effects by blocking viral binding to target cells and stimulating the innate immune response, thereby leading to the failure of the serial passaging of viral progeny in these cells, and these EDVs may serve as a promising vector for delivering drugs targeting TG tissues for antiviral purposes.
Familial hypercholesterolemia leads to the early development of cardiovascular diseases at a young age due to the prolonged exposure of the arterial vessel wall to high concentrations of atherogenic lipids. Serotonin plays a significant role in the development and progression of atherosclerotic processes. Monoamine has a damaging effect on the vascular wall, stimulates the proliferation of vascular smooth muscle cells and fibroblasts, and participates in platelet activation and aggregation. The aim of the work was the demonstration of the importance of serotonin, transporters, and receptors in the pathogenesis of atherosclerotic plaque formation. The study was performed on immature mice of the C57BL/6JGpt-Ldlrem1Cd82/Gpt (Ldlr+/−) line (main group) and C57BL/6 mice of comparable age and sex demographics (control group). Morphological manifestations of early signs of atherosclerosis (pre-lipid stage and lipoidosis stage, which were confirmed by Sudan III staining) in the gene-modified mice’s aorta were determined. Morphological changes in the aorta correlated with changes in the left ventricle of the heart, where lipid content also increased. No atherosclerotic changes in the control-group mice were detected. A statistically significant increase in the expression of the membrane serotonin transporter and 5HT2A and 5HT2B receptors in both the aorta and left ventricle was also found in the animals of the main group. Serotonin and its receptors and transporter may become new therapeutic targets for the treatment and prevention of atherosclerotic vascular lesion progression in children and adults.
Plastic overconsumption has emerged as a major environmental pollutant, with degraded micro- and nanoplastic (MNP) particles being consumed by a vast variety of species. MNPs, particles < 5 mm, contain endocrine-disrupting chemicals (EDCs), which can bind to hormone receptors and disrupt the proper endocrinological function of a variety of organs. This review explores the toxicological impact of MNPs on the hypothalamus, pituitary gland, thyroid, pineal body, ovaries, and testes, as well as the effects of the endocrinological regulatory axes, including the hypothalamic–pituitary–gonadal (HPG), hypothalamic–pituitary–thyroid (HPT), and hypothalamic–pituitary–adrenal (HPA) axes. The disruption of these hormonal feedback systems leads to reproductive dysfunction, neurotoxicity, cytotoxicity, immunotoxicity, and metabolic disorders. The gonads are particularly susceptible, with studies demonstrating oxidative stress, cellular apoptosis, and infertility due to MNP exposure. Given the widespread presence of MNPs and their impact on human health, further research is critical to understand their long-term effects and develop strategies to reduce exposure.
The gut microbiota constitutes a complex community of microorganisms (including bacteria, viruses, fungi, and protozoa) within the intestinal tract. Over the years, an increasing number of studies have highlighted the bidirectional communication between the gut microbiota and the central nervous system (CNS), a relationship commonly referred to as the “microbiota–gut–brain axis”. In particular, the crosstalk between the gut microbiota and the brain has been associated with the pathogenesis and progression of various CNS disorders. Phages, or bacteriophages, viruses that specifically infect bacteria, constitute the most abundant viral component within the gut microbiota. However, despite their abundance and significance in the gut microbial community, studies exploring the relationship between phages and the CNS remain surprisingly limited. This review examines the biological interplay between gut-resident phages and the CNS. Furthermore, we discuss the current literature linking phages to CNS-related pathologies.
4-coumarate-CoA ligase (4CL) plays a crucial role in the phenylpropanoid metabolic pathway and is a key enzyme involved in plant growth and stress responses. Black rot, caused by Xanthomonas campestris pv. campestris (Xcc) is a major bacterial disease affecting the production of global cruciferous crop-like cabbage (Brassica oleracea var. capitata). However, the role of 4CL genes in cabbage resistance to black rot remains unclear. In this study, transcriptome sequencing was conducted using resistant cabbage MY and susceptible cabbage LY at 0, 6, 24, and 48 h post-inoculation. KEGG analysis identified the enrichment of the phenylpropanoid biosynthesis pathway, and significant expression changes of 4CL genes were determined through the expression heat map. Further genome-wide analysis revealed 43 Bol4CL gene family members on the cabbage genome distributed across nine chromosomes. Gene structure and protein motif analysis revealed similarities in motifs within the same evolutionary branch, but variations in gene structure. A combination of Bol4CL gene expression profiles and differentially expressed genes (DEGs) from the transcriptome identified Bol4CL41 as a key gene for further study. Inoculation of overexpressed Bol4CL41 T2 generation stably expressed cabbage seedlings demonstrated significantly larger lesion areas compared to wild type cabbage, indicating that Bol4CL41 negatively regulates resistance to black rot in cabbage. The analysis of multi-time point transcriptomes in cabbage and the functional study of the Bol4CL gene family enhance our understanding of the mechanisms underlying plant disease resistance. This provides compelling evidence and experimental support for elucidating the mechanisms of black rot resistance in cabbage.
AVRO is an adjunctive four-drug regimen designed to increase the effectiveness of current standard treatment of glioblastoma (GB). AVRO is a repurposed drug regimen consisting of the antinausea drug aprepitant, the antidepressant vortioxetine, the emphysema treatment drug roflumilast, and the antipsychotic drug olanzapine. All four are EMA/FDA approved for nononcology indications, all four have strong research evidence showing inhibition of GB growth, and all four carry a low side effect risk. The goal of adding AVRO is to further retard GB growth, improving survival. Aprepitant is an antinausea drug that blocks NK-1 signaling, with a database of 59 studies showing growth inhibition in 22 different cancers, 12 of which were specific to GB. Fully 30 studies demonstrated that the SSRI class of antidepressants inhibited GB growth; accordingly, we chose one such agent, vortioxetine, to add to AVRO. Elevation of intracellular cAMP slowed GB growth in 21 independent studies. Accordingly, we added the emphysema treatment drug roflumilast, which inhibits cAMP degradation. Among the 27 currently marketed D2-blocking antipsychotic drugs, 24 have preclinical evidence of GB growth inhibition in a combined 84 independent study database. One of these 24 drugs is olanzapine, added to AVRO. Given the short median survival of GB as of mid-2025, the clinician and researcher community will benefit from wider awareness of the anti-GB effects of these four nononcology drugs.
Head and neck squamous cell carcinoma (HNSCC) remains challenging to treat despite multimodal therapeutic approaches. Cisplatin treatment is effective and cost-efficient, although chemoresistance and disease recurrence limit its efficacy. Understanding the mechanisms of cisplatin resistance and the identification of compounds to target resistant tumor cells are critical for improving patient outcomes. We have demonstrated that cisplatin-induced senescent HN30 HNSCC cells can be eliminated by ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor that has senolytic properties. Here, we report the development of a cisplatin-resistant cell line (HN30R) for the testing of ABT-263 and the PROTAC BET degraders ARV-825 and ARV-771. ABT-263 was ineffective in sensitizing HN30R cells to cisplatin, largely due to a lack of senescence induction. However, the BET degraders in combination with cisplatin promoted apoptotic cell death in both HN30 and HN30R cells. The effectiveness of ARV-825 did not appear to depend on the cells entering into senescence, indicating that it was not acting as a conventional senolytic. ARV-825 treatment downregulated BRD4 and its downstream targets, c-Myc and Survivin, as well as decreased the expression of RAD51, a DNA repair marker. These results suggest that the BET degraders ARV-825 and ARV-771 may be effective in improving the response of chemoresistant head and neck cancer to cisplatin treatment.
Metal nanostructure-assisted solar-driven interfacial evaporation systems have emerged as a promising solution to achieve sustainable water production. Herein, we fabricated photothermal films of a bumpy gold nanoshell with controlled shell thicknesses (11.7 nm and 16.6 nm) and gap structures to enhance their photothermal conversion efficiency. FDTD simulation of bumpy nanoshell modeling revealed that thinner nanoshells exhibited higher absorption efficiency across the visible–NIR spectrum. Photothermal films prepared by a three-phase self-assembly method exhibited superior photothermal conversion, with films using thinner nanoshells (11.7 nm) achieving higher surface temperatures and faster water evaporation under both laser and sunlight irradiation. Furthermore, evaporation performance was evaluated using different support layers. Films on PVDF membranes with optimized hydrophilicity and minimized heat convection achieved the highest evaporation rate of 1.067 kg m−2 h−1 under sunlight exposure (937.1 W/m2), outperforming cellulose and PTFE supports. This work highlights the critical role of nanostructure design and support layer engineering in enhancing photothermal conversion efficiency, offering a strategy for the development of efficient solar-driven desalination systems.
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. It is generally accepted that IBD is characterized by an inappropriate immune response to the intestinal microbiome in genetically susceptible individuals. Despite the available treatment options ranging from salicylates and corticosteroids, to immunosuppressants and biologics, there is still a high unmet medical need for patients who respond poorly to drugs or are not able to tolerate them. Microbiome-based therapeutics offer a valid treatment strategy for IBD with enhanced safety. A butyrate-producing consortium of six commensal strains (MH002) was evaluated in a series of in vitro, ex vivo, and in vivo experiments mimicking multiple IBD-related dysfunctions, namely disrupted intestinal permeability and immune activation. MH002 rapidly produced high levels of butyrate in fed-batch cultures, and significantly increased butyrate levels within one day after administration to IBD-derived gut microbial communities in vitro. Both in Caco-2/peripheral blood mononuclear cells (PBMCs) co-cultures, and IBD patients-derived organoids and colonic explants, MH002 reduced inflammation and restored epithelial barrier integrity. In addition, MH002 promoted wound repair in vitro. Finally, MH002 protected mice and rats from chemically induced colitis. Altogether, results showed that MH002 presents a novel therapeutic avenue for the treatment of IBD.
The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.
Hepatocellular carcinoma (HCC) presents significant intertumoral heterogeneity, complicating prognosis and treatment. To address this, we performed an integrated single-cell RNA-sequencing analysis of HCC specimens using Seurat and identified malignant cells via Infercnv. Through a systematic evaluation of 101 machine learning algorithms used in combination, we developed tumor-cell-specific gene signatures (TCSGs) that demonstrated strong predictive performance, with area under the curve (AUC) values ranging from 0.72 to 0.74 in independent validation cohorts. Risk stratification based on these signatures revealed distinct therapeutic vulnerabilities: high-risk patients showed increased sensitivity to sorafenib, while low-risk patients exhibited enhanced responses to immunotherapy and transarterial chemoembolization (TACE). Pharmacogenomic analysis with Oncopredict identified four chemotherapeutic agents, including sapitinib and dinaciclib, with risk-dependent efficacy patterns. Furthermore, CRISPR/Cas9-dependency screening prioritized SRSF7 as essential for HCC cell survival, a finding confirmed by the identification of protein-level overexpression in tumors via immunohistochemistry. This multi-omics framework bridges single-cell characterization to clinical decision-making, offering a clinically actionable prognostic system that can be used to optimize therapeutic selection in HCC management.
Bipolar disorder (BD) and schizophrenia (SCH) are results of the complex interactions between genetic and environmental factors, and the underlying pathophysiology is not yet completely understood. The current diagnostic criteria for psychiatric diagnosis are based purely on clinical phenomenology and they are limited to psychiatrist judgment after a standardized clinical interview, with no precise biomarkers used to discriminate between the disorders. Besides gaps in the understanding and diagnosis of these diseases, there is also a need for personalized and precise approaches to patients through customized medical treatment and reliable monitoring of treatment response. To fulfill existing gaps, the establishment of disorder biomarker sets is a necessary step. LC-MS lipidomic blood sample analysis is one of the ongoing omics approaches. In the last ten years, several studies have identified alterations in lipid metabolism associated with BD and SCH, and this review summarizes current knowledge on their lipidomic patterns, which is essential for identifying lipid biomarkers. Currently, findings indicate decreases in plasmalogens and acyl-carnitines, along with increases in certain triacylglycerol species, shared by both conditions. In contrast, serum LC-MS lipidomic profiles of sphingolipids including ceramides could be unique to BD, indicating the need for further investigation in future studies.
Yam (Dioscorea spp.) provides various nutritional and medicinal benefits, including a high starch content, dietary fiber, essential micronutrients, and bioactive compounds. The molecular mechanisms underlying tuber expansion have not yet been clarified. Rapid alkalinization factor (RALF) genes, which mediate various processes in plants, are thought to contribute to the regulation of tuber growth; however, their role in yam development, especially in gibberellin (GA)-mediated processes, remains unclear. Here, we characterized seven DrRALF genes in the yam genome. Analysis of gene duplication demonstrated that the expansion of DrRALF genes was primarily driven by whole-genome duplication or segmental duplication. Phylogenetic analysis revealed that DrRALF genes were concentrated in specific clusters, indicating that their functions are relatively conserved. DrRALF5 was specifically expressed in the roots, and DrRALF2, DrRALF3, DrRALF4, and DrRALF6 were highly expressed in flowers. DrRALF1, DrRALF2, DrRALF3, DrRALF4, DrRALF5, and DrRALF6 were shown to play a role in tuber expansion. Subsequent qRT-PCR validation of four selected DrRALF genes confirmed the regulation of DrRALF2, DrRALF4, DrRALF5, and DrRALF6 by GA and PP333 (paclobutrazol, a GA biosynthesis inhibitor). Yeast one-hybrid assays further showed that the DrRALF6 promoter region interacted with the GA-signaling protein, DrDELLA1. Our findings provide novel insights into the regulatory network controlling yam tuber expansion, especially through the interaction between DrRALF6 and GA signaling pathways. Our results clarify the molecular mechanisms involved in tuber growth and propose a promising strategy for improving yam production through genetic manipulation of the GA-RALF signaling pathway.
Ruxolitinib, a clinically approved JAK1/2 inhibitor used in the treatment of hematologic malignancies and inflammatory conditions, has been shown to interfere with the function of cytotoxic T lymphocytes (CTLs). Previous studies supported the involvement of the multidrug resistance transporter P-glycoprotein (Pgp/ABCB1) in CTL biology; however, the nature of its regulation remains unclear. To address this, we investigated the impact of ruxolitinib on Pgp expression and function in human CD8+ T cells. We demonstrate that CD8+ T lymphocytes express Pgp dynamically at both the mRNA and protein levels across naïve, short-term, and long-term activation states. Ruxolitinib increased the calcein accumulation in human Pgp-overexpressing NIH-3T3 cells and in CTLs and directly modulated Pgp function by increasing its basal ATPase activity in a concentration-dependent manner (10–100 μM), similar to the effect of the known Pgp substrate/modulator verapamil. Although measurable ATPase stimulation and transport inhibition were observed at supratherapeutic concentrations of ruxolitinib, its Pgp-mediated efflux may also occur at therapeutically relevant concentrations. In contrast, at therapeutically relevant plasma concentrations (1–3 μM), ruxolitinib significantly stabilized the mRNA expression of Pgp during early T-cell receptor (TCR) activation and inhibited the TCR-induced upregulation of Pgp, CD8, and PD-1 surface markers, suggesting its interference with activation-associated differentiation. At these same concentrations, ruxolitinib also impaired CCL19-directed transmigration of CTLs across human umbilical vein endothelial cell (HUVEC) monolayers, indicating disruption of lymphoid homing cues. Collectively, these findings demonstrate that ruxolitinib modulates Pgp at both the transcriptional and functional levels, with distinct concentration dependence. The ability of ruxolitinib to alter CTL activation and migration at clinically relevant plasma concentrations highlights the need for careful evaluation of JAK inhibitor–mediated immunomodulation and its implications for vaccination, transplantation, and T cell-based immunotherapies.
Gastroesophageal reflux disease (GERD) is associated with inflammatory and neoplastic changes in the esophageal epithelium. Despite widespread PPI use, esophageal adenocarcinoma (EAC) incidence continues to rise, implicating non-acidic reflux components such as pepsin in disease progression. We performed transcriptomic profiling to assess pepsin-induced changes and the protective effect of amprenavir in vitro. Het-1A (normal) and BAR-T (Barrett’s) cells (n = 3) were treated at pH 7.0 with pepsin and/or 10 μM amprenavir for 1 h. RNA-seq identified DEGs (FDR ≤ 0.05, |log₂FC| ≥ 0.375), and Ingenuity Pathway Analysis revealed enriched pathways. Pepsin exposure altered mitochondrial function, oxidative phosphorylation, epithelial integrity, signaling, and inflammatory pathways in both cell lines. Amprenavir attenuated these transcriptomic perturbations, preserving mitochondrial and stress-response pathways. Notably, BAR-T cells exhibited heightened activation of wound-healing and epithelial repair pathways, whereas Het-1A cells showed greater mitochondrial and systemic stress pathway alterations. Pepsin drives transcriptomic dysregulation in esophageal epithelial cells under non-acidic conditions, and amprenavir shows potential to counteract peptic injury. Further studies are needed to validate these findings and explore amprenavir’s therapeutic utility in GERD management and EAC prevention.
Marantodes pumilum (MP) is one of the traditional plants to which various medicinal properties are attributed. Studies on the medicinal properties of MP and its characteristics are becoming more extensive and are attracting more and more attention. In this review, the findings on the pharmacological properties of MP have been summarised and analysed. The results show that in addition to its phytoestrogenic effects on the female reproductive system, MP also has bone-remodelling properties, anti-obesity, anti-cancer, anti-gout, antimicrobial, anti-inflammatory and wound-healing effects, as well as effects on the cardiovascular system. These findings show that MP has great potential for the prevention and complementary treatment of various diseases. However, further research is needed to explore its full clinical potential.
Acetaminophen, or paracetamol (PCM), is a common painkiller used to treat aches, pain, and fever. Nevertheless, PCM has been reported to be hepatotoxic and nephrotoxic in humans. Thus, there is a need to identify how this side effect can be treated. Previous studies have shown that Leea species possess antioxidative, anthelmintic, anti-cytotoxic, hepatoprotective, and nephroprotective properties. However, the role of Leea guineensis (LG) in modulating PCM-induced hepatotoxicity or nephrotoxicity remains unknown. Herein, we investigate the possibility of Leea guineensis leaf extract (LGE) to ameliorate PCM toxic effects, evaluate hepatic and renal function, oxidative stress markers, and safety, and perform molecular docking to predict affinities of Leea guineensis extract compounds for their targets compared to PCM. An in vivo rat model was used for Leea guineensis extract or silymarin (SLM, standard drug) at various concentrations, and it was co-administered with PCM. We observed that Leea guineensis extract is rich in phytochemical constituents, and its treatment in rats did not significantly affect body weight. Our data showed that PCM increased bilirubin, creatinine, uric acid, Alanine aminotransferase (ALT), and cholesterol levels but decreased Aspartate aminotransferase (AST) in plasma. Moreover, it increased lipid peroxidation (MDA) levels in the liver and kidneys, while the total protein was elevated in the latter. Interestingly, Leea guineensis extract and SLM abrogated the elevated parameters due to PCM toxicity. Importantly, histopathological examination showed that Leea guineensis extract demonstrated the potential to ameliorate hepatic and renal lesions caused by PCM intoxication, thus demonstrating its safety. Furthermore, comparative molecular binding affinities of the study ligands binding the target corroborate the experimental findings. Our study shows that L. guineensis leaf extract, through its rich phytochemicals, can protect the liver and kidneys against the toxic effects of paracetamol in a dose-dependent manner.
Impulse control disorders (ICDs) are a debilitating non-motor symptom of Parkinson’s disease (PD), often associated with dopaminergic therapy. However, their occurrence in some patients but not others suggests additional biological mechanisms, including the gut microbiome. In this study, we analyzed 191 PD patients (14 with ICDs, 177 without) using 16S rRNA gene sequencing to explore the association between gut microbiota and ICDs. No significant differences were observed in alpha or beta diversity between groups, but several bacterial taxa showed differential abundances. Notably, Methanobrevibacter and Intestinimonas butyriciproducens were enriched in ICD patients. Functional pathway analysis revealed differences in metabolic pathways, including enrichment of xenobiotic degradation and nicotinate metabolism in the ICD group. These findings suggest that specific gut microbial taxa and their associated metabolic functions may contribute to ICDs in PD, highlighting a potential non-dopaminergic mechanism and opening new avenues for microbiome-targeted intervention.
This study develops a dual-mode antibacterial orthodontic adhesive by integrating quaternary ammonium salt-modified large-pore mesoporous silica nanoparticles (QLMSN@CHX). The material integrates two antibacterial mechanisms: (1) contact killing via covalently anchored quaternary ammonium salts (QACs) and (2) sustained release of chlorhexidine (CHX) from radially aligned macropores. The experimental results demonstrated that QLMSN@CHX (5 wt%) achieved rapid biofilm eradication (near-complete biofilm eradication at 24 h) and prolonged antibacterial activity, while maintaining shear bond strength comparable to commercial adhesives (6.62 ± 0.09 MPa after 30-day aging). The large-pore structure enabled controlled CHX release without burst effects, and covalent grafting ensured negligible QAC leaching over 30 days. The composite demonstrated good biocompatibility with human dental pulp mesenchymal stem cells at clinically relevant concentrations. This dual-mode design provides a clinically viable strategy to combat bacterial contamination in orthodontic treatments, with potential applications in other oral infections. Future studies will focus on validating efficacy in complex in vivo biofilm models.
To enhance the signal intensity of kynurenines, which are present at trace concentrations in biological fluids, a novel analytical approach was developed, combining pressure-assisted electrokinetic injection (PAEKI) with a mixed micelle system based on sodium dodecyl sulfate (SDS) and Brij-35. The method was applied to key compounds of the kynurenine pathway, including L-tryptophan, kynurenine, 3-hydroxykynurenine, and kynurenic acid, as well as to the aromatic amino acids (AAs) L-tyrosine and L-phenylalanine. PAEKI was performed by electrokinetic injection for 2 min at −6.5 kV (reversed polarity) and 0.5 psi (3.45 kPa) using a fused silica capillary (50 cm in length, 50 µm inner diameter). The background electrolyte (BGE) consisted of 20 mM Na2B4O7 (pH 9.2), 2 mM Brij-35, 20 mM SDS, and 20% (v/v) methanol (MeOH). The limit of detection (LOD) using a diode array detector (DAD) was 1.2 ng/mL for kynurenine and ranged from 1.5 to 3.0 ng/mL for the other analytes. The application of PAEKI in conjunction with micellar electrokinetic capillary chromatography (MEKC) and solid-phase extraction (SPE) of artificial urine samples resulted in a 146-fold increase in signal intensity for kynurenines compared to that observed using the hydrodynamic injection (HDI) mode. The developed method demonstrates strong potential for determining kynurenine pathway metabolites in complex biological matrices.
Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by progressive neuronal dysfunction and loss and represent a significant global health challenge. Oxidative stress, neuroinflammation, and neurotransmitter dysregulation, particularly affecting acetylcholine (ACh) and monoamines, are key hallmarks of these conditions. The current therapeutic strategies targeting cholinergic and monoaminergic systems have some limitations, highlighting the need for novel approaches. Metallodrugs, especially ruthenium and platinum complexes, are gaining attention for their therapeutic use. Among metal complexes, gold(I) and silver(I) N-heterocyclic carbene (NHC) complexes exhibit several biological activities, but their application in NDDs, particularly as monoamine oxidase (MAO) inhibitors, remains largely unexplored. To advance the understanding of this field, we designed, synthesized, and evaluated the biological activity of a new series of Au(I) and Ag(I) complexes stabilized by NHC ligands and bearing a carboxylate salt of tert-butyloxycarbonyl (Boc)-N-protected proline as an anionic ligand. Through in silico and in vitro studies, we assessed their potential as acetylcholinesterase (AChE) and MAO inhibitors, as well as their antioxidant and anti-inflammatory properties, aiming to contribute to the development of potential novel therapeutic agents for NDD management.
Loop diuretics like furosemide are commonly used in heart failure (HF) treatment, but their effects on disease progression are still unclear. Furosemide treatment accelerates HF deterioration in a swine model, but the mechanism of acceleration is poorly understood. We hypothesized that furosemide activates inflammatory signaling in the failing left ventricular (LV) myocardium, leading to adverse remodeling of the extracellular matrix (ECM). A total of 14 Yorkshire pigs underwent permanent transvenous pacemaker implantation and were paced at 200 beats per minute; 9 non-instrumented pigs provided controls. Seven paced animals received normal saline, and seven received furosemide at a dose of 1 mg/kg intramuscularly. Weekly echocardiograms were performed. Furosemide-treated animals reached the HF endpoint a mean of 3.2 days sooner than saline-treated controls (mean 28.9 ± 3.8 SEM for furosemide and 32.1 ± 2.5 SEM for saline). The inflammatory signaling protein transforming growth factor-beta (TGF-β) and its downstream proteins were significantly (p ≤ 0.05) elevated in the LV after furosemide treatment. The regulatory factors in cell proliferation, mitogen-activated protein kinase signaling pathway proteins, and matrix metalloproteinases were elevated in the furosemide-treated animals (p ≤ 0.05). Our data showed that furosemide treatment increased ECM remodeling and myocardial fibrosis, reflecting increased TGF-β signaling factors, supporting prior results showing worsened HF.
DNA-deaminase AID plays a pivotal role in adaptive immunity, antibody diversification and epigenetic regulation. AID catalyzes cytidine deamination in immunoglobulin genes, facilitating somatic hypermutation (SHM), class-switch recombination (CSR) and gene conversion (GC). However, the dysregulation of AID activity can lead to oncogenic mutations and immune disorders such as hyper-IgM syndrome type 2 (HIGM2). At present the number of studies investigating the role of AID polymorphic variants in the promotion of pathology is low. The current review examines the structural and functional aspects of AID, focusing on the impact of amino acid substitutions—both natural polymorphisms and artificial mutations—on its catalytic activity, substrate binding and interactions with regulatory proteins. Additionally, a bioinformatic analysis of single-nucleotide polymorphisms of AID deposited in the dbSNP database was performed. SNPs leading to amino acid substitutions in the primary protein structure were analyzed. The bioinformatic analysis of SNPs in the AID gene predicts that among 208 SNPs causing amino acid substitutions in the primary protein structure, 62 substitutions may have significant negative impact on the functioning of AID. The integration of computational predictions with experimental data underscores the importance of AID regulation in maintaining immune homeostasis and highlights potential markers for immune-related pathologies. This comprehensive analysis provides insights into the molecular mechanisms of AID dysfunction and its implications for disease.
Vitamins are chemical compounds, or a group of closely related compounds known as vitamers, which are crucial for an organism’s metabolic functions. Vitamins are categorized as either water-soluble or fat-soluble, with this second group composed of vitamins A, D, E, and K. The low aqueous solubility of these compounds often necessitates the use of pharmaceutical excipients to benefit from their medicinal efficiency. A successful example of this is the formation of the inclusion complexes with cyclodextrins (CDs), a group of cyclic oligosaccharides, composed of glucose subunits forming a macrocyclic ring. CD complexes with fat-soluble vitamins have been consistently utilized to accomplish diverse objectives, with CDs predominantly employed as solubilizers and absorption enhancers. This article examines studies detailing the synthesis and the biological, physicochemical, and structural characteristics of the inclusion complexes formed between fat-soluble vitamins and different cyclodextrins. This research demonstrates that although the fat-soluble vitamins form stable complexes with various CDs, the kind of CDs employed significantly influences the resultant properties of the complex formed.
Osteosarcoma (OSA) is the most common primary bone malignancy in dogs, characterized by aggressive growth and high metastatic potential. Despite advances in treatment, the prognosis for affected animals remains poor, mainly due to metastatic disease. Metastasis is a complex process that involves forming new blood vessels in the primary tumor (angiogenesis), intravasation, the transport of cancer cells to other locations, extravasation, and the growth of cancer cells in the secondary site. Gold nanoparticles (AuNPs), due to their unique physicochemical properties, are considered promising tools in cancer therapy, both as drug delivery systems and potential anti-metastatic agents. Previously, it has been demonstrated that 500 µg/mL glutathione-stabilized gold nanoparticles (Au-GSH NPs) inhibit cancer cell extravasation—one of the steps of the metastatic cascade. This study aimed to evaluate the anti-metastatic properties of Au-GSH NPs through their influence on OSA cell migration, proliferation, and colony formation in vitro, as well as their antiangiogenic properties on the chick embryo chorioallantoic (CAM) model. Additionally, we investigated whether these effects are associated with changes in alpha-2-macroglobulin (A2M) expression, as it was previously demonstrated to play an essential role in the metastatic cascade. Au-GSH NPs significantly inhibited migration and colony formation in canine osteosarcoma cells (from OSCA-8, OSCA-32, and D-17 cell lines) at 200 µg/mL concentrations. Interestingly, at 500 µg/mL, Au-GSH NPs inhibited angiogenesis on the CAM model and cancer cell migration, but fewer colonies were formed. These results may be directly related to the higher efficiency of Au-GSH NPs uptake by OSA cells at the dose of 200 μg/mL than at the dose of 500 μg/mL, as demonstrated using Microwave Plasma Atomic Emission Spectroscopy (MP-AES). Moreover, this is the first study that demonstrates a significant increase in A2M expression in cancer cells after Au-GSH NPs treatment. This study provides new insight into the potential use of Au-GSH NPs as anti-metastatic agents in canine osteosarcoma, indicating that their anti-metastatic properties may be related to A2M. However, further in vitro and in vivo studies are needed to explore the molecular mechanism underlying these effects and to evaluate the clinical relevance of AuNPs in veterinary oncology.
Necrotizing enterocolitis (NEC) is a serious GI disease of premature infants, marked by intestinal inflammation and necrosis. Recent research has highlighted the potential role of oxidative stress (OS) and ferroptosis in its pathogenesis. We previously identified a deficiency in Glutathione Peroxidase (GPX) 4 and lipid radical accumulation, prompting further investigation. Human intestinal tissue from a prior study was processed, and it underwent RNA and protein isolation, Immunohistochemistry, Immunofluorescence, and acid digestion for iron and selenium analysis via Inductively coupled mass spectrometry (ICP-MS). NEC was induced in human enteroids using lipopolysaccharide (LPS) and hypoxia, followed by RNA/protein isolation and lipidomic analysis. Humans with NEC had significantly higher levels of GPX2 (p = 0.0003). Enteroids exposed to NEC conditions had significantly decreased amounts of NADPH compared to initial controls (p = 0.0091), but similar levels compared to post-24 h controls (p = 0.3520). Patients with NEC had significantly higher levels of iron compared to controls via the bathophenanthroline-based assay (p = 0.0102) and with ICP-MS (p = 0.0148). There were several significant alterations in lipid distribution between NEC and control patients, but not in the fatty acid profiles. Our study suggests that oxidative stress, iron dysregulation, and altered lipid metabolism contribute to NEC pathogenesis.
Multiple myeloma (MM) is frequently associated with cytogenetic abnormalities, with high-risk cytogenetics linked to poorer survival. Acute kidney injury (AKI) is common in MM, but its relationship with high-risk cytogenetics remains underexplored. This study aimed to assess the association between high-risk cytogenetics and AKI in newly diagnosed MM patients and to evaluate their impact on overall survival, relapse-free survival, and progression to chronic kidney disease (CKD) in the first two years after diagnosis. We conducted a single-center retrospective cohort study including patients newly diagnosed with MM between 2018 and 2022. We enrolled 122 patients. AKI was observed in 36.9% of patients, rising to 62.3% among those with high-risk cytogenetics. High-risk cytogenetics (OR: 3.32; 95% CI: 1.17–6.40; p = 0.024), CKD (OR: 9.14; 95% CI: 2.92–18.65; p < 0.001), kappa free light chains, hypercalcemia, difference in free light chain (dFLC), and bone marrow plasmocyte percentage were independently associated with AKI. Both AKI (HR: 2.71; 95% CI: 1.18–6.23; p = 0.019) and high-risk cytogenetics (HR: 3.33; 95% CI: 1.13–9.76; p = 0.029) were independently associated with lower overall survival. Among survivors without prior CKD, progression to CKD was higher in those with AKI (30.7% vs. 9.3%; p = 0.041). High-risk cytogenetics were significantly associated with AKI in MM patients. Both factors independently predict worse survival and increased risk of CKD progression.
Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting.
Alcoholic liver disease (ALD) is a type of liver disease with complex pathogenic factors. In 2019, alcohol caused 11 million life-years to be lost globally, and the mortality rate has continued to rise. This study aims to explore the exclusive gene profile of AH and construct an mRNA-lncRNA regulatory network through an integrative analysis and database validation to reveal potential key biomarkers. We obtained expression data for alcoholic hepatitis from the GEO database; screened differentially expressed genes (DEGs) through a weighted gene co-expression network analysis (WGCNA); conducted a GO&KEGG analysis; and focused on the enrichment pathways for the top 20 genes. Hub genes were selected using cytoHubba and MCODE to construct the mRNA-lncRNA regulatory network, and key genes were confirmed using GSE167308 and GSE28619. We obtained 2552 differentially expressed mRNAs and 555 differentially expressed lncRNAs from three databases. Differentially expressed genes are mainly involved in pathways such as lipid metabolism disorders, complement activation, the activation of cancer-related pathways, the excessive activation of inflammatory immunity, and the initiation of cell adhesion and fibrosis. Based on the hub gene analysis, we screened out 43 key genes. By constructing the key mRNA-lncRNA–pathway network, we identified 12 mRNAs (AQP1, ELOVL7, ITPR3, KRT19, KRT23, LAMC2, MMP7, PROM1, SPINT1, STK39, TNFRSF21, and VTCN1) and 14 lncRNAs that play an important role in the occurrence and development of alcoholic hepatitis. To sum up, this article mainly expounds upon the key genes in the occurrence and development of alcoholic hepatitis. The key genes are mainly concentrated within signaling pathways such as metabolic pathways, fatty acid metabolism, and cancer pathways. Twelve differentially expressed mRNAs in the co-expression network can be used as biomarkers and intervention targets for the diagnosis and treatment of alcoholic hepatitis.
Glioblastoma (GBM), a highly malignant brain tumor, arises within a complex microenvironment that plays a critical role in facilitating tumor progression, ensuring survival, and enabling immune evasion, ultimately contributing to therapeutic resistance. Cancer-associated fibrosis is increasingly recognized as a key factor in the tumor pathophysiology, particularly in extracranial cancers, and reported therapeutic strategies in several cancers consist of the current use of the standard-of-care treatment combined with anti-fibrotic drugs. However, it remains unclear how the fibrotic changes associated with the GBM microenvironment contribute to the transformation of GBM from a chemosensitive state to a chemoresistant one. Here, we developed an in vitro model that mimics a fibrosis-like mechanism using the U-87MG GBM cell line. To achieve this, we identified the optimal experimental conditions (i.e., U-87MG cultured in serum-deprivation medium in the presence of recombinant TGF-B1 at 5 ng/mL for 72 h) that effectively induced fibrosis, as suggested by the counter-regulated expression of E- and N-cadherin and sustained levels of α-SMA and collagen I. As expected, U-87MG fibrotic cells were demonstrated to be more resistant to TMZ (predicted EC50 = 35 µM) as compared to the non-fibrotic counterpart (EC50 not achieved here; predicted EC50 = 351 µM). Accordingly, the anti-fibrotic uPAcyclin—a new derivative cyclic compound inspired as a A6 decapeptide drug—showed a significant cytotoxic effect, sensitizing resistant U-87MG fibrotic cells to TMZ. This highlights that targeting fibrosis may help to overcome TMZ resistance in GBM.
About a quarter of COVID-19 patients develop acute kidney injury (AKI), worsening prognosis and increasing mortality. Severe COVID-19 often triggers a hyperactive immune response, influencing disease outcomes. This study examined the correlation between kidney injury biomarkers, inflammatory mediators, and mortality in COVID-19 patients. Blood samples from 390 COVID-19 patients were collected at admission and before the outcome. Serum Cystatin C (CysC), albumin, and plasma NGAL were measured via nephelometry, while inflammatory mediators (IL-4, IL-6, IL-10, IL-15, IFN-γ, TNF-α, and IL-1β) were assessed by ELISA. Most patients were male, with hypertension and diabetes as common comorbidities, and a high ICU admission rate. Lower albumin and elevated CysC and NGAL were linked to mortality. Increased inflammatory mediators correlated with lower albumin and higher CysC and NGAL, reinforcing the connection between systemic inflammation and kidney dysfunction. Elevated cytokines and kidney injury biomarkers, including NGAL, CysC, and low albumin, are strongly associated with higher mortality in COVID-19 patients. These findings highlight the role of inflammation and kidney function markers in identifying high-risk individuals, improving patient management, and mitigating complications. Monitoring these biomarkers remains crucial for managing long-term health impacts and future outbreaks
Gonadotropin-Releasing Hormone (GnRH) is a crucial neuropeptide that regulates reproductive functions in vertebrates. The study identifies and characterizes (GnRH) in the brain of Tenualosa ilisha, an iconic and lucrative Clupeiform fish from River Ganga, India. The current study aimed to analyze the GnRH gene in T. ilisha using an in silico study. The GnRH gene of T. ilisha comprises a full-length nucleotide sequence of 605 base pairs with an open reading frame of 312 base pairs, which encodes 103 deduced amino acids (aa), respectively. It was found that leucine (L) is the most abundant amino acid in the GnRH protein. Additionally, the ligand interactions of the GnRH were analyzed using computational approaches. The structural validation showed an excellent stereochemical quality of the GnRH protein sequence, with over 88% of residues in Ramachandran plot-favored regions. The binding site prediction revealed 6 ligand-binding pockets, with the largest pocket containing 12 amino acids. After ADME screening, 16 drug-like compounds were docked to GnRH protein. Top five ligands N-Ac-(4-Cl-Phe)-Trp-Lys-AlaNH2, LHRH_LYS (6), Seabream_GnRH, Leuprolide, and LHRH_Des-tyr (5) had binding affinities ranging from −7.5 to −5.6 kcal/mol. The stable binding site was confirmed by 100 ns molecular dynamics simulations, with RMSD values below 10 Å and key residues retaining ligand contacts. The GnRH-protein resulted in the development of a suitable peptide sequence of T. ilisha, showing similarity with the similar anadromous American shad (Alosa sapidissima). This will certainly aid in future therapeutic and captive breeding advances, thereby fostering the culture and conservation of the wild species.
Protein C (PC) is the main anticoagulant protein of the hemostasis system. It can inhibit the blood clotting cascade before the formation of a thrombus, while its concentration can decrease significantly during strong activation of blood clotting. The PC concentration was found to decrease during systemic lupus erythematosus (SLE) (with a median of 75%) and depended heavily on the inflammation index. It was also associated with the accumulation of soluble fibrin monomeric (SFMCs) (with a median of 7 µg/mL). A low PC level was detected during severe ischemic heart disease (IHD) (with medians of 60 and 63%, respectively). These pathologies also were associated with clotting activation. During abdominal aortic aneurysm (AAA), the PC level in blood plasma before surgery was found to range from 40% to 119%. A decrease in the PC level in the blood plasma of patients with AAA before surgery, lower than 78%, was associated with high blood loss (more than 1.5 L). A decrease in the PC level can lead to an imbalance between coagulation and anticoagulation. Thus, during the treatment of complex pathologies associated with the activation of coagulation, specific attention should be paid not only to classic markers of thrombus formation but also to the state of the anticoagulant link.
Uncomplicated hypertension (UH) during pregnancy represents a common condition, worsening maternal and fetal prognosis. However, no single biomarker has proven optimal for determining the risk of UH. We developed an early risk multivariate model for UH, integrating hemodynamics with biochemistry, focusing on the relationship between blood pressure (BP) indices, uric acid (UA), and angiogenesis-related factors (AF). We collected and analyzed data on 24 h ambulatory BP monitoring, demographic, epidemiological, clinical, and laboratory variables from 132 pregnancies. The main predictors were BP indices and serum UA and AF levels. Uncomplicated hypertension, defined as the presence of gestational hypertension or worsening of essential hypertension beyond the 20th week, was the main outcome. The combined second-degree polynomial transformation of UA and the AF (sFlt-1/PIGF) ratio, called the UA-AF Index, consistently showed a positive association with UH. The models incorporating nighttime BP indices combined with the UA-AF Index outperformed the others, with the best-performing model based on the nocturnal systolic BP (SBP). Specifically, in the best-fitting model (nighttime SBP + UA-AF Index as predictors), each 1 mmHg increase in nocturnal SBP was associated with a 10% higher risk of UH, while each one-unit increase in the UA-AF Index raised the likelihood of UH by more than twofold (accuracy: 0.830, AUC 0. 874, SE 0.032, p-value < 0.001, 95%CI 0.811–0.938). The combination of nighttime blood pressure indices, serum uric acid, and angiogenesis-related factors may provide added value in the assessment of uncomplicated hypertension during pregnancy.
Staphylococcus lugdunensis is a coagulase-negative staphylococcus known for its significant pathogenic potential, often causing severe infections such as endocarditis and bacteremia, with virulence comparable to S. aureus. Despite general susceptibility to most antibiotics, the emergence of oxacillin-resistant strains is increasingly concerning. This study conducted whole-genome sequencing on 20 S. lugdunensis isolates from Chang Gung Memorial Hospital to explore their genetic diversity, antimicrobial resistance mechanisms, and mobile genetic elements. The lugdunin biosynthetic operon, essential for antimicrobial peptide production, was present in multilocus sequence typing (MLST) types 1, 3, and 6 but absent in STs 4, 27, and 29. Additionally, IS256 insertion elements, ranging from 7 to 17 copies, were identified in four strains and linked to multidrug resistance. CRISPR-Cas systems varied across STs, with type III-A predominant in ST1 and ST6 and type IIC in ST4, ST27, and ST29; notably, ST3 lacked CRISPR systems, correlating with a higher diversity of SCCmec elements and an increased potential for horizontal gene transfer. Phage analysis revealed stable phage–host associations in ST1, ST6, and ST29, whereas ST4 displayed a varied prophage profile. Phenotypic resistance profiles generally aligned with genomic predictions, although discrepancies were observed for aminoglycosides and clindamycin. These findings highlight the complex genetic landscape and evolutionary dynamics of S. lugdunensis, emphasizing the need for genomic surveillance to inform clinical management and prevent the spread of resistant strains.
The possibilities of small-cell lung cancer (SCLC) therapy were strictly limited for years, leading to high patient mortality rates. New approaches to SCLC treatment are being proposed, including chemoimmunotherapy. However, biomarkers enabling appropriate personalization of therapy in SCLC patients have not been identified yet. Even though molecular subtyping (ASCL1, NEUROD1, POU2F3, and YAP1) seems pivotal in the management of SCLC, expression of other genes might be potentially valuable during patients’ stratification. Due to their crucial role in tumorigenesis and SCLC invasiveness, benefits arising from MET and SLFN11 gene evaluation are suggested. Our study was designed to evaluate the relationship between the mRNA expression of these genes and chemoimmunotherapy efficacy in SCLC patients. A total of 35 patients with extensive-stage SCLC (ES-SCLC) treated with first-line chemoimmunotherapy were involved in the study. mRNA expression of MET and SLFN11 genes was evaluated using the RT-qPCR technique in FFPE tissue collected from all patients. Molecular results were correlated with clinicopathological features and outcome of disease (OS, PFS). We detected SLFN11 expression in 60% (21 of 35) of the samples. SLFN11 expression was higher in patients with longer PFS (p = 0.05) and with the T4 feature in the TNM scale (p = 0.08). MET mRNA was expressed in all FFPE tissues. We observed that risk of progression and death was higher in patients with higher expression of MET mRNA (p = 0.06 and p = 0.04, respectively). Our study showed that MET and SLFN11 expression might serve as additional biomarkers for prediction of chemoimmunotherapy efficacy in ES-SCLC patients.
Anthozoa is a species-rich class with an innate immune system that acts as a defensive tool and shares many of its cellular pathways with mammalian immune responses. In addition to immune-related strategies (e.g., allorecognition and xenorecognition), anthozoans have evolved to use compounds or toxins for chemical communication, defense, or predation, which may exhibit biological activities useful for human health, mainly antiviral, antibacterial, anti-inflammatory, anticancer, and antitumor properties of pharmaceutical interest. These compounds/toxins can be alkaloids, amino acids, proteins, ceramides, diterpenes, and sesquiterpenes and are mainly distributed into Hexacorallia and Octocorallia. Anthozoans are enriched in defensive enzymes, which can either be found in anthozoan species or their symbionts and help them survive in hostile conditions. Studies related to genomics and transcriptomics using advanced sequencing efforts revealed the presence of genetic elements in anthozoans that help them survive against abiotic and biotic stressors in the marine environment. This review presents developments and highlights the current state of knowledge about anthozoans’ chemical weaponry that can drive further bioprospection of anthozoan species producing compounds and toxins which may be useful in biotechnological applications. Omics research in Anthozoa is still nascent, and more efforts are required to fully understand the chemical ecology, diversity, and possible biotechnological applications of cnidarian genes and their products.
Sepsis remains a critical global health challenge characterized by life-threatening organ dysfunction arising from a dysregulated host response to infection. Immunothrombosis refers to the intersection of immune activation and coagulation pathways, particularly relevant in the context of sepsis. A growing body of evidence identifies immunothrombosis, a tightly interwoven process between innate immunity and coagulation. While immunothrombosis serves as a host defense mechanism under physiological conditions, its aberrant activation in sepsis precipitates microvascular thrombosis, organ ischemia, and progression toward disseminated intravascular coagulation (DIC). This review provides a comprehensive overview of the cellular contributors to immunothrombosis, including neutrophils, monocytes, platelets, and endothelial cells, and elucidates the signaling cascades, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and inflammasome activation, that govern their interplay. We further highlight emerging molecular mediators, including extracellular traps, tissue factor expression, and cytokine amplification loops, that collectively promote pathological thromboinflammation. A deeper understanding of these interconnected pathways offers critical insights into the pathogenesis of sepsis and unveils potential targets for timely intervention. Ultimately, this review aims to bridge immunological and hematological perspectives to inform the development of novel therapeutic strategies against sepsis-induced coagulopathy.
Acute kidney injury (AKI) resulting from ischemia/reperfusion (I/R) poses a significant clinical challenge due to its high mortality and complex pathophysiology. Here, the protective actions of Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced adenosine triphosphate depletion and recovery (ATP-D/R) injury in human kidney-2 (HK2) cells are examined. During ATP-D/R, expression levels of CHCHD2 were significantly reduced. The overexpression of CHCHD2 substantially reduced the levels of ROS, lipid peroxidation, apoptosis, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), whereas the knockdown of CHCHD2 exacerbated cellular injury. Mechanistic studies further demonstrated that overexpression of CHCHD2 restored Nrf2 expression under ATP-D/R conditions, facilitated its nuclear translocation, and upregulated the downstream antioxidant enzyme HO-1. In contrast, the knockdown of Nrf2 reduced the cytoprotective actions of CHCHD2. These findings indicate that CHCHD2 reduces cellular damage by enhancing antioxidant defenses and reducing apoptosis through activating the Nrf2 axis, underscoring its potential as a therapeutic target for AKI.
Pheochromocytoma, a rare catecholamine-secreting tumor, poses significant perioperative challenges due to its potential for severe hemodynamic instability. Careful management of patients with pheochromocytoma is critical for patient safety and favorable outcomes. The diagnostic workup focuses on biochemical analysis of plasma or urinary metanephrines, followed by imaging for tumor localization and genetic testing to identify hereditary syndromes. Preoperative management emphasizes adequate alpha-adrenergic blockade followed by beta-blockade to stabilize cardiovascular function. Anesthetic planning requires meticulous attention to volume status, cardiovascular optimization, and intraoperative monitoring to mitigate the risks of hypertensive crises and hypotension. Postoperative care must account for ongoing hemodynamic and metabolic fluctuations. A multidisciplinary, protocol-driven approach is essential to improve outcomes in patients undergoing pheochromocytoma resection. This paper provides a comprehensive overview of the genetic, biochemical, clinical, and anesthetic considerations involved in the diagnosis and perioperative management of pheochromocytoma.
Alzheimer’s disease (AD) is characterized by progressive cognitive decline strongly associated with impaired adult hippocampal neurogenesis (AHN). Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)—such as transcriptional alterations in quiescent states—and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-β and Tau pathology, supporting their potential as early biomarkers of disease progression. In this review, we synthesize recent advances in therapeutic strategies aimed at restoring AHN, encompassing pharmacological agents, natural products, and non-pharmacological interventions such as environmental enrichment and dietary modulation. Emerging approaches—including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions—highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)—a novel composite metric that quantifies hippocampal neurogenic capacity relative to amyloid burden, while adjusting for demographic and cognitive variables. By integrating neurogenic potential, cognitive performance, and pathological load, NII provides a framework for stratifying disease severity and guiding personalized therapeutic approaches. Despite ongoing challenges—such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies—this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments.
This study presents an integrated experimental and theoretical investigation of two pharmacologically significant neolignans—magnolol and honokiol—with the aim of characterizing their structural and spectroscopic properties in detail. Experimental Fourier-transform infrared (FT-IR), ultraviolet–visible (UV-Vis), and nuclear magnetic resonance (1H NMR) spectra were recorded and analyzed. To support and interpret these findings, a series of density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were conducted using several hybrid and long-range corrected functionals (B3LYP, CAM-B3LYP, M06X, PW6B95D3, and ωB97XD). Implicit solvation effects were modeled using the CPCM approach across a variety of solvents. The theoretical spectra were systematically compared to experimental data to determine the most reliable computational approaches. Additionally, natural bond orbital (NBO) analysis, molecular electrostatic potential (MEP) mapping, and frontier molecular orbital (FMO) visualization were performed to explore electronic properties and reactivity descriptors. The results provide valuable insight into the structure–spectrum relationships of magnolol and honokiol and establish a computational benchmark for further studies on neolignan analogues.
Wound healing is a complex biological process that benefits from advanced biomaterials capable of modulating inflammation and promoting tissue regeneration. In this study, cerium oxide nanoparticles (CeO2NPs) were green-synthesized using Hemerocallis citrina extract, which served as both a reducing and stabilizing agent. The CeO2NPs exhibited a spherical morphology, a face-centered cubic crystalline structure, and an average size of 9.39 nm, as confirmed by UV-Vis spectroscopy, FTIR, XRD, and TEM analyses. These nanoparticles demonstrated no cytotoxicity and promoted fibroblast migration, while significantly suppressing the production of inflammatory mediators (TNF-α, IL-6, iNOS, NO, and ROS) in LPS-stimulated RAW264.7 macrophages. Gene expression analysis indicated M2 macrophage polarization, with upregulation of Arg-1, IL-10, IL-4, and TGF-β. Aligned polycaprolactone/polylactic acid (PCL/PLA) nanofibers embedded with CeO2NPs were fabricated using electrospinning. The composite nanofibers exhibited desirable physicochemical properties, including porosity, mechanical strength, swelling behavior, and sustained cerium ions release. In a rat full-thickness wound model, the CeO2 nanofiber-treated group showed a 22% enhancement in wound closure compared to the control on day 11. Histological evaluation revealed reduced inflammation, enhanced granulation tissue, neovascularization, and increased collagen deposition. These results highlight the therapeutic potential of CeO2-incorporated nanofiber scaffolds for accelerated wound repair and inflammation modulation.
Heterozygous mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase (GCase), are major risk factors for Parkinson’s Disease (PD). Ambroxol, a small chaperone originally used as a mucolytic agent, has been shown to cross the blood–brain barrier, enhance glucocerebrosidase activity, and reduce α-synuclein levels, making it a promising therapeutic candidate for disease-modifying effects in GBA1-associated PD (GBA1-PD). This study aimed to develop a method to quantify ambroxol levels in human plasma and cerebrospinal fluid (CSF) using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Ambroxol was determined by online solid-phase extraction (SPE), coupled with LC-MS/MS, by gradient elution on a monolithic column. Detection employed a 3200 QTRAP tandem mass spectrometer in the positive electrospray ionization mode. Calibration curves exhibited linearity across the analyzed ranges in both plasma and CSF. The recovery rate ranged from 106.7% to 113.5% in plasma and from 99.0% to 103.0% in CSF. No significant matrix effect was observed. Intra-day and inter-day precisions were below 11.8% in both matrices, and accuracy ranged from 89.9% to 103.1% in plasma and from 96.3% to 107.8% in CSF. We evaluated and confirmed the stability of the analyte in plasma and CSF across various storage conditions. The method was successfully validated according to European Medicine Agency (EMA) guidelines and its applicability was confirmed in the context of a multicenter, randomized, double-blind, placebo-controlled, phase II study, designed to monitor the ambroxol levels in the plasma and CSF of GBA1-PD.
WRN helicases play a key role in DNA replication, repair, and other processes in a variety of tumors. It has become one of the hot targets of genotoxic drugs, but the effect and mechanism of targeting WRN against prostate cancer is still unclear. In our previous study, we found a quinazoline compound kzl052, which has a WRN-dependent inhibitory effect on prostate cancer cells, but its molecular mechanism needs to be further explored. In this study, kzl052 significantly inhibited the growth of PC3 (IC50 = 0.39 ± 0.01 μM) and LNCaP (IC50 = 0.11 ± 0.01 μM) cells in vitro and showed a good inhibition effect on PCa in vivo. It inhibits PC3 cell growth by binding to WRN proteins and affecting its non-enzymatic function. Then the mechanism of kzl052 against prostate cancer progression was revealed to be by regulating the stability of DNA replication forks and the RB pathway. This study will provide a theoretical basis and treatment strategy for targeting WRN helicase in the treatment of prostate cancer.
Several studies suggest a relationship between phthalates (PAEs) and allergic diseases in children. Therefore, we speculated that PAE exposure may be an important environmental factor causing allergic diseases. The present study employed meta-analysis and network toxicology to analyze the interactions and assess potential pathogenic pathways between prenatal and postnatal PAE exposure and childhood allergic diseases. This study found that prenatal PAEs exposure was positively associated with childhood wheezing and eczema (OR = 1.03, 1.05), and postnatal PAEs exposure was positively associated with childhood wheezing, eczema, and rhinitis (OR = 1.10, 1.05, 1.06). PAE exposure from dust may elicit distinct effects compared to direct exposure to PAEs. Furthermore, a large number of overlapping genes between disease targets and PAEs were identified. Enrichment analysis highlighted the association of PAE-targeted genes with biological pathways integral to allergic diseases. Molecular docking results indicated a strong link between the PAEs and the core proteins, such as SRC, AKT1, and HSP90AA1. These proteins are critically involved in the regulation of immune–inflammatory processes underlying allergic diseases. This discovery not only enhances our understanding of the relationship between environmental pollutants and child health but also provides a robust reference for experimental studies on the induction of childhood diseases by early-life exposure to environmental pollutants.
Recently, marketing authorizations were granted by the Federal Drug Administration (FDA) for pegcetacoplan and avacincaptad pegol, which inhibit C3 and C5 complement components, respectively. These two drugs were demonstrated to slow down the growth of atrophic areas in the retina. These authorizations represent a huge breakthrough for patients suffering from geographic atrophy (GA), the late stage of the dry form of Age-related Macular Degeneration (AMD). Until then, no treatment was available to treat this blinding disease. However, these two new compounds inhibiting the complement system are still not available for patients outside of the United States, and they are not devoid of drawbacks, including a poor effect on vision improvement, an increased risk of occurrence of the neovascular form of AMD and the burden of patients receiving recurrent intravitreal injections. Thus, the important medical need posed by GA remains incompletely answered, and new therapeutic options with alternative modes of action are still required. Oxidative stress and inflammation are two major potential targets to limit the progression of atrophic retinal lesions. Dimethyl fumarate, dimethyl itaconate and other activators of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) display antioxidants and immunomodulatory properties that have shown evidence of efficacy in in vitro and in vivo models of dry AMD. Tecfidera®, whose active principle is dimethyl fumarate, is already commercialized for the treatment of autoimmune diseases such as multiple sclerosis and psoriasis. The aim of this review is to present the rationale and the design of the clinical trial we initiated to test the effectiveness and safety of repurposing Tecfidera®, which could represent a new therapeutic alternative in patients with the dry form of AMD.
Peptidylarginine deiminase 4 (PAD4) catalyzes protein citrullination, a post-translational modification implicated in type 1 diabetes mellitus (T1DM). This study examined PAD4 expression and activity in the pancreas of streptozotocin (STZ)-induced diabetic Wistar rats. Animals were divided into three groups: (A) STZ-induced diabetic rats (60 mg/kg, i.p.), (B) non-diabetic controls, and (C) diabetic rats treated with Cl-amidine (5 mg/kg), a pan-PAD inhibitor, from week six post-induction. Analyses included PAD4 mRNA and protein expression, citrullinated histone H3 (CitH3), calcium concentration, and neutrophil elastase activity. Diabetic rats exhibited increased PAD4 expression, CitH3 levels, and NETosis markers, alongside reduced pancreatic calcium, suggesting calcium consumption during PAD4 activation. Cl-amidine treatment attenuated NETosis. These results implicate PAD4 in T1DM pathogenesis via NETosis and support the utility of STZ-induced diabetic rats as a model for PAD4-targeted studies. Cl-amidine may represent a promising therapeutic approach to reduce pancreatic inflammation in T1DM.
Throughout human history, wild plant resources have played an invaluable role, serving as critical sources of food, medicine, and industrial materials. This study examined the callus cultures of Cistanche deserticola Y.C. Ma, a medicinal desert plant, by subjecting them to abiotic stress under controlled in vitro conditions. The secondary metabolite profiles were then analyzed using GC-MS and qTOF-UHPLC-MS. The GC-MS analysis revealed several bioactive compounds of pharmaceutical interest, such as γ-sitosterol and homovanillyl alcohol. PhGs, including echinacoside and salidroside, were quantified for the first time across 16 callus samples exposed to various stress treatments. The application of 0.1% Na2CO3 for 50 days resulted in the highest accumulation of echinacoside (13,378.9 µg/mL), and heavy metal stress notably increased salidroside levels to 27.0 µg/mL. There was a clear correlation between callus pigmentation and metabolic activity: orange and white calli produced significantly more PhGs than dark calli. These results suggest that C. deserticola callus cultures could be a sustainable, controllable platform for producing high-value secondary metabolites. This reinforces the importance of wild plant resources in modern science and industry.
Cortisol, the main glucocorticoid in teleost, plays a central role in mediating the physiological response to stress by regulating metabolism, immune function, and growth. While its transcriptional effects are well known, its role in modulating chromatin accessibility in fish skeletal muscle remains poorly understood. In this study, we investigated the epigenomic and transcriptomic changes induced by cortisol in a juvenile rainbow trout’s (Oncorhynchus mykiss) skeletal muscle using ATAC-seq and RNA-seq. Fish were treated with a single intraperitoneal dose of cortisol (10 mg/kg) or vehicle, and muscle samples were collected 3 h post-treatment. ATAC-seq analysis revealed a total of 163,802 differentially accessible regions (DARs), with an important enrichment of open regions near transcription start sites and promoters. A total of 1612 and 1746 differentially accessible genes (DAGs) were identified in the cortisol and control groups, respectively. Motif enrichment analysis identified 89 transcription factors to be significantly enriched, among which key stress-responsive regulators such as Fos, AP-1, FoxO1/3, Mef2a/b/c, Klf5/10, and ATF4 were prominently represented. RNA-seq analysis identified 4050 differentially expressed genes (DEGs), with 2204 upregulated genes involved in autophagy, mitophagy, and FoxO signaling, while 1864 downregulated genes were enriched in spliceosome and chromatin remodeling pathways. Integrative analysis revealed 174 overlapping genes between ATAC-seq and RNA-seq datasets, highlighting pathways linked to autophagy and ATP-dependent chromatin remodeling. Four selected DEGs (sesn1, sesn2, cullin3, samtor) were validated by qPCR, showing high concordance with transcriptomic data. These findings provide new insights into cortisol-mediated regulation of chromatin dynamics and gene expression in teleost skeletal muscle and underscore the importance of epigenetic mechanisms in fish stress responses.
Hemophilia, an X-linked bleeding disorder, is characterized by a deficiency in coagulation factors. It manifests as spontaneous bleeding, leading to severe complications if not properly managed. In contrast, acquired hemophilia is an autoimmune condition marked by the development of inhibitory antibodies against coagulation factors. Both forms present significant diagnostic and therapeutic challenges, highlighting the need for advanced genetic, molecular, laboratory, and clinical assessments. Recent advances in artificial intelligence have opened new avenues for the management of hemophilia. Machine learning and deep learning technologies enhance the ability to predict bleeding risks, optimize treatment regimens, and monitor disease progression with greater precision. Artificial intelligence-driven applications in medical imaging have also improved the detection of joint damage and hemarthrosis, ensuring timely interventions and better clinical outcomes. Moreover, the integration of artificial intelligence into clinical practice holds the potential to transform hemophilia care through predictive analytics and personalized medicine, promising not only faster and more accurate diagnoses but also a reduction in long-term complications. However, ethical considerations and the need for data standardization remain critical for its widespread adoption. The application of artificial intelligence in hemophilia represents a paradigm shift towards precision medicine, with the promise of significantly improving patient outcomes and quality of life.
Skin cancer, particularly melanoma, remains a major public health concern due to its high mortality rate. Current treatment options, including chemotherapy with dacarbazine and doxorubicin, have shown limited efficacy, achieving only a 20% objective response rate over six months, along with severe side effects such as cardiotoxicity. Given these limitations, there is a growing interest in herbal medicine as a source of novel anticancer compounds. Bambusa stenostachya, a bamboo species native to Taiwan, was investigated for its potential anti-melanoma properties using network pharmacology and molecular docking. LC-MS analysis identified seven bioactive compounds, including quinic acid and isovitexin, which satisfied Lipinski’s drug-likeness criteria. Among the seven bioactive compounds identified, five belong to the flavonoid family, while two are classified as phenolic compounds that modulate signaling pathways related to cancer and exhibit antioxidant activity, respectively. Through pathway enrichment analysis, four key melanoma-associated genes (PIM1, MEK1, CDK2, and PDK1) were identified as potential therapeutic targets. Ensemble docking results demonstrated that naringin-7-rhamnoglucoside exhibited the highest binding affinity (−6.30 kcal/mol) with phosphoinositide-dependent kinase-1, surpassing the affinities of standard chemotherapeutic agents. Additionally, the average docking scores for naringin-7-rhamnoglucoside and the remaining three proteins were as follows: PIM1 (−5.92), MEK1 (−6.07), and CDK2 (−5.26). These findings suggest that the bioactive compounds in B. stenostachya may play a crucial role in inhibiting melanoma progression by modulating metabolic and signaling pathways. Further in vitro and in vivo studies are necessary to validate these computational findings and explore the potential of B. stenostachya as a complementary therapeutic agent for melanoma.
Understanding the binding interactions between protein-bound uremic toxins (PBUTs) and human serum albumin (HSA) is critical for advancing treatments for chronic kidney disease (CKD). While previous studies have suggested that putrescine, a diamine PBUT, exhibits moderate binding affinity to HSA, this study provides evidence of the contrary. Using isothermal titration calorimetry and saturation transfer difference nuclear magnetic resonance , we demonstrate that putrescine’s interaction with HSA is weak, non-specific, and thermodynamically negligible in the range of conditions studied. Unlike earlier studies relying on spectroscopy techniques such as UV–visible absorption and fluorescence, which may overestimate binding strength, the results presented here highlight the limitations of indirect methodologies and underscore the importance of more sensitive approaches for accurate energy characterization. Our findings suggest that putrescine only weakly interacts non-specifically with HSA and may bind more preferentially to other plasma proteins, contributing to its accumulation in CKD patients.
Biotechnology has increasingly focused on cyanobacteria as these microorganisms are a rich source of secondary metabolites with significant potential for various industries. Cyanobacterial metabolites have been described to have a wide range of biological activities, including cytotoxicity in cancer cells, inhibition of pathogenic bacteria and fungi, and inhibition of various enzymes, demonstrating a great diversity of bioactive compounds. The cyanobacterium Microcystis aeruginosa is well known for its toxicity and production of the cyanotoxin microcystin. However, another peptide produced by this cyanobacterium, microginins, has significant biotechnological potential. These linear pentapeptides were initially discovered for their angiotensin-converting enzyme (ACE) inhibitory activity. Subsequent studies have explored the full potential of this peptide, revealing its ability to inhibit other enzymes as well. This review aims to compile and systematize the microginins with biotechnological potential described in the literature, as well as outline their main structural characteristics and the predominant methodologies for their isolation and identification.
Advancing age in men significantly contributes to declining sperm fertility. Information on age-related proteomic changes in spermatozoa is limited. This study involved normal fertile Arab men in three age groups: young adult (21–30 years; n = 6), late adult (31–40 years; n = 7), and advanced age (40–51 years; n = 5). Gradient-purified spermatozoa were analyzed using LC-MS/MS and proteomic data were processed using Progenesis QI (QIfp) v3.0 and UniProt/SwissProt. Significantly enriched annotations and clustering of proteins in the proteomic datasets were identified (2-fold change; p < 0.05). A total of 588 proteins were identified, with 93% shared across the three groups. Unique proteins were MYLK4 for the young adult group, PRSS57 for the late adult group, and HMGB4, KRT4, LPGAT1, OXCT2, and MGRN1 for the advanced age group. Furthermore, 261 (44%) proteins were differentially expressed (p < 0.05) across the three groups. Functional enrichment analysis suggested an aging-related significant increase in pathways associated with neurodegenerative diseases and protein folding, alongside decreases in glycolysis/gluconeogenesis, flagellated sperm motility, acetylation, phosphoprotein modifications, oxidation processes, and Ubl conjugation. Cluster analysis highlighted significantly upregulated proteins in young adults (e.g., H2BC1, LAP3, SQLE, LTF, PDIA4, DYNLT2) and late adults (e.g., ATP5F1B, ODF2, TUBA3C, ENO1, SPO11, TEX45, TEKT3), whereas most proteins in the advanced age group exhibited downregulation (e.g., SPESP1, RAB10, SEPTIN4, RAB15, PTPN7, USP5, ANXA1, PRDX1). In conclusion, this study revealed aging-associated proteomic changes in spermatozoa that impact critical processes, including spermatogenesis, motility, metabolism, and fertilization, potentially contributing to fertility decline. These changes provide a molecular framework for developing therapies to preserve sperm proteostasis and enhance fertility in older men.
Extracellular vesicles (EVs) are lipid membrane-enclosed particles released by all cells and can be isolated from various sources, even from solid tissues. This study focuses on isolating and characterizing EVs from mouse lymph nodes (LNs). Male C57BL/6 mice were injected with complete Freund’s adjuvant, with or without ovalbumin. Inguinal and popliteal LNs were incised 9 days after immunization, and EV isolation was carried out using a combination of differential centrifugation and size-exclusion chromatography. The characteristic morphology of small and large EVs was confirmed by transmission electron microscopy. Particle size distribution and concentration were determined by nanoparticle tracking analysis, while protein and lipid contents were measured by bicinchoninic acid assay, and sulfo-phospho-vanillin assays, respectively, to calculate the protein-to-lipid ratio. Immune and EV markers were analyzed by using flow cytometry and Western blot assay, revealing significant changes between immunized mice compared to controls. This study establishes a novel protocol for isolating and characterizing EVs from LNs and highlights the impact of immunization on EV properties, offering insights into their roles in immune processes.
Among the fundamental pathological processes, tumorigenesis is arguably the most complex [...]
The study aimed to identify the variants of SARS-CoV-2 (Severe Acute Respiratory Syndrome related coronavirus-2) virus isolates within the window of March 2021 to February 2022 in Bangladesh and investigate their comparative mutational profiles, preferences and phylogenetics. After the collection of the sample specimen and RNA extraction, the genome was sequenced using Illumina COVID Seq, and NGS data analysis was performed in DRAGEN COVID Lineage software (version 3.5.9). Among the 96 virus isolates, 24 (25%) were from Delta (clade 21A (n = 21) and 21J (n = 3)) and 72 (75%) were from Omicron (clade 20A (n = 6) and 20B (n = 66)). In Omicron and Delta, substitutions were much higher than deletions and insertions. High-frequency nucleotide change patterns were similar (for C > T, and A > G) in both of the variants, but different in some (i.e., G > T, G > A). Preferences for specific amino acids over the other amino acids in substitutions and deletions were observed to vary in different proteins of these variants. Phylogenetic analysis showed that the most ancestral variants were from clade 21A and clade 20A, and then the other variants emerged. The study demonstrates noteworthy variations of Omicron and Delta in mutational pattern and preferences for amino acids and protein, and further study on their biological functional impact might unveil the reason behind their mutational strategies and behavioral changes.
Plastics pollution is a critical global environmental issue, with growing concern over the increasing presence of nanoplastic particles. Plastics are major environmental pollutants that adversely affect human health, particularly when plastics from food sources enter the body and pose potential risks to reproductive health. Echinacea purpurea is an immunologically active medicinal plant containing phenolic acids and alkylamides. Nanoparticles present a promising approach to enhance the effectiveness, stability, and bioavailability of Echinacea purpurea ethanol extract (EE) active components. This study aimed to determine the protective effects of chitosan-silica-Echinacea purpurea nanoparticles (CSE) against reproductive injury induced by polystyrene nanoplastics (PS-NPs) in male rats. The results showed that CSE dose-dependently reduced oxidative damage and protected intestinal and reproductive health. Furthermore, CSE improved gut microbiota dysbiosis, preserved barrier integrity, and attenuated PS-NPs-induced inflammation in the colon, brain, and gonads. Inflammatory factors released from the gut can enter the bloodstream, cross the blood–brain barrier, and potentially modulate the hypothalamic–pituitary–gonadal (HPG) axis. CSE has also been shown to elevate neurotransmitter levels in the colon and brain, thereby repairing HPG axis dysregulation caused by PS-NPs through gut–brain communication and improving reproductive dysfunction. This study enhances our understanding of CSE in modulating the gut–brain and HPG axes under PS-NPs-induced damage. CSE demonstrates the capacity to provide protection and facilitate recovery by mitigating oxidative stress and inflammation, restoring gut microbiota balance, and preserving hormone levels in the context of PS-NPs-induced injury.
Glycogen synthase kinase-3 (GSK-3)—particularly the GSK-3β isoform—plays a pivotal role in regulating dendritic cell (DC) functions, including maturation, cytokine production, and antigen presentation. In immature DCs, GSK-3β is continuously active, and its inhibition has been shown to enhance DC maturation and function. As a key upstream kinase of β-catenin, GSK-3 inhibition activates β-catenin in both human and murine DCs—a pathway traditionally linked to its immunomodulatory effects. However, our recent findings challenge this paradigm by uncovering β-catenin-independent, dual roles of GSK-3β in DCs. Our study reveals that while GSK-3β enhances DC-mediated cross-priming of CD8 T cells, it concurrently impairs the generation of memory CD8 T cells. These findings have significant implications for vaccine development and cancer immunotherapy, where both effective T-cell priming and durable memory responses are critical. This mini-review provides an in-depth analysis of mechanistic insights into GSK-3β’s paradoxical functions and discusses potential strategies to fine-tune GSK-3 activity for optimized immunotherapeutic outcomes.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex multisystem conditions that pose significant challenges in healthcare. Accumulated research evidence suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating potential shared metabolic dysfunctions. This study aims to systematically explore shared metabolic disturbances in the muscle tissue of patients. Utilizing genome-wide metabolic modeling, we identified key metabolic irregularities in the muscle of patients with ME/CFS, notably the downregulation of the alanine and aspartate metabolism pathway and the arginine and proline metabolism pathway. Further, in silico knockout analyses suggested that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. In addition, assessments of metabolomic levels in Long COVID patients also showed the significant downregulation of ASP during post-exertional malaise (PEM) in both muscle and blood. Consequently, we propose that a combination of l-ornithine and l-aspartate (LOLA) is a potential candidate to alleviate metabolic symptoms in ME/CFS and Long COVID for future clinical trials.
Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are related diseases with poorly understood pathophysiology. While therapy options for IBD have increased, treatment options for PSC remain limited. Galectin-3 is a multifunctional lectin expressed in intestinal epithelial cells, and is abundant in immune cells such as macrophages, with roles in cell adhesion, apoptosis, inflammation and fibrosis being associated with IBD and PSC disease development and progression. In addition, galectin-3 is also a visceral fat-derived protein whose systemic levels are increased in obese individuals, the latter correlating with a poorer prognosis in IBD and PSC patients. On the other hand, decreased galectin-3 expression in the inflamed mucosal tissues of mice and patients with IBD possibly indicate a protective role of this lectin in IBD. However, galectin-3 loss or inhibition is protective in most animal models of liver fibrosis but exacerbates the severity of autoimmune liver disease. Hence, with PSC being a slowly progressing autoimmune hepatobiliary disease closely related to IBD, further studies evaluating galectin-3 as a therapeutic target or biomarker for the severity of IBD and the occurrence of PSC are still needed. This review summarizes studies that have analyzed expression patterns and functions of galectin-3 in IBD and PSC. Current evidence suggests that strategies to block galectin-3 are not advised for patients with IBD and PSC-IBD.
Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations.
Antimicrobial food packaging is considered a promising technology to improve food safety by inhibiting or reducing the growth of food microorganisms and minimizing the need for preservatives. This study aimed to develop and evaluate carboxymethyl cellulose (CMC) films integrated with bacteriocins for antibacterial efficacy. Plantaricin W was assessed as a potential bacteriocin for activation of CMC to control the dangerous food-borne pathogen, Listeria monocytogenes. Minced beef samples were inoculated with L. monocytogenes ATCC BAA-679 and treated with plantaricin W-activated food packaging. The results showed a significant reduction of the target pathogen by approximately 1 log cycle compared to the control group. Enterocin F4-9 is a novel bacteriocin that acts on Gram-negative microbes that were not affected by plantaricin W. Therefore, a novel food packaging activated with plantaricin W and enterocin F4-9 was developed to broaden their antimicrobial activity. The effect of this film on meat-associated microbes was investigated. The results demonstrated that the film significantly reduced the counts of mesophilic and psychotropic bacteria by 86.67% and 96.67%, respectively. Additionally, the pH values of the treated meat samples were significantly lower than those of the untreated controls. The obtained findings indicated that bacteriocin-activated CMC films could potentially be utilized as antimicrobial packaging in modern food technology.
The intrauterine environment is increasingly recognised as a critical period for the emergence of mental health vulnerabilities. This review explores how adverse maternal exposures, such as psychological stress, infection, malnutrition, and environmental toxins, can disrupt foetal neurodevelopment via epigenetic mechanisms, contributing to the risk of psychiatric and neurodevelopmental disorders. Focusing primarily on human studies, we synthesise evidence on DNA methylation, histone modifications, and non-coding RNAs as key pathways through which the intrauterine environment influences gene regulation in the developing brain. We examine how timing of exposure, foetal sex, and gene–environment interactions modulate these effects, with particular attention to disorders such as schizophrenia, autism spectrum disorder, depression, and anxiety. The placenta emerges as a central mediator, both reflecting and shaping epigenetic changes in response to maternal signals. We also discuss the reversibility of epigenetic marks and highlight emerging interventions, including nutritional supplementation and maternal mental health support, that may buffer or reverse prenatal epigenetic programming. Methodological challenges are addressed, including tissue specificity and causal inference, and future directions are proposed toward integrating epigenetic biomarkers into early risk assessment and precision mental health and psychiatry. This review emphasises the importance of the prenatal period as a window of vulnerability and opportunity for shaping lifelong mental health.
ABCG2 is a crucial ATP-binding cassette (ABC) transporter involved in multidrug resistance and essential physiological and pharmacological processes. In recent years, multiple ABCG2 structures have been resolved using cryo-electron microscopy (cryo-EM), providing significant insights into its conformational states during its transport cycle. However, even more than 25 years after its description, a high-resolution X-ray crystallographic structure is still unavailable, limiting the understanding of its dynamic transitions, as well as leaving aspects of the transport cycle unresolved and open to discussion. Given the complexity of ABCG2, a multidisciplinary approach is essential in order to fully elucidate its mechanism. This review compiles recent advances in ABCG2 structural biology, highlights unresolved controversies, and explores future directions to bridge the gap between structure and function. Moving forward, integrating multiple structural and functional approaches will be key to uncovering the intricate workings of this enigmatic transporter. In particular, detailed structural insights will be crucial to identifying new ABCG2 substrates and designing selective inhibitors, with important implications for therapeutic development.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of rare diseases characterized by autoimmune-associated inflammation and vessel damage. Based on the clinical manifestations and involvement of immune components, three disease syndromes are distinguished: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In this review, we present the current data on the epidemiology, the clinical manifestations of each syndrome, and the most up-to-date classification criteria. The role of the underlying genetic and epigenetic abnormalities, as well as their interplay, is described. The immunological diversification of AAV is also described, with a focus on the immune cell dysfunctions detected in patients. In conclusion, we emphasize the urgent need to unravel the sophisticated mechanisms of this disease, which would enable the development of new, effective therapeutic strategies.
Cannabinoid receptor 1 (CB1) signalling is critical for weight gain and for milk intake in newborn pups. This is important as in humans, low birth weight increases the risk for attention-deficit hyperactivity disorder (ADHD). Moreover, some children with ADHD also have Tourette syndrome (TS). However, it remains unclear if insufficient CB1 receptor signalling may promote ADHD/TS-like behaviours. Here, ADHD/TS-like behaviours were studied from postnatal to adulthood by exposing postnatal wild-type CB1 and Cannabinoid receptor 2 (CB2) knockout mouse pups to SR141716A (rimonabant), a CB1 receptor antagonist/inverse agonist. Postnatal disruption of the cannabinoid system by SR141716A induced vocal-like tics and learning deficits in male mice, accompanied by excessive vocalisation, hyperactivity, motor-like tics and/or high-risk behaviour in adults. In CB1 knockouts, rearing and risky behaviours increased in females. In CB2 knockouts, vocal-like tics did not develop, and males were hyperactive with learning deficits. Importantly, females were hyperactive but showed no vocal-like tics. The appearance of vocal-like tics depends on disrupted CB1 receptor signalling and on functional CB2 receptors after birth. Inhibition of CB1 receptor signalling together with CB2 receptor stimulation underlie ADHD/TS-like behaviours in males. This study suggests that the ADHD/TS phenotype may be a single clinical entity resulting from incorrect cannabinoid signalling after birth.
Emerging evidence suggests that the timing of eating and exercise over the course of the day is paramount to metabolism and physical function. This review highlights seminal studies showing that adipocyte AMPKα2 signaling controls circadian adipose tissue–skeletal muscle communication. Day-restricted feeding has been shown to improve exercise performance via adipocyte-specific activation of AMPKα2, which controls fat–muscle crosstalk in a time-of-day dependent manner. This review also discusses corroborating experimental studies designating mesenchymal stem cells as key cellular mediators, showing that exercise in the afternoon leads to better metabolic effects in humans, and illustrating how incorrect timing of food intake leads to leptin resistance and metabolic dysregulation. Multi-omics strategies have shed light on the molecular mechanisms underlying such effects of time, showing the circadian control of metabolic processes across tissues. These results advance our knowledge of chronometabolism and offer exciting temporal intervention treatments for metabolic diseases, such as time-restricted feeding, timed exercise, and chronopharmacological targeting of AMPK. Fat–muscle crosstalk, physical performance, and metabolic health outcomes can possibly be optimized by synchronizing dietary and exercise timing with endogenous circadian rhythms.
Helicobacter pylori (H. pylori) infection is a leading cause of gastritis, peptic ulcers, and gastric cancer, affecting more than half of the global population. Its persistence in the acidic gastric environment and its ability to evade host immunity present major treatment challenges. Although antibiotics remain the standard therapy, rising antimicrobial resistance has reduced treatment efficacy, prompting the search for alternative and adjunct approaches. Emerging therapies include probiotics, antimicrobial peptides (AMPs), and plant-derived compounds, which target H. pylori through membrane disruption, immunomodulation, or direct antimicrobial activity. Novel drug delivery systems and microbiota-sparing interventions are also being investigated. Additionally, vaccine development offers a promising strategy for long-term protection, though challenges related to antigenic variability and host-specific responses remain. Despite these advances, treatment variability and the limited clinical validation of alternatives hinder progress. A multifaceted approach integrating microbiome research, host–pathogen interactions, and new therapeutic agents is essential for future success.
Secreted bacteriolytic proteases L1 and L5 of the Gram-negative bacterium Lysobacter capsici XL hydrolyze peptide bridges in bacterial peptidoglycans. Such specificity of action determines the prospects of these enzymes for medicine with the view of creating new antimicrobial drugs to combat antibiotic-resistant strains of pathogens. This research concerns the development of successful expression systems for producing active enzymes L1 and L5 in sufficient amounts for comprehensive studies. Based on L. capsici XL strains with deletions in the alpA (enzyme L1) and alpB (enzyme L5) genes and the constructed expression vectors pBBR1-MCS5 PT5–alpA and pBBR1-MCS5 PT5–alpB, we obtained expression strains L. capsici PT5–alpA and L. capsici PT5–alpB, respectively. The yields of enzymes L1 and L5 in the developed strains increased by 4 and 137 times, respectively, as compared to the wild-type strain. The cultivation of the expression strains was successfully scaled up under non-selective conditions in a 10-L bioreactor. After fermentation, the yields of enzymes L1 and L5 were 35.48 mg/L and 57.11 mg/L, respectively. The developed homologous expression systems of bacteriolytic proteases L1 and L5 have biotechnological value as compared to those obtained by us earlier based on heterologous expression systems, which have lower yields and labor-intensive purification schemes.
The FIC domain-containing protein Sofic has recently been shown to provide robust protection to bacteria against phage infection. Sofic acts as a toxic protein, inducing abortive infection through the AMPylation of target proteins during phage invasion. However, the molecular mechanisms regulating Sofic’s toxic activity remain elusive. In this study, we identified a small gene encoding a short protein located downstream of Sofic in the genome, named AS1 (anti-Sofic1), which functions as an antitoxic protein to counteract Sofic’s toxicity. The crystal structure of Sofic revealed that the protein functions as a dimer in solution, with dimerization being indispensable for its toxic activity. Importantly, structural analysis indicated that ATP binding induces a conformational change in the C-terminal domain (CTD) of Sofic, underscoring the critical role of the CTD in mediating its toxic effects. In vitro colony-forming assays confirmed that the interaction between the CTD and the Amylase domain is crucial for Sofic’s toxic activity. Overall, our results provide molecular insights into the regulatory mechanisms of Sofic in antiviral immunity.
Bacterial cellulose (BC), an extracellular polysaccharide synthesized by various bacterial strains. It exhibits high tensile strength, water retention, crystallinity, and biocompatibility, making it valuable in biomedical, cosmetic, food, textile, and paper industries. This study examined the effects of six carbon sources on BC production by Komagataeibacter sucrofermentans, identifying fructose as the most effective. A Box–Behnken experimental design was employed to investigate the effects of three variables (fructose concentration, temperature, and cultivation time) on cellulose yield. The optimized cultivation conditions were: fructose concentration of 227.5 g/L, temperature of 28.0 °C, and cultivation time of 295 h, resulting in a BC yield of 63.07 ± 2.91 g/L. Subsequently, BC’s potential as a bacteriophage carrier was assessed. Escherichia coli phage T4 and Staphylococcus aureus phage vB_SauS_CS1 (CS1) were immobilized within BC hydrogels, and their antibacterial activities were assessed through in vitro experiments. These findings suggest BC’s promise as a phage delivery platform for biomedical applications.
Breast cancer remains a leading cause of mortality among women worldwide. Surgery, radiation therapy, chemotherapy, and hormone-based treatments are standard therapeutic approaches, but drug resistance and adverse effects necessitate the search for novel anticancer agents. Quinazolinedione derivatives have emerged as potential anticancer compounds due to their cytotoxic and apoptosis-inducing properties. This study aimed to evaluate the apoptotic induction of previously reported quinazolinedione derivatives on MCF-7 breast cancer cells. The cytotoxic effect was assessed using the MTT assay, apoptosis was quantified by Annexin V-PE/7AAD staining and flow cytometry, and apoptosis-related protein expression was analyzed via multiplexed bead-based immunoassays. These findings indicate that two derivatives in the series significantly reduced the cell viability in a dose-dependent manner. Apoptosis was induced primarily through the intrinsic apoptotic pathway as evidenced by the upregulation of caspase-9 and p53 and the downregulation of Bcl-2 and p-Akt. These results highlight quinazolinedione derivatives as promising candidates for breast cancer therapy prompting further investigation into their molecular mechanisms and potential clinical applications.
The prevalence, pathogenesis, and long-term consequences of hypertension differ significantly across the sexes, and pregnancy is a special physiological stress test that can reveal a woman’s underlying cardiovascular sensitivity. In addition to being direct risks to the health of the mother and fetus, hypertensive disorders of pregnancy (HDPs), especially preeclampsia, are also reliable indicators of future hypertension and cardiovascular disease in those who are afflicted. Fetal sex has a substantial impact on maternal vascular adaptation, according to new data from placental transcriptomics and epigenetics. This may be due to variations in the expression of angiogenic, immunomodulatory, and vasoactive genes. Sex-specific patterns of placental function, inflammation, and endothelium control are specifically influenced by X-linked gene dosage, escape from X-inactivation, and sex chromosomal composition. These biological variations highlight the placenta’s potential function as a mediator and indicator of maternal cardiovascular risk, and they may help to explain why the incidence and severity of hypertensive pregnancy challenges vary depending on the fetal sex. The purpose of this review is to summarize the state of the art regarding how placental genetics and fetal sex influence maternal hypertensive risk both during and after pregnancy. Additionally, it will investigate how these findings may influence sex-specific cardiovascular screening, prediction, and prevention methods.
The biological complexity of sarcopenia presents a major challenge for therapeutic intervention due to the wide range of degenerative changes it induces in skeletal muscle. This study demonstrates the potential of liposomal controlled release systems to address these challenges by combining two bioactive agents with complementary actions: caffeine (CAF), encapsulated in DMPC-based liposomes, and hyaluronic acid methacrylate (HAMA), encapsulated in DOPC-based liposomes. A hybrid system was also developed to deliver both substances simultaneously, aiming to restore tissue function through combined metabolic, anti-inflammatory, and regenerative effects. The liposomes exhibited nanoscale dimensions, spherical morphology, and intact membrane structure, as confirmed by electron microscopy. DLS analysis indicated good colloidal stability and monodisperse size distribution across all formulations, with improved stability observed in the hybrid system. Drug release studies showed a time-dependent profile, with HAMA releasing rapidly and CAF releasing gradually, supporting a dual-action therapeutic approach tailored to the multifactorial pathology of sarcopenia. The biological assays, performed in an established in vitro sarcopenia model, revealed the potential of liposomes co-delivering caffeine and HAMA to mitigate oxidative stress, preserve mitochondrial function, and reduce apoptosis in H2O2-damaged myotubes.
MiaA is responsible for the addition of the isopentyl modification to adenine 37 in the anticodon stem loop of specific tRNAs in Escherichia coli. Mutants in miaA have pleotropic effects on the cell in E. coli and play a role in virulence gene regulation. In addition, MiaA is necessary for stress response gene expression by promoting efficient decoding of UUX-leucine codons, and genes with elevated UUX-leucine codons may be a regulatory target for i6A-modified tRNAs. Understanding the temporal nature of the i6A modification status of tRNAs would help us determine the regulatory potential of MiaA and its potential interplay with leucine codon frequency. In this work, we set out to uncover additional information about the synthesis of the MiaA. MiaA synthesis is primarily driven at the transcriptional level from multiple promoters in a complex operon. However, very little is known about the post-transcriptional regulation of MiaA, including the role of sRNAs in its synthesis. To determine the role of small RNAs (sRNAs) in the regulation of miaA, we constructed a chromosomal miaA-lacZ translational fusion driven by the arabinose-responsive PBAD promoter and used it to screen against an Escherichia coli sRNA library (containing sRNAs driven by the IPTG-inducible PLac promoter). Our genetic screen and quantitative β-galactosidase assays identified CsrB and its cognate protein CsrA as potential regulators of miaA expression in E. coli. Consistent with our hypothesis that CsrA regulates miaA post-transcriptional gene expression through binding to the miaA mRNA 5′ UTR, and CsrB binds and regulates miaA post-transcriptional gene expression through sequestration of CsrA levels, a deletion of csrA significantly reduced expression of the reporter fusion as well as reducing miaA mRNA levels. These results suggest that under conditions where CsrA is inhibited, miaA mRNA translation and thus MiaA-dependent tRNA modification may be limited.
Maturity-onset diabetes of the young (MODY)—a monogenic form of diabetes—accounts for approximately 1–2% of all diabetes cases, with GCK-MODY being the second most commonly diagnosed type. Although the inherited nature of the disease implies that the interplay between maternal glycemia and fetal genotype directly influences neonatal outcomes, clinical guidelines for MODY-complicated pregnancies remain underdeveloped. A systematic literature search in the PubMed, Scopus, Web of Science, and Cochrane databases was conducted following the PRISMA guidelines. The study protocol has been logged in the PROSPERO registry with the identification number CRD42024609390. Data, such as MODY type, the gestational age at delivery, mode of delivery, insulin administration, mutational status of the fetus, fetal birthweight (FBW), occurrence of small-/large-for-gestational age fetus, shoulder dystocia, and neonatal hypoglycemia, were extracted and evaluated. Among 19 studies selected for the final analysis, 15 investigated perinatal outcomes in the GCK-MODY variant. Women diagnosed with GCK-MODY treated with insulin delivered approximately 1–2 weeks earlier than those managed with diet alone. FBW was significantly higher in GCK-negative as compared to GCK-positive offspring. Accordingly, fetal macrosomia was notably more common among unaffected neonates. In GCK-affected fetuses, insulin therapy was associated with a significantly lower FBW. Fetal genotype critically modifies perinatal outcomes in GCK-MODY pregnancies. In the absence of fetal genotyping, conservative management should be prioritized to mitigate the risks of fetal growth restriction and iatrogenic prematurity. As data regarding other types of MODY in pregnancy remain sparse, there is an urgent need for more research in this area.
Interest in metformin as a potential anticancer agent for colorectal cancer (CRC) has increased. However, compelling epidemiological links and strong preclinical evidence suggest that metformin has variable efficacy in patients with CRC. This variability highlights the need to identify the patients who are most likely to benefit from effective stratification. We aimed to review the evidence concerning the diverse roles of metformin in CRC prevention and treatment, focusing on identifying and validating the predictive biomarkers essential for selecting patient subgroups that are likely to respond positively. We explored the various molecular pathways through which metformin acts and investigated how these diverse mechanisms might explain the observed differences in patient responses. Epidemiological studies and large meta-analyses have consistently reported reduced CRC incidence and improved survival among patients with diabetes treated with metformin. However, successfully extending these benefits broadly across all patients with CRC or achieving predictable outcomes in advanced disease settings remains a significant challenge. This review consolidates the current knowledge, highlights how different mechanisms interact, critically assesses clinical evidence in light of patient heterogeneity, and advocates for the development and implementation of biomarker-guided personalized therapeutic strategies as key to optimally utilizing the potential of metformin in CRC management. The current challenges and vital future research priorities in this critical area are also outlined.
Exposure to extremely low-frequency magnetic fields (ELF-MF) can induce biological alterations in human cells, including peripheral blood mononuclear cells (PBMCs). However, the molecular mechanisms and key regulatory factors underlying this cellular response remain largely unknown. In this study, we analyzed the proteomic profiles of PBMCs isolated from three human subjects. PBMCs were exposed to 50 Hz, 1 mT of ELF-MF for 24 h and compared to unexposed PBMCs from the same individuals. ELF-MF exposure altered the expression levels of several PBMC proteins without affecting cell proliferation, cell viability, or cell cycle progression. A total of 51 proteins were upregulated, 36 of which were intercorrelated and associated with the Cellular Metabolic Process (GO:0044237) and Metabolic Process (GO:0008152). Among them, solute carrier family 25 member 4 (SLC25A4), which catalyzes the exchange of cytoplasmic ADP for mitochondrial ATP across the inner mitochondrial membrane, was consistently upregulated in all ELF-MF–exposed samples. Additionally, 67 proteins were downregulated, many of which are linked to T cell costimulation (GO:0031295), Cell activation (GO:0001775), and Immune system processes (GO:0002376) included ASPSCR1, PCYT1A, PCYT2, QRAS, and REPS1. In conclusion, ELF-MF exposure induces metabolic reprogramming in human PBMCs, characterized by the upregulation of mitochondrial proteins and downregulation of immune-activation-related proteins, without compromising cell viability or proliferation.
This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications.
Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K+ (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC’s effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS.
Gene therapy for hemophilia B offers the advantage of a single administration with sustained therapeutic effects. This study evaluated the systemic safety, efficacy, biodistribution, and immunogenicity of AAV8-FIX-TripleL, a recombinant adeno-associated virus type 8 (AAV8) vector encoding a modified factor IX (FIX) variant with increased activity. In this good laboratory practice (GLP)-compliant study, 180 male FIX-knockout hemophilia B mice were randomized into 12 groups (n = 15) and received intravenous AAV8-FIX-TripleL at therapeutic (5 × 1011 VG/kg) or supraphysiological (5 × 1012 VG/kg) doses on Day 1. The mice were sacrificed on Days 2, 15, 28, and 91 for comprehensive evaluations, including hematological and biochemical assessments, histopathological examination, FIX protein/activity analysis, immunogenicity assessment, and vector biodistribution via quantitative polymerase chain reaction (qPCR) in major organs. AAV8-FIX-TripleL demonstrated dose-dependent increases in FIX activity and protein levels, with FIX activity exceeding physiological levels and the maintenance of a favorable safety profile. Biodistribution analysis confirmed predominant hepatic accumulation and vector persistence up to 91 days post-injection, with minimal off-target distribution. These findings indicate that AAV8-FIX-TripleL is a promising gene therapy candidate for hemophilia B, as it has robust expression, sustained efficacy, and a favorable safety profile, and that further translational studies are warranted.
This study aimed to design dual-responsive chitosan–polylactic acid nanosystems (PLA@CS NPs) for controlled and targeted ledipasvir (LED) delivery to HepG2 liver cancer cells, thereby reducing the systemic toxicity and improving the therapeutic selectivity. Two formulations were developed utilizing ionotropic gelation and w/o/w emulsion techniques: LED@CS NPs with a size of 143 nm, a zeta potential of +43.5 mV, and a loading capacity of 44.1%, and LED-PLA@CS NPs measuring 394 nm, with a zeta potential of +33.3 mV and a loading capacity of 89.3%, with the latter demonstrating significant drug payload capacity. Since most drugs work through interaction with DNA, the in vitro affinity of DNA to LED and its encapsulated forms was assessed using stopped-flow and other approaches. They bind through multi-modal electrostatic and intercalative modes via two reversible processes: a fast complexation followed by a slow isomerization. The overall binding activation parameters for LED (cordination affinity, Ka = 128.4 M−1, Kd = 7.8 × 10−3 M, ΔG = −12.02 kJ mol−1), LED@CS NPs (Ka = 2131 M−1, Kd = 0.47 × 10−3 M, ΔG = −18.98 kJ mol−1) and LED-PLA@CS NPs (Ka = 22026 M−1, Kd = 0.045 × 10−3 M, ΔG = −24.79 kJ mol−1) were obtained with a reactivity ratio of 1/16/170 (LED/LED@CS NPs/LED-PLA@CS NPs). This indicates that encapsulation enhanced the interaction between the DNA and the LED-loaded nanoparticle systems, without changing the mechanism, and formed thermodynamically stable complexes. The drug release kinetics were assessed under tumor-mimetic conditions (pH 5.5, 10 mM GSH) and physiological settings (pH 7.4, 2 μM GSH). The LED@CS NPs and LED-PLA@CS NPs exhibited drug release rates of 88.0% and 73%, respectively, under dual stimuli over 50 h, exceeding the release rates observed under physiological conditions, which were 58% and 54%, thereby indicating that the LED@CS NPs and LED-PLA@CS NPs systems specifically target malignant tissue. Release regulated by Fickian diffusion facilitates tumor-specific payload delivery. Although encapsulation did not enhance the immediate cytotoxicity compared to free LED, as demonstrated by an in vitro cytotoxicity in HepG2 cancer cell lines, it significantly enhanced the therapeutic index (2.1-fold for LED-PLA@CS NPs) by protecting non-cancerous cells. Additionally, the nanoparticles demonstrated broad-spectrum antibacterial effects, suggesting efficacy in the prevention of chemotherapy-related infections. The dual-responsive LED-PLA@CS NPs allowed controlled tumor-targeted LED delivery with better selectivity and lower off-target toxicity, making LED-PLA@CS NPs interesting candidates for repurposing HCV treatments into safer cancer nanomedicines. Furthermore, this thorough analysis offers useful reference information for comprehending the interaction between drugs and DNA.
Organisms respond to environmental stress primarily through the autonomic nervous system and hypothalamic–pituitary–adrenal (HPA) axis, regulating metabolism, psychological states, and immune function and modulating memory, reward processing, and immune responses. The HPA axis plays a central role in stress response, exhibiting distinct activation patterns under acute versus chronic social defeat stress. However, differences in physiological impacts and regulatory pathways between these stress conditions remain understudied. This study integrates RNA sequencing and behavioral analyses to reveal that acute social defeat stress triggers transient anxiety-like behaviors, accompanied by systemic inflammation and immediate-early gene (IEG) activation. In contrast, chronic social defeat stress induces long-term behavioral and physiological alterations, including neurotransmitter imbalance (e.g., reduced GABA and increased glutamate), sustained activation of maladaptive pathways (e.g., IL-17 signaling), and disrupted corticosterone synthesis. These findings highlight the dynamic regulatory role of the HPA axis under varying stress conditions, providing novel insights into mental health disorders such as anxiety and depression. The study identifies potential therapeutic targets to mitigate chronic social defeat stress effects and offers a theoretical foundation for personalized interventions.
The wolf fish Hoplias malabaricus is a Neotropical species characterized by remarkable karyotypic diversity, including seven karyomorphs (KarA-G) with distinct sex chromosome systems. This study investigated the homologous XY (KarF) and XY1Y2 (KarG) sex chromosome systems present in this species by integrating cytogenetics and genomics to examine sex chromosomes’ composition through characterization of repeatome (satellite DNA and transposable elements) and sex-linked markers. Our analysis indicated that both karyomorphs are little differentiated in their sex chromosomes content revealed by satDNA mapping and putative sex-linked markers. Both repeatomes were mostly composed of transposable elements, but neither intra- (male versus female) nor interspecific (KarF x KarG) variations were found. In both systems, we demonstrated the occurrence of sex-specific sequences probably located on the non-recombining region of the Y chromosome supported by the accumulation of sex-specific haplotypes of HmfSat10-28/HmgSat31-28. This investigation offered valuable insights by highlighting the composition of homologous XY and XY1Y2 multiple sex chromosomes. Although homologous, the large Y chromosome in KarF corresponds to two separate linkage groups (Y1 and Y2) in KarG implying a specific meiotic arrangement involving the X chromosome in a meiotic trivalent chain. This scenario likely influenced recombination rates and, as a result, the genomic composition of these chromosomes.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), utilizes its spike protein to infect host cells. In addition to angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1), AXL acts as a spike protein receptor and mediates infection, especially in respiratory cells with low ACE2 expression. Angiotensin II (1–8) can be cleaved into shorter peptides within the biological system. Antibody-based binding assays showed that angiotensin II causes a two-fold increase in the binding between the spike protein and AXL, but not ACE2 or NRP1. While a longer peptide, angiotensin I (1–10), did not affect the spike–AXL binding, shorter lengths of angiotensin peptides exhibited enhancing effects. The C-terminal deletions of angiotensin II to angiotensin (1–7) or angiotensin (1–6) resulted in peptides with enhanced activity toward spike–AXL binding with a similar capacity as angiotensin II. In contrast, the N-terminal deletions of angiotensin II to angiotensin III (2–8) or angiotensin IV (3–8) as well as the N-terminal deletions of angiotensin (1–7) to angiotensin (2–7) or angiotensin (5–7) produced peptides with a more potent ability to enhance spike–AXL binding (2.7-fold increase with angiotensin IV). When valine was substituted for tyrosine at position 4 in angiotensin II or when tyrosine at position 4 was phosphorylated, spike–AXL binding was increased, suggesting that modifications to tyrosine trigger enhancement. Angiotensin IV also enhances spike protein binding to ACE2 and NRP1. Thus, angiotensin peptides may contribute to COVID-19 pathogenesis by enhancing spike protein binding and thus serve as therapeutic targets.
Glioblastoma multiforme (GBM) is a highly aggressive, treatment-resistant grade IV brain tumor with poor prognosis that grows rapidly and invades surrounding tissues, complicating surgery and frequently recurring. Although the crucial role of endogenous peptides has been highlighted for several tumors, the specific peptidomic profile of GBM remains unexplored to date. This study aimed to perform a preliminary characterization of the low molecular mass proteome fraction of Cavitron Ultrasonic Surgical Aspirator (CUSA) fluid collected from different tumor zones, i.e., the core and tumor periphery of newly diagnosed (ND) and recurrent (R) GBM. The samples, pooled by tumor type and collection zone, were centrifuged through molecular cut-off filter devices to collect the non-retained fraction of the proteome <10 kDa for direct full-length LC-MS analysis. A total of 40 and 24 peptides, fragments of 32 and 18 proteins, were marked as ND and R GBM COREs, respectively, while 132 peptides, fragments of 46 precursor proteins, were identified as common and included proteins which were cancer-related or involved in GBM pathophysiology. Besides providing a preliminary overview of the unexplored peptidome of GBM, this pilot study confirms peptidomics as a promising tool to discover potential GBM biomarkers in the perspective of clinical applications increasingly oriented towards a precision medicine approach. Data are available via ProteomeXchange with the identifier PXD060807.
Self/non-self-discrimination is a fundamental aspect of adaptive immunity, which helps prevent harmful autoimmune responses. However, infectious agents can also act as environmental catalysts for autoimmune diseases. In this study, we investigated the role of molecular mimicry to self-antigens in epitope recognition in relation to infectious and autoimmune diseases. To this end, we performed BLAST searches against the human proteome, utilizing known virus-specific B and T cell peptide epitopes identified in association with autoimmune or infectious diseases in humans as our queries. Additionally, similar control analyses were carried out using non-B and non-T cell epitopes, consisting of random viral peptide sequences. Overall, our results endorsed a major role of molecular mimicry in instigating or sustaining autoimmunity associated with viral infections and challenged the prevailing view on self/non-self-discrimination for T cells. Additionally, we uncovered many virus-specific epitopes among those identified in association with infectious diseases with high similarity to self-antigens, which are primarily derived from human coronaviruses and various flaviviruses. Recognition of these epitopes could lead to autoimmunity against human proteins that are in cellular components concerning cell motility, cell membrane projections, and cellular synapses.
Retinal ribbon synapses are continuously active chemical synapses. The eponymous synaptic ribbon is anchored to the active zone neurotransmitter release sites of ribbon synapses, recruits synaptic vesicles and guides ribbon-associated synaptic vesicles to the release sites. RIBEYE is the major protein component of synaptic ribbons. But likely, additional proteins contribute to ribbon synapse function. The synaptic ribbon of photoreceptor synapses is embedded into a highly polarized microtubule cytoskeleton. Interestingly, proteins of the photoreceptor primary cilium, such as NPHP4 and other ciliary proteins, including KIF3A, were shown to be localized to photoreceptor synaptic ribbons. Previous studies demonstrated that the microtubule motor protein KIF13B catalyzes secretory vesicle transport to the plus ends of microtubules and identified an interaction of KIF13B with NPHP4 at primary cilia. However, the localization of KIF13B, a kinesin-3 family motor protein, in the retina is still unknown. In the present study, we used two different antibodies against KIF13B and high-resolution confocal microscopy, super-resolution structured illumination microscopy (SR-SIM), and post-embedding immunogold electron microscopy to determine the localization of KIF13B in retinal photoreceptors. Apart from its localization at the primary photoreceptor cilium, we found a strong enrichment of KIF13B at photoreceptor synaptic ribbons. The synaptic ribbon is needed for the synaptic enrichment of KIF13B as shown by analyses of synaptic ribbon-deficient RIBEYE knockout mice. These findings suggest that KIF13B performs vesicle trafficking functions at the photoreceptor synaptic ribbon complex at the interface between the synaptic ribbon and the presynaptic microtubule transport system.
Immunoglobulin A vasculitis (IgAV), previously known as Henoch–Schönlein purpura (HSP), is a type of non-thrombocytopenic small-vessel vasculitis. HSP is the most common systemic vasculitis in pediatric patients, and it is characterized by purpura, arthritis or arthralgia, gastrointestinal pain, and renal dysfunction. This retrospective analysis also examines a range of demographic factors, including sex, geographic and environmental influences, age, and medication, to evaluate their potential effects on the pediatric population affected by HSP. The five-year hospital-based retrospective analysis included 138 hospitalized children diagnosed with HSP during hospitalization. Blood sample analysis was conducted to assess various immunological parameters, including levels of immunoglobulins (IgA and IgE), complement components (C3 and C4), C-reactive protein, fibrinogen, the erythrocyte sedimentation rate (ESR), and allergen panels. Elevated IgE levels and normal IgA serum concentrations were found to be strongly associated with infectious diseases in pediatric HSP patients. Patients with recurrent infectious diseases consistently exhibited elevated IgE levels and normal IgA levels during treatment despite no identified allergens, alongside an increased risk of disease recurrence.
In the original publication [...]
B cells contribute to innate and adaptive immunity. In the former, Toll-like receptor (TLR) activation promotes the expansion of inflammatory B cells. In the latter, B cell receptor (BCR) activation results in the production of antibodies or autoantibodies. Antigen processing and presentation are closely associated with major histocompatibility class II (MHC-II) and its companion protein, class II invariant peptide (CLIP). The impact of autophagy on the regulation of these unique mechanisms of B cell activation and subset expansion has not been fully explored. The results from the current study show that activating autophagy with rapamycin (RAPA) or inhibiting autophagy with hydroxycholoroquine (HCQ) differentially influences the TLR9 and BCR activation of B cells. These differences include the selective expansion of B1 and B2 B cell subsets, the regulation of the cell-surface expression of MHC-II and CLIP, and the ability of distinct B cell subsets to present peptide antigens. These novel findings demonstrate that the unique B cell activation mechanisms induced by TLR9 and BCR activation are differentially influenced by RAPA and HCQ, owing to the selective modulation of B cell subset expansion, and antigen processing and presentation by MHC-II proteins.
Network-based GWAS (NetWAS) has advanced brain imaging research by identifying genetic modules associated with brain alterations. However, how imaging risk genes exert functions in brain diseases, particularly their mediation through imaging quantitative traits (iQTs), remains underexplored. We propose a module-level polygenic risk score (MPRS)-based NetWAS framework to uncover genetic modules associated with Alzheimer’s disease (AD) through the mediation of an iQT, using amygdala density as a case study. Our framework integrates genotype data, brain imaging phenotypes, clinical diagnosis of AD, and protein–protein interaction (PPI) networks to identify AD-relevant modules (ADMs) influenced by iQT-associated genetic variants. Specifically, we conducted a genome-wide association study (GWAS) of amygdala density (N=1515) to identify variants associated with iQT. These variants were mapped onto a PPI network and network propagation was performed to prompt amygdala modules. The meta-GWAS of AD (N1=63,926; N2=455,267) was used to calculate MPRS to further identify AD-relevant modules (ADMs). Four modules that showed significant differences in MPRS between AD and controls were identified as ADM. Post-hoc analyses revealed that these ADMs demonstrated strong modularity, showed increased sensitivity to early stages of AD, and significantly mediated the link between ADMs and AD progression through the amygdala. Furthermore, these modules exhibited high tissue specificity within the amygdala and were enriched in AD-related biological pathways. Our MPRS-based framework bridges genetics, intermediate traits, and clinical outcomes and can be adapted for broader biomedical applications.
Environmental pollution remains a significant challenge in animal production. The “ideal protein” concept refers to an amino acid profile that precisely meets the animal’s nutritional requirements, optimizing nutrient utilization and minimizing waste excretion. This study applied untargeted metabolomics to explore metabolic changes induced by limiting AA. Two experimental diets were used in 47-day-old growing rabbits: Met+ (with a methionine level balanced to its optimal utilization) and Met− (with a methionine level that was clearly limiting). A total of 68 blood samples were taken for untargeted metabolomics analysis and 88 were taken for targeted plasmatic urea nitrogen analysis, collected at 08:00 (in ad libitum feeding animals) and 21:00 (after a feeding event in 10 h fasting animals). Our results revealed that both sampling time and diet (at each time point) exerted a significant modulatory influence on the metabolome. Interestingly, the difference between the metabolomes obtained with the different diets was less pronounced at 08:00, likely due to the caecotrophy effect, compared to 21:00, when higher intake and lower caecotrophy frequency were observed. This study identifies pseudourine, citric acid, pantothenic acid, and enterolactone sulfate as promising metabolites that could be targeted in order to refine the ideal protein concept, thus improving nutrient efficiency and reducing the environmental impact of animal production.
HIKESHI-related hypomyelinating leukodystrophy (HHL) is a life-threatening disorder caused by homozygous pathogenic variants in HIKESHI. Symptoms include infantile onset progressive spastic dystonic quadriplegia, nystagmus, failure to thrive, diffused hypomyelination, and severe morbidity or death following febrile illness. V54L variants in HIKESHI are particularly prevalent within the Ashkenazi Jewish population. Here, we identified a novel P78S disease-causing variant in HIKESHI in a patient of Christian Arab origin, presenting with clinical and radiologic features characteristic of HHL. In silico analysis suggests that the mutated residue may affect the HIKESHI protein’s dimerization domain. We generated a comprehensive set of induced pluripotent stem cells (iPSCs) from the index case and two additional HHL patients. To investigate mechanisms potentially linked to febrile illness in HHL, we used these cells to study the heat shock (HS) response. HHL-iPSCs showed dramatically decreased levels of HIKESHI compared with healthy controls following HS. In addition, they exhibited increased HSP70 mRNA levels in response to HS, suggesting an increased sensitivity. HHL-iPSCs had impaired HSP70 translocation to the nucleus. Our results provide a human-relevant model for HHL.
The rising prevalence of type 2 diabetes is linked to an increased risk of cardiovascular diseases, with the diabetic heart being particularly vulnerable to ischemia–reperfusion (IR) injury. Chronic hyperglycemia contributes to an increase in reactive oxygen species and impacts the homeostasis of biochemical pathways, including the polyol pathway, increasing susceptibility to damage. Aldose reductase (AR), a key enzyme in this pathway, has been targeted for therapeutic intervention, with AR inhibitors showing potential in mitigating diabetic complications. This study investigated IR injury in cardiomyocytes following high glucose exposure and assessed the AR inhibitor Epalrestat as a protective agent. Cardiomyocyte function was evaluated by measuring lactate dehydrogenase (LDH) release, FM1-43 membrane incorporation, cell viability, intracellular calcium accumulation, and superoxide anion formation. High glucose exposure and simulated IR led to increased LDH release, FM1-43 incorporation, intracellular calcium, and superoxide levels, alongside reduced cell viability in a dose-dependent manner. However, Epalrestat treatment during high glucose exposure significantly reduced IR-induced injury. These findings suggest that high glucose exacerbates IR injury in cardiomyocytes, with the polyol pathway playing a critical role. Targeting this pathway with AR inhibitors like Epalrestat may offer a protective strategy against diabetic heart complications.
Dendritic cells (DCs) play a central role in the immunopathogenesis of rheumatoid arthritis (RA), yet their regulation by tumor necrosis factor alpha (TNF) and associated receptors remains poorly characterized. We applied a single-cell multi-omics approach (CITE-seq) to profile peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors, before and after in vitro TNF stimulation. Using integrated analysis of surface protein expression and transcriptomic data, we focused on phenotypic and transcriptional changes in dendritic cell populations. DCs from RA patients exhibited elevated surface expression of CD14 and CD16, indicative of an inflammatory phenotype, and showed marked responsiveness to TNF. Upon stimulation, RA-derived DCs upregulated genes involved in antigen presentation (CD83, LAMP3), lymph node migration (CCR7, ADAM19), and inflammation (TRAF1, IL24) whereas such activation was absent in healthy controls. Our data reveal a TNF-responsive, pro-inflammatory transcriptional program in dendritic cells from RA patients and underscore the relevance of the TNF receptor profile in shaping DC function. These findings provide new insights into the immunobiology of RA and identify dendritic cells as potential targets for personalized immunomodulatory therapy.
Multiple myeloma (MM or plasma cell myeloma) is a heterogenous B-cell malignant tumor that typically exhibits a high recurrence rate, resistance to drugs, and molecular diversity of tumor subclones. Given the limited efficacy of standard therapy options, cellular immunotherapy featuring a chimeric antigen receptor (CAR) has proven tangible potential in treatment for relapsed and refractory forms of MM. The rational choice of a tumor target which shows high selectivity, stable expression, and biological significance is key to the successful implementation of CAR therapy. This review has summarized and analyzed data from the literature on biological properties, the features of expression, and the clinical development stages of CAR cell products for MM treatment which target BCMA, GPRC5D, FcRH5, SLAMF7, CD38, CD138, TACI, APRIL, CD19, TNFR2, CD44v6, CD70, NKG2D ligands, etc. Special focus is on strategic approaches to overcoming antigenic escape, such as multi-specific CAR constructs, logical activation sequences, and controlled safety systems. The analysis underscores the need for integrating the molecular selection of targets with cutting-edge bioengineering solutions as a key trend for raising the efficacy, stability, and safety of cellular therapy in the case of MM.
Duchenne muscular dystrophy (DMD) manifests as a hereditary condition that diminishes muscular strength through the progressive degeneration of structural muscle tissue, which is brought about by deficiencies in the dystrophin protein required for the integrity of muscle cells. DMD is among four different types of dystrophinopathy disorders. Current studies have established that long non-coding RNAs (lncRNAs) play a significant role in determining the trajectory and overall prognosis of chronic musculoskeletal conditions. LncRNAs are different in terms of their lengths, production mechanisms, and operational modes, but they do not produce proteins, as their primary activity is the regulation of gene expression. This research synthesizes current literature on the role of lncRNAs in the regulation of myogenesis with a specific focus on certain lncRNAs leading to DMD increments or suppressing muscle biological functions. LncRNAs modulate skeletal myogenesis gene expression, yet pathological lncRNA function is linked to various muscular diseases. Some lncRNAs directly control genes or indirectly control miRNAs with positive or negative effects on muscle cells or the development of DMD. The research findings have significantly advanced our knowledge about the regulatory function of lncRNAs on muscle growth and regeneration processes and DMD diseases.
Granulosa cells (GCs) are essential for follicular growth and development, and their functional state critically impacts folliculogenesis. TAp73α, a transcriptionally active isoform of the p73 gene, is crucial for maintaining follicular integrity. In this study, we demonstrate that TAp73α overexpression promotes ferroptosis in bovine GCs by downregulating SLC7A11, depleting intracellular glutathione (GSH), and enhancing lipid peroxidation, particularly under Erastin treatment. By contrast, TAp73α knockdown restores antioxidant capacity, elevates GSH levels, and attenuates ferroptosis. To elucidate the underlying mechanism, untargeted metabolomic profiling revealed that TAp73α overexpression significantly altered the metabolic landscape of GCs, with marked enrichment in the glutathione metabolism pathway. Notably, betaine—a metabolite closely linked to redox homeostasis—was markedly downregulated. Functional assays confirmed that exogenous betaine supplementation restored SLC7A11 expression, increased GSH levels, and alleviated oxidative damage induced by either H2O2 or TAp73α overexpression. Moreover, betaine co-treatment effectively reversed lipid peroxide accumulation and mitigated TAp73α-induced ferroptosis. Collectively, our findings identify a novel mechanism by which TAp73α promotes ferroptosis in granulosa cells through the suppression of betaine and glutathione metabolism, highlighting betaine as a key metabolic modulator with promising protective potential.
Nitric oxide (NO), a simple yet remarkably versatile molecule, stands today as a pivotal player in virtually all body systems and cellular compartments [...]
In this study, we investigated the solvent performance of six heavy oils from Xinjiang, China, for coal–oil co-liquefaction (COCL). Autoclave experiments revealed that shale oil vacuum residue (SOVR) provided the best liquefaction performance. The oils were characterized using FT-IR, 13C-NMR, 1H-NMR, and column chromatography, which revealed that they were mainly composed of aliphatic compounds, with minor aromatic and substituted aromatic compounds. The pyrolytic degradation quality indices (PDQIs), solubility parameter (δC), and polycyclic aromatic hydrocarbon content (HA2 + HA3) were calculated and correlated with liquefaction performance. The results showed a strong linear relationship between HA2 + HA3 and oil yield (R2 = 0.90), and the aromatic content (AR) was also positively related to oil yield. This study suggests that AR content and HA2 + HA3 are effective indicators for evaluating the solvent performance of heavy oils in COCL.
We have previously reported on a novel monoclonal antibody (mAb) we designated F5, which was raised against a glycopeptide derived from the tandem repeat (TR) region of Mucin-4 (MUC4), a heavily O-glycosylated protein that is overexpressed in many pancreatic cancer cells. This mAb was highly specific for the MUC4 glycopeptide antigen in glycan microarrays, ELISA and SPR assays, selectively stained tissue derived from advanced-stage tumors, and bound MUC4+ tumor cells in flow cytometry assays. The mAb was also unique in that it did not cross-react with other commercial anti-MUC4 mAbs that were raised in a similar but non-glycosylated TR sequence. Here we describe the selective conjugation of a novel near-infrared dye to this mAb and in vivo biodistribution of this labeled mAb to various MUC4-expressing tumors in mice. The labeled mAb were selectively distributed to both cell-derived xenograft (CDX) flank tumors and patient-derived xenograft (PDX) tumors that expressed MUC4 compared to those that were MUC4-negative. Organ distribution analysis showed high uptake in MUC4+ relative to MUC4− tumors. These results suggest that mAb F5 may be used to develop MUC4-targeted, passive antibody-based immunotherapies against Pancreatic Ductal Adenocarcinomas (PDACs) which are notorious for being refractory to many chemo- and radiotherapies
Programmed Death-Ligand 1 (PD-L1) is a major target for immunotherapy using checkpoint inhibitors (CPIs), particularly in lung cancer treatment. Tumoral PD-L1 expression has been recognized as a natural predictor of CPI response. This predictive relationship is primarily due to its upregulation by interferon-gamma, which is released by immune cells (mainly T lymphocytes and natural killer cells) in proximity to tumor cells, driving an immune resistance mechanism. However, PD-L1 expression is modulated at multiple levels, including oncogenic signaling pathways, and transcriptional and post-transcriptional regulations, potentially leading to false positive predictions. Conversely, variable glycosylation of PD-L1 may compromise the accuracy of immunohistochemical measurements, resulting in false negative predictive data. In addition, PD-L1 expression demonstrates relative instability throughout treatment courses (e.g., chemotherapy and tyrosine kinase inhibitors), further limiting its clinical utility. In this review, we focused on the molecular mechanisms governing PD-L1 expression with a special emphasis on lung cancer. We also discussed biomarker strategies for optimizing patient selection for checkpoint inhibitor therapy where multimodal/multi-omics meta-biomarker approaches are emerging. Such comprehensive PD-L1-enriched biomarker strategies require evaluation through large-scale prospective studies, particularly in lung cancer, where numerous competing predictive candidates exist for CPI response.
Aberrant DNA methylation is a hallmark of colorectal cancer (CRC), contributing to tumor progression through the silencing of tumor suppressor genes and activation of oncogenes. Indicaxanthin (IND), a dietary betalain pigment from Opuntia ficus indica, has shown antiproliferative effects in CRC models, yet its epigenetic impact remains unexplored. In this study, we investigated the effects of IND on the methylome of Caco-2 cells using Reduced Representation Bisulfite Sequencing (RRBS). IND induced a global hypermethylation profile, particularly at gene promoters and CpG islands. Among the differentially methylated genes, 60% were protein-coding, and 10% encoded transcription factors, including PAX5 and TFAP4, both hypermethylated at active enhancers. Functional enrichment analysis revealed pathways beyond canonical intestinal functions, suggesting altered cell identity and plasticity. Transcription factor targets (SOX10, NFKB1, AHR, ARNT) were significantly enriched among the affected genes, several of which are involved in transdifferentiation processes. Methylation changes also indicated potential reprogramming toward epithelial cell types from pulmonary or neuroectodermal origin. Moreover, IND induced selective hypomethylation of Alu elements on chromosome 21 and hypermethylation of rDNA loci, hinting at suppressed ribosomal biogenesis. Overall, these findings highlight the epigenetic remodeling potential of IND and its possible role in modulating cell fate and metabolism in CRC cells.
A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence or presence of the ester group, showed the strongest cytotoxic effect towards all tested cancer cell lines with the IC50 0.68–2.88 µM. In addition, it was demonstrated that these compounds inhibit cancer cell proliferation by inducing G2/M phase arrest in HeLa cells. The structure–activity relationship was analyzed and it confirmed the importance of the core structural features like a dioxolane ring and free-rotating trimethoxyphenyl group for cytotoxicity. Moreover, the R configuration of the ester group at the C-8′ position proved to be substantial since its epimer was inactive. The molecular docking studies revealed that the most potent compounds have a different binding mode to β-tubulin than podophyllotoxin; however, the benzothiazole fragment docked in a similar location as the trimethoxyphenyl group of podophyllotoxin, exhibiting similar hydrophobic interactions. These findings clearly indicate that podophyllotoxin–benzothiazole derivatives could be addressed for further pharmacological studies in anticancer research.
Zebrafish is a well-recognized model for studying human genetic disorders. Recently, we proposed the homozygous cdkl5sa21938 mutant zebrafish as a model of CDKL5 deficiency disorder (CDD), a developmental epileptic encephalopathy with diverse symptoms. This study aimed to explore Cdkl5-associated molecular mechanisms in zebrafish and assess their similarity to those in mammals. We conducted RNA sequencing on whole cdkl5−/− zebrafish and wild-type siblings at 5 and 35 days post-fertilization (dpf) to compare their gene expression profiles. Most significant differentially expressed genes (DEGs) were related to muscle, neuronal, and visual systems which are affected in CDD. Gene Ontology analysis revealed downregulated DEGs enriched in muscle development, extracellular matrix, and actin cytoskeleton functions at both stages, while upregulated DEGs were enriched in eye development functions at 35 dpf. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of downregulated DEGs in focal adhesion and extracellular matrix (ECM)-receptor interaction pathways at both stages. Neuronal development DEGs were mainly downregulated at both stages, while synaptic signaling DEGs were upregulated at 35 dpf. Crossing cdkl5−/− mutants with the Hb9:GFP transgenic line showed fewer motor neuron cells with shorter axons compared to the wild type, which may explain the impaired motor phenotype observed in zebrafish and CDD patients. Moreover, we identified key downregulated DEGs related to cartilage development at both stages and bone development at 35 dpf, potentially explaining the skeletal defects seen in zebrafish and CDD individuals. In conclusion, Cdkl5 loss in zebrafish leads to dysregulation of genes involved in CDKL5-associated functions in mammals, providing new insights into its less studied functions and phenotypes.
Bullous pemphigoid (BP) and pemphigus vulgaris (PV) represent the most prevalent conditions among autoimmune bullous skin diseases, considered a major cause of severe morbidity and, in certain cases, mortality. The hallmark of the two diseases is the presence of autoantibodies directed against proteins located in the basement membrane of the skin, which determines the formation of blisters. In recent years, interest in the role of microbiota in relation to health-disease status has progressively increased. In particular, based on the gut–skin axis, accumulating evidence has emerged on the potential association between the composition and diversity of microbial communities in the gut, skin, and even in the oral cavity and the risk of developing BP and PV. Dysbiosis, characterized by a generally higher relative abundance of Firmicutes and a depletion of probiotics/beneficial species, might contribute to the pathogenesis of both diseases. Despite the still limited number of studies and the need for further large-scale multicenter studies, the knowledge gathered so far is suggestive of a novel modifiable risk factor representing a potential target for adjuvant treatments of these disabling and life-threatening conditions.
Rosavin, a glycoside isolated from Rhodiola rosea, exhibits various biological activities, including potential modulation of metabolic pathways. Despite promising findings in animal models, its effects on many human bone cells remain unexplored. This study aimed to investigate, for the first time, the in vitro effects of rosavin on human osteoblasts (HOBs), focusing on BMP-2 expression, cell morphology, and culture confluence as indicators of osteogenic activity. HOB cultures were treated with 50 µM or 100 µM rosavin for 21 days. BMP-2 expression was measured by ELISA, collagen production was assessed via Sirius Red staining, and cell morphology and confluence were evaluated using phase-contrast microscopy. A significant increase in BMP-2 expression was observed in the 100 µM rosavin group compared to the mineralization control (p < 0.05), particularly on days 14 and 21. Both rosavin-treated groups exhibited higher confluence than controls, with the 50 µM group showing unexpectedly greater confluence than the 100 µM group. Rosavin at 50 µM also promoted a cuboidal morphology characteristic of active HOBs. The presence of collagen validated both the successful progression of the mineralization process and the correct implementation of the experimental protocol. Rosavin enhances BMP-2 expression and supports HOB proliferation and morphological maturation in vitro. These findings suggest its potential as a supportive agent in the prevention or treatment of metabolic bone diseases. Further research is necessary to determine its bioavailability, safety profile, and therapeutic relevance in clinical settings.
Systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS), are traditionally characterized by chronic inflammation and immune-mediated damage to joints and other tissues. However, many patients also experience symptoms such as widespread pain, persistent fatigue, cognitive dysfunction, and autonomic disturbances that cannot be attributed directly or entirely to peripheral inflammation or structural pathology. These conditions suggest the involvement of interactions between the nervous and immune systems, which probably include both peripheral and central components. This review summarizes the current knowledge of neurological and neuroimmune mechanisms that may contribute to these symptoms in SARDs. Glial cell activation and neuroinflammation within the central nervous system (CNS), small-fiber neuropathy (SFN) affecting peripheral nociceptive pathways, central pain sensitization, and autonomic nervous system dysfunction will be discussed. In addition, the role of molecular mediators, including cytokines, neuropeptides, and microRNAs, that could potentially modulate neuroimmune signaling will be highlighted. Integrating findings from pathology, immunology, and neuroscience, this review seeks to provide a useful framework for understanding neuroimmune dysregulation in SARDs. It also highlights the clinical relevance of these mechanisms and summarizes new directions for diagnosis and treatment.
SARS-CoV-2, a β-coronavirus, primarily affects the lungs, with non-specific lesions and no cytopathic viral effect in the skin. Cutaneous antiviral mechanisms include activation of TLR/IRF pathways and production of type I IFN. We evaluated the antiviral mechanisms involved in the skin of COVID-19 patients, including skin samples from 35 deceased patients who had contracted COVID-19 before the launch of the vaccine. Detection of SARS-CoV-2 in the skin was performed using transmission electron microscopy and RT-qPCR. Microscopic and molecular effects of the virus in skin were evaluated by histopathology, RT-qPCR, and immunohistochemistry (IHC). The results revealed the presence of SARS-CoV-2 and microscopic changes, including microvascular hyaline thrombi, perivascular dermatitis, and eccrine gland necrosis. There was increased transcription of TBK1 and a reduction in transcription of TNFα by RT-qPCR in the COVID-19 group. IHC revealed reduced expression of ACE2, TLR7, and IL-6, and elevated expression of IFN-β by epidermal cells. In the dermis, there was decreased expression of STING, IFN-β, and TNF-α and increased expression of IL-6 in sweat glands. Our results highlight the role of type I IFN in the skin of COVID-19 patients, which may modulate the cutaneous response to SARS-CoV-2.
Peptides are currently vital components in nutrition with physiological advantages beyond a basic diet. This systematic review aims to explain their significance in metabolic, behavioral, and musculoskeletal health, focusing on their therapeutic benefits, molecular mechanisms, and bioactivities. This systematic review analyzed clinical trials from PubMed and Scopus databases in the time range of 2019 to 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, that investigated the role of peptides in human nutrition. Eight randomized clinical trials (RCTs) met the predefined metabolic, behavioral, and musculoskeletal health inclusion criteria. Peptides are derived from various sources, including milk, fish, and plants, and show various bioactive characteristics such as anti-inflammatory effect, improved muscle protein synthesis, and immune modulation. Some important findings emphasize their potential to govern metabolic processes, defend against chronic diseases, and enhance gut health. For instance, glucagon-like peptide (GLP-1) controls taste perception and appetite stimulation, and collagen peptides strengthen the musculoskeletal system. Peptides display intriguing potential as nutrients for addressing global health challenges, including behavioral responses, aging, and metabolic syndrome. Future investigations would focus on bioavailability, optimizing dosage, and demographic-specific treatments.
This review highlights recent findings on the versatile serpin protein, pigment epithelium-derived factor (PEDF), in relation to cancer diagnosis, treatment and prognosis. PEDF was initially discovered in the eye but has since been reported to be relevant to various biological roles in the body, and when awry, to clinically lead to various disease states such as neoplasia. At the preclinical stage, potent effects have been reported in studies focussing on apoptosis, metastasis, oxidative stress, immune stimulation and metabolism. Apart from full-length proteins, short peptides based on PEDF have shown promise against cancer. For diagnosis and prognosis, PEDF levels in tumour specimens or in circulation have the potential to serve as biomarkers, most probably in combination with other biomarkers of cancer initiation and progression. Lastly, this review discusses the growing list of studies that point out the perceived pro-cancerous effects of PEDF, though this is clearly outweighed by the anticancer publications. Thus, this review provides a comprehensive and balanced listing of the oncological studies associated with this protein to date, drawing conclusions on whether this potent antiangiogenic protein and its peptides can be used in the future for better cancer treatment, especially against metastasis.
Growing evidence underscores the pivotal roles of both in situ-resident and -non-resident cardiac cells in the repair mechanisms following myocardial infarction (MI). MI continues to be a predominant cause of death and disability, posing a significant threat to global health and well-being. Despite advances in medical care, current therapies remain insufficient in preventing ventricular remodeling and heart failure post-MI. We seek to clarify the underlying regenerative mechanisms by which distinct cell types contribute to the repair of MI injury and to systematically assess the translational potential and therapeutic efficacy of these cell-based approaches in clinical applications. This review conducts a comprehensive analysis of recent research progress on the roles of non-cardiac stem cells in situ and cardiac cells derived from explants in MI repair. These cells contribute to the repair process through multiple mechanisms, including cell proliferation and differentiation, angiogenesis, paracrine signaling, immune regulation and fibrosis modulation. Our analysis reveals the intricate mechanisms of MI repair and highlights the necessity for developing age-specific therapeutic strategies for certain cell types. This review offers novel insights into cell-based treatment for MI and provides a scientific foundation for future clinical trials of cardiac regenerative medicine.
Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in Aβ1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application.
The global obese population accounts for approximately 30% of the total population and continues to increase. White adipocytes, which accumulate in the body for energy storage, are associated with obesity. Mechanisms that activate browning of white adipocytes are an attractive therapeutic target for obesity and metabolic disorders. Exosomes are nano-sized biovesicles that play a role in cell-to-cell communication though the transfer of cargos such as microRNAs. Although milk exosomes contain many endogenous microRNA molecules, the role of microRNAs in milk exosomes is limited. Therefore, the aim of this study was to investigate the effects of milk exosomes on the browning of white adipocyte. Mouse pre-adipocytes (3T3-L1) and human adipose-derived stem cells (hADSCs) were differentiated and exposed to milk exosomes. Compared to control, milk exosomes promoted the expression of thermogenic genes and cellular mitochondrial energy metabolism in both 3T3-L1 cells and hADSCs. Additionally, milk exosomes were orally administered to mice fed a high-fat diet. As the intake of milk exosomes increased, the mice’s body weight decreased. Milk exosomes also increased the protein levels of thermogenic genes and mitochondrial-related genes in mouse adipose tissue. The overexpression of miR-11987, which is abundant in milk exosomes, in both 3T3-L1 cells and hADSCs led to the increased expression of thermogenic genes and mitochondrial activity. Our results support that bovine-specific miR-11987 in milk exosomes promotes the browning of white adipocytes. Therefore, milk exosome and milk exosomal miR-11987 could have significant clinical implications for obesity and metabolic syndrome.
Prostate cancer (PCa) therapy faces challenges due to tumor heterogeneity, plasticity, and progression. Metabolic reprogramming, a dynamic process, has emerged as a key focus in PCa treatment. However, conventional therapies targeting cancer-specific metabolic pathways or employing chemosensitizers are often limited by compensatory mechanisms and metabolic complexity. This review highlights the roles of transcription factors, including AR, p53, c-Myc, HIF-1, Nrf2, and PPARγ, in regulating PCa metabolism by influencing signaling pathways, enzymes, and gene expression. Multi-target compounds, particularly natural products, show potential for disrupting multiple metabolic enzymes, opening up new research possibilities. Notable examples include β-elemene, juglone, tannic acid, and withaferin A, which target critical metabolic processes through enzyme inhibition, transcription factor modulation, epigenetic changes, and protein interaction disruption. Naturally derived metabolites can elicit transversal responses in diverse metabolic pathways, particularly in p53 and MYC transcription factors. Additionally, compounds such as pentacyclic terpenoids (ursolic acid with ursane skeleton), sulforaphane, and isothiocyanate-related moieties may induce metabolic and epigenetic changes through S-adenosyl methionine (SAM) and acetyl-CoA modulation, potentially affecting new areas of research through metabolic processes. We propose a cooperative crosstalk between metabolic reprogramming and transcription factors/epigenetic modulation in PCa. This approach holds potential for expanding PCa therapeutics and opening new avenues for research.
Complete chloroplast genome sequences are widely used in the analyses of phylogenetic relationships among angiosperms. As a species-rich genus, species diversity centers of Saxifraga L. include mountainous regions of Eurasia, such as the Alps and the Qinghai–Tibetan Plateau (QTP) sensu lato. However, to date, datasets of chloroplast genomes of Saxifraga have been concentrated on the QTP species; those from European Alps are largely unavailable, which hinders comprehensively comparative and evolutionary analyses of chloroplast genomes in this genus. Here, complete chloroplast genomes of 19 Saxifraga species were de novo sequenced, assembled and annotated, and of these 15 species from Alps were reported for the first time. Subsequent comparative analysis and phylogenetic reconstruction were also conducted. Chloroplast genome length of the 19 Saxifraga species range from 149,217 bp to 152,282 bp with a typical quadripartite structure. All individual chloroplast genome included in this study contains 113 unique genes, including 79 protein-coding genes, four rRNAs and 30 tRNAs. The IR boundaries keep relatively conserved with minor expansion in S. consanguinea. mVISTA analysis and identification of polymorphic loci for molecular markers shows that six intergenic regions (ndhC-trnV, psbE-petL, rpl32-trnL, rps16-trnQ, trnF-ndhJ, trnS-trnG) can be selected as the potential DNA barcodes. A total of 1204 SSRs, 433 tandem repeats and 534 Large sequence repeats were identified in the 19 Saxifraga chloroplast genomes. The codon usage analysis revealed that Saxifraga chloroplast genome codon prefers to end in A/T. Phylogenetic reconstruction of 33 species (31 Saxifraga species included) based on 75 common protein coding genes received high bootstrap support values for nearly all identified nodes, and revealed a tree topology similar to previous studies.
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that severely impacts patients’ quality of life. Although current therapies have improved symptom management, they often fail to alter disease progression and are associated with immunosuppressive side effects. This study evaluated the immunomodulatory potential of resolvin D2 (RvD2), a pro-resolving lipid mediator, using a murine model of colitis and the ex vivo treatment of intestinal mucosal biopsies from CD patients, comparing its effects to those of conventional anti-TNFα therapy. To determine the optimal concentration of RvD2 for application in human tissue explant cultures, an initial in vitro assay was conducted using intestinal biopsies from mice with experimentally induced colitis. The explants were treated in vitro with varying concentrations of RvD2, and 0.1 μM emerged as an effective dose. This concentration significantly reduced the transcriptional levels of TNF-α (p = 0.004) and IL-6 (p = 0.026). Intestinal mucosal biopsies from fifteen patients with CD and seven control individuals were analyzed to validate RNA-sequencing data, which revealed dysregulation in the RvD2 biosynthetic and signaling pathways. The real-time PCR confirmed an increased expression of PLA2G7 (p = 0.02) and ALOX15 (p = 0.02), while the immunohistochemical analysis demonstrated the reduced expression of the RvD2 receptor GPR18 (p = 0.04) in intestinal tissues from CD patients. Subsequently, samples from eight patients with active Crohn’s disease, eight patients in remission, and six healthy controls were used for the serum analysis of RvD2 by ELISA, in vitro treatment of intestinal biopsies with RvD2 or anti-TNF, followed by transcriptional analysis, and a multiplex assay of the explant culture supernatants. The serum analysis demonstrated elevated RvD2 levels in CD patients both with active disease (p = 0.02) and in remission (p = 0.002) compared to healthy controls. The ex vivo treatment of intestinal biopsies with RvD2 decreased IL1β (p = 0.04) and TNFα (p = 0.02) transcriptional levels, comparable to anti-TNFα therapy. Additionally, multiplex cytokine profiling confirmed a reduction in pro-inflammatory cytokines, including IL-6 (p = 0.01), IL-21 (p = 0.04), and IL-22 (p = 0.009), in the supernatant of samples treated with RvD2. Altogether, these findings suggest that RvD2 promotes the resolution of inflammation in CD and supports its potential as a promising therapeutic strategy.
Osteogenesis imperfecta (OI) is a rare bone dysplasia that occurs with a frequency of 1/15,000–20,000 live births. It is characterized by increased susceptibility of bone fractures, skeletal deformities, low stature, and low bone mass. It results in impaired production of type I collagen. About 90% of people with OI have heterozygous mutations in the COL1A1 and COL1A2 genes. Fibroblast growth factor 23 (FGF23) is a protein involved in the regulation of phosphate and 1,25-dihydroxyvitamin D3 metabolism on a negative feedback basis. FGF23 is secreted by osteocytes in response to increased serum calcitriol and phosphorus. The purpose of this study was to evaluate the concentration of FGF23 among children with osteogenesis imperfecta and the differences in reference values in a healthy population of children and adolescents. Then, this study sought to evaluate how the course of osteogenesis imperfecta, including type of disease, number of bone fractures, and bone mineral density, are related to FGF23 concentration. The study included 47 children aged 3 to 17 years with a diagnosis of osteogenesis imperfecta, confirmed by genetic tests. The patients were hospitalized at the Department from August 2019 to September 2020 and were treated with intravenous infusions of sodium pamidronate. The course of the disease was analyzed, including the number of bone fractures, clinical symptoms, and anthropometric parameters, and bone densitometry was performed by dual X-ray absorptiometry (DXA) in Total Body Less Head (TBLH) and Spine options with Z-score evaluation. FGF23 concentration was determined by the ELISA method. The study was prospective in nature. Results: The mean level of FGF23 in the study group of patients was 645.09 pg/mL and was within the reference values for the developmental age population. There was no significant correlation between FGF23 concentration and anthropometric measurements: body weight (p = 0.267), height (p = 0.429), gender (p = 0.291), or pubertal stage (p = 0.223) in the study group of patients. FGF23 levels were not related to the number of fractures (p = 0.749), the number of sodium pamidronate cycles administered (p = 0.580), bone mineral density parameters (Z-score), the form of osteogenesis imperfecta (p = 0.156), or the genetic test result (p = 0.573). FGF23 levels decrease with age (r = −0.32, p = 0.030) and BMI (r = −0.34, p = 0.020). The level of FGF23 in patients with osteogenesis imperfecta is lower among older children and those having a higher BMI. This index cannot be a diagnostic tool in this group of patients, for no differences were found between the concentrations in patients with osteogenesis imperfecta and the developmental age population.
Clinacanthus nutans (Burm.f.) Lindau is a Southeast Asian medicinal plant traditionally used for treating skin inflammation and infections. This study evaluated its wound-healing potential through anti-inflammatory, cytoprotective, and antiviral mechanisms. HPLC-DAD analysis identified schaftoside as the major flavonoid in the 95% ethanolic leaf extract. In the lipopolysaccharide (LPS)-stimulated murine macrophage cell line (RAW 264.7), both C. nutans extract (5 and 50 μg/mL) and its flavonoid schaftoside (5 and 20 μg/mL) significantly downregulated the expression of pro-inflammatory genes, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2), under both pre-treatment and post-treatment conditions. ELISA confirmed dose-dependent inhibition of human COX-2 enzymatic activity, reaching up to 99.3% with the extract and 86.9% with schaftoside. In the endothelial cell models (CCL-209), the extract exhibited low cytotoxicity and effectively protected cells from LPS-induced apoptosis, preserving vascular integrity critical to tissue regeneration. Antiviral assays demonstrated suppression of HSV-2 replication, particularly during early infection, which may help prevent infection-related delays in wound healing. Collectively, these findings suggest that C. nutans and schaftoside promote wound repair by attenuating inflammatory responses, supporting endothelial survival, and controlling viral reactivation. These multifunctional properties highlight their potential as natural therapeutic agents for enhancing wound-healing outcomes.
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In this study, utilizing ex vivo, in silico, and in vitro approaches, we investigated the LCS1269 effects on two potential targets, DNA and Top I. We also elucidated the influence of LCS1269 on signaling pathways and GBM cell viability. Based on our docking data and competition studies results, we demonstrated that LCS1269 may bind to DNA, demonstrating selectivity toward AT-rich regions. We also showed that LCS1269 could dock both Top I/DNA binary complex and Top I active sites. LCS1269 caused Top I dysfunction and downregulated the expression of Top I. Moreover, the LCS1269 treatment of GBM cells facilitated DNA damage and the activation of the ATM/Chk1/BRCA1/Rad51 pathway. Meanwhile, DNA damage response induction and ATM/Chk1/BRCA1/Rad51 pathway activation were insufficient to prevent GBM cell death triggered by LCS1269 treatment. Our work shows that DNA and Top I are promising molecular targets of LCS1269, thus providing insight on several novel mechanisms of its anti-tumor activity. Nonetheless, we did not perform a biophysical validation of the LCS1269–DNA interaction, which is a limitation of our study.
Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated calmodulin (CaM) variants, the cellular mechanism(s) underlying this posttranslational modification was investigated in cultured cardiomyocytes. Whole-cell LTCCs decreased by ≈75% after silencing the gene coding for casein kinase 2 (CK2), a constitutively active kinase in cardiomyocytes, or after its pharmacological inhibition. The overexpression of the dominant negative phosphoresistant single, double T79A/S81A, or triple T79A/S81A/S101A CaM variants resulted in a similar inhibition. In contrast, the overexpression of CaM WT or its double T79D/S81D and triple T79D/S81D/S101D phosphomimetic variants curtailed the downregulation of LTCCs caused by CK2 partial knockdown, suggesting that CK2 is responsible for the posttranslational modification of these CaM target residues. Catecholamines, triggering the protein kinase A (PKA) cascade, partially rescued LTCCs treated with siRNA without or after the overexpression of either CaM WT or stimulating CaM phosphomimetic variants. More importantly, they thwarted the negative impact of the phosphoresistant CaM variants, altogether arguing that CK2 and PKA are acting in synergy to regulate the activity of LTCCs. We conclude that CK2-mediated phosphorylation processes exacerbate the Ca2+ load associated with heart failure.
The parathyroid and thymus glands are key components of the endocrine and immune systems, respectively, with intriguing developmental, anatomical, and functional interrelationships. This study starts from the hypothesis that, given their shared embryological origin, it is plausible that the thymus and parathyroid glands interact functionally and may share pathological pathways. The present study explores the developmental pathways, spatial proximity, and potential cross-talk between these glands. Recent studies suggest that parathyroid hormone (PTH) may influence thymic function, including T-cell maturation and immune regulation, while thymic signaling molecules could impact calcium homeostasis and parathyroid activity. Understanding the functional and etiopathogenical relations between these endocrine glands offers new insights into endocrine–immunological crosstalk, and therapeutic approaches targeting disorders such as hypoparathyroidism, thymomas, myasthenia gravis and thymic hypoplasia. Perspectives and conclusion: Future research is essential to discover the molecular mechanisms underpinning this dynamic interrelation and its broader implications for health and disease. Because there is still very little data on this interaction, in-depth studies are necessary on large groups of patients. This research proposes a cross-study of the receptors for the main substances secreted by the two categories of endocrine glands. At the same time, it is essential to carry out an in-depth study on the cervico-pericardial ligaments through the lens of this glandular interaction. These ligaments could contain the main blood and nerve communication pathway between the parathyroids and the glands.
The GLABROUS1 enhancer-binding protein (GeBP) gene family, a plant-specific class of transcriptional regulators, is involved in multiple biological processes, including the formation of trichomes, plant growth, and environmental adaptation. However, the functional characterization of SlGeBP genes in tomato remains poor, particularly regarding their roles in regulating developmental processes and stress response mechanisms. In this study, 11 SlGeBP family members were identified from the tomato genome and 97 GeBP proteins from six species were classified into three groups. A wide range of elements linked to phytohormone, stress, and plant development were presented on the promoter sequences. Gene expression profile analysis revealed a comprehensive expression during the vegetative and immature fruit development stages. Analysis of the expression level under nine hormones and seven stresses can help us to understand the responsiveness of SlGeBP genes associated with hormone induction and stress tolerance. Subcellular localization analysis exhibited that SlGeBP1 and SlGeBP5 were localized in the nucleus, and the yeast two-hybrid assay confirmed that SlGeBP1 could interact with SlGeBP5. This study will help us to understand the potential function of the SlGeBP family and may establish a basis for further research on phytohormone signaling and stress resistance.
The study investigated the antinociceptive effects of four compounds (F1–F4) based on a 1H-isoindole-1,3(2H)-dione core, using various in vivo pain models—tonic (formalin test), neurogenic (capsaicin and glutamate tests), neuropathic (oxaliplatin-induced model of peripheral neuropathy as well as the streptozotocin-induced model of painful diabetic neuropathy), and inflammatory (carrageenan-induced). Pharmacokinetic parameters were also assessed. In the capsaicin test, F1, F2, and F4 (5–20 mg/kg) significantly reduced pain, while compound F3 was only active at 20 mg/kg. In the glutamate test, F1, F2, and F3 (5–20 mg/kg) demonstrated the most pronounced effect. In phase I of the formalin test, compounds F1 and F2 were active at doses of 5 and 10 mg/kg, respectively, while F3 and F4 exhibited activity only at the 20 mg/kg dose. In phase II, a dose-dependent reduction in pain was observed, with the weakest effect noted at F4. At a dose of 20 mg/kg, the compounds significantly reduced edema and carrageenan-induced pain, but to a lesser extent than ketoprofen. The compounds tested (10 mg/kg) showed significant anti-allodynic activity in the oxaliplatin- and streptozotocin-induced neuropathy pain models. All compounds demonstrated favorable pharmacokinetic results. The results of this study indicate that the compounds have a broad analgesic spectrum of activity.
Pasta, due to its convenience, follows bread as the most common cereal product in the human diet. Typical wheat pasta is a high-energy product, since it contains a large amount of starch; at the same time, it is characterized by a low content of health-promoting ingredients, such as dietary fiber, minerals, vitamins, and polyphenols. Food industry by-products, or even waste, can be applied as a source of many bioactive substances, thus enriching pasta with bioactive ingredients. Two by-products, Cherry Pomace (CP) and Red Potato Pulp (RPP) were applied as health-promoting supplements for wheat pasta, at three levels (10, 20, and 30%). The antioxidant potential of the resulting pasta was examined (by DPPH, ABTS, FRAP, and FOMO methods), and the antioxidant’s content was also tested. The amount of polyphenols determined by HPLC was higher in the case of CP than in RPP, and the main ones were 5-O-Caffeoylquinic acid and Cyanidin 3-O-rutinoside in CP, whereas for RPP it was Pelargonidin 3-(4‴-p-coumaroylrutinoside)-5-glucoside. Fortified pasta samples were characterized by a higher content of total polyphenols and phenolic acids, flavonoids, flavanols, and anthocyanins. In pasta with a share of CP, some polyphenols were unstable during pasta production. Pasta with a share of CP was characterized by very high antioxidant activity due to a high level of phenolic acids and anthocyanins acting synergistically. It was also characterized by a higher content of phytosterols. A 30% addition of CP into pasta is considered the most beneficial in terms of increasing the health-promoting properties of such a product.
Spinal cord injury (SCI) results in a significant loss of motor, sensory, and autonomic function, imposing substantial biosocial and economic burdens. Traditional approaches, such as stem cell therapy and immune modulation, have faced translational challenges, whereas neuromodulation and digital brain–spinal cord interfaces combining brain–computer interface (BCI) technology and epidural spinal cord stimulation (ESCS) to create brain–spine interfaces (BSIs) offer promising alternatives by leveraging residual neural pathways to restore physiological function. This review examines recent advancements in neuromodulation, focusing on the future translation of clinical trial data to clinical practice. We address key considerations, including scalability, patient selection, surgical techniques, postoperative rehabilitation, and ethical implications. By integrating interdisciplinary collaboration, standardized protocols, and patient-centered design, neuromodulation has the potential to revolutionize SCI rehabilitation, reducing long-term disability and enhancing quality of life globally.
The ocular surface is susceptible to a wide spectrum of inflammatory, degenerative, and neurotrophic diseases that can impair vision. The complex pathophysiology and limited therapeutic options associated with these conditions continue to pose significant clinical challenges. Nerve Growth Factor (NGF), a neurotrophin initially recognized for its role in neuronal survival and differentiation, has emerged as a key regulator of ocular surface homeostasis and repair. Beyond its neurotrophic functions, NGF is suggested to influence epithelial proliferation, immune responses, tear secretion, and angiogenesis. Experimental and clinical studies have implicated NGF in both the pathogenesis and potential treatment of various ocular surface diseases, including allergic conjunctivitis, neurotrophic keratopathy (NK), immune-mediated and herpetic keratitis, and dry eye disease (DED), as well as post-surgical corneal wound healing. Notably, recombinant human NGF (rhNGF, cenegermin) has been approved as the first topical biologic therapy for NK. Despite encouraging clinical outcomes, challenges such as high treatment costs, limited long-term data, and potential proangiogenic effects remain. This review consolidates current evidence on the role of NGF in ocular surface health and disease, highlighting its biological mechanisms, clinical applications, and future therapeutic potential.
Coagulation factor XII (FXII), the initiator of the intrinsic coagulation pathway, is not involved in hemostasis but is associated with pathological thrombosis. Bacterial infections activate coagulation cascades, although the underlying mechanisms remain not fully understood. Here, we revealed that FXII exhibits antibacterial activity through its heavy chain (hFXII) against Pseudomonas aeruginosa (P. aeruginosa), a Gram-negative bacterium. We constructed an FXII-deficient (FXII−/−) mouse model and demonstrated that FXII plays a critical role in antibacterial functions. FXII and hFXII significantly reduced bacterial loads via intravenous injection, confirming their antibacterial activity in FXII−/−. To further investigate the pathophysiological implications of FXII in the P. aeruginosa-induced disseminated intravascular coagulation (DIC) mouse model, FXII and hFXII effectively reduced DIC-related bacterial infections, alleviated organ damage, and decreased fibrin deposition, consequently improving survival rates. This study indicates that FXII exhibits both in vitro and in vivo antibacterial activity, primarily mediated through its heavy chain. In thrombotic diseases triggered by Gram-negative bacterial infections, the antibacterial functions of FXII may influence the progression of the disease. These results not only redefine the critical role of the intrinsic coagulation pathway in innate immune defense but also provide novel insights into the prevention and treatment of severe infection-related diseases.
Liver fibrosis can progress to irreversible cirrhosis if the underlying causes remain, and this can in turn develop into hepatocellular carcinoma (HCC). Despite these adverse outcomes, liver fibrosis can be reversed. Consequently, research has focused on substances that target liver fibrosis to prevent or reduce its progression. This study deals with the potential anti-fibrotic action of 3-hydroxy-β-ionone (3-HBI), a bioactive compound found in many plants. To assess the putative effects of 3-HBI, pro-inflammatory cytokine production and the expression of genes and proteins associated with the TGF-β/SMAD2/3 pathway were monitored following exposure to 3-HBI. Initially, cells of the human hepatic stellate cell line LX-2 were treated with TGF-β1 to simulate fibrogenesis. Following the exposure of activated LX-2 cells to 3-HBI, the production of pro-fibrotic substances was significantly reduced. Molecular docking studies revealed that 3-HBI exhibited a high binding affinity for key proteins in the TGF-β/SMAD2/3 pathway. Analyses using qRT-PCR and Western blotting revealed that 3-HBI suppressed the expression of TIMP1, MMP2, MMP9, COL1A1, COL4A1, SMAD2, SMAD3, SMAD4, MMP2, and ACTA2. Together, these findings demonstrate that 3-HBI inhibited the activation of LX-2 cells and significantly reduced the proinflammatory responses triggered by TGF-β1. Accordingly, we confirmed the noteworthy potential of 3-HBI as a therapeutic agent to prevent and treat liver fibrosis, effected by its modulation of the TGF-β/SMAD2/3 signaling pathway.
Hereditary α-tryptasemia (HαT)—a genetic trait caused by increased α-tryptase-encoding typtase alpha/beta-1 (TPSAB1) copy number—is associated with adult mastocytosis. The primary objective was to assess the association between α-tryptase and pediatric mastocytosis. We also want to evaluate whether the KIT p.D816V mutation in peripheral blood leukocytes (PBLs) reliably predicts systemic mastocytosis (SM) in children. A prospective cohort of 68 children from a referral center in Slovenia with cutaneous mastocytosis (CM) underwent tryptase genotyping by droplet digital PCR and examination for KIT p.D816V in PBL using a sensitive PCR test. A significant majority of patients (57 of 68; [83.8%]) had at least one α-tryptase-encoding gene; none had HαT. 7 of the 68 (10.3%) who were positive for KIT p.D816V in PBL, one fulfilled diagnostic criteria for indolent SM, and another was diagnosed with monoclonal mast cell activation syndrome. One of those individuals had an increased basal serum tryptase (BST) level (14.5 ng/mL). We found a high presence of germline α-tryptase in children with CM, but not HαT. By employing sensitive examination for KIT p.D816V in PBL, in combination with clinical data and other examinations, our study suggests that KIT p.D816V in PBL may indicate systemic disease in children with CM.
The limited efficacy of antipsychotics in treating the negative and cognitive symptoms of schizophrenia has prompted the exploration of adjuvant therapies. Several drugs developed for other indications—including caffeine, metformin, and furosemide—have shown procognitive potential. This study evaluated the effects of these agents on behavioral parameters using the reward-based Ambitus test, and on the cerebral D2 dopamine receptor (D2R) expression and binding. The drugs were administered individually and in combination in a schizophrenia-like triple-hit animal model (Lisket rats), derived from the Long Evans (LE) strain. Lisket rats received 14 days of drug treatment via drinking water; water-drinking LE rats served as the controls. The Ambitus test was conducted before treatment and on days 11–14. Caffeine enhanced activity without affecting learning or memory. Metformin and furosemide reduced exploratory behavior but improved reference memory; these effects were inhibited by caffeine co-administration. Although no statistically significant behavioral differences were found compared to water-treated Lisket rats, a trend toward reduced exploratory visits was observed in the triple-combination group. Lisket rats exhibited moderately reduced D2R binding in the cortex and increased binding in the hippocampus. Caffeine alone and in combination enhanced hippocampal D2R binding, while furosemide increased cortical D2R expression. This study is the first to highlight the behavioral and molecular effects of these non-antipsychotic agents in a schizophrenia model, supporting their potential for adjunctive use.
This study aimed to develop polylactic acid (PLA)-based membranes incorporating tramadol (TMD) using air jet spinning (AJS), ensuring stable physicochemical properties and biocompatibility. Two groups were fabricated: 10% PLA membranes (control) and 10% PLA membranes loaded with TMD in an 80:1 ratio (experimental). Characterization included scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-VIS), and biocompatibility assays with human osteoblasts using resazurin, crystal violet staining, and 5-chloromethylfluorescein diacetate for fluorescence microscopy. SEM revealed a homogeneous, randomly distributed fiber pattern, with diameters under 5 µm and no structural voids. DSC and TGA indicated that TMD was uniformly incorporated, increased the thermal capacity, and slightly lowered the onset and inflection degradation temperatures. FT-IR confirmed the chemical compatibility of TMD with PLA, showing no structural alterations. UV-VIS detected sustained TMD release over 72 h. Biocompatibility tests showed no cytotoxic effects; cell viability and proliferation in TMD-loaded membranes were comparable to controls. Statistical analysis used ANOVA and Wilcoxon tests. 10% PLA membranes loaded with TMD at an 80:1 ratio exhibited stable physicochemical characteristics and favorable biocompatibility, supporting their potential use in drug delivery systems.
The field of colloid systems is still a developing scientific area, but a very promising one for many practical applications [...]
The essential micronutrient zinc is known to inhibit gastric acid secretion (GAS), where its homeostasis is strictly regulated. We hypothesized that the gastric bitter taste receptors, TAS2Rs, regulate the following: (i) zinc-modulated proton secretory activity (PSA) as a key mechanism of GAS and (ii) zinc homeostasis in immortalized parietal cells. To confirm this hypothesis, human gastric tumor cells (HGT-1) were exposed to 100–1000 µM of zinc salts for 30 min in order to quantitate their TAS2R-dependent PSA and intracellular zinc concentration using a fluorescence-based pH sensor and ICP-MS, respectively. Thereby, we identified TAS2R43 as a key player in parietal cell PSA and zinc homeostasis, with both conclusions being verified by a CRISPR-Cas9 knockout approach. Moreover, by regulating the zinc importer protein ZIP14, TAS2R43 proved to perform a protective role against excessive zinc accumulation in immortalized parietal cells.
Rare genetic movement disorders usually manifest early in life with dystonia, parkinsonism, chorea, or a combination thereof. These are often associated with neurodevelopmental delay, intellectual disability, speech problems, retinal abnormalities, seizures, ataxia, spasticity, or systemic features. Due to their vast number and pheno–genotypic heterogeneity, the diagnosis of these disorders can be challenging. However, recognising their core motor phenomenology as well as clinical, laboratory, and neuroradiological clues can expedite appropriate diagnostic workup, molecular diagnosis, and adequate treatment. In this review, we outline diagnostic clues to rare movement disorders (RMDs), focusing on those that present mainly with dystonia, parkinsonism, or paroxysmal dyskinesia due to genetic causes. Additionally, we provide a decision tree approach linking clinical, genetic, and imaging testing. Finally, we highlight selected RMDs that should not be missed, as they possess established treatments that can hinder their progression, prevent irreversible or life-threatening sequelae and, in certain cases, lead to complete symptom remission.
Salt accumulation in arable lands causes significant abiotic stress, resulting in a 10% loss in global arable land area and jeopardizing food production and agricultural sustainability. In order to attain high and sustainable food production, it is imperative to enhance traditional agricultural practices with modern technology to enable the restoration of arable lands afflicted by salinity. This review consolidates recent rice-specific advancements aimed at enhancing salt stress resilience through integrated strategies. We explore the functions of primary and secondary metabolic pathways, organic amendments, microbial symbiosis, and plant growth regulators in reducing the negative impacts of salt. Furthermore, we highlight the significance of emerging genetic and epigenetic technologies, including gene editing and transcriptional regulation, in developing salt-tolerant rice cultivars. Physiological studies reveal salt stress responses in rice plants, biochemical analyses identify stress-related metabolites, microbial investigations uncover beneficial plant–microbe interactions, and molecular approaches enable the identification of key genes—together providing essential insights for developing salt-tolerant rice varieties. We present a comprehensive overview of the multilayered strategies—ranging from agronomic management and physiological adaptations to molecular breeding and microbial applications—that have been developed and refined over recent decades. These approaches have significantly contributed to understanding and improving salinity tolerance mechanisms in rice. This review provides a foundational framework for future research and practical implementation in stress-resilient rice farming systems.
Lactylation and PANoptosis are emerging modes of tumor progression regulation; however, their interplay and effect on the prognosis for lung adenocarcinoma (LUAD) remain unclear. This research analyzed both bulk and single-cell transcriptomic profiles of LUAD and identified 506 potential markers related to lactylation and PANoptosis. Employing 117 machine learning approaches and 5 LUAD datasets, lactylation and PANoptosis-related signatures (LAPRS) and further predictive nomograms were constructed with 85 prognostic genes. The performance of LAPRS was validated with multifaceted validation, including Kaplan–Meier analysis, time-dependent ROC curves and comparison with 55 existing LUAD models. LAPRS enabled the stratification of LUAD patients into high- and low-risk subgroups. Through additional investigation, high-risk individuals showed elevated genomic alterations, reduced immune infiltration, and poorer immunotherapy response, while low-risk individuals showed better drug sensitivity and a higher tumor mutation burden. Further analysis via 18 models and experimental validation revealed APOL1 as a poor prognostic factor, potentially interacting with the lactylation-related gene VIM through TNF signaling. This research clarifies the mechanistic roles of lactylation and PANoptosis in LUAD and proposes APOL1 as a novel prognostic marker, offering insights for therapeutic stratification.
Lymphangioleiomyomatosis (LAM) is a rare progressive disease that affects women of reproductive age and is characterized by cystic lung destruction, airflow obstruction, and lymphatic dysfunction. Current diagnostic methods are costly or lack sufficient specificity, highlighting the need for novel non-invasive approaches. Exhaled breath analysis using real-time proton mass spectrometry (PTR-MS) presents a promising strategy for identifying disease-specific volatile organic compounds (VOCs). This cross-sectional study analyzed exhaled breath samples from 51 LAM patients and 51 age- and sex-matched healthy controls. PTR-time-of-flight mass spectrometry (PTR-TOF-MS) was employed to identify VOC signatures associated with LAM. Data preprocessing, feature selection, and statistical analyses were performed using machine learning models, including gradient boosting classifiers (XGBoost), to identify predictive biomarkers of LAM and its complications. We identified several VOCs as potential biomarkers of LAM, including m/z = 90.06 (lactic acid) and m/z = 113.13. VOCs predictive of disease complications included m/z = 49.00 (methanethiol), m/z = 48.04 (O-methylhydroxylamine), and m/z = 129.07, which correlated with pneumothorax, obstructive ventilation disorders, and radiological findings of lung cysts and bronchial narrowing. The classifier incorporating these biomarkers demonstrated high diagnostic accuracy (AUC = 0.922). This study provides the first evidence that exhaled breath VOC profiling can serve as a non-invasive additional tool for diagnosing LAM and predicting its complications. These findings warrant further validation in larger cohorts to refine biomarker specificity and explore their clinical applications in disease monitoring and personalized treatment strategies.
The SNCA gene, encoding alpha-synuclein, is implicated in the pathogenesis of Parkinson’s disease (PD), with several single-nucleotide polymorphisms (SNPs) linked to increased risk. This study systematically evaluated the association between common SNCA polymorphisms and PD through a meta-analysis of cohort and case–control studies published before 20 November 2023. Eligible studies were identified via comprehensive searches of PubMed, Scopus, and Web of Science, and pooled odds ratios with 95% confidence intervals were calculated under allelic, dominant, and recessive models. Heterogeneity and publication bias were assessed, and subgroup and sensitivity analyses were performed. Twenty-seven studies were included. SNP rs11931074 showed consistent associations with PD across all models, with low heterogeneity and no evidence of publication bias. rs356219 and rs356165 were also significantly associated with PD, although regional differences contributed to heterogeneity. In contrast, rs2583988 showed marginal significance in the allelic model, which was lost after sensitivity analyses. No associations were found under dominant or recessive models for this SNP. These findings confirm rs11931074 as a robust PD risk variant and support the roles of rs356219 and rs356165 while suggesting weaker evidence for rs2583988. Large, multi-ethnic studies are warranted to elucidate underlying mechanisms and support precision medicine in PD.
Precision prevention strategies for cervical cancer that integrate genetic biomarkers provide opportunities for personalized risk assessment and optimized preventive measures. An HPV infection–Precancerous–Cancer risk assessment model incorporating genetic polymorphisms and DNA methylation was developed to better understand the regression and progression of cervical lesions by HPV infection status. Utilizing a virtual cohort of 300,000 Taiwanese women aged 30 years and older, our model simulated the natural history of cervical cancer, capturing transitions from a healthy state through precancerous lesions (LSILs and HSILs) to invasive carcinoma and incorporating the possibility of regression between states. Genetic and epigenetic markers significantly influenced disease transitions, demonstrating heterogeneous risks among women with distinct molecular biomarker profiles. Guided by these individual risk profiles, tailored preventive strategies including varying intervals for Pap smear screening, HPV DNA testing, and HPV vaccination showed improved efficiency and effectiveness in reducing cervical cancer incidence compared to uniform approaches. The proposed dynamic transition model of cervical neoplasms incorporating genetic biomarkers can facilitate the development of an individualized risk-based approach for guiding precision prevention towards the goal of cervical cancer elimination.
Antibody-mediated rejection (ABMR) remains a major cause of renal graft dysfunction and loss. The histological hallmark of antibody-mediated rejection is progressive tissue damage, in which extracellular matrix turnover plays an important role. This turnover is mainly regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Recent studies suggest that MMP/TIMP imbalance may favor the progression of renal damage, inflammation, and fibrosis, but the utility of these molecules as a biomarker of antibody-mediated turnover has not been fully explored. We measured plasma MMP and TIMP levels by ELISA in 15 patients with antibody-mediated renal transplant rejection and 12 patients without rejection. There was a significant increase in MMP-1, MMP-2, and MMP-3 concentrations in the plasma of patients with rejection, directly correlating with the severity of different renal lesions. In contrast, TIMP-3 levels were elevated in patients without rejection, showing a negative correlation with the severity of histopathological lesions. The concentrations of these molecules demonstrated good diagnostic capacity for patients with rejection. Our results show that MMP-1, MMP-2, MMP-3, and TIMP-3 could be potential biomarkers of rejection.
One of the most prevalent types of cancer among women is ovarian cancer. The search for ovarian cancer markers is constantly ongoing. Evaluation of LAG-3 and TIM-3 protein expression in ovarian cancer tissue and its role in distinguishing the clinical signs stated were the objectives of this study. Methods: A total of 58 ovarian cancer patients were recruited for this study. The cohort was split into two groups: one for high-grade serous ovarian cancer (HGSOC) and another for ovarian cancer that was not HGSOC (non-HGSOC). LAG-3 and TIM-3 protein expression in ovarian cancer tissue samples was evaluated by immunohistochemistry. StatView 5.0 software (Carry, NC, USA) was used for all statistical analyses. Both LAG-3 and TIM-3 proteins mostly showed positive, moderately positive, or strongly positive expression. This study shows that LAG-3 could be a marker associated with BMI in the non-HGSOC group. TIM-3 may be a marker associated with age in a group of all ovarian cancers. LAG-3 expression is associated with TIM-3 expression in the total cohort and the HGSOC and non-HGSOC groups.
Wild fruits are distributed worldwide, but are consumed mainly in developing countries, where they are an important part of the diet. Still, in many other countries, they are consumed only locally. Blackthorn (Prunus spinosa L.) is an underutilized species rich in fibres and phenolic compounds, making it suitable as a potential functional food for supporting human health. Cold (Cw) and hot (Hw) water-extracted (poly)phenolic polysaccharide–protein complexes, differing in carbohydrate, phenolic and protein contents, were isolated from blackthorn fruits and characterized. The complexes exhibited molecular weights of 235,200 g/mol (Cw) and 218,400 g/mol (Hw), and were rich in pectic polymers containing galacturonic acid, arabinose, galactose and rhamnose, indicating a dominance of homogalacturonan (HG) [→4)-α-D-GalA(1→4)-α-D-GalA(1→]n and a low content of RGI [→2)-α-L-Rha(1→4)-α-D-GalA(1→2)-α-L-Rha(1→]n sequences associated with arabinan or arabinogalactan. Minor content of glucan, probably starch-derived, was also solubilized. Pectic polysaccharides were highly esterified and partly acetylated. Pharmacological testing was performed in male Dunkin–Hartley guinea pigs, a model with human-like airway reflexes. Both complexes affected airway defense mechanisms. Particularly, Hw significantly suppressed citric acid-induced cough, similar to codeine, and reduced bronchoconstriction comparably to salbutamol in a dose-dependent manner. These findings support further exploration of Hw as a natural antitussive and bronchodilatory agent.
Endometriosis is a complex gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to chronic pain and infertility. Immunohistochemistry (IHC) serves as a vital technique for elucidating the molecular and cellular differences between ectopic endometriotic tissues and eutopic endometrium. IHC reveals significant variations in the expression of inflammatory markers, adhesion molecules, and cell cycle regulators. This literature review compiles findings from various studies that assess the role of key proteins, such as leukemia inhibitory factor (LIF), cyclooxygenase-2 (COX-2), and b-cell lymphoma 2 (BCL-2), across different menstrual phases and lesion types. Notably, elevated LIF levels and increased mast cell activity in ectopic tissues underscore the inflammatory landscape of endometriosis. Additionally, altered expression of adhesion molecules like integrins and cluster of differentiation 44 (CD44) suggests modified cellular interactions, while apoptotic markers reveal a survival advantage for ectopic cells. These insights enhance our understanding of endometriosis pathophysiology.
AbstractMild repetitive head injury is a serious health problem with long-term negative consequences. Changes in brain neurobiology were assessed with MRI in a model of head injury designed to reflect the human experience. Rats were maintained on a reverse light-dark cycle and head impacted daily at 24 h intervals over three days while fully awake under red light illumination. There was no neuroradiological evidence of brain damage. Rats were imaged for changes in blood brain barrier permeability, edema and gray matter microarchitecture, and resting state functional connectivity. Data were registered to a 3D MRI rat atlas with 173 segmented brain areas providing site-specific information on each imaging modality. Changes in BBB permeability were minimal and localized to the hippocampus and cerebellum. There was evidence of cytotoxic edema in the basal ganglia, thalamus, and cerebellum. There was a global decrease in connectivity and an increase in gliosis in the thalamus, cerebellum, and hippocampus. This study shows a sequelae of neuropathology caused by mild repetitive head injury that is commonly observed in clinical practice using MRI in patients. As such, it may serve as a model for testing the efficacy of new therapeutics using any or all of the measures as biomarkers to assess drug efficacy.
AbstractClinical investigations have suggested a potential link between cataracts and Alzheimer’s disease (AD). However, whether cataract has an impact on the progression of AD remains unclear. The objective of this research was to determine the relationship between cataracts and AD. A cataract model was established in APP/PS1 [mutant amyloid precursor protein (APP) and a mutant presenilin-1 (PS1) gene] micevialens puncture. Behavioural assays were used to evaluate cognitive function. Immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assays (ELISA) were applied to detect AD-related pathology. Visual signals were markedly obstructed following surgery to induce cataracts, and these mice presented an increased cerebral amyloid-beta (Aβ) load, while no significant alterations in the levels of enzymes associated with Aβ metabolism were detected. In addition, compared with control mice, cataract model mice presented increased astrogliosis and microgliosis, along with elevated levels of proinflammatory factors. Moreover, cataract model mice presented more pronounced cognitive impairments than did control mice. Our study offers experimental confirmation that cataract considerably contributes to the pathogenesis of AD, thereby emphasizing the importance of visual signals in maintaining cognitive well-being.
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AbstractEpisodic memory, our ability to recall past experiences, is supported by structures in the medial temporal lobe (MTL) particularly the hippocampus, and its interactions with fronto-parietal brain regions. Understanding how these brain regions coordinate to encode, consolidate, and retrieve episodic memories remains a fundamental question in cognitive neuroscience. Non-invasive brain stimulation (NIBS) methods, especially transcranial magnetic stimulation (TMS), have advanced episodic memory research beyond traditional lesion studies and neuroimaging by enabling causal investigations through targeted magnetic stimulation to specific brain regions. This review begins by delineating the evolving understanding of episodic memory from both psychological and neurobiological perspectives and discusses the brain networks supporting episodic memory processes. Then, we review studies that employed TMS to modulate episodic memory, with the aim of identifying potential cortical regions that could be used as stimulation sites to modulate episodic memory networks. We conclude with the implications and prospects of using NIBS to understand episodic memory mechanisms.
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AbstractNeuronal injury in glaucoma persists despite effective intraocular pressure (IOP) control, necessitating neuroprotective strategies for retinal ganglion cells (RGCs). In this study, we investigated the neuroprotective role of the γ-hydroxybutyrate analog HOCPCA in a glaucoma model, focusing on its effects on CaMKII signaling, oxidative stress, and neuroinflammatory responses. Retinal tissue from high IOP animal models was analyzedviaproteomics.In vitromouse retinal explants were subjected to elevated pressure and oxidative stress, followed by HOCPCA treatment. HOCPCA significantly mitigated the RGC loss induced by oxidative stress and elevated pressure, preserving neuronal function. It restored CaMKIIα and β levels, preserving RGC integrity, while also modulating oxidative stress and neuroinflammatory responses. These findings suggest that HOCPCA, through its interaction with CaMKII, holds promise as a neuroprotective therapy for glaucoma.
AbstractThe advancement of tissue clearing technology has significantly propelled neuroscience research. Nevertheless, the fluorescent proteins used in traditional transgenic mouse strains were not specifically optimized for tissue clearing procedures, resulting in a substantial decrease in fluorescent intensity after clearing. In this study, we developed theCi1reporter mouse strain (where Ci stands for the Chinese Institute for Brain Research, CIBR) based on the bright red fluorescent protein mScarlet. TheCi1reporter exhibits no fluorescence leakage in various organs or tissue types and can be readily crossed with multiple tissue-specific Cre lines. Compared to theAi14mouse strain, theCi1reporter strain demonstrates lower non-specific leakage, stronger fluorescence intensity in different tissues, and better preservation of fluorescence following tissue clearing treatment. The creation of theCi1reporter provides a more effective tool for both neuroscience and other biomedical research applications.
AbstractGrowth and differentiation factor 15 (GDF15) is a significant player in cellular stress and energy homeostasis. GDF15 is elevated in cancer cachexia, chemotherapy-induced anorexia, hyperemesis gravidarum, and mitochondrial disorders. Here we analyze GDF15 in anorexia nervosa (AN), a psychiatric disorder characterized by low weight and persistent restriction of food intake. While no significant difference in plasma GDF15 concentration was seen across the three included groups; active AN, recovered AN, and healthy controls, a subgroup of study participants with high GDF15 plasma was noted to a significantly higher extent in the AN groups. Sparse partial least squares discriminant analysis (sPLS-DA) identified six markers related to inflammatory processes or cellular stress from a set of 74 markers that distinguished AN with high GDF15 from the rest, with fibroblast growth factor 21 (FGF21) being the most important contributor. Moreover, FGF21 plasma concentration was significantly higher in the group with high GDF15, suggesting an involvement of mitochondrial dysfunction. In fact, mitochondrial polygenic risk score (PRS) was significantly associated with AN risk in a large AN case-control cohort. In line with this, we also report elevated liver expression of GDF15 in theanx/anxmouse displaying anorexia associated with mitochondrial dysfunction. We conclude that mitochondrial dysfunction should be further explored in AN. Clinical trials of GDF15 immunoneutralization in patients with AN and high levels of GDF15 are worthy of consideration.
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AbstractIn attention-deficit/hyperactivity disorder (ADHD), emotional features account for heterogeneity and exacerbate severity of behavioral and functional impairments, beyond cognitive and comorbidity features. Yet, debate remains about the extent to which, in ADHD, such emotional features are a “core feature”, i.e. whether ADHD should be conceptualized as encompassing difficulties with regulating not only activity, attention, and impulses but also processing and regulating emotions. We aimed to address this issue by examining the extent to which in adolescents, ADHD polygenic scores (PGSs) are associated with electrophysiological indices of affective-motivational processing, measured during a monetary punishment/reward feedback paradigm. ADHD PGSs were negatively associated, inn= 166 adolescents (Mage= 15.76 years,SD= 1.07; 42.77% girls), with amplitude values of an occipitoparietal event-related potential (i.e. late positive potential) and were positively associated, inn= 84 adolescents (Mage= 15.76 years,SD= 1.05; 41.67% girls), with fronto-centro-parietal alpha event-related desynchronization. Across analyses, covariates were anxiety, depression, and ADHD with comorbid disruptive behavior disorder PGSs; ADHD, internalizing, and oppositional defiant disorder severity; childhood maltreatment; current ADHD medication; and baseline values of the outcome. Findings were replicated in sensitivity analyses with blocks of conceptually related covariates entered separately. In adolescents, electrophysiological indices of affective-motivational processing are associated principally with genetic liability for ADHD but not comorbidity genetic liability or comorbidity manifest symptoms.
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AbstractBackgroundIn order to appraise the risk-benefit balance of the three available dual orexin receptor antagonists (DORAs; daridorexant, lemborexant, and suvorexant) for the management of adults with insomnia, we conducted a systematic review and random-effects model network meta-analysis.MethodsIncluded were all published double-blind, randomized, placebo-controlled trials of these agents. Outcomes included subjective time to sleep onset at month 1 (sTSO, primary), subjective total sleep time at month 1 (sTST, co-primary), subjective wake after sleep onset at month 1, Insomnia Severity Index scores at month 1, all-cause discontinuation, discontinuation due to adverse events, and the incidence of individual adverse events such as somnolence, dizziness, falls, headache, nasopharyngitis, and upper respiratory tract infection.ResultsThis meta-analysis included eight trials (5198 adults, average age = 56.33 years, 67.84% female). The treatment arms included daridorexant 25 mg/day (DAR25), daridorexant 50 mg/day (DAR50), lemborexant 5 mg/day (LEM5), lemborexant 10 mg/day (LEM10), suvorexant 20 mg/day (15 mg/day for people ≥65years, SUV20/15), and placebo. All active-treatments outperformed placebo in terms of all efficacy outcomes. The standardized mean difference (95% CI) in primary outcomes ranged from; sTSO: −0.430 (−0.568, −0.292) for LEM10 to −0.164 (−0.296, −0.031) for SUV20/15 and sTST: −0.475 (−0.593, −0.357) for DRA50 to −0.206 ( −0.330, −0.082) for LEM5. An additional sensitivity analysis suggested that DRA25, LEM10, and SUV20/15 were associated with a higher incidence of somnolence compared to a placebo.ConclusionsConsidering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults.
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AbstractSchizophrenia (ScZ) is characterized by prominent perceptual abnormalities. A deeper understanding of the neural mechanisms underlying these abnormalities is crucial for developing precise treatment strategies. Our study aimed to address the following primary questions. First, the functional role of various sub-oscillations within the alpha band remains unclear. Second, we aimed to identify biomarkers for the diagnostic purposes of ScZ. Third, the broader question of whether the diagnostic biomarker can also function as a treatment biomarker remains unknown. Resting-state EEG data from 55 ScZ patients and 61 healthy controls were analyzed to compare different sub-oscillations in the alpha band and their correlation with clinical symptoms (as measured by the general psychopathology scale). We discovered that distinct topographic patterns in low (~8 Hz) and high (~12 Hz) alpha may serve specific diagnostic and evaluative purposes respectively. Moreover, a pronounced gender bias was also observed. Low-alpha-band activity appeared to have more diagnostic relevance in females. On the other hand, the high-alpha difference was more relevant for evaluating the severity of symptoms in ScZ males. Our research has brought new insights into the neural oscillation mechanism of schizophrenia, which could substantially assist the formulating diagnosis of ScZ and the development of its treatment strategies.
AbstractSerum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P< 10−5) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P< 5 × 10−8) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.
AbstractPost-traumatic stress disorder (PTSD) is a delayed-onset or prolonged persistent psychiatric disorder caused by individuals experiencing an unusually threatening or catastrophic stressful event or situation. Due to its long duration and recurrent nature, unimodal neuroimaging tools such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and electroencephalography (EEG) have been widely used in the diagnosis and treatment of PTSD for early intervention. However, as compared with an unimodal approach, a multimodal imaging approach can better capture integrated neural mechanisms underlying the occurrence and development of PTSD, including predisposing factors, changes in neural activity, and physiological mechanisms of symptoms. Moreover, a multimodal neuroimaging approach can aid the diagnosis and treatment of PTSD, facilitate searching for biomarkers at different stages of PTSD, and explore biomarkers for symptomatic improvement. However, at present, the majority of PTSD studies remain unimodal, while the combination of multimodal brain imaging data with machine learning will become an important direction for future research.
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AbstractDepression and anxiety are disabling and high incidence mental disorders characterized by phenotypic heterogeneity. Currently available treatments show severe limitations. Thus, there is an urgent need for effective treatments in this population. In the search for novel rapid-acting antidepressants, the psychedelic psilocybin has emerged as a promising therapy in several clinical trials. However, its antidepressant mechanism of action is still not well understood. The aim of the present study was to evaluate the therapeutic potential of psilocybin in ameliorating the adverse behavioural and neurochemical consequences of chronic stress. To this end, a chronic unpredictable mild stress (CUMS) animal model was used, and psilocybin treatment was administered (two doses of 1 mg/kg, i.p., administered 7 days apart). Psilocybin reversed impairments in anhedonia and behavioural despair dimensions of depressive phenotype but not in apathy-related behaviour. Psilocybin administration was also able to exert an anxiolytic-like effect on treated animals. Physiological alterations caused by stress, indicative of a hyperactive hypothalamic-pituitary-adrenal axis (HPA), were not reversed by psilocybin. When neuroplasticity-related proteins were assessed in cerebral cortex, brain-derived neurotrophic factor (BDNF) was found to be decreased in stressed animals, and treatment did not reverse such impairment. Psilocybin administration increased the expression and function of serotonin-2A-receptor (5HT2AR) in brain cortex of control and CUMS groups. Furthermore, psilocybin treatment caused a selective increase in the expression of glucocorticoid-receptor (GR) in brain cortex of CUMS mice. In conclusion, psilocybin was able to rescue impairments in the depressive phenotype, and to induce anxiolytic-like effects. Furthermore, an enhancement in sensitivity to psilocybin-induced HTR was observed following a booster dose. Altogether, this work provides new knowledge on the putative benefit/risk actions of psilocybin and contributes to the understanding of the therapeutic mechanism of action of psychedelics.
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AbstractConsidering the complexity of serotonergic influence on emotions, we conducted a comprehensive investigation of the interplay between emotion processing and the serotonergic system using simultaneous functional and molecular neuroimaging during pharmacological challenge while disentangling the effects of serotonin transporter (SERT) binding, genotype, and diagnosis of major depressive disorder (MDD). Herein, 153 subjects (44 with MDD) performed a facial emotion processing task during functional magnetic resonance imaging (fMRI) before and after an acute intravenous application of 8 mg citalopram or placebo. Patients with MDD were assessed again after at least three months of antidepressant treatment. Citalopram administration resulted in a reduced fMRI activation in regions involved in fear processing, including the anterior cingulate cortex (ACC), when viewing fearful faces contrasted against happy or neutral faces. ACC activation correlated negatively with striatal/thalamic SERT availability across drug conditions as measured by [11 C]DASB positron emission tomography. Across groups, citalopram-induced changes in ACC activation correlated with emotional attribution, indicating stronger reductions for subjects with higher self- versus other- attribution. Moreover, striatal SERT availability mediated the influence of the number of 5-HTTLPR/rs25531 LAalleles on ACC activation under placebo. Patients with MDD exhibited increased activations in the intraparietal and superior frontal sulcus in response to fearful versus happy faces at baseline, and along the parieto-occipital/calcarine fissure after treatment. We interpret our findings on multiple levels of the serotonergic-emotional interaction within the context of enhanced passive coping and acute anxiolytic effects of citalopram following potential changes in serotonin or SERT availability.
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AbstractMajor depressive disorder (MDD) ranks among the leading causes of disability worldwide. An additional burden arises from treatment-resistance, defined by a lack of response to two or more adequate pharmacotherapeutic treatment trials. Unlike in MDD, where the serotonin 1A receptor subtype (5-HT1A) has commonly been used to study pathophysiological alterations, treatment-resistant depression (TRD) subjects represent a less investigated cohort. In this cross-sectional study, 5-HT1Areceptor binding was assessed in 33 subjects with TRD with stable medication and 44 healthy control (HC) subjects. Positron emission tomography scans with the radioligand [carbonyl-11C]WAY-100635 were acquired and 5-HT1Areceptor nondisplaceable binding potential (BPND) was quantified using the multilinear reference tissue model 2. Regional BPNDin amygdala, anterior cingulate cortex, hippocampus, insula, orbitofrontal cortex, dorsal raphe nucleus and median raphe nucleus was assessed using a multivariate analysis of covariance (MANCOVA). The MANCOVA showed a significant effect of group (F = 3.349,p< 0.05) and sex (F = 2.428,p< 0.05). The subsequent pairwise comparison revealed a lower BPNDby 17.45% in the TRD group in the dorsal raphe nucleus (mean difference ± SE = −0.59 ± 0.24,p< 0.05) and by 18.39% in the median raphe nucleus (mean difference ± SE = −0.71 ± 0.30,p< 0.05). Our results extend previously reported alterations of 5-HT1Areceptor distribution in non-resistant depression to TRD. Ultimately, this knowledge may contribute to clarifying the role of serotonin and help to address the urgent issue of treatment resistance in depression.
AbstractA delay in brain maturation is a hypothesized pathomechanism of attention-deficit/hyperactivity disorder (ADHD). Differences in emotion regulation are associated with phenotypic and prognostic heterogeneity in ADHD. The development of emotion regulation is driven, in part, by brain maturation. Whether the difference between an individual’s brain age predicted by machine-learning algorithms trained on neuroimaging data and that individual’s chronological age, i.e. brain-predicted age difference (brain-PAD) predicts differences in emotion regulation, and whether ADHD problems add to this prediction is unknown. Using data from the Adolescent Brain Cognitive Development Study, we examined, in 2711 children (Mage= 120.09 months,SD= 7.61; 54.15% female; 61.23% white), whether adjusting for action cancellation (inhibition), age, sex assigned at birth, psychotropic treatment, and pubertal status, brain-PAD in late childhood predicts self-reported emotion regulation in early adolescence (at 3-year follow-up), and whether parent-reported ADHD problems predict self-reported emotion regulation above and beyond brain-PAD. Greater brain-PAD predicted greater expressive suppression (b= 0.172,SE= 0.051,pFDR= 0.004), whereas ADHD problems did not (b= 0.041,SE= 0.022,pFDR= 0.124), model marginalR2= 0.020. This pattern of results was replicated across sensitivity tests. Neither brain-PAD, nor ADHD problems predicted cognitive reappraisal,pFDRs = 0.734. Clinically, consistent with earlier findings linking greater brain-PAD to psychopathology, we observed that greater brain-PAD in childhood—but not ADHD problems—predicted expressive suppression in early adolescence. Expressive suppression is implicated in the etiology, maintenance, and treatment of numerous psychopathologies, highlighting the relevance of brain-PAD in understanding developmental risk mechanisms. Conceptually, these findings further validate brain-PAD as a valuable tool for advancing developmental neuroscience.
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AbstractCellular prion protein (PrPC) and tau are highly expressed in the brain and overlap at the cellular level in neurons. Both proteins contribute directly to neurodegeneration processes in a misfolding state, although in their natural conformation, they play important roles in neurogenesis that could have a common link according to the recent literature. In this sense, it is well known that the proteinase-K resistant PrPCisoform (PrPSc), the prion, is the causal agent of prionopathies. And misfolded tau, which is responsible for tauopathies, is considered “prion-like” because it displays similar behavior to prions in terms of self-aggregation and spreading properties. At the physiological level, PrPCpotentiates neuronal differentiation while tau intervenes in axonal maturation and elongation. Likewise, recent studies from our laboratory reported that PrPCdirectly affects the alternative splicing of tau through inhibition of GSK3β while tau, in turn, can regulatePRNPtranscription. In this review, we first describe the biology and physiological roles of PrPCand tau in the central nervous system (CNS). Second, in the effort to improve our understanding of a possible cooperation between them in various cellular circumstances, we also discuss the molecular convergence points between PrPCand tau in neurodegeneration and in natural neuronal physiology.
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AbstractNeuropathic pain is a serious neurological disorder caused by lesioned somatosensory neurons characterized by multiple pathologies. Transient receptor potential vanilloid 1 (TRPV1) channels and opioid receptors are co-expressed in dorsal root ganglia (DRG) and play a crucial role in the development of neuropathic pain. Here, we investigated the possible involvement of TRPV1 channels and µ-opioid receptors in mediating the antinociception of the KATPopener, nicorandil, in neuropathic pain in four nociceptive models: chronic constriction injury of the sciatic nerve (CCI), formalin, capsaicin, and acetic acid writhing tests. Nicorandil (150 mg/kg, twice, 2 h apart, PO) administered to male rats (i) reversed the effects of CCI on nociceptive threshold and cumulative scores assessed by von Frey and acetone test, respectively; (ii) reduced licking time and number of flinches in biphasic formalin and capsaicin tests, and (iii) reduced the number of writhes in the acetic acid test; and (iv) combined nicorandil-capsaicin abolished acetic acid induced writhing response. Similarly, ipsilateral intraplantar injection of nicorandil (37.5 mg/paw, twice, ipl) inhibited nociceptive responses induced by capsaicin, formalin, and acetic acid. Immunohistochemical analysis revealed that nicorandil blunted the CCI-induced elevation of TRPV1 protein expression in DRG. The beneficial effects of nicorandil in all models were attenuated by naloxone. Molecular docking supported the interaction between nicorandil and TRPV1. Histologically, nicorandil improved the pathological changes induced by CCI in the sciatic nerve and DRG. Collectively, these results demonstrate that nicorandil exhibits antinociceptive effects in neuropathic and nociceptive pain via mechanisms involving TRPV1 modulation and opioid receptor signaling. Further investigation is warranted to explore the mechanism of action of nicorandil as an alternative treatment option for neuropathic pain.
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AbstractCerebral ischemia–reperfusion injury (CIRI) induces significant microglial inflammation. V-type immunoglobulin domain–containing suppressor of T cell activation (VISTA), a novel inhibitory immune checkpoint, participates in myeloid cell metabolism. This study aims to investigate the molecular mechanisms of VISTA’s protective effects on CIRI by modulating microglial metabolism. In this study, differentially expressed genes (DEGs) were extracted from GSE77986 to identify hub gene VISTA. Transient middle cerebral artery occlusion (tMCAO) and oxygen–glucose deprivation and reoxygenation (OGD/R) were conducted to mimic CIRI. AAVMG1.2-VSIR was injected intracerebroventricularly into Cx3cr1Cremice, while over-expression plasmids were transfected into BV2 to intervene VISTA. The mice underwent LONGA scoring, H&E, Nissl, and TTC staining. Western blot and qRT-PCR were conducted for VISTA, IL-6, TNFα, IL-1β, and IL-10. Microglial proliferation was assessed by Edu staining and CCK8. RNA-sequencing (RNA-seq) analysis was used to investigate downstream pathways. Tricarboxylic acid (TCA) cycle intermediates were measured using ELISA. ACOD1/IκBα/NF-κB pathway was validated by Western blot. Eight DE-ICGs were identified through differential analysis, with VSIR exhibiting the highest expression. Additionally, VISTA was found decreased in microglia around the infarction site. Compared with CIRI group, VISTA reduced the infarct volume, improved neurological deficit, and decreased IL-6, TNFα, and IL-1β, while increasing IL-10, and suppressing microglia proliferation. RNA-seq showed that the DEGs primarily participated in microglial glucose metabolism and the IκBa/NF-κB pathway. VISTA promoted ACOD1 expression and itaconate (ITA). The protective function on CIRI and inhibitory effect on IκBa/NF-κB of VISTA were abrogated by ACOD1 knockdown.
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AbstractRetrospective diagnosis of a seizure type is pivotal for effective management and treatment of epilepsy. Previously, we demonstrated that RNA signatures could discriminate between non-epileptic spells and epileptic seizures. Here, we investigate the utility of alternative RNA splicing to distinguish generalized versus focal epileptic seizures. Blood samples were collected at baseline, 4–6 h post-seizure, and at discharge from 27 patients undergoing video-electroencephalogram (vEEG) monitoring at the Emory University Hospital. Epileptologists determined seizure classification through vEEG data review. RNA was extracted, sequenced, and analyzed for RNA expression and transcript usage. Classification models were generated to distinguish between patients who had a focal or generalized seizure. The study shows transcriptomic profile changes following EEG-verified focal and generalized seizures. Compared to baseline, focal seizure exhibits limited changes in transcriptomic expression 4–6 h post-seizure and discharge samples. In contrast, generalized seizures demonstrated a broader transcript response, with 74 differentially expressed transcripts at 4–6 h and 70 at discharge. The changes were also evident across different time points between focal and generalized seizure. The study for the first time described the landscape of isoform switching in seizure type. Notably, significant isoform switching without differences in gene expression was observed. We identified 2689 isoform switches linked to 1249 genes among which 742 genes were sensitive to nonsense-mediated mRNA decay (NMD). Significant switches were observed in genes such as CORO1C, ZBTB44, SNHG1, and RPS17. Notably, we also observed novel isoforms, including CD300 (MSTRG.26116.1), RNF216 (MSTRG.52862.7), and RN7SL1 (MSTRG.17010.3) which exhibited significant switching, revealing potential new regulators of gene expression. Differentially expressed transcripts were utilized as classifiers for machine learning (ML) modeling using random forest (rf) and radial support vector machine (rSVM) algorithms, achieving ~ 83% accuracy in classifying generalized seizures, and multivariate adaptive regression splines (mars) algorithm achieving 100% accuracy in identifying focal seizure events. Our findings of blood transcript expression changes, including isoform switch analysis, underscore the potential of blood-based transcriptome analysis for retrospectively distinguishing seizure types and identifying biomarkers for epilepsy management.
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AbstractAttention-deficit/hyperactivity disorder, or ADHD, is a neurodevelopmental disorder with poorly understood molecular mechanisms. Recent studies have proposed that gene expression involved in regulating synaptic transmission in the striatum may play a role in ADHD pathogenesis. To explore the molecular basis of ADHD, we utilized proteomic analysis using whole striatal tissues from early adult thyroid hormone-responsive protein-overexpressing (THRSP-OE) mice, which displayed defining characteristics of predominantly inattentive ADHD (ADHD-PI). We focused on the striatal brain region due to its critical role in the regulation of attention, motivation, and reward processing. Moreover, the striatum modulates dopaminergic pathways that are known to be impaired in ADHD. Our analysis revealed an innate overexpression of Snap25 protein in THRSP-OE mice, indicating possible alterations in the SNARE protein complex and potential neurotransmitter dysregulation. Furthermore, a binding affinity study showed reduced dopamine D1 receptor binding concentrations and pronounced low dopamine levels in THRSP-OE mice. Repeated seven-day injections of methylphenidate improved the low dopamine levels, reducing the EEG theta/beta ratio in this animal model. These findings suggest new markers specific to the ADHD-PI presentation and further support the role of Snap25 dysregulation and possible SNARE protein complex alterations in ADHD-PI.
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AbstractMetformin is an anti-diabetic drug used in the management of type 2 diabetes (T2D). Metformin has different pleiotropic effects, such as anti-inflammatory, antioxidant, antithrombotic, and vasculoprotective. Metformin has neuroprotective effects against neurodegenerative diseases and ischemic stroke. Conversely, metformin may exacerbate the pathogenesis of ischemic stroke. This controversial point may be related to the impact of metformin on the different signaling pathways, such as AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15). Many studies have reported the effect of metformin on ischemic stroke, with AMPK signaling only. However, little has been explored about the impact of metformin on the GDF-15 signaling in ischemic stroke. Accordingly, this review aims to discuss the role of metformin in the neuropathology of ischemic stroke regarding the AMPK and GDF-15 signaling pathways.
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AbstractThe cognitive and regulatory processes within higher-order brain structures that regulate the hypothalamic–pituitary–adrenal (HPA) axis and the limbic system orchestrate a complex stress response system. In order to address this, we collected 48 tissue samples from the amygdala (Amy), hippocampus (Hip), thalamus (Tal), hypothalamus (HT), pituitary gland (PG) and adrenal gland (AG). We applied ATAC-seq, a method for profiling accessible chromatin, to map the epigenetic landscape of these brain and endocrine tissues in pigs and generate foundational baseline chromatin accessibility datasets that can serve as a reference for future studies. A total of 321,584 consensus peaks, representing open chromatin regions across various samples and tissues in the pig genome, were identified. Screening for transcription factor binding motifs within these chromatin-accessible regions revealed 377 significantly enriched motifs in at least one tissue (p≤ 0.001). Among the 93 motifs enriched in only one tissue, some showed concordant expression of their corresponding transcription factors, includingGRHL2andKLF5in the PG, andGATA4/6, andHAND2in the AG. Differentially accessible regions (DARs), particularly in promoter regions, between brain and endocrine tissues were identified, with functional specificities in the AG, including cortisol synthesis and secretion, as well as tyrosine metabolism. The cytokine-cytokine receptor interaction and neuroactive ligand-receptor interaction pathways showed greater enrichment and open chromatin accessibility in brain regions compared to endocrine tissues (PG or AG). This study provides valuable insights into brain transcriptional regulation and adds a novel layer of information for future research on genetic improvement and animal welfare.
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AbstractExcitotoxic damage caused by high extracellular levels of glutamate in the spinal cord results in neuronal loss and severe locomotor impairment. This study investigates the efficacy of NeuroAiD II (MLC901), an herbal formulation, in promoting nerve regeneration following spinal cord injury (SCI) induced by kainic acid (KA). KA, a potent glutamate receptor agonist, causes excitotoxic damage in the spinal cord, leading to neuronal loss and locomotor impairment. To explore the potential of MLC901, KA-injured rats were treated with MLC901, and nerve regeneration was evaluated using various techniques. In this study, KA was administered intrathecally between the T12 and T13 vertebrae in rats, resulting in incomplete paraplegia. MLC901 was then tested for its neuro-regenerative potential. Various assessments were conducted to evaluate the effects of MLC901 treatment, including behavioral, electrophysiological, and histopathological analyses. Behavioral tests, such as the Basso, Beattie, and Bresnahan (BBB) open field test, running wheel, grid walk, inverted grid, and sensory tests, showed significant improvements in locomotor activity in treated rats. Electrophysiological recordings indicated that, while KA injection caused reduced amplitude and delayed latency, MLC901 treatment helped restore lost connections on days 14 and 28. Histopathological and immunohistochemical analyses also revealed improved tissue integrity and neuron survival. The study concludes that MLC901 significantly enhances locomotor recovery, somatosensory evoked potentials, and tissue preservation following SCI. These findings suggest that MLC901 holds promise as a neuro-regenerative therapy for spinal cord injuries.
AbstractParkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor and non-motor symptoms. PD neuropathology is due to the progressive deposition of mutant alpha-synuclein (α-Syn) in the dopaminergic neurons of the substantia nigra pars compacta (SNpc). This effect initiates oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis of the dopaminergic neurons in the SNpc. PD neuropathology, which is closely associated with inflammatory and oxidative disorders, disrupts different vital cellular pathways. Notably, the current anti-PD medications only relieve the symptoms of PD without averting the underlying neuropathology. Thus, it is advisable to search for novel drugs that attenuate the progression of PD neuropathology. It has been shown that phosphatidylinositol 3-kinase (PI3K), AKT, and glycogen synthase kinase 3 beta (GSK3β) signaling pathways are affected in PD. PI3K/AKT pathway is neuroprotective against the development and progression of PD. However, the over-activated GSK3β signaling pathway has a detrimental effect on PD neuropathology by inducing inflammation and oxidative stress. Dysregulation of the PI3K/AKT/GSK3β signaling pathway provokes brain insulin resistance (BIR), neuroinflammation, and neuronal apoptosis, the hallmarks of PD and other neurodegenerative diseases. However, the mechanistic role of the PI3K/AKT/GSK3β signaling pathway is not fully clarified. Therefore, in this review, we intend to discuss the role of the PI3K/AKT/GSK3β signaling pathway in PD pathogenesis and how PI3K/AKT activators and GSK3β inhibitors have helped effectively manage PD.
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AbstractSH-SY5Y cells are widely used as an in vitro neuronal model, yet reliable differentiation protocols tailored for tauopathy research remain limited. Effective differentiation is essential for studying tau aggregation, propagation, and neurodegenerative mechanisms. Here, we present an optimized two-step differentiation protocol for TauP301L-expressing SH-SY5Y cells that enhances neuronal maturation and tauopathy modeling, providing a physiologically relevant system for investigating tau seeding. SH-SY5Y cells expressing TauP301L-EGFP under an inducible system were differentiated using a two-step protocol consisting of retinoic acid (RA) for 72 h, followed by brain-derived neurotrophic factor (BDNF) and RA for 72 h. Differentiated neurons were then exposed to exogenous P301L tau peptide fibrils to assess their susceptibility to tau seeding and aggregation. Differentiation resulted in increased neurite outgrowth, cholinergic marker expression (ChAT upregulation, TH downregulation), and upregulation of the mature 2N4R tau isoform. Western blot analysis showed increased T22 and pSer262 tau immunoreactivity in seeded cells, consistent with tau conformational changes and pathological phosphorylation. These findings may reflect early stages of tau misfolding but do not confirm oligomer formation. Seeding also induced neurite remodeling, varicosity formation, and reduced neurite diameter—features consistent with tau-mediated pathology involving cytoskeletal changes, organelle accumulation, or axonal transport defects. This optimized differentiation protocol provides an experimentally tractable tauopathy model for investigating tau propagation and neuronal dysfunctions in a controlled human cell context. Compared to existing SH-SY5Y differentiation methods, our system provides faster neuronal maturation, controlled TauP301L induction, and enhanced tau isoform expression, making it a valuable platform for studying early tau misfolding events and therapeutic interventions in tauopathies.
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AbstractMultiple sclerosis (MS) is an autoimmune neurodegenerative disorder, with relapsing–remitting MS (RRMS) being the most common subtype. Interferon-γ (IFN-γ) plays a dual role in MS pathogenesis. MicroRNAs (miRNAs) have emerged as potential diagnostic biomarkers. This study examined the effect of relative expression of hsa-miR-24-3p and hsa-miR-181d-3p, plasma IFN-γ levels, and theIFNGrs2069727 T/C variant on MS risk, evaluating their interrelationships and diagnostic potential. This case–control study comprised two overlapping groups—a genetic polymorphism group (330 RRMS, 330 healthy controls (HCs)) and a miRNA group (25 glatiramer acetate (GA)-treated RRMS patients, 25 treatment-naïve RRMS patients, and 25 HCs)- collected at the Ankara Bilkent City Hospital Neurology Polyclinic. TheIFNGrs2069727 T/C variant did not display a statistically significant disparity between RRMS patients and HCs. Significantly elevated hsa-miR-24-3p and hsa-miR-181d-3p relative expression levels were observed in GA-treated and treatment-naïve RRMS patients compared to HCs. Conversely, age-adjusted plasma IFN-γ concentrations were markedly lower in GA-treated and treatment-naïve RRMS patients versus HCs. Individuals with low plasma IFN-γ levels (≤ 1.311 pg/mL) demonstrated significantly elevated hsa-miR-24-3p relative expression compared to the high IFN-γ group (> 1.311 pg/mL). Conversely, subjects with low hsa-miR-181d-3p levels (≤ 2.90) exhibited significantly higher plasma IFN-γ concentrations relative to those with high hsa-miR-181d-3p levels (> 2.90). In the GA-treated group, EDSS negatively correlated with age-adjusted plasma IFN-γ. This study identified age-adjusted plasma IFN-γ, hsa-miR-24-3p, and hsa-miR-181d-3p expression as potential blood-based biomarkers for RRMS diagnosis and analyzed them alongside disability scores. The miRNAs in this study can be further evaluated as prospective therapeutic targets.
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AbstractPanax ginseng (PG)is a medicinal plant used for many years to treat many diseases. The current study aimed to investigate the possible prophylactic and therapeutic effects of PG extract on doxorubicin (DOX)-induced testicular toxicity in rats. 32 adult male Sprague–Dawley rats (200–250 g) were used in the experiment. The experimental groups were designed as control (normal saline, intraperitoneal), DOX (18 mg/kg, intraperitoneal), PG (200 mg/kg, gavage), and PG + DOX (200 mg/kg, gavage). After treatment, serum levels of testosterone, interleukin-1β (IL-1β), glutathione (GSH), luteinizing hormone (LH), superoxide dismutase (SOD), lactate dehydrogenase (LDH), catalase (CAT), follicle stimulating hormone (FSH), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) were measured. Then, gene expression, histopathological, and immunohistochemical analyses were performed on testicular tissues. Compared to DOX, treatment with PG + DOX showed a significant improvement in serum levels of FSH, testosterone, LH, TNF-α, IL-1β, MDA, SOD, LDH, GSH, and CAT. It was also observed that PG + DOX decreased nuclear factor-κB and cyclooxygenase-2 expression levels, increased androgen receptor expression, restored testicular histopathological structure, and significantly improved spermatogenesis. The results of the present study showed that PG may have an ameliorative effect against DOX-induced male reproductive toxicity, as DOX causes male reproductive toxicity. It can be concluded that PG is one of the effects that protect against DOX-induced testicular toxicity in rats by reducing lipid peroxidation and activating the antioxidant system. In light of this information, PG may be a useful agent to prevent the testicular toxicity observed in men receiving DOX treatment.
AbstractParkinson’s disease (PD) pathogenesis involves complex interactions between genetic factors. We employed two-sample Mendelian randomization (MR) integrating tissue-specific gene regulatory networks to identify causal genes and regulatory elements modulating PD risk. Two-sample MR analysis identified 79 putative causal genes for PD. A subset of the 79 causal genes was enriched within chr17q21.31 and chr16p11.2 cytobands that have been previously linked to neurodevelopmental disorders. Functional enrichment analysis of the 79 genes revealed autophagosome-lysosome fusion as a key process. Ten genes (ELOVL7,HSD3B7,PLEKHM1,PRSS53,SNCA,STX1B,STX4,ZSWIM7,LINC02210, andRP11-1072 A3.3) showed causal associations with tissue-specific expression patterns driving risk or protection for PD. Further investigation into their tissue-specific isoform expression profile revealed isoform-specific contributions to disease risk (or protection). These findings highlight the critical role of isoform-specific expression of causal genes in modulating PD risk, particularly relating to autophagosome-lysosome fusion. While our findings provide new insights into PD susceptibility, we acknowledge that the observed isoform-specific changes may, in part, reflect sample selection bias. Therefore, further experimental verification is needed to confirm the importance of incorporating tissue-specific gene isoform profiles in understanding PD causal mechanisms.
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AbstractLong non‐coding RNAs (lncRNAs) play an important role in the regulation of skeletal muscle transcriptional processes, but their involvement in spaceflight‐ or inactivity‐induced muscle atrophy remains poorly understood. To address this gap we simulated the space environment by combining microgravity, irradiation and stress in a mouse model. This simulation resulted in the differential expression (threshold set atP< 0.01) of 6191 protein‐coding genes (3525 downregulated and 2666 upregulated compared to controls) and 465 lncRNAs, of which 27% were downregulated and 73% upregulated compared to controls. Particularly several previously identified lncRNAs involved in muscle regulation were affected, including H19 (log fold change, logFC: −2.0), Gm29773 (logFC: −1.4), Pvt1 (logFC: 0.63), Kcnq1ot1 (logFC: 0.31) and Lncpint (logFC: 0.86). To determine whether similar changes occurred in humans, we examined the expression of lncRNAs during long‐term (3 months) head‐down tilt bed rest, a model for microgravity‐induced muscle atrophy. We found that Kcnq1ot1 and Lncpint (human homologues KCNQ1OT1 and LINC‐PINT) were upregulated in response to simulated microgravity. In addition KCNQ1OT1 was increased in a human 3‐Din vitromodel of muscle atrophy. These results are the first to demonstrate the involvement of lncRNAs in spaceflight‐ and severe inactivity‐induced muscle atrophy, in particular KCNQ1OT1 and LINC‐PINT. Our study provides novel insights into the contribution of lncRNAs to muscle atrophy caused by the space exposome and has broader implications for understanding and combating muscle atrophy in clinical scenarios of prolonged inactivity. Future research can build on these findings to investigate the therapeutic potential of lncRNAs in muscle atrophy.imageKey pointsThe combination of unloading, irradiation and stress led to a significant reduction in skeletal muscle mass and marked transcriptional responses (6191 differentially expressed genes) in the skeletal muscle of mice.The simulated space exposome led to the differential expression of 465 long non‐coding RNAs (lncRNAs) in mouse skeletal muscle.Two lncRNAs upregulated in mice – Kcnq1ot1 and Lncpint – were also upregulated in human muscle after 3 months of bed rest (human homologues KCNQ1OT1 and LINC‐PINT).KCNQ1OT1, but not LINC‐PINT, was upregulated in a human 3‐Din vitromodel of muscle atrophy.This study offers fundamental insights into the role of lncRNAs in muscle atrophy induced by the space exposome. These findings have broader implications for understanding and mitigating muscle atrophy in clinical settings, such as prolonged inactivity.
AbstractHistomorphometric differences in cell‐matrix properties were analysed between ascending thoracic aortic aneurysm (ATAA), dissection (ATAAD) and non‐aneurysmal patients, as well as across the circumference of the aneurysms in ATAA cases. Fresh anterior aortic wall samples were collected during surgery. A significant radius‐to‐intima‐media thickness (IMT) ratio variation was observed among ATAA patients, indicating patient‐specific adaptive responses. The radius‐IMT ratio was significantly lower in ATAAD patients. The quantity and quality of elastin and the quantity of collagen were particularly reduced in ATAAD compared to ATAA and non‐aneurysmal aortas. Matrix degradation was accompanied by an increase in the density of vascular smooth muscle cells (VSMCs), albeit with reduced expression of VSMC contractile markers (calponin and α‐smooth muscle actin (α‐SMA)). Concomitantly ATAA and ATAAD samples exhibited increased markers (matrix metalloproteinase (MMP)‐2/9) of proteolysis. Based on radius‐IMT ratios we roughly identified ‘thickening’ and ‘thinning’ (i.e. hypertrophic and hypotrophic) aneurysm variants to capture the substantial variation in the loss of mechanical homoeostasis in ATAA. Interestingly we did not find conspicuous differences along the circumference of excised aneurysms in ATAA, except for an increased IMT heterogeneity in ‘thinning’ aneurysms. We conclude that during aneurysm formation wall stress homoeostasis may remain partially intact, particularly in ‘thickening’ ATAA. Our study underscores the current critique that aneurysm dimensions are poor risk predictors; therefore there is a crucial need for better‐informed preventive intervention in ATAAD.imageKey pointsAscending thoracic aortic aneurysm (ATAA) variants can be categorised as aortic medial thickening (hypertrophic) or aortic medial thinning (hypotrophic) based on the radius‐to‐intima‐media thickness (IMT) ratio, reflecting distinct disruptions in mechanical homoeostasis.Morphological patterns arise from dynamic interactions in the aortic medial layer between vascular smooth muscle cells (VSMCs) and the extracellular matrix (ECM).Increased number of synthetic VSMCs in the medial layer of ATAA patients is a compensatory response to maintain vessel elasticity and structural integrity.In acute type A aortic dissection (ATAAD) aortas with medial thinning are characterised by ECM breakdown and maladaptive remodelling.ATAA development is circumferentially homogeneous, despite the occurrence of inter‐ and intrapatient variability in vascular architecture, composition and VSMC characteristics.
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AbstractElevated cytoplasmic [Ca2⁺] and protein kinase C (PKC) activation are key signalling events driving secretion in pancreatic acinar cells after stimulation by the secretagogues cholecystokinin (CCK) and acetylcholine (ACh). Although both ACh and CCK binding to their cognate receptors activates Gq/11proteins, leading to inositol 1,4,5‐trisphosphate (IP₃)‐mediated Ca2⁺ release and diacylglycerol (DAG)‐dependent PKC activation, it has been proposed that physiological CCK stimulation bypasses this canonical pathway, instead mobilizing Ca2⁺ via production of nicotinic acid adenine dinucleotide phosphate (NAADP). We reassessed the role of Gq/11signalling in CCK‐induced responses using a bioluminescence resonance energy transfer (BRET) assay, demonstrating that both CCK1 (CCK1R) and muscarinic M3 receptors (M3R) engage Gq/11along with other Gα subunits. Importantly YM‐254890, a Gq/11antagonist, inhibited coupling through Gq/11but did not alter the interactions of CCK1R or M3R with other G protein families. YM‐254890 eliminated CCK1R‐ and M3R‐induced Ca2⁺ signals in isolated acinar cells. Consistent with thein vitrodata, systemic CCK injection, intrinsic neural stimulation or feeding failed to elicit Ca2⁺ responsesin vivoin mice pre‐treated with YM‐254890, indicating that physiological stimulation of Ca2+signalling events requires Gq/11activation. Additionally YM‐254890 suppressed Ca2⁺‐activated Cl⁻ currents, a key event underlying fluid secretion, and amylase secretion in acini after CCK or ACh stimulation. These findings establish that CCK‐ and ACh‐induced exocrine pancreatic secretion strictly requires Gq/11activation, leading to IP₃ generation, DAG production and downstream signalling that is essential for physiological function.imageKey pointsAn increase in cytoplasmic Ca2+and PKC activity after CCK and ACh stimulation following feeding is a pivotal event in the activation of fluid secretion and exocytosis from pancreatic acinar cells.In contrast to ACh, it has been suggested that at physiological concentrations, CCK stimulation results in the production of nicotinic acid dinucleotide adenine phosphate, without activating the canonical Gq/11pathway, and the production of inositol 1,4,5,‐trisphosphate (IP3) and diacylglycerol (DAG).After having established that YM‐254890 is an exquisitely selective Gq/11inhibitor, we show that Ca2+signals stimulatedin vitroandin vivoin response to both M3R and CCK1R stimulation are completely inhibited by YM‐254890.YM‐254890 completely abrogates Ca2+‐activated Cl−current activation, pivotal for fluid secretion together with amylase secretion stimulated by both M3R and CCK1R activation.We conclude that ACh and CCK stimulation results in Gq/11 activation, an increase in IP3and DAG, and this event is fundamentally important for exocrine function.
AbstractElectrophysiological mapping is essential for understanding these mechanisms and guiding therapeutic treatments. However, approaches such as invasive electrical mapping, body surface mapping and electrocardiographic imaging face challenges, including low spatial resolution, far‐field interference and signal processing limitations. By contrast, panoramic optical mapping, using fluorescent dyes, offers high spatial resolution and allows direct measurement of cellular action potentialex situ. Can the integration of panoramic optical mapping with electrical mapping overcome the limitations of the above‐cited techniques and provide deeper insights into arrhythmic mechanisms? To investigate this, we developed an experimental setup that combines 3‐D panoramic optical mapping with multi‐electrode epicardial electrical mapping and non‐invasive electrical mapping (torso‐tank setup) for electrocardiographic imaging in Langendorff‐perfused rabbit hearts. Our results confirm the feasibility of using simultaneous optical and electrical mapping under sinus rhythm, as well as in atrial and ventricular arrhythmias, using time, frequency and phase analyses. During sinus rhythm and ventricular tachycardia, wavefront propagation showed concordance between modalities, where diverges are observed for atrial arrhythmias. Dominant frequency analysis could recover the frequency of activation better than the inverse of cycle length, and outcomes from all mapping modalities agreed. Reconstructed electrograms presented a good similarity compared to electrograms. By correlating optical and electrical mapping, clinically relevant arrhythmia markers and targets for ablation, from invasive and non‐invasive mapping can be better understood and localised. This platform could also serve as a test bed for studying drug effects, connecting changes from cellular action potential levels to whole‐heart electrophysiology.imageKey pointsCardiac arrhythmias are still a significant challenge in electrophysiology, with advancements in experimental and clinical research improving our understanding of mechanisms and target for ablation.Current electrical mapping technology, both invasive and non‐invasive, is used in science and by commercial systems to identify arrhythmic episodes and mechanisms, but has several limitations mimicking the true electrophysiology behaviour.Optical mapping uses fluorescent dyes to measure transmembrane action potentials with high spatial resolution. When combined with electrical mapping, it can enhance cardiac arrhythmia studies and mapping technologies.A novel 3‐D platform that integrates panoramic and electrical mapping techniques (epicardium, non‐invasive torso‐tank and electrocardiographic imaging) is presented and validated in isolated rabbit hearts, highlighting that the mapping strategies do not always agree, helping to further improve commercial systems.
AbstractDisruptions in both circadian clock and mitochondrial dynamics in the skeletal muscle (SkM) have been associated with insulin resistance and sarcopenia. Emerging evidence, in resting conditions and in response to metabolic challenges like exercise, suggests the intricate interplay between the circadian clock, mitochondrial dynamics and SkM function. However the molecular mechanisms that connect the circadian clock to mitochondrial dynamics and SkM function remain poorly understood. This review focuses on the role of circadian clock proteins, particularly brain and muscle Arnt‐like protein‐1 (BMAL1), in regulating mitochondrial dynamics and examines how their dysregulation contributes to metabolic and SkM deterioration. By exploring their interaction we aim to identify potential therapeutic targets that could improve metabolic health and muscle function.image
AbstractBlindness is a significant condition that triggers the ability of the brain to adapt to environmental changes through plasticity processes. This study examined somatosensory processing, multisensory integration, kinesthetic motor imagery (MI) and mirror neuron system (MNS) activity in response to auditory stimuli in visually impaired (VI) individuals. The study included 21 individuals with total vision loss, and the findings were compared with 21 participants with normal vision. The somatosensory temporal discrimination threshold (STDT) was used to evaluate somatosensory processing, while transcranial magnetic stimulation (TMS) was employed to measure kinesthetic MI activity and MNS activity in response to auditory stimuli. The results showed that VI individuals had significantly lower STDT values than the control group in conventional STDT measurements. STDT values measured 50, 100 and 300 ms after auditory stimuli in the auditory–tactile sensory integration paradigm. VI participants have significantly lower STDT values than the control group in the auditory–tactile sensory integration test. Most of the participants, who were congenitally blind, exhibited TMS activity during MI processes similar to that of sighted individuals. However, no TMS measurements indicative of MNS activation in response to auditory stimuli were detected in VI individuals using the stimulus paradigm applied in the study. The findings suggest that VI individuals perform better than sighted individuals in both somatosensory processing and multisensory integration while exhibiting similar MI performance to sighted individuals.imageKey pointsVisually impaired (VI) individuals have better somatosensory processing capacity than sighted individuals.The multisensory processing capacities of VI individuals are superior to those of sighted individuals.The enhanced sensory processing and multisensory integration capacities observed in VI individuals may be related to secondary cross‐modal plasticity that develops due to vision loss.
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AbstractN‐Methyl‐d‐aspartate receptors (NMDARs) are a family of ligand‐gated ionotropic glutamate receptors that mediate a slow, calcium‐permeable component to excitatory neurotransmission. The GluN2D subunit is enriched in GABAergic inhibitory interneurons in cortical tissue. Diminished levels of GABAergic inhibition contribute to multiple neuropsychiatric conditions, suggesting that enhancing inhibition might have therapeutic utility, thus making GluN2D modulation an attractive drug target. Here, we describe the actions of a GluN2C/GluN2D‐selective positive allosteric modulator, (+)‐EU1180‐453, which has improved drug‐like properties, such as increased aqueous solubility, in comparison to the first‐in‐class GluN2C/GluN2D‐selective prototypical positive allosteric modulator, (+)‐CIQ. (+)‐EU1180‐453 doubles the NMDAR response at lower concentrations and produces a greater degree of maximal potentiation at 30 µM compared with (+)‐CIQ. Usingin vitroelectrophysiological recordings, we show that (+)‐EU1180‐453 potentiates triheteromeric NMDARs containing at least one GluN2C or GluN2D subunit and is active at both exon5‐lacking and exon5‐containing GluN1 splice variants. (+)‐EU1180‐453 increases glutamate efficacy for GluN2C/GluN2D‐containing NMDARs both by prolonging the deactivation time and by potentiating the peak response amplitude. We show that (+)‐EU1180‐453 selectively increases synaptic NMDAR‐mediated charge transfer onto postnatal day 11–15 CA1stratum radiatumhippocampal interneurons but is without effect on CA1 pyramidal cells. This increased charge transfer enhances inhibitory output from GABAergic interneurons onto CA1 pyramidal cells in a GluN2D‐dependent manner. (+)‐EU1180‐453 also shifts excitatory‐to‐inhibitory coupling towards increased inhibition and produces enhanced gamma‐band power from carbachol‐induced field potential oscillations in hippocampal slices. Thus, (+)‐EU1180‐453 can enhance overall circuit inhibition, which could prove therapeutically useful for the treatment of anxiety, depression, schizophrenia and other neuropsychiatric disorders.imageKey points(+)EU‐1180‐453 is a GluN2C/GluN2D positive allosteric modulator and is active at triheteromeric receptors.(+)EU‐1180‐453 is active at exon5‐containing and exon5‐lacking GluN1‐containing receptors.(+)EU‐1180‐453 selectively potentiates the interneuron network and can enhance carbachol‐induced gamma‐band power.
AbstractGravity changes with respect to the 1gterrestrial condition induce several cardiovascular alterations, from fluid shift and blood volume reduction to orthostatic hypotension and venous pooling. Micro‐gravity and hyper‐gravity exposure characterizes space missions and aeronautical flights, as well as terrestrial analogues such as centrifuges, bed rest studies, and parabolic flights. Despite a growing number of clinical measures becoming available, cardiac function in these extreme conditions is still incomplete and difficult to obtain. Thus, computational haemodynamics provides a powerful and reliable tool to understand the cardiac response. We propose a 0D‐1D multiscale cardiovascular model to investigate the steady‐state acute cardiac response to gravity changes (from 0gto 3g). The model combines a 1D description of the coronary circulation and arterial tree, with a 0D parameterization of the peripheral microcirculation, the venous return, the cardiopulmonary and the cerebrovascular‐ocular circulations. The overall model is equipped with short‐term regulation mechanisms, and accounts for gravity and posture changes. After a thorough validation using measured data from literature involving the most common central haemodynamic parameters (i.e. HR, MAP, SV and CO), the model provides an in‐depth description of the cardiac response from micro‐ (0g) to hyper‐gravity (3g), highlighting: (i) a different behaviour between left and right heart haemodynamics; (ii) an improvement in cardiac efficiency and cardiac performance in micro‐gravity; (iii) a worsening of cardiac efficiency and an energy supply/demand impairment both at heart and coronary levels in hyper‐gravity. Therefore, the modelling approach proves to be an important tool in shedding light on space medicine.imageKey pointsGravity changes from micro‐ to hyper‐gravity induce several cardiovascular alterations, from fluid shift and blood volume reduction to orthostatic hypotension and venous pooling.Although the overall cardiovascular response is clear, details of the cardiac function in these extreme conditions are still incomplete and difficult to obtain.We propose a validated multiscale cardiovascular model to investigate the steady‐state acute cardiac response to gravity changes (from 0gto 3g).After a thorough validation against the most common central haemodynamic parameters in literature, present results show: (i) a different behaviour between left and right heart haemodynamics; (ii) an improvement of cardiac efficiency and cardiac performance in micro‐gravity; (iii) an energy supply/demand impairment in hyper‐gravity.The computational approach is a useful and reliable tool in exploring the response of cardiac parameters which are difficult to investigate experimentally, aiming to shed light on the cardiac function under altered gravitational force.
AbstractParkinson's disease (PD) is a complex, progressive neurodegenerative disorder driven by multiple pathogenetic factors, including oxidative stress, mitochondria dysfunction, neuroinflammation and ion imbalance. Recent evidence highlights the significant role of potassium channels in the pathophysiology of PD. We recently identified a PD‐linked genetic mutation in theKCNJ15gene (KCNJ15p.R28C), encoding the inwardly rectifying potassium channel Kir4.2, within a four‐generation family with familial PD. However, the role of the Kir4.2 channel in neurodegenerative diseases remains largely unexplored. This study aimed to elucidate the impact of theKCNJ15p.R28C(Kir4.2R28C) mutation on the biophysical and biochemical properties of Kir4.2. Employing Kir4.2‐overexpressing HEK293T cells as a model, we investigated how the mutation affects the channel's functional properties, total protein expression, intracellular processing in the endoplasmic reticulum and lysosomes and plasma membrane trafficking. Patch clamp studies revealed that the Kir4.2R28Cmutation results in loss of channel function with significant dominant‐negative effects. This dysfunction is partially attributed to the substantial reduction in overall mutant channel protein expression compared to the wild‐type (Kir4.2WT). We observed that both Kir4.2WTand Kir4.2R28Cproteins undergo glycosylation during the post‐translational modification process, albeit with differing protein turnover efficiencies. Furthermore, the Kir4.2R28Cmutant exhibits reduced stability and compromised plasma membrane trafficking capacity compared to Kir4.2WT. These findings suggest that the Kir4.2R28Cmutant has unique biomolecular and biophysical characteristics distinct from the Kir4.2WTchannel, which potentially elucidates its role in the pathogenesis of PD.imageKey pointsInwardly rectifying potassium channels are increasingly recognized for their critical role in the complex pathogenesis of Parkinson's disease (PD).We previously identified a genetic mutation, Kir4.2R28C, in the inwardly rectifying potassium channel Kir4.2, which strongly segregates with familial PD in a multi‐generational pedigree.This study confirms Kir4.2R28Cas a loss‐of‐function mutation with significant dominant‐negative effects, impairing channel activity even in heterozygous conditions.The Kir4.2R28Cmutation significantly reduces overall protein levels, impairs protein stability and disrupts plasma membrane trafficking inin vitrocell models.
AbstractThe circadian‐regulated transcriptional repressor REV‐ERB‐α is a key mediator of skeletal muscle oxidative capacity, enhancing exercise performance when activated. Conversely its global genetic ablation leads to impaired performance. Simultaneously the kynurenine (KYN) pathway, involved in tryptophan degradation, produces neurotoxic metabolites under stress and inflammation, contributing to CNS dysfunction and fatigue. These mechanisms may underlie the fatigue and performance impairments caused by exhaustive exercise (EE). This study investigated the interplay between REV‐ERB‐α and the KYN pathway in acute and chronic EE models. Time course analyses revealed that EE downregulated REV‐ERB‐α in skeletal muscle, correlated with KYN pathway alterations. Notably KYN metabolism shifted towards a neurotoxic profile, characterized by reduced KYN aminotransferase 1 (KAT1) and increased KYN 3‐monooxygenase (KMO) expression in skeletal muscle, with increased KYN levels in the hippocampus.In vitroexperiments using C2C12 myoblasts showed that REV‐ERB‐α knockout upregulated KAT1 and KMO, whereas overexpression selectively reduced KMO. Pharmacological activation of REV‐ERB‐α with SR9009 upregulated KAT1 in skeletal muscle and reduced KMO in the hippocampus of mice. These findings reveal a dynamic relationship between REV‐ERB‐α and the KYN pathway, linking peripheral and central responses to EE. This study highlights REV‐ERB‐α and the KYN pathway as critical regulators of exercise‐induced fatigue and suggests potential therapeutic targets to mitigate its effects, offering novel insights into the molecular basis of performance impairments associated with EE.imageKey pointsExcessive exercise can impair performance and induce fatigue; however the underlying biological mechanisms remain incompletely understood.Although REV‐ERB‐α activation enhances skeletal muscle oxidative capacity and exercise performance, its deletion impairs both parameters.This study demonstrates that excessive exercise decreases REV‐ERB‐α levels in skeletal muscle and disrupts the kynurenine (KYN) pathway by downregulating KYN aminotransferase 1 (KAT1), an enzyme involved in a neuroprotective branch of the pathway.These alterations affect both skeletal muscle and the brain, suggesting a potential link between physical fatigue and brain function.REV‐ERB‐α suppresses KYN 3‐monooxygenase (KMO), a key enzyme in the KYN pathway that promotes the formation of potentially neurotoxic metabolites, thereby revealing a novel mechanism and a potential therapeutic target.
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AbstractAtrial fibrillation (AF) is the most common arrhythmia, characterized by irregular atrial electrical activity resulting in asynchronous atrial contraction. AF is accompanied by extensive structural remodelling of atria, including extracellular matrix expansion (fibrosis), which affects both AF maintenance and treatment outcomes. However, no fibrosis‐specific therapies are currently available for AF. To identify the prominent pathways in atrial fibroblasts (Fb) that modulate atrial fibrosis and arrhythmogenesis, we developed the first atrial Fb signalling network model. This expands on the well‐established ventricular model by integrating atrial‐relevant elements involved in fibrogenesis and/or differentially expressed in chronic AF (vs. normal sinus rhythm) patients and connections based on experimental evidence in an Fb‐related context. Our findings indicate that under high profibrotic signals, e.g. angiotensin‐II (AngII) and transforming growth factor β, inhibition of Ca2+fluxes reduced the abundance of key fibrotic markers such as collagen I, collagen III, periostin, plasminogen activator inhibitor‐1, connective tissue growth factor and α‐smooth muscle actin, via modulation of the Ca2+/calmodulin‐dependent protein kinase II/Smad3 pathway and extra domain A of fibronectin via the calcineurin pathway. Mechanistically, we found that the Ca2+‐dependent regulation of collagen I and III is primarily at the level of gene transcription, with collagen I and collagen III exhibiting similar dynamics in the Fb model. Overall, our study highlights the pivotal role of Ca2+signalling in the evolution of AF‐associated fibrogenesis and provides novel insights into potential anti‐AF therapeutic strategies targeting fibrotic responses. Future work will investigate in greater detail the upstream mechanisms driving Ca2+increases in atrial Fbs during AF.imageKey pointsA fibroblast signalling network was developed incorporating new atrial‐informed elements and reactions to identify the prominent pathways that modulate atrial fibrosis and associated arrhythmogenesis, including atrial fibrillation (AF).The model was validated against experimental data in cardiac fibroblasts. For atrial‐specific validation, we focused on the model responses to AF‐relevant profibrotic inputs, i.e. angiotensin‐II (AngII) and transforming growth factor β (TGFβ).The analysis underscores the critical role of Ca2+signalling in mediating profibrotic responses under AF‐relevant stimuli, AngII and TGFβ and shows that Ca2+/calmodulin‐dependent protein kinase II/Smad3 and calcineurin mediate the Ca2+‐dependent upregulation of key fibrotic markers.
AbstractHigh‐frequency mossy fibre (MF) inputs trigger a sustained increase in excitability to perforant pathway (PP) inputs in CA3 pyramidal cells (CA3‐PC) by reducing Kv1.2 levels at distal apical dendrites, known as long‐term potentiation of intrinsic excitability (LTP‐IE). LTP‐IE enhances excitatory postsynaptic potential (EPSP)‐to‐spike coupling at PP synapses, facilitating Hebbian LTP of synaptic weights. Prolonged hyperexcitability is detrimental, yet it is little understood how LTP‐IE is restored in CA3‐PCs. Here we show that MF‐induced LTP‐IE can be reversed through the burst firing of a CA3‐PC elicited by PP or recurrent synaptic inputs. This reversal was impeded by the oxidative bias of cellular redox state or intracellular Zn2+signalling. Because high‐frequency PP inputs to MF‐primed CA3 pyramidal cells not only induce homosynaptic LTP but also restore hyperexcitability, this input‐specific bidirectional regulation of intrinsic excitability may provide a cellular basis for understanding ensemble dynamics in the CA3 network.imageKey pointsIntrinsic excitability plays a pivotal role in recruiting principal cells to neuronal memory ensembles.Mossy fibre inputs prime hippocampal CA3 pyramidal cells by enhancing their intrinsic excitability and excitatory postsynaptic potential (EPSP)‐to‐spike coupling at perforant path (PP) synapses.High‐frequency PP inputs to such primed cells not only induce long‐term potentiation of synaptic weights but also restore the high excitability state to baseline.This input‐specific bidirectional regulation of intrinsic excitability may offer a cellular basis for understanding the ensemble dynamics in the hippocampal CA3 network.
AbstractMetformin is increasingly used to treat diabetes in pregnancy, but the effects on adult offspring health remain under‐explored. The present study investigated the long‐term cardiovascular effects in male and female offspring of maternal metformin treatment using a well‐established mouse model of obese glucose intolerant pregnancy. Female mice were given chow, or an obesogenic diet with/without 300 mg kg−1day−1oral metformin during gestation. At 3, 6 and 12 months of age, male and female offspring were studied longitudinally with tail‐cuff plethysmography and echocardiography. At 12 months, tissues were collected for wire myography, histology and molecular analyses. Female offspring of obese dams had elevated blood pressure throughout life, cardiac diastolic dysfunction at 3 months, and increased femoral vasoconstrictor reactivity and aortic wall remodelling at 12 months. Metformin treatment did not ameliorate these effects and led to obesity‐induced hypertension at 12 months. Irrespective of metformin, male offspring of obese pregnancy had cardiac diastolic dysfunction from 6 months without changes in blood pressure. Male metformin‐exposed offspring also showed cardiomegaly, increased cardiac collagen and vascular sympathetic hyperreactivity, suggesting metformin exposure worsened the cardiovascular phenotype. These findings show that maternal obesity caused sex‐specific cardiovascular aberrations in aged offspring. Maternal metformin was not corrective and introduced further sex‐dependent cardiovascular alterations. Further long‐term offspring follow up of both sexes is needed for informed decisions about metformin during pregnancy.imageKey pointsThe oral medication metformin is increasingly used to treat diabetes in pregnancy.Metformin readily crosses the placenta, and long‐term effects on offspring cardiovascular health remain unexplored in human and animal studies.In a mouse model of maternal diet‐induced obesity with impaired glucose tolerance, female and male offspring developed hypertension and diastolic cardiac dysfunction, respectively, by 12 months of age (equivalent to middle age in humans).Maternal metformin treatment worsened the cardiovascular phenotype and introduced further sex‐dependent cardiovascular alterations in both male (cardiac stiffening, vascular dysfunction) and female (obesity‐induced hypertension) offspring.This work highlights that long‐term cardiovascular follow up in offspring of both sexes from human pregnancies treated with metformin is crucial to make more informed decisions about metformin use in diabetic pregnancy.
AbstractMicroglia are resident immune cells critical in maintaining brain homeostasis via their surveillance and phagocytosis function. Under disease contexts such as seizures and epilepsy, microglial phagocytic signalling is activated in response to both inflammatory and non‐inflammatory cell death. This process involves a range of well‐characterized ‘find me’ and ‘eat me’ signals, phagocytic receptors, and less well‐characterized intracellular signalling pathways. In addition, epigenetic and transcriptional regulators orchestrate microglial responses to seizures, including the integration of phagocytic and inflammatory pathways. Interestingly, although inhibiting phagocytosis has been shown to improve neuronal survival and cognitive performance after seizures, it paradoxically increases the risk of developing spontaneous recurrent seizures. Reconciling these dual effects requires a deeper understanding the spatiotemporal dynamics of microglial phagocytosis. The objective of this review is to examine the mechanisms and impact of microglial phagocytosis in the context of epilepsy and to highlight unresolved questions that warrant further investigation in this emerging field.image
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AbstractPeak inspiratory pressure‐generating capacity is preserved in themdxmouse model of Duchenne muscular dystrophy in early disease, despite profound diaphragm muscle weakness and reduced electrical activation, revealing adequate compensation by extra‐diaphragmatic muscles. Respiratory system compensation is lost as disease progresses, with the emergence of reduced peak inspiratory pressure‐generating capacity in advanced disease. We hypothesised that extra‐diaphragmatic inspiratory muscles compensate for diaphragm dysfunction in early dystrophic disease, supporting the maintenance of peak respiratory performance inmdxmice. We reasoned that extra‐diaphragmatic muscle dysfunction would emerge with progressive disease, leading to the loss of peak inspiratory pressure‐generating capacity in advanced dystrophic disease. We measured ventilation, inspiratory pressure, and obligatory (diaphragm, intercostal and parasternal) and accessory (sternomastoid, cleidomastoid, scalene and trapezius) respiratory muscle form, function and EMG activity in early (4 months) and advanced (16 months) dystrophic disease. Despite obligatory and accessory muscle dysfunction, including structural remodelling, weakness and reduced EMG activity, peak inspiratory pressure‐generating capacity and ventilation are preserved in early disease. Obligatory and accessory muscle dysfunction progressively declines with advanced disease, with the emergence of reduced peak inspiratory pressure‐generating capacity. However, although there was evidence of progressive accessory muscle dysfunction, more profound remodelling was seen in the diaphragm muscle comparing early and advanced dystrophic disease. In conclusion, in early dystrophic disease, peak inspiratory performance is compensated. A progressive decline in diaphragm and extra‐diaphragmatic muscles contributes to respiratory system compromise in advanced disease. Further loss of compensation afforded by extra‐diaphragmatic muscles probably contributes to end‐stage respiratory failure.imageKey pointsWe characterised obligatory and accessory respiratory muscle form, function and control in early and advanced disease in themdxmouse model of Duchenne muscular dystrophy.Profound diaphragm muscle remodelling, immune cell infiltration, elevated cytokine concentrations and dysfunction present in early disease, but peak inspiratory performance is fully compensated. The burden of breathing is shared across many muscles, revealed as remodelling, elevated cytokine concentrations, weakness and impaired control in several obligatory and accessory muscles.Peak inspiratory performance declines in advanced disease with evidence of progressive remodelling in the diaphragm muscle with extensive fibrosis and further decline in the form, function and control of accessory muscles of breathing.Diaphragm remodelling with profound fibrosis, more so than progressive accessory muscle remodelling (although evident), is the striking phenotype at 16 months of age when the decline in peak inspiratory performance appears.The progressive decline to end‐stage disease (∼20–22 months of age inmdxmice) probably relates to continued profound loss of diaphragm contractile function and loss of compensatory support provided by extra‐diaphragmatic muscles. Logistically convenient models of rapid, progressive muscular dystrophy are required to facilitate the study of end‐stage disease.
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AbstractIt is unclear whether cortical and spinal excitability modulations contribute to enhanced stretch–shortening cycle (SSC) performance. Therefore, this study investigated cortical and spinal excitability modulations during and following shortening of SSC contractions compared with pure shortening (SHO) contractions. Participants (n= 18) performed submaximal voluntary plantar flexion contractions while prone on the dynamometer bench. The right foot was strapped onto the dynamometer's footplate attachment, and the resultant ankle joint torque and crank arm angle were recorded. Cortical and spinal excitability modulations of the soleus muscle were analysed by eliciting compound muscle actional potentials via electrical nerve stimulation, cervicomedullary motor‐evoked potentials (CMEPs) via electrical stimulation of the spinal cord, and motor‐evoked potentials (MEPs) via magnetic stimulation of the motor cortex. Mean torque following stretch was significantly increased by 7 ± 3% (P =0.029) compared with the fixed‐end reference (REF) contraction, and mean torque during shortening of SSC compared with SHO was significantly increased by 12 ± 24% (P =0.046). Mean steady‐state torque was significantly lower by 13 ± 3% (P =0.006) and 9 ± 12% (P =0.011) following SSC compared with REF and SHO, respectively. Mean steady‐state torque was not significantly different following SHO compared with REF (7 ± 8%,P= 0.456). CMEPs and MEPs were also not significantly different during shortening of SSC compared with SHO (P≥ 0.885) or during the steady state of SSC, SHO and REF (P≥ 0.727). Therefore, our results indicate that SSC performance was not associated with cortical or spinal excitability modulations during or after shortening, but rather driven by mechanical mechanisms triggered during active stretch.imageKey pointsA stretch–shortening cycle (SSC) effect of 12% was observed during EMG‐matched submaximal voluntary contractions of the human plantar flexors.The SSC effect was neither associated with cortical or spinal excitability modulations nor with stretch‐reflex activity.The SSC effect was likely driven by mechanical mechanisms related to active muscle stretch, which have long‐lasting effects during shortening.Residual force depression following SSC was not attenuated by the long‐lasting mechanical mechanisms triggered during active muscle stretch.Steady‐state torques were lower following shortening of SSCsversuspure shortening and fixed‐end contractions at the same final ankle joint angle, but the torque differences were not correlated with cortical or spinal excitability modulations.
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AbstractElectrical tuning allows auditory, vestibular, and electrosensory receptor cells to filter sensory signals and selectively transmit specific stimulus frequencies. In auditory hair cells, electrical tuning results from membrane potential resonance produced by voltage‐gated Ca and K(Ca) channels, with variable kinetics that generate different tuning properties. Such resonance has been observed only up to ∼1 kHz, however. Additionally, in most species that employ electrical tuning, hearing is constrained to this relatively low‐frequency range, raising the question of whether electrical tuning can extend to higher frequencies. Here we investigated this possibility by studying tuning and transduction properties of Knollenorgans, a class of tuberous electroreceptors of mormyrid electric fish. These organs, which generate spike‐like receptor potentials, detect species‐specific electric organ discharges (EODs). To test whether fish with brief EODs had correspondingly high‐frequency electrical tuning, we recorded tuning curves from Knollenorgans of three species,Brevimyrus niger, Gnathonemus petersii, andPollimyrus adspersus, which have EODs with spectral components exceeding 5 kHz. All species had receptors tuned to a range of frequencies tiling the species‐specific EOD spectrum, with best frequencies extending beyond 10 kHz inP. adspersus. We also computed the impulse response of each Knollenorgan by reverse‐correlating spikes elicited by white noise stimuli. After incorporation of a spike threshold non‐linearity, convolving the impulse response with arbitrary stimulus waveforms successfully predicted spike patterns experimentally evoked by these inputs. These analyses demonstrate that differential electrical tuning properties of Knollenorgans produce distinct, well‐timed spike responses that reliably encode time‐varying electrical signals at frequencies up to 20 kHz.imageKey pointsKnollenorgans, among the tuberous electroreceptors of mormyrid electric fish, are modified hair cells that transduce electrical signals into spike‐like receptor potentials.Knollenorgans in three species of mormyrids are tuned to frequencies matched to the frequencies present in the species‐typical electric organ discharges, suiting them for electric communication.The frequency of highest sensitivity of Knollenorgans can extend well beyond 10 kHz, far exceeding the limit for electrical tuning mechanisms estimated from mechanosensitive hair cells.The timing and probability of spiking by Knollenorgans are accurately predicted by a model composed of linear filtering followed by non‐linear rectification and spike thresholding.Differential filtering by different Knollenorgans produces distinct outputs to the same input, with high‐tuned receptors effectively transmitting well‐timed spikes, on a microsecond time scale, in response to electrical stimuli up to 20 kHz.
AbstractLow cardiorespiratory fitness increases the risk for cardiometabolic disease. Endurance exercise training promotes cardiorespiratory fitness and improves cardiometabolic risk factors, but with great heterogeneity. Here, we tested the hypothesis that the metabolic phenotype imparted by low parental (inborn) cardiorespiratory fitness would be overcome by early‐life exercise training, and that exercise adaptations would be influenced in part by inborn fitness. At 26 days of age, male and female rat low‐capacity runners (LCR,n =20) and high‐capacity runners (HCR,n =20) generated by artificial selection were assigned to either sedentary control (CTRL,n =10) or voluntary wheel running (VWR,n =10) for 6 weeks. Post‐intervention, whole‐body metabolic phenotyping was conducted, and the respiratory function of isolated skeletal muscle and liver mitochondria was assayed. Transcriptomic and proteomic profiling of these tissues was performed using RNA‐sequencing and mass spectrometry, respectively. Daily VWR volume was 1.8‐fold higher in HCR‐VWR compared to LCR‐VWR. In LCR, VWR reduced adiposity and enhanced glucose tolerance, coincident with elevated total energy expenditure. Although intrinsic skeletal muscle mitochondrial respiratory function was unchanged, estimated skeletal muscle oxidative capacity increased in VWR groups. In liver mitochondria, VWR increased both maximal oxidative capacity and ATP‐linked respiration only in HCR. Transcriptomic and proteomic profiling revealed extensive remodelling of skeletal muscle and liver tissue by VWR, elements of which were both shared and distinct based on inborn fitness. Early‐life exercise partly offsets the metabolic effects of low inborn fitness, but molecular adaptations to VWR are dependent on inborn fitness, with potential implications for personalized exercise medicine.imageKey pointsLow cardiorespiratory fitness is a heritable trait associated with increased risk for cardiometabolic disease.Endurance exercise training promotes cardiorespiratory fitness and metabolic health but how genetic (inborn) fitness influences exercise‐induced adaptations is unclear.We used rats selectively bred for low (LCR) or high running capacity (HCR) to test whether: (1) early‐life voluntary wheel running (VWR) could offset poor metabolic health in LCR rats and (2) inborn fitness modulates adaptations to VWR.VWR improved body composition and glucose tolerance in LCR rats but did not alter mitochondrial respiratory function.Molecular analyses revealed that VWR induced shared and distinct changes in skeletal muscle and liver depending on inborn fitness, highlighting individualized biological responses.These findings suggest that genetic factors linked to fitness influence how the body adapts to exercise, with implications for personalized exercised medicine.
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AbstractNeuroscientists, behavioural scientists, mechanical engineers and roboticists collaborate in the broad field of whisker science to investigate tactile sensing and movement in mammals. Much of this research is focussed on the study of laboratory rodents, with important insights already gained from studying their whisker movements, control behaviours and the sensory processing of whisker signals. The findings of whisker behaviour studies in the laboratory have also formed the foundation for research in other captive settings, such as in zoos. However, without inspiration from more natural environments and stimuli, researchers are probably missing out on describing other important whisker behaviours, which may in turn give researchers better insights into the brain areas, signals and behaviours associated with active whisker touch sensing. Taking inspiration from recent findings from the field and zoo, developing more social and active foraging tasks for the laboratory would probably enrich whisker behaviour studies, as would including a wider variety of species. In the longer‐term, a more integrated approach, with collaboration across laboratory, captive and field settings, will help to develop more natural behavioural tasks representative of what an animal experiences in the real world, which would give us greater insights into the natural sensory behaviours of mammals. This has implications for the fields of neuroscience, sensory biology and evolutionary biology, as well important applications for captive mammal health and welfare.image
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AbstractHyperpolarization‐ and cyclic nucleotide‐activated channels (HCN orIhchannels) play an important role for the integrative dynamics of many types of neurons. In the retina, the multiple types of bipolar cells constitute parallel channels that connect the outer and inner retina. Differences in synaptic inputs and differential expression and localization of specific voltage‐gated ion channels shape and modulate bipolar cell visual responses. Here, we examined the expression and function of HCN2‐mediatedIhin rod bipolar cells (RBCs) of rat retina. Using immunolabelling, we observed HCN2 channels in dendrites, cell bodies and axon terminals of RBCs. With whole‐cell voltage‐clamp recording, we observed that ZD7288 and Cs+blockedIhin RBCs, and from activation/deactivation data, we developed a Hodgkin–Huxley‐type kineticIhmodel that closely reproduced physiological responses. Applying a ZAP current stimulus, we found that the bandpass frequency–response characteristics of RBCs were blocked by Cs+, could be restored by dynamic clamp injection of a positiveIhconductance (in Cs+) and could be eliminated by injecting a negativeIhconductance (in control), suggesting thatIhis necessary and sufficient for bandpass filtering properties in the examined voltage range. Implementing our kinetic model forIhin morphologically realistic compartmental models closely mimicked physiological bandpass characteristics, with little influence of the subcellular location of theIhconductance. Our results demonstrate how the specific kinetic properties ofIhin RBCs determine their frequency–response properties, supporting an important role ofIhin the functional dynamics of RBC visual responses.imageKey pointsHyperpolarization‐ and cyclic nucleotide‐activated (HCN) channels are found throughout the nervous system and contribute to physiological activities including rhythmic neuronal behaviour and control of the resting membrane potential.Unlike most voltage‐gated channels, HCN channels are activated by hyperpolarizing voltages and, in some cells, generate bandpass behaviour, thereby amplifying certain frequencies of transmitted signals.We demonstrate that HCN2 channels are located at the dendrites, soma and axon terminals of rod bipolar cells, which are important for transmitting visual signals at night.Chemically blocking or electronically subtracting the HCN channels eliminates bandpass behaviour, whereas electronically adding the channels restores bandpass behaviour.We have implemented a Hodgkin–Huxley‐type kinetic model for HCN channels that allows for computer simulations with realistic models of rod bipolar cells.We demonstrate that HCN channels are necessary and sufficient to confer bandpass properties and thus contribute to understanding how these voltage‐gated ion channels generate diverse visual signals.
AbstractAcute intermittent hypercapnic hypoxia (IHH) evokes persistent increases in vascular sympathetic activity and blood pressure. Whether myocardial contractility is enhanced to contribute to this pressor response is unknown. We hypothesized that IHH would augment left ventricular systolic function. Twenty‐four healthy participants (nine females; aged 25 ± 4 years) underwent 40 consecutive 1 min bouts of 40 s of hypercapnic hypoxia (: 48 mmHg; : +5 mmHg) and 20 s of normocapnic normoxia. Cardiac, haemodynamic, respiratory and sympathetic measurements were made at rest and during three 5 min stages of progressive lower body negative pressure (LBNP) (−15, −30 and −45 mmHg) before and after IHH. Following IHH, stroke work [Δ: 64 mJ; 95% confidence interval (CI) = 14–113;P= 0.007], longitudinal strain (Δ: −0.9%; CI = −0.1 to −1.7;P= 0.007) and single‐beat estimates of preload‐recruitable stroke work (PRSWsb; Δ: 0.9 mJ mL−1; CI = 0.2–1.5;P= 0.004) were enhanced. Across LBNP stages, IHH further enhanced ejection fraction (Δ: 1.0%; CI = 0.0–2.0;P= 0.041), stroke work (Δ: 44 mJ; CI = 23–66;P< 0.001), longitudinal strain (Δ: −0.5%; CI = 0.0 to −0.9;P= 0.047), end‐systolic elastance (Δ: 0.15 mmHg mL−1; CI = 0.05–0.25;P= 0.004) and PRSWsb(Δ: 0.60 mJ mL−1; CI = 0.36–0.85;P< 0.001). Linear end‐systolic pressure–volume relationships (+0.13 ± 0.06 mmHg mL−1,P= 0.024) and preload‐recruitable stroke work slopes (+0.83 ± 0.17 mJ mL−1,P< 0.001) were also increased post‐IHH. Ventricular stiffness (E/E′ratio) and relaxation (peak diastolic strain rate) were unaltered by IHH (P> 0.236), whereas the passive/active diastolic filling (E/A) ratio was reduced (P= 0.022), potentially via increased atrial kick contribution (P= 0.068). We demonstrate that increased left ventricular systolic function following acute IHH contributes to the pressor response in addition to the established vasopressor arm in humans.imageKey pointsAcute intermittent hypercapnic hypoxia evokes persistent sympathoexcitation and increased arterial pressure, known to be mediated by increased vasoconstrictor signalling.Chronic intermittent hypoxia increases cardiac contractility associated with cardiac sympathetic and structural remodelling. However, whether increases in contractility manifest acutely following intermittent hypercapnic hypoxia is unknown.We show increases in indices of cardiac systolic performance at rest and across progressive hypovolaemia following acute intermittent hypercapnic hypoxia.Diastolic relaxation was unchanged, but reductions in the ratio of passive filling to atrial kick during diastole, potentially as a result of increased mitral inflow velocity during atrial filling, suggest that the increases in contractility may extend to the atria.
AbstractTendons are collagen‐rich tissues that are necessary for movement and, as such, are exposed to mechanical forces. Mechanical loading impacts tendon formation, homeostasis and injury. Frequent injury and poor healing of tendon is a major clinical issue. An improved understanding of how tendon cells respond to mechanical forces is needed to advance new therapies to treat tendon injuries and limit degeneration caused by aberrant mechanical loading. In this review, we highlight recent discoveries in how mechanical stimulation impacts tendon and enthesis formation during development, as well as tendon maintenance and degradation during adulthood. We focus on understanding the cell‐level mechanotransduction mechanisms, which include calcium signalling, activation of specific cell receptors and ion channels, and the effect on primary cilia and other downstream cell signalling pathways. These recently identified mechanotransducers in tendon cells show promise as future therapeutic targets, which can be leveraged for tendon healing.image
AbstractIt has long been established that microglia are integral to the CNS immune system. Their surveying and adaptive nature is key in brain development and maintaining homeostasis as well as in the manifestation and progression of neuropathology. However with advancing technology it is becoming increasingly recognised that they do not serve this role in isolation. Previously most work has focused on microglia‐derived signalling, with less attention on the sensing and signalling capacity of macroglia (astrocytes, oligodendrocytes). Recent developments in single‐cell transcriptomics have allowed extensive analysis of cell profiles in health and disease; these studies have drawn attention to the capacity of macroglia to also engage in immune signalling pathways. This is particularly relevant in neuropathologies, including in Alzheimer's disease (AD), where specific disease‐associated profiles of glia (DAGs) have been established. These changes are predominantly related to immune pathways, which were long considered limited to immune cells, including cytokine and chemokine production, antigen presentation and phagocytosis. There is an increasing body of evidence that glia should be considered as active components of the CNS immune system forming a glia‐specific immune‐like network, whereby macroglia, acting as sensors of the CNS microenvironment, function within this network to co‐ordinate diverse CNS effect(s)/function(s). To gain an in‐depth understanding of AD pathology, the intimate molecular dialogue of glia needs to be elucidated. This review aims to examine the evidence for macroglia‐derived immune signalling and its relevance in health and disease.image
AbstractCa2+‐dependent exocytosis initiates with the formation of fusion pores comprising thesolubleN‐ethylmaleimide‐sensitive factorattachment proteinreceptor (SNARE) complex. Although cellular signalling typically occurs in transient oscillations on the order of tens of seconds, it remains unclear how such rapid SNARE phosphorylation influences fusion pore kinetics, analogous to transient regulation observed in ion channels. Here we demonstrate that protein kinase A (PKA)‐mediated phosphorylation of SN25b (the neuronal isoform of synaptosome‐associated protein of 25 kD) modulates secretion rate and fusion pore kinetics in PC12 cells (rat pheochromocytoma derivatives). Upon acute application of KCl and forskolin, cells overexpressing SN25b exhibited a reduced secretion rate compared to the control. This reduction was occluded by overexpressing a PKA‐phosphodeficient mutant, SN25b‐T138A, rather than a PKA‐phosphomimetic mutant, SN25b‐T138E. Notably, SN25b, SN25b‐T138A or SN25b‐T138E did not alter the fraction of incomplete fusion events or quantal size compared to the control. Further kinetic analysis indicated that SN25b‐T138A destabilized initial fusion pores by promoting the closure and dilatation of fusion pores. Mechanistically,in situproximity ligation assays showed that SN25b‐T138A reduced its interaction with the other t‐SNARE syntaxin‐1 compared to the control and SN25b, correlating with destabilized fusion pores. Moreover, compared to SN25b‐T138E, SN25b‐T138A decreased whole‐cell Ca2+currents and weakened its interaction with synaptobrevin‐2 and L‐type Ca2+channel subunits. These changes in interaction were associated with increased secretion and full‐fusion rate, implying efficient disassembly after dilatation. Together, PKA‐mediated phosphorylation of SN25b rapidly modulates fusion pore kinetics in response to transient signalling oscillations, thereby fine‐tuning exocytotic efficiency in real time.imageKey pointsProtein kinase A (PKA)‐mediated SNAP‐25 phosphorylation rapidly reduces the rate of secretion.PKA‐phosphodeficiency of SNAP‐25 destabilizes the kinetics of initial fusion pores, correlating with its decreased interaction with syntaxin‐1.PKA‐phosphodeficiency of SNAP‐25 decreases the interaction with synaptobrevin‐2 and the L‐type calcium channel subunit, leading to efficient priming.PKA‐mediated SNAP‐25 phosphorylation rapidly regulates fusion pore kinetics and shapes exocytotic kinetics on the order of tens of seconds.
AbstractCardiovascular disease is the predominant cause of mortality globally, with both morbidity and mortality rates escalating annually. Non‐coding RNAs are essential in the regulation of cardiovascular disease. Exosomes are lipid bilayer vesicles that are released by many types of cells. They carry biomolecules such as proteins and nucleic acids (e.g. microRNAs, circular RNAs and long non‐coding RNAs). The physiological condition of the mother cell significantly affects their composition and biological activity. In cardiovascular disorders, macrophages generate exosomes that facilitate intercellular communication, potentially resulting in new therapeutic strategies for these conditions. In this article, we examine the impact of exosomal non‐coding RNAs derived from macrophages on the functionality and condition of immune cells, vascular smooth muscle cells, endothelial cells, cardiomyocytes and cardiac fibroblasts. They facilitate intercellular communication via several mechanisms. Non‐coding RNAs generated from macrophage exosomes significantly influence cellular functional states and might offer new approaches for preventing and treating cardiovascular disorders. Owing to insufficient clinical evidence, additional extensive investigations are required to assess the therapeutic potential of these non‐coding RNAs in cardiovascular disorders.image
AbstractAnatomical changes associated with intra‐uterine growth restriction (IUGR) have been observed in different age groups and linked to cardiovascular complications. This study analysed the electrocardiogram (ECG) in pre‐adolescents with severe IUGR, comparing QRS complex and T‐wave biomarkers with controls. Computer simulations explored links between anatomical re‐modelling and ECG biomarkers, providing insights into the potential cardiovascular risk associated with IUGR‐induced re‐modelling. Clinical recordings were analysed using principal component analysis (PCA) to compute spatially transformed leads, enhancing QRS complex and T‐wave delineation for depolarization and repolarization assessment. Transformed leads analysis revealed a 4‐ms increase in QRS complex duration (QRS ) and a 2‐ms increase in the T peak‐to‐end interval (T ) in IUGR subjects compared to controls. We conducted electrophysiologicalin silicosimulations using anatomical models based on clinical IUGR data. These models, derived from a reference control, incorporated key geometric changes associated with IUGR, the apex‐base length, basal diameter, wall thickness () and ventricular tissue volume, to assess their impact on depolarization and repolarization intervals.In silicoPCA leads showed increased QRS , QRS amplitude and T in globular models, consistent with clinical data. Despite the QRS increase, the QT interval increases but is not linearly related to the change. These findings suggest that cardiac re‐modelling primarily influences the depolarization cycle, notably QRS , while repolarization intervals increase but are not directly related to the increase. The study highlights the impact of geometric and volumetric changes in IUGR‐related cardiac re‐modelling, also emphasizing the need for further research on electrophysiological re‐modelling and its effects on cardiac function.imageKey pointsIntrauterine growth restriction (IUGR) is associated with long‐term cardiovascular complications, including changes in the heart's electrical activity.Cardiac re‐modelling as a consequence of IUGR can lead to electrical changes that can be assessed through an electrocardiogram (ECG).This study analysed ECGs in pre‐adolescents with severe IUGR, revealing prolonged depolarization duration (QRS complex duration) and repolarization (T peak‐to‐end interval) compared to healthy controls.Computational models incorporating clinically observed anatomical changes, such as increased ventricular wall thickness and altered heart geometry, were used to assess their impact on electrical function, and determine whether these structural modifications contribute to the ECG alterations observed in clinical data.Both clinical data analysis and simulation findings showed significant shifts in depolarization‐based biomarkers and smaller, and non‐linear changes to geometrical changes, in repolarization intervals, highlighting how cardiac re‐modelling in IUGR affects heart function as measured by ECG.
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AbstractThe intestinal mucosa has evolved to facilitate interactions between the host and the constellation of intestinal microbes, collectively termed the microbiota. A well‐orchestrated balance exists in the healthy mucosa where microbes and microbial products first encounter a barrier formed by a single layer of intestinal epithelial cells (IECs). This homeostasis exists at a harsh interface between the highly vascularized mucosa and the anaerobic intestinal lumen. This steep oxygen gradient establishes ‘physiological hypoxia’ as a central metabolic characteristic of the mucosa. Recently, interest in understanding the dynamic host–microbe interplay has identified microbial metabolites that support host functions at several different levels. Of singular relevance are short‐chain fatty acids, particularly butyric acid. Studies have demonstrated that IECs have evolved to benefit from butyrate through a plethora of functions, including energy procurement, metabolism, barrier and wound healing regulation, production of antimicrobial peptides, etc. Butyrate is consumed by differentiated colonic epithelial cells preferentially for energy, creating a distinct butyrate gradient along the intestinal cryp‐tvillus axis. The depletion of butyrate and butyrate‐producing microbes during active inflammation, termed dysbiosis, promotes disease and attenuates tissue healing responses. Furthermore, in a disease state, the butyrate gradient is disrupted leading to reduced utilization of butyrate and inhibition of proliferation of colonic stem cells. Emerging studies suggest that chemical modifications to butyrate could be useful in targeting select IEC functions for particular benefits to the host. In this review, we consider how butyrate molecular mimicry may play out in the setting of mucosal health and disease and discuss current discoveries on endogenous and synthetic butyrate‐like compounds and their pathways.image
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AbstractHysteresis is a ubiquitous phenomenon and a salient feature of the adaptation of cardiac ventricular repolarization (VR) duration to changes in heart rate (HR), an expression of ultra‐rapid cardiac memory. Against a background of a handful of previous studies, this review focuses on non‐invasive electrophysiological assessment of the adaptation of VR duration and heterogeneity (aka dispersion) to changes in HR. Four different modalities were used: atrial pacing (incremental and step up/down), ventricular pacing (step up/down), and atropine‐induced continuous HR increase in healthy subjects and patients who either had permanent pacemakers or were scheduled for ablation of supraventricular tachycardia or had long QT syndrome type 1 (LQT1). Vectorcardiography according to Frank, with orthogonal leadsX,Y, andZ, was used for signal recording and beat‐to‐beat analysis. The RR interval (instantaneous HR) was the input. VR duration was assessed by the QT and QTpeakintervals and VR dispersion by T amplitude, T area, and the ventricular gradient. The main results were that independent of modality, VR duration adaptation follows a mono‐exponential pattern, is reproducible, and at a stable HR it takes 2–3 min to reach steady state. In contrast, VR dispersion adaptation is more rapid and roller‐coaster‐like, presumably due to local differences in adaptation time. In LQT1 patients, VR duration adaptation time is reduced giving less time for electro‐mechanical adaptation and coronary perfusion at HR increase. In conclusion, the patterns of adaptation of VR duration and VR dispersion differ, and further studies might provide information on these phenomena of both pathophysiological and therapeutic relevance.image
AbstractEnhanced untrained muscle strength and force steadiness following unilateral resistance training (i.e.cross‐education) are attributed to neural responses. However, the mechanisms of these adaptations for spinal motoneurons remain underexplored. Therefore, we examined maximal voluntary force (MVF), steady force variability (CovF) and longitudinally tracked motor unit adaptations in 10 individuals completing a 4 week unilateral strength intervention compared to nine controls. High‐density surface EMG was recorded from the biceps brachii during steady (10% MVF) and trapezoidal (35% MVF) contractions. The relative proportion of common synaptic input (CSI) to motoneurons and its variability (CSI‐V) were estimated using coherence and spectral analysis. Indirect estimates of persistent inward currents using firing rate hysteresis (∆F) and motor unit recruitment thresholds (MURTs) were assessed during ramps (35% MVF). MVF increased in both the trained (+14%,P< 0.001) and untrained limbs (+6%,P= 0.004), and CovF decreased in both limbs (P< 0.001). Greater CSI was observed on both sides (P< 0.01), concomitant with reduced CSI‐V (P< 0.01). ∆Fincreased exclusively in trained limbs [+1.61 ± 0.71 pulse per second (pps);P< 0.001], and both sides exhibited lower MURTs (P< 0.001). In trained limbs, MVF gains were strongly associated with changes in CSI, MURT and ∆F(R2> 0.70,P< 0.01), while the contralateral muscle MVF increase was associated exclusively with CSI and MURT (R2> 0.65,P< 0.01). In both limbs, lower CovF was strongly associated with reduced CSI‐V (R2> 0.70,P< 0.01). Our findings suggest that enhanced untrained muscle force and steadiness are mediated by increased relative strength of shared synaptic input with respect to independent noise and decreased variability of this shared input, with trained muscle MVF gains being associated with ∆F.imageKey pointsUnilateral resistance training improves strength and force steadiness in the contralateral untrained limb, suggesting neural adaptations without directly overloading the muscle.Despite established force‐related modifications, specific untrained limb responses in the relative shared synaptic input distribution and intrinsic motoneuron properties remain largely unknown.A 4 week unilateral training intervention enhanced muscle strength and force steadiness in the untrained limbs of 10 individuals, alongside a greater proportion of shared synaptic input, reduced variance in common input and lower motor unit recruitment thresholds.We demonstrated that the neural mechanisms underlying improved strength and force steadiness in muscles without mechanical overloading are associated with a higher relative shared input to motoneurons and reduced variance in these common input components.
AbstractCentral terminals of primary afferents and dorsal horn neurons usually exhibit spontaneous activity, the two phenomena being interrelated. Spontaneous activity may constitute a system for adjusting the level of excitation of spinal circuits and the processing of somatosensory information. Superficial dorsal horn neurons fire action potentials in a coordinated form, giving rise to population events. These population events are altered by peripheral inflammation, suggesting their implication in central sensitisation. In this work, we aimed to define the role of primary afferents in the occurrence of this coordinated activity. Channelrhodopsin‐2, archaerhodopsin‐3 or the hM4Di‐DREADD receptor were expressed in primary afferents by Cre‐recombination under control of the advillin promoter. Dorsal roots and superficial dorsal horn neurons were simultaneously recorded usingin vitrospinal cord slices from neonatal mice. Depolarisation of primary afferents by activation of channelrhodopsin‐2 inhibited dorsal root activity and the coordinated firing of dorsal horn neurons. DREADD activation reduced the activity in the afferents and depressed coordinated activity in dorsal horn neurons. In contrast, hyperpolarisation of afferents by archaerhodopsin‐3 augmented dorsal root responses and increased the coordinated activity of spinal neurons. The present results demonstrate a direct implication of primary afferents in the generation of coordinated spontaneous firing in superficial dorsal horn neurons.imageKey pointsThe input of somatosensory information through primary afferents is a process subjected to regulation at the level of the spinal cord, even before it reaches second‐order neurons.Primary afferent and spinal cord neurons exhibit spontaneous activity, which is altered in pathological models of pain.This study demonstrates the role of primary afferents as a fundamental coordinating element for the spontaneous activity of dorsal horn neurons.These results show that modulating the activity of the central terminals of primary afferents may have profound implications in both the excitability of spinal cord circuits and the processing of somatosensory information.
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AbstractDehydration is prevalent and adversely affects exercise performance; however, its influence on cellular responses to exercise remains unclear. Thus, this study examined the intramuscular responses to resistance‐exercise (RE) in RE‐trained men under dehydrated and euhydrated states. Eleven men (21 ± 1 years, 175.9 ± 6.2 cm, 79.2 ± 12.3 kg, 18.4% ± 6.7% fat) completed two identical lower‐body RE sessions, either with (DEHY) or without (EUHY) fluid‐restriction from 24 h before to 3 h after RE. At pre‐RE (PRE), 1 h, and 3 h post‐RE, muscle samples were collected and analysed for protein content of AKT/mTOR/p70S6K/rpS6 and their corresponding phosphorylation sites, REDD1 and selected autophagy markers, cathepsin L, H2O2concentration, fibre cross‐sectional area (CSA), and muscle water content. Significant time × condition interaction effects revealed that p‐rpS6S240/244was greater in DEHY than EUHY at PRE and increased from PRE to 1 h and 3 h in both conditions. In DEHY, REDD1 increased from PRE to 1 h and 3 h, active‐cathepsin L decreased from 1 h to 3 h and was greater than EUHY at 1 h, and muscle water content increased from 1 h to 3 h. Significant condition main effects revealed that p‐S6KT389and H2O2were greater, and CSA was smaller, in DEHYversusEUHY. Significant time main effects revealed that p‐AKTS473and p‐mTORS2448increased from PRE to 1 h and 3 h, LC3‐I decreased from PRE and 1 h to 3 h, LC3‐II decreased from PRE to 1 h and 3 h, and LC3‐II/LC3‐I decreased from PRE to 1 h and increased from 1 h to 3 h. These results suggest that performing RE in a dehydrated state imposes additional stress on the muscle, leading to greater cellular stress and growth signalling.imageKey pointsDehydration can negatively impact exercise performance, overall health, and cognitive function in humans.Water makes up about 70% of muscle mass, and dehydration has been shown to decrease muscle size in humans. However, the mechanisms by which dehydration affects muscle response on anabolic and catabolic signalling have only been observed inin vitrostudies, leaving the processes in humans still not fully understood.Following 24 h of dehydration, there was an increase in the activation of rpS6 at rest. Additionally, young men exhibited greater activation of S6K during resistance exercise (RE) while dehydrated compared to when they were adequately hydrated.Concurrently, stress (H2O2and REDD1) and proteolytic (active‐cathepsin L) responses were elevated after RE in a dehydrated state compared to an adequately hydrated state.Our research offers new insights into the importance of hydration in muscle responses to exercise, particularly for individuals who are frequently dehydrated.
AbstractIn the activation process of Kv channels, the S4 segment of the voltage‐sensing domain (VSD) moves in the outward direction. A conserved phenylalanine in the transmembrane S2 helix of the VSD is viewed as operating as a charge transfer centre (CTC) that interacts with a positively charged arginine of the S4 helix. This phenylalanine is highly sensitive to diverse substitutions. Kv2.1 subunits can form functional homotetrameric channels on their own whereas ‘silent’ Kv6.4 subunits can only contribute to functional heterotetrameric channels. We used concatenated dimers of Kv2.1 and Kv6.4 subunits to define the stoichiometry and position of these subunits in functional heterotetrameric channels. Our results demonstrate that mutating the phenylalanine F273 of the Kv6.4 subunits in Kv 2.1_6.4 channels built of dimers to diverse other amino acids at the CTC affects steady‐state activation only moderately whereas it strongly shifts steady‐state inactivation by 40 mV toward more depolarized potentials compared to Kv2.1_6.4 wild‐type channels. Mutating the Kv6.4 subunits in this heterotetramer slowed down the recovery from closed‐state inactivation without impacting open‐state inactivation. Moreover, results with the specific Kv2.1 blocker guangxitoxin suggest that Kv6.4 subunits may partly activate Kv2.1_6.4 channels. It is concluded that F273 in the silent Kv6.4 subunit of Kv2.1_6.4 channels has a unique role in controlling activation and the recovery from inactivation.imageHighlightsThis study quantifies the functional effects of Kv6.4 mutations in Kv2.1_6.4 channels on activation and inactivation.Highly diverse mutations of the phenylalanine in the charge transfer centre of Kv6.4 reveal its unique role in Kv2.1_6.4 channels in closed state inactivation.The specific Kv2.1 blocker guangxitoxin unmasks that Kv6.4 subunits can partly activate Kv2.1_6.4 channels.
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AbstractSudden unexpected death in epilepsy (SUDEP) is the most extreme consequence of epilepsy. SUDEP typically occurs at night. Because humans sleep at night, these nighttime deaths are often attributed to seizures arising from sleep. Nocturnal mice also experience more seizure‐associated deaths during the nighttime. This could represent timing that is under circadian control. To examine this, male and femaleScn1aR1407X/+mice, a model of the epileptic encephalopathy Dravet syndrome, in which patients experience spontaneous seizures that often result in death, were housed in constant darkness and the timing of seizure associated death was assessed. We found that the timing of sudden death following seizures persists in constant darkness and peaks during the subjective nighttime. This circadian rhythm of death was independent of the timing of potentially fatal seizures and more frequently occurred while awake. Potentially fatal seizures resulted in prolonged unconsciousness, which also exhibited a circadian rhythm peaking during the subjective night. These findings provide support for circadian regulation, independent of seizure timing and sleep, in the nighttime risk of seizure‐associated death. Nighttime seizures may increase risk of SUDEP via multiple mechanisms, as evident by peak spontaneous sudden death and profoundly impaired consciousness following seizures during the subjective night.imageKey pointsSudden unexpected death in epilepsy, or SUDEP, is a devastating outcome of intractable epilepsy.Converging lines of evidence indicate that there is a time‐of‐day preference for SUDEP, with more SUDEP occurring during the night.Several animal models of the epileptic encephalopathy Dravet syndrome (DS), including the one employed in our study, recapitulate key features of DS in patients, including a high rate of seizure‐related death and more of the deaths occurring at night.Here, we removed light/dark photocycles, by housing animals in constant darkness, and identify nighttime preponderance of death, suggesting that this is under circadian regulation.We further carefully characterize fatalvs. non‐fatal seizures in our animals and identify features that may prove to be useful biomarkers to predict which seizures may become fatal.
AbstractThe spontaneous, phasic contractions of collecting lymphatic vessels are critical for lymph transport and interstitial fluid homeostasis. Phasic contractions are initiated by action potentials in lymphatic muscle and conduct along the vessel to trigger contraction waves. Contractions are regulated by pressure and shear stress (SS), but only limited aspects of that regulation are understood. Numerical models predict that pressure promotes retrograde propagation of contraction waves, whereas nitric oxide (NO) production associated with phasic contractions (pulsatile NO) promotes antegrade conduction and extends the pressure range over which contractions propel lymph. These predictions were tested using 3−4‐valve segments of rat mesenteric lymphatic vessels using pressure myography and protocols that imposed forward flow, elevated inflow pressure (Pin) or elevated outflow pressure (Pout), each with/without intact NO signalling. NO bioavailability and flow‐induced responses were enhanced byl‐arginine supplementation. Spatiotemporal maps generated from video images were used to quantify the direction and extent of contraction wave conduction. Our results show that (1) contraction waves are normally biased towards retrograde conduction at equalPin/Poutlevels. (2)Pinelevation promotes antegrade conduction, whereasPoutelevation promotes retrograde conduction. (3) Imposed flow is inhibitory, reducing contraction amplitude and frequency and limiting the extent of contraction wave conduction without a significant effect on conduction direction. (4) Pulsatile NO does not significantly influence the conduction direction or extend the pressure range over which spontaneous contractions occur. Our findings support the idea that pressure is the dominant regulator of lymphatic pacemaking and pumping, with pulsatile NO having only minimal influence.imageKey pointsThe degree to which spontaneous, phasic contractions of lymphatic collecting vessels are regulated by pressure and shear stress is not fully understood.Numeric models predict that nitric oxide (NO) production associated with phasic contractions (pulsatile NO) promotes antegrade conduction of contraction waves, whereas pressure elevation promotes retrograde conduction; pulsatile NO production is also thought to extend the pressure range over which phasic contractions occur.Ex vivomethods were used to control pressure/flow in 3−4 valve segments of collecting lymphatics from rat mesentery, with preserved or inhibited NO signalling.The relatively long vessel segments limited the absolute levels of imposed flow/SS, sol‐arginine supplementation was used to enhance NO bioavailability.Our findings support a scheme whereby pressure is by far the dominant mechanism determining the pacemaking site of lymphatic collectors, and challenge existing dogma about the importance of pulsatile NO production in regulating their behaviour.
The hippocampal formation (HF) plays a key role in avian spatial navigation. Previous studies suggest that the HF may serve different functions at various stages in pigeons’ long-distance outdoor homing flight. However, it remains unclear whether the HF exhibits specific neural responses during these stages. In this study, we employed a wearable bimodal data recording system to simultaneously capture flight trajectories and hippocampal local field potential (LFP) signals of pigeons (either sex) during outdoor homing navigation. Our results revealed significant differences in hippocampal neural responses across the initial decision-making (DM) and en route navigation (ER) stages. Specifically, elevated LFP power in theta (4–12 Hz) and beta (12–30 Hz) bands was detected during the DM stage compared to the ER stage, while the high gamma (60–120 Hz) band exhibited the opposite pattern. In addition, we examined typical theta-beta phase-amplitude coupling (PAC) during the ER stage. Additionally, stage-specific hippocampal responses remained consistent across release sites. Notably, the difference in hippocampal responses across stages diminished along with the accumulation of homing experience. These results offer new insights into the role of the avian HF in homing flight navigation and suggest parallels between avian and mammalian hippocampal mechanisms in spatial learning.Significance StatementIt remains unclear whether the hippocampal formation (HF) exhibits specific neural responses during various stages in the long-distance outdoor navigation of pigeons. By recording hippocampal local field potentials (LFPs) and positional data during natural outdoor flights, we reveal distinct neural response patterns that differentiate between initial decision-making and sustained navigation stages. We detected band-specific power and coupling responses between different navigation stages, consistent across multiple release sites. Additionally, we found that the LFP responses differences across stages gradually diminish along with the accumulation of the homing experience. Our study offers new insights into the role of the avian HF in outdoor homing flight.
Recent evidence highlights the importance of glutamatergic neurons in the basal forebrain (BF) in promoting cortical activity; however, whether BF glutamatergic neurons are involved in regulating general anesthesia and the underlying neural circuits remains unclear. Here, the authors show that the activity of BF glutamatergic neurons decreased during the induction of isoflurane anesthesia and restored during the emergence in mice. Optogenetic activation of BF glutamatergic neurons accelerated the emergence from isoflurane anesthesia, decreased isoflurane sensitivity, and increased arousal score of mice. Moreover, optogenetic activation of BF glutamatergic neurons decreased EEG delta power and burst-suppression ratio, while increased pupil size and respiration rate of mice during isoflurane anesthesia. Similar results were observed during the optogenetic activation of BF glutamatergic terminals in the ventral tegmental area (VTA). Additionally, the authors found that the activity of BF glutamatergic neurons and VTA glutamatergic neurons synchronously fluctuate during isoflurane anesthesia, and optogenetic activation of BF glutamatergic terminals in the VTA potently increased the calcium signals of VTA glutamatergic neurons during isoflurane anesthesia. Collectively, their study illustrated that BF glutamatergic neurons promote isoflurane anesthesia emergence via activating VTA glutamatergic neurons. Both male and female mice were used in this study.Statement of SignificanceGeneral anesthesia is widely used in modern medicine; however, its specific neural mechanisms remain poorly understood. The basal forebrain (BF) is a critical component of the ascending arousal system, and its glutamatergic neurons were implicated in sleep–wake behavior and cortical activity. Here, we report that optogenetic activation of BF glutamatergic neurons significantly promoted cortical activation, behavioral emergence and physiological indicators in mice under isoflurane anesthesia. Photostimulation of BF glutamatergic terminals in the ventral tegmental area (VTA) produced similar effects, and significantly increased the activity of VTA glutamatergic neurons. Our findings illustrated that BF glutamatergic neurons promote emergence from isoflurane anesthesia via VTA glutamatergic neurons, highlighting a potential target for attenuating anesthesia depth and accelerating anesthesia emergence in clinical anesthesia.
Microsaccades are miniature saccades performed during visual fixation that were shown to play a pivotal role in active sensing. Recent studies suggested that pre-microsaccadic attention may underlie the enhanced visual processing at the stimulus site. However, the neuronal mechanism underlying this phenomenon at the foveal scale remains unknown. Using voltage-sensitive dye imaging we investigated the neural responses to uninstructed, spontaneous microsaccades in the fovea of the primary visual cortex (V1) in behaving monkeys (macaque, male). We found that prior to microsaccades onset toward a small visual stimulus, the neuronal activity at the current and future landing stimulus sites was enhanced relative to microsaccades away from the stimulus. This enhancement was spatially confined to the current and future landing stimulus sites, which appeared to merge along the microsaccades ( < 1 deg ) trajectory in V1. Finally, we found a pre-microsaccadic increased synchronization at the current stimulus site. Our findings shed new light on neural modulations preceding microsaccades and suggest a link to neural signatures of attention.Significance statementMicrosaccades are miniature eye-movements that occur during visual fixation. Behavioral studies have suggested that pre-microsaccadic attention enhances visual processing in the fovea. However, the underlying neuronal mechanisms at the foveal scale remain unknown. Using voltage-sensitive dye imaging in monkeys, we investigated how microsaccades influence neural activity in the foveal region of the primary visual cortex. Just before a microsaccade toward a small visual stimulus, neural activity was enhanced at both the current and future landing stimulus locations, compared to microsaccades directed away. This enhancement appeared over the microsaccade path and was accompanied by increased synchronization at the current stimulus location. Our findings reveal novel neural modulations preceding microsaccades, and suggest a link between microsaccades and neural signatures of attention.
Structural neuroimaging studies of typical development reveal increases in grey matter volume during childhood, followed by shrinkage in adolescence and early adulthood. With neuropil constituting the bulk of grey matter, these developmental changes may reflect neuropil reorganization accompanied by alterations in cellular membranes, as well as changes in related energy demand. Phosphorus magnetic resonance spectroscopy (31P MRS) allows in vivo assessment of changes in the brain’s high-energy phosphates – phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) - as well as metabolites associated with synthesis and degradation of membrane phospholipids (MPLs) – phosphocholine (PC) and phosphoethanolamine (PE), and their breakdown products, glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE). Forty-nine children and adolescents aged 6 to 14 years at baseline (37 boys, 12 girls) were assessed on up to three occasions approximately 12 months apart. MPL precursor levels decreased across all examined regions over time, including cortical and subcortical gray matter and two major white matter tracts. Breakdown products increased in the prefrontal cortex (PFC) in younger children but decreased in their older counterparts. While ATP and Pi decreased across most regions, PCr changes were heterochronic and regional: Hippocampal increases were more pronounced in older children, whereas most of the remaining regions showed no change. Changes in MPL precursors were positively associated with change in PFC cortical thickness, suggesting that the expansion and contraction of neuropil are coupled with structural brain changes during childhood and adolescence. Thus, in vivo31P MRS provides new insights into the neurobiological mechanisms of normal brain development.Significance StatementIn childhood and adolescence, structural neuroimaging reveals marked changes in the brain’s grey matter, most likely indicating contraction and expansion of its main component – the neuropil. The neurobiological mechanisms of these changes are, however, poorly understood. In the first of its kind longitudinal study of 6- to 14-year-old children, we examined in vivo changes in metabolites associated with brain energetics and the synthesis and degradation of membrane phospholipids using phosphorus magnetic resonance spectroscopy. We identify developmental changes in the metabolites associated with contraction and expansion of the neuropil and their coupling with structural changes in late-to-mature brain regions of the prefrontal cortex, indicating candidate mechanisms of brain development.
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Rhythms at a population level are a defining characteristic of both normal and pathological cortical activity, but it is unclear howsuch rhythms interactwith activity of specific neurons to impact task performance on a trial-by-trial basis. We address this by employing a challenging visual detection task in which male rhesus macaques must signal the presentation of a shape embedded in a noisy background. We analyzed the rhythmic activity in the local field potential (LFP) and single neuron activity in area V4, a brain area strongly implicated in shape perception, prior to such presentations and focused on two different frequency ranges: alpha/beta (10-30 Hz), in which coherence was particularly strong and spatially extensive, and gamma (50-70 Hz), which has traditionally been strongly associated with single unit activity. We find that within sessions there were periods of time during which successful detection was associated with the absence of rhythmic activity prior to shape presentation in either frequency range. During these periods, rhythmic activity in both frequency bands could predict whether the shape would be detected by the animal at the time of, as well as before, shape presentation on a trial-to-trial basis with high accuracy. Importantly, for both frequency ranges, the individual neurons carrying the most relevant information with regard to the task had the weakest coupling to the LFP rhythms. These results are consistent with spatially-distributed rhythmic activity acting as a source of decision noise in the context of rapid visual detection by reducing the moment-to-moment reliability of task-relevant information carried by individual neurons.Significance StatementAlthough rhythmic activity in the brain has been studied for over 100 years, its relevance to information processing remains unresolved. In this study we show for the first time that, in the context of a challenging visual detection task, rhythmic activity in local populations of neurons prior to appearance of the visual stimulus can predict mistakes on a trial-by-trial basis. Furthermore, this activity is linked to task-relevant signals at a neuronal level because the individual neurons with the weakest coupling to these rhythms are the most reliable.
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Negative and cognitive symptoms impair functioning in patients with psychotic illnesses (i.e., schizophrenia spectrum disorders (SZ) and bipolar I disorder with psychotic features (BD)). Disruptions in mesocorticolimbic circuitry are hypothesized to underpin negative symptoms and cognitive impairment in patients with psychosis and may also facilitate reward-motivational deficits. In male and female patients with psychosis (N=44) and healthy controls (HC=27), we used neuroimaging to define gray matter morphology and white matter microstructure. We examined negative symptom severity with the Clinical Assessment Interview for Negative Symptoms (CAINS), effort allocation during reward processing with the Effort Expenditure for Rewards Task (EEfRT), and cognitive performance with the MATRICS Cognitive Consensus Battery (MCCB). Reduced nucleus accumbens volumes in patients with psychosis were associated to higher CAINS total and Motivation and Pleasure subscale scores as well as lower effort expenditure for medium (50%) and high (88%) reward probability conditions during the EEfRT. The fornix showed reduced fractional anisotropy in patients with psychosis. Negative associations were present between CAINS Motivation and Pleasure subscores and MCCB composite and subscale scores. Lower gray matter volume in cerebellar lobule VI corresponded with impaired effort allocation during medium and high reward probability conditions and lower cognitive performance. However, lobule VI was not correlated with CAINS scores. While nucleus accumbens volume may serve as marker of negative symptoms in psychotic illnesses, cerebellar lobule VI morphology may inform on cognitive impairment in patients with SZ and BD. The nucleus accumbens and lobule VI may each contribute to reduced effort allocation during reward processing.Significance StatementImproving negative symptoms and cognitive impairment in SZ and BD remains an unmet clinical need. This study reveals that, in SZ and BD, structural changes in the nucleus accumbens and cerebellar lobule VI are associated with negative symptoms and cognitive impairments, respectively. The current findings also suggest that reductions in nucleus accumbens and cerebellar lobule VI volume may also underpin impaired reduced effort allocation during reward processing. This study provides impetus for further probing supratentorial and cerebellar circuitry to further understand negative and cognitive symptoms experienced by patients with psychotic illness and their associations with reward-motivational deficits.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by death of lower and upper motor neurons. Although the mechanism behind the selective neuron loss is still unclear, several heterogenous genes have been causally linked to ALS.KIF5Aencodes for a neuronally enriched kinesin involved in protein transport and mutations within this gene have been causally linked to different motor neuron diseases. The mutations identified in ALS patients are mostly predicted to alter its mRNA splicing, leading to a frameshift mutation and an aberrant 39 amino acid-long sequence in the C-terminal domain of KIF5A.Here we found that ALS-related KIF5A mutations induce the accumulation of the mutant form of the protein in human motoneurons, which are also characterized by the cytosolic mislocalization of TDP-43. This ALS hallmark was even exacerbated upon overexpression of the ALS-KIF5A protein in cells differentiated from healthy controls and primary neurons, suggesting a pathological connection between the cellular load of the mutant protein and TDP-43 pathology. While the terminal domain of the WT isoform is characterized by an acid isoelectric point (pI), the ALS variant presents a basic pI due to the altered aminoacidic composition of this sequence. We thus generated a KIF5A ALS isoform that retained part of the aberrant sequence but with lower pI. The overexpression of this mutated variant led to significantly lower protein aggregation and TDP-43 mislocalization than the ALS mutant. Our data show that re-establishing the correct pI rescues KIFA aggregation and significantly reduces the cytoplasmic mislocalization of TDP-43.Significance StatementAmyotrophic Lateral Sclerosis is a lethal neurodegenerative disease to which no cure is still known. Heterogenous genes have been causally linked to ALS, yet, the exact pathomechanism responsible for neuronal death remains unclear. One such gene is KIF5A which encodes for a neuronally enriched kinesin. Identified mutations cause incorrect mRNA splicing resulting in an aberrant C-terminal aminoacidic sequence. Here, we identified TDP-43 cytosolic enrichment, a hallmark common to many ALS models, in two distinct hiPSC-derived motoneuron lines harboring the ALS mutation KIF5Ac2993-1 G>A. Moreover, we generated a KIF5A isoform that retained most of the aberrant sequence but did not promote protein aggregation nor TDP-43 mislocalization upon overexpression. These results shed further light on the pathobiochemistry of the ALS-KIF5A cases.
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning, alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca²⁺) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca2+ATPase (SERCA) pump may help to stabilize cytosolic Ca2+levels and exert neuroprotective effects in AD neurons. In the current manuscript we demonstrate synaptoprotective properties of several SERCA PAMs using anin vitromodel of amyloid toxicity. Based onin vitroexperiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer’s disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.Significance statementAlzheimer’s disease (AD) is a significant medical and social burden, yet no treatment currently exists. One of the hallmarks of AD is disrupted Ca²⁺ signaling, which contributes to neuronal dysfunction and degeneration. In the current study, we demonstrate the potential of the SERCA pump positive allosteric modulators (PAMs) as promising disease-modifying agents. Through anin vitroscreening, we identified NDC-9009 as the most effective SERCA PAM, promoting robust cytosolic calcium clearance and exhibiting neuroprotective properties. Furthermore, using miniature fluorescence in vivo imaging, a significant restoration of hippocampal neuronal ensembles activity and cognitive function after chronic administration of NDC-9009 in the transgenic AD mouse model was demonstrated.
Prestin’s voltage-driven motor activity confers sound-elicited somatic electromotility on auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in ∼50 dB hearing threshold shifts across frequency, supporting the causal association of the prestin-coding gene,SLC26A5, with hereditary hearing loss, DFNB61. However, ∼50% reduction in prestin-mediated OHC electromotility barely affects cochlear function, and it is currently unknown how much electromotility is minimally required to support normal hearing. We generated mouse models harboring two deafness-associated prestin variants, p.A100T and p.P119S, and found that these missense variants do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to 70-80% reductions in OHC electromotility. Homozygous and compound heterozygous mice of either sex for these missense variants suffered congenital hearing loss; however, they still retained relatively low hearing thresholds at lower frequencies, pointing to the clinical possibility that a small augmentation of OHC electromotility could benefit those with DFNB61 hearing loss. These mice were also found to be prone to audiogenic seizures. This study thus provides insights into the minimum OHC electromotility required for normal cochlear operation and reveals the unappreciated importance of prestin for central gain control.Significance statementPrestin is abundantly expressed in the auditory outer hair cells and is essential for normal cochlear operation. Hence, reduction of prestin expression is often taken as indicative of reduced cochlear function in diseased or aged ears. However, this assumption overlooks the fact that cochlear function can tolerate surprisingly large reductions in prestin motor activity. DFNB61 mouse models generated and characterized in this study provide an opportunity to gauge the amount of prestin motor activity needed to sustain normal hearing sensitivity. This knowledge is crucial not only for understanding the pathogenic roles of deafness-associated variants that impair OHC electromotility but also for unraveling how prestin contributes to cochlear amplification.
A major challenge in cerebellar physiology is determining how the stereotypic, conserved circuitry of the cerebellar cortex, with its dominant parasagittal and transverse architectures, underlies its fundamental computations and contributions to behavior. Recent advances have allowed for the resolution of Purkinje cell dendritic activity at large scales, but the full roles of these Purkinje cell dynamics during behavior remain undetermined. To interrogate Purkinje cell dynamics at the population level during behavior, we implemented a novel approach for awake, chronic, wide-field Ca2+imaging of the cerebellar cortex. We performed wide-field cerebellar recordings in mice of both sexes exhibiting sparse expression of the Ca2+indicator GCaMP6s, which importantly allowed for the resolution of both dendritic and somatic Purkinje cell activity. Blind source separation of wide-field dynamics using spatial independent component analysis (sICA) extracts components consisting of either Purkinje cell dendrites or somata, with distinct activity and spatial properties. These independent components (ICs) tend to be either parasagittally organized and likely reflective of dendritic activity, or more spatially distributed populations of Purkinje cell somata. We observe broad, bilateral activation of both these dendritic and somatic ICs during behavior, but they exhibit distinct and divergent patterns of spatial correlations occurring primarily along the parasagittal and transverse directions, consistent with the main geometry of the cerebellar cortex. Somatic correlation dynamics are robustly modulated by prediction errors and reflect ultimate behavioral outcomes. These results provide a novel link between cerebellar structure and function, with the correlation dynamics of Purkinje cell activity a key feature during behavior.Significance statementThe cerebellar cortex exhibits highly conserved, elegant cytoarchitecture, but a full understanding of how this organization contributes to cerebellar processing is limited. We performed wide-field Ca2+recordings of the primary output neurons of the cerebellar cortex, Purkinje cells, and find that they are organized into distinct networks, which are either parasagittally organized or distributed populations of somatic activity. While both networks are highly engaged during behavior, they exhibit distinct spatial correlation dynamics consistent with the main geometry of the cerebellar cortex, with somatic correlation dynamics conveying information about prediction error and behavioral outcomes. Together, these results provide new insights into the functional organization of Purkinje cells and implicate somatic network correlation dynamics as a key feature of cerebellar processing.
Puberty triggers significant changes. However, besides the pruning of synapses, little is known about more long-range alterations during brain maturation. Actin filament formation – a process ignited by actin nucleators - is crucial for life and also a driving force behind cellular morphology changes. Yet, the physiological importance of especially the more recently discovered, evolutionary younger actin nucleators largely remain elusive. We demonstrate the consequences of deficiency for the actin nucleator Cobl in the mouse brain. We identify remarkably layer- and age-restricted corticalCoblKO phenotypes in dendritic arborization that first transiently emerge in layer V in rather young adolescent male mice and then manifested in a similar but more pronounced manner in layer II/III during the age of emerging adulthood.CoblKO phenotypes were observed in the somatosensory cortex, prefrontal cortex and motor cortex. In WT mouse cortices, we discovered an increase in dendritic arbor complexity occurring during emerging adulthood and thereby identified a long-range process for cortical rewiring upon brain maturation. This dendritic arbor expansion is transient and largely erased during mature adulthood. The transient dendritic arbor expansion during emerging adulthood was accompanied by transient length changes of dendritic spines. Molecularly, the process thus seems to relate to alterations in actin dynamics. Importantly, both of these changes were completely absent inCoblKO mice. Increased risk-taking ofCoblKO mice point towards a lack of maturity. These observations revealed the actin nucleator Cobl as first molecular component crucial for the identified emerging adulthood-related changes of neurons towards brain maturation.Significance statementPuberty triggers significant changes. We discovered a transient increase in dendritic arbor complexity occurring during emerging adulthood. This identified a long-range process for cortical rewiring during the age of emerging adulthood. Also dendritic spines were transiently rearranged. Both processes turned out to be dependent on the actin nucleator Cobl. We discovered remarkably layer- and age-specific corticalCoblKO phenotypes in dendritic arborization. These first transiently emerged in layer V in adolescent mice and then manifested in a similar but more pronounced manner in layer II/III during the age of emerging adulthood. This identified the actin nucleator Cobl as the first crucial component for the discovered reorganizations towards brain maturation.
Crows, renowned for advanced cognitive abilities and vocal communication, rely on intricate auditory systems. While the neuroanatomy of corvid auditory pathways is partially explored, the underlying neurophysiological mechanisms are largely unknown. This study used functional ultrasound imaging (fUSi) to investigate sound-induced cerebral blood volume (CBV) changes in the field L complex of the auditory telencephalon in two female crows. FUSi revealed frequency-specific CBV responses, showing a tonotopic organization within the field L complex, with low frequencies in posterior dorsal region and high frequencies in the anterior ventral region. Machine learning analyses showed fUSi signals could be used to classify sound types accurately, in both awake and anesthetized states. Variable CBV responses to longer sound stimuli suggest a delineation of subregions within the field L complex. Together, these findings highlight the potential of fUSi for providing high-resolution insights into functional systems in corvids, enabling future exploration of experimental task-related cognitive dynamics.Significance StatementThis study highlights the use of functional ultrasound imaging (fUSi) to explore auditory processing in crows, marking the first application of this technique in songbirds. By revealing the frequency map of the crow's auditory system and demonstrating the ability of fUSi to classify sound types, the research uncovers the neural dynamics supporting complex auditory functions. The findings suggest conserved auditory organization across avian species and provide insights into the evolution of audio-vocal behaviors in birds. This work paves the way for future studies on the neural underpinnings of cognition and communication in corvids, offering significant implications for comparative neuroscience and neuroethology.
Music can effectively induce emotional arousal, which is associated with the release of stress hormones that are important for the emotional modulation of memory. Thus, music may serve as a powerful modulator of memory and mood, making it a promising therapeutic tool for memory and mood disorders such as Alzheimer’s disease or depression. However, music’s impact on memory depends on its features, timing, and ability to elicit emotional arousal. In the current study, we manipulated various features of music played during post-encoding memory consolidation to elicit emotional arousal and impact subsequent memory in men and women. We found that larger increases and moderate decreases in post-encoding music-induced emotional arousal from baseline resulted in gist vs. detail trade-offs in memory, with improved general memory but impaired detailed memory, while moderate increases in arousal from baseline corresponded to improved detailed memory, but impaired general memory. Importantly, relative to controls, music-induced emotional arousal demonstrated unique impacts on detailed memory that are crucial in supporting episodic memory. These findings suggest that music intervention does not uniformly impact memory and has important implications in developing personalized music-related interventions for those with memory and mood impairments.Significance StatementMusic may be a powerful tool for modulating memory and mood, offering therapeutic potential for disorders like Alzheimer’s and depression. We found that individual differences in emotional arousal following music exposure influenced both general memory and detailed memory performance. Compared to controls, music specifically impacted memory for details, highlighting its potential to target specific memory aspects. These findings suggest that music interventions may not uniformly enhance memory, emphasizing the need for personalized approaches in treating memory and mood impairments.
Rapid eye movement (REM) sleep is primarily regulated by the brainstem pons. In particular, the sublaterodorsal tegmentum (SubLDT) in the dorsal pons contains neurons whose activity is selective to REM sleep. Elucidation of the precise identities of these neurons and their roles in REM sleep regulation is challenging, however, due to the functional and molecular heterogeneity of the SubLDT. A recent study revealed that corticotropin-releasing hormone-binding protein (Crhbp)-positive neurons in the SubLDT projecting to the medulla play a crucial role in REM sleep regulation and that loss of theseCrhbp-positive neurons underlies sleep deficits observed in Parkinson’s disease. The firing patterns of these neurons during sleep/wake, however, remained unknown. Here, we used an opto-tagging method and conducted cell-type-specific recordings fromCrhbp-positive neurons using a glass pipette microelectrode in unanesthetized male mice. We recorded 58Crhbp-positive neurons and found that many of these neurons are REM sleep-active neurons (41.4%) and that the remaining neurons are mostly either wake-active, wake/REM sleep-active, or NREM sleep-active. In addition, projection-specific recordings revealed that the medulla-projectingCrhbp-positive neurons are mostly REM sleep-active neurons (75.0%). Based on clustering analysis and spike waveform analysis, REM sleep-activeCrhbp-positive neurons can be further divided into different subtypes according to their electrophysiological properties, suggesting thatCrhbp-positive neurons play diverse roles in REM sleep regulation.Significance statementReduced REM sleep is a risk for dementia and mortality, suggesting it has critical roles in health. The mechanisms and functions of REM sleep, however, remain largely elusive. Classical electrophysiological studies identified neurons in the pons that are active during REM sleep, and a recent study revealed thatCrhbp-positive neurons within the same area contribute to REM sleep regulation. The relationship between the neurons identified in each study, however, remained unknown. Loss ofCrhbp-positive neurons underlies sleep deficits in Parkinson’s disease, underscoring the importance of characterizing these neurons. Our study revealed that many of theCrhbp-positive neurons are REM sleep-active and comprise distinct subtypes in regard to firing patterns, suggesting their diverse roles in REM sleep regulation.
Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.Significance statementHistone deacetylase 3 (HDAC3) is a negative regulator of synaptic plasticity and memory. However, the mechanism that regulates HDAC3 activity remains poorly understood. This study demonstrates the pivotal nature of Serine 424 of HDAC3 to bidirectionally regulate long-term potentiation, a form of synaptic plasticity, and long-term memory formation. Serine 424 is a phosphorylation site, suggesting that phosphorylation of HDAC3 is a key regulatory mechanism controlling its regulation of gene expression required for long-term memory. Indeed, expression of a Serine 424 phospho-null in the aging brain ameliorated age-dependent long-term synaptic plasticity and long-term memory deficits in aging male and aging female mice. Thus, this study provides new insight into the regulation of HDAC3 activity involved in cognitive processes.
Evoked responses in the mouse primary visual cortex can be modulated by the temporal context in which visual inputs are presented. Oddball stimuli embedded in a sequence of regularly repeated visual elements have been shown to drive relatively large deviant responses, a finding that is generally consistent with the theory that cortical circuits implement a form of predictive coding. These results can be confounded by short-term adaptation effects, however, that make interpretation difficult. Here we use various forms of the oddball paradigm to disentangle temporal and ordinal components of the deviant response, showing that it is a complex phenomenon affected by temporal structure, ordinal expectation, and event frequency. Specifically, we use visually evoked potentials to show that deviant responses occur over a large range of time in male and female mice, cannot be explained by a simple adaptation model, scale with predictability, and are modulated by violations of both first and second-order sequential expectations. We also show that visual sequences can lead to long-term plasticity in some circumstances.Significance StatementVisual experience and temporal context can modulate evoked responses in mouse V1. There remains disagreement about whether this reflects predictive coding in visual circuits and whether visual mismatched negativity, which has important cross-over implications for human clinical work, constitutes evidence supporting this theory or reflects simple neural adaptation. This work strongly supports the former interpretation by demonstrating complex experience-dependent deviant responses that cannot be easily explained by a simple adaptation model. We use statistically rigorous analysis of the local field potential to show that oddball evoked deviance signals reflect relative timing, event frequency, 1stand 2ndorder sequence expectations and scale as a function of event probability.
Chronic neuropathic pain is a persistent and debilitating outcome of traumatic central nervous system injury, affecting up to 80% of individuals. Post-injury pain is refractory to treatments due to the limited understanding of the brain-spinal cord circuits that underlie pain signal processing. The corticospinal tract (CST) plays critical roles in sensory modulation during skilled movements and tactile sensation; however, a direct role for the CST in injury-associated neuropathic pain is unclear. Here we show that complete, selective CST transection at the medullary pyramids leads to hyperexcitability within lumbar deep dorsal horn and hindlimb allodynia-like behavior in chronically injured adult male and female mice. Chemogenetic regulation of CST-targeted lumbar spinal interneurons demonstrates that dysregulation of activity in this circuit underlies the development of tactile allodynia in chronic injury. Our findings shed light on an unrecognized circuit mechanism implicated in CNS injury-induced neuropathic pain and provide a novel target for therapeutic intervention.Significance StatementCNS injury-induced neuropathic pain affects millions of people worldwide. A significant challenge in developing efficient therapeutics is the lack of suitable animal models that accurately replicate key features of human conditions, such as chronic onset of allodynia. We found a nuanced temporal evolution of sensory responses following a selective corticospinal tract (CST) lesion. Initially, there was a reduced tactile response, which later progressed to an exaggerated response characterized by increased mechanical hypersensitivity, a key feature of allodynia. We further identified a heterogenous population of CST-targeted spinal interneurons in the deep dorsal horn that modulate tactile sensory responses. These findings reveal a pivotal role for the CST in the development of CNS injury-induced chronic neuropathic pain.
Humans use multiple sensory systems to estimate body orientation in space. Sensory contributions change depending on context. A predominant concept for the underlying multisensory integration (MSI) is the linear summation of weighted inputs from individual sensory systems. Changes of sensory contributions are typically attributed to some mechanism explicitly adjusting weighting factors. We provide evidence for a conceptually different mechanism that performs a multisensory correction if the reference of a sensory input moves in space without the need to explicitly change sensory weights. The correction is based on a reconstruction of the sensory reference frame motion (RFM) and automatically corrects erroneous inputs, e.g., when looking at a moving train. The proposed RFM estimator contains a nonlinear dead-zone that blocks corrections at slow velocities. We first demonstrate that this mechanism accounts for the apparent changes in sensory contributions. Secondly, using a balance control model, we show predictions of specific distortions in body sway responses to perturbations caused by this nonlinearity. Experiments measuring sway responses of 24 subjects (13 female, 11 male) to visual scene movements confirmed these predictions. The findings indicate that the central nervous system resolves sensory conflicts by an internal reconstruction of the cause of the conflict. Thus, the mechanism links the concept of causal inference to shifts in sensory contributions, providing a cohesive picture of MSI for the estimation of body orientation in space.Significance statementHow the central nervous system (CNS) constructs body orientation in space from multiple sensory inputs is a fundamental question in neuroscience. It is a prerequisite to maintain balance, navigate and interact with the world. To estimate body orientation, the CNS dynamically changes the contribution of individual sensory inputs depending on context and reliability of the cues. However, it is not clear how the CNS achieves these dynamic changes. The findings in our study resolve major aspects of this question. Importantly, the proposed solution using nonlinear multisensory feedback contrasts with traditional approaches assuming context-dependent gain-scaling of individual inputs. Thus, our findings demonstrate how complex, intelligent, and unintuitive behavior can emerge from a comparably simple nonlinear feedback mechanism.
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The removal of no-longer-relevant information from visual working memory (WM) is important for the functioning of WM, given its severe capacity limitation. Previously, with an “ABC-retrocuing” WM task, we have shown that removing information can be accomplished in different ways: by simply withdrawing attention from the newly irrelevant memory item (IMI; i.e., via “passive removal”); or by or “actively” removing the IMI from WM (Shan and Postle, 2022). Here, to investigate the neural mechanisms behind active removal, we recorded electroencephalogram (EEG) signals from human subjects (both sexes) performing the ABC-retrocuing task. Specifically, we tested the hijacked adaptation model, which posits that active removal is accomplished by a top-down-triggered down-modulation of the gain of perceptual circuits, such that sensory channels tuned to the to-be-removed information become less sensitive. Behaviorally, analyses revealed that, relative to passive removal, active removal produced a decline in the familiarity landscape centered on the IMI. Neurally, we focused on two epochs of the task, corresponding to the triggering, and to the consequence, of active removal. With regard to triggering, we observed a stronger anterior-to-posterior traveling wave for active versus passive removal. With regard to the consequence(s) of removal, the response to a task-irrelevant “ping” was reduced for active removal, as assessed with ERP, suggesting that active removal led to decreased excitability in perceptual circuits centered on the IMI.Significance StatementThe removal of no-longer-relevant information from working memory is critical for the flexible control of behavior. However, to our knowledge, the only explicit accounts of this operation describe the simple withdrawal of attention from that information (i.e., “passive removal”). Here, with measurements of behavior and electroencephalography (EEG), we provide evidence for a specific mechanism for the active removal of information from WM–hijacked adaptation–via the top-down triggering of an adaptation-like down-regulation of gain of the perceptual circuits tuned to the to-be-removed information. These results may have implications for disorders of mental health, including rumination, intrusion of negative thoughts, and hallucination.
The error negativity or error-related negativity (Ne/ERN), a correlate of errors in choice tasks, is related to post-error adjustments indicating that it signals the need for behavioral adjustments following errors. However, little is known how the error monitoring system selects appropriate post-error adjustments for a given error to ensure that future errors are effectively prevented. This could be achieved by monitoring error precursors indicating potential error sources and then scale the Ne/ERN according to the strength of the error precursor upon error occurrence. We isolated such an error precursor in alpha oscillations and tested whether it predicts the size of the Ne/ERN. 28 Participants (23 female, 5 male) had to classify a target in one hemifield but ignore a distractor in the opposite hemifield. Because responding to the distractor always led to an error, misallocating spatial attention to the distractor as reflected in posterior alpha was a viable error precursor in this paradigm. We found that an alpha asymmetry reversal indicated a shift of spatial attention to the distractor on error trials and predicted the Ne/ERN on a single-trial level. The Ne/ERN in turn predicted alpha asymmetry on the next trial indicating a shift of spatial attention away from the distractor. This is consistent with the idea that the error monitoring system scales the Ne/ERN according to the strength of error precursors to select appropriate post-error adjustments of behavior.Significance StatementThis study reports evidence that the error monitoring system uses misallocation of spatial attention to distracting information as an error precursor to scale error signals in the brain. This ensures that error signals convey information about the type and strength of behavioral post-error adjustments that are necessary for a given error. The idea of monitoring error precursors that reflect specific error sources significantly extends existing theories of error monitoring mechanisms in the brain.
Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer’s disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule, has been shownin vitroto interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice (both sexes) develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target.Significance StatementNeuronal endosome dysfunction appears early in Alzheimer’s disease (AD) and is linked to memory loss. Genes and risk factors associated with AD often increase rab5 activity, a protein that disrupts endosomal signalling when hyperactivated. APPL1, a key rab5 partner, worsens this dysfunction via its interaction with APP-βCTF, a protein fragment associated with AD. To explore APPL1’s role, we created a genetically modified mouse that overexpresses APPL1 in neurons. This model provides the first in vivo evidence that APPL1 overexpression triggers key AD-like effects: rab5 hyperactivation, enlarged early endosomes, loss of cholinergic neurons, reduced synaptic plasticity in memory-related brain regions, and memory deficits. These findings highlight APPL1’s role in AD pathogenesis and its potential as a therapeutic target.
Juvenile zebra finches learn to sing by imitating conspecific songs of adults during a sensitive period early in life. Area X is a basal ganglia nucleus of the song control circuit specialized for song-related sensory-motor learning during song development. The structural plasticity and the molecular mechanisms regulating neuronal structure in Area X during song development and maturation are unclear. In this study, we examined the structure of spiny neurons, the main neuron type in Area X, at key stages of song development in male zebra finches. We report that dendritic arbor of spiny neurons expands during the sensitive period for song learning, and this initial growth is followed by pruning of dendrites and spines accompanied by changes in spine morphology as the song circuit matures. Previously, we showed that overexpression of miR-9 in Area X impairs song learning and performance and alters the expression of many genes that have important roles in neuronal structure and function (Shi et al., 2018). As an extension of that study, we report here that overexpression of miR-9 in spiny neurons in juvenile zebra finches reduces dendritic arbor complexity and spine density in a developmental stage-specific manner. We also show that miR-9 regulates structural maintenance of spiny neurons in adulthood. Together, these findings reveal dynamic microstructural changes in the song circuit during the sensitive period of song development and provide evidence that miR-9 regulates neuronal structure during song development and maintenance.Significance StatementSong development in juvenile zebra finches provides a model to study sensitive period plasticity for language development and related neural developmental disorders in humans. Area X is a basal ganglia nucleus essential for song-related sensory-motor learning in the zebra finch. We show that dendritic arbor of spiny neurons in Area X undergoes an initial growth and expansion followed by pruning of dendrites and spines during song development, and that this process is regulated by miR-9 in a developmental stage specific manner. These findings reveal the temporal profiles of structural development of key neurons in the basal ganglia song circuit and reveal a possible molecular mechanism for restricting sensitive period plasticity during vocal development.
Opioid abuse poses a major healthcare challenge. To meet this challenge, the brain mechanisms underlying opioid abuse need to be more systematically characterized. It is commonly thought that the addictive potential of opioids stems from their ability to enhance the activity of ventral tegmental area (VTA) dopaminergic neurons. Indeed, activation of mu opioid receptors (MORs) dis-inhibits VTA dopaminergic neurons projecting to the nucleus accumbens, providing a substrate for the rewarding effects of opioids. However, the abuse potential of opioids has also been linked to their ability to suppress pain and aversive states. Although medial VTA dopaminergic neurons are commonly excited by aversive stimuli, the effects of MOR signaling on this circuitry have not been systematically explored. To fill this gap, a combination of anatomical, optogenetic, and electrophysiological approaches were used to study the afferent circuitry of paranigral VTA (pnVTA) dopaminergic neurons and its modulation by MOR signaling in male and female mice. These studies revealed that aversion-linked glutamatergic neurons in the lateral hypothalamus, ventrolateral periaqueductal gray, and lateral habenula innervated a subset of pnVTA dopaminergic neurons and that activation of presynaptic MORs suppressed their ability to drive pnVTA spiking. A distinct set of pnVTA dopaminergic neurons were innervated by lateral hypothalamus GABAergic neurons, which also were subject to MOR modulation. Thus, MORs robustly inhibit the ability of brain circuits coding aversive states to drive the activity of pnVTA dopaminergic neurons, suggesting that the addictive potential of opioids may stem in part from their ability to act as negative reinforcers.Significance StatementOpioid abuse is a severe, worldwide problem. The ventral tegmental area (VTA) is part of the brain circuitry underlying opioid dependence. Previous work has shown that opioid activation of mu opioid receptors (MORs) suppresses GABAergic inhibition of VTA dopaminergic neurons, enhancing dopamine release and reward. However, the central mechanisms responsible for the ability of opioids to alleviate pain are less clear. Here we demonstrate that MORs suppress the ability of neurons in three aversion-related brain regions to drive spiking in dopaminergic neurons located in the paranigral region of the VTA – a sub-region linked to pain perception. Thus, these studies add a new dimension to our understanding of the central actions of opioids and their potential role in opioid abuse.
Spinal interneurons shape motor neuron activity. Gata3+V2b neurons are a major inhibitory spinal population. These neurons are present at multiple spinal levels in mice, suggesting an important function in motor control. In zebrafish, our previous work showed that V2b neurons are evenly distributed along the spinal cord, where they act to slow down locomotion. However, the timing of V2b activity during locomotion, their postsynaptic targets other than motor neurons, and their recruitment across different behaviors remain unknown. In this study, we address these questions using larval zebrafish. First, via optogenetic mapping of output in the rostrocaudal axis, we demonstrate that V2b neurons robustly inhibit motor neurons and other major spinal populations, including V2a, V1, commissural neurons and other V2b neurons. V2b inhibition is patterned along the rostrocaudal axis, providing long-range inhibition to motor and V2a neurons but more localized inhibition of V1 neurons. Next, by recording V2b activity during different visually and electrically evoked movements, we show that V2b neurons are specifically recruited for forward swims and turns, but not for fast escape movements. Furthermore, a subset of V2b neurons also exhibited short-latency sensory-evoked activity preceding motor initiation. Finally, we show that V2b inhibition occurs in phase with the leading edge of the motor burst, in contrast to V1 inhibition which occurs in phase with the falling edge of the motor burst. Taken together, these data show that in axial motor networks, V2b neurons act via multiple targets to produce in phase, leading inhibition during locomotion.Significance statementSpinal interneurons are critical for executing and regulating movements. However, it has been challenging to understand their functions and interconnections because the spinal cord circuit is complex, with many long-range connections that are challenging to map. Using optogenetics in the larval zebrafish, we mapped the connectivity and activity of an inhibitory spinal population: V2b neurons. We show that V2b neurons not only inhibit motor neurons but also other major excitatory and inhibitory populations. With electrophysiology and calcium imaging, we recorded V2b activity during different behaviors and found that V2b neurons inhibit their targets on the rising phase of motor bursts, preferentially during slow locomotion. These results suggest that V2b neurons have a distinctive role in motor control.
The nature of motor deficits in Parkinson disease (PD) and aspects of their improvements with ʟ-DOPA replacement therapy (LDRT) offer potential insights into striatal dopamine actions. The defining and most LDRT responsive feature of PD, bradykinesia, is a complex phenomenon exhibiting impairments of both simple and complex limb movements. LDRT significantly remediates the former but not the latter. LDRT pharmacodynamics has two major components, the Short Duration Response (SDR), with a time course of seconds to minutes, and the Long Duration Response (LDR), with a time course of days to weeks. LDRT pharmacodynamics suggests different striatal dopamine actions on different time scales. While many studies used PD subjects to investigate striatal dopamine actions, few take LDRT pharmacodynamics into account. Correlating bradykinesia features and LDRT pharmacodynamics with our present understanding of striatal dopamine actions suggests that LDRT failure to improve complex movement performance reflects loss of phasic dopaminergic signaling. The SDR is likely a result of partially restored tonic/volume striatal dopamine neurotransmission. There is no existing explanation for the LDR. Recent experiments isolating the LDR cast doubt on prior accounts of how LDRT remediates bradykinesia. Interactions between the SDR and LDR may give rise to novel properties. Longer duration effects of striatal dopaminergic signaling need to be incorporated into studies of striatal dopamine actions in both preclinical and clinical experiments. Careful studies of PD bradykinesia and LDRT pharmacodynamics offer potential avenues for future explorations of striatal dopamine actions. Systematic preclinical experiments are needed to optimize design of clinical experiments.
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Opioid use disorder (OUD) is a chronic disease of the brain, and it currently continues at crisis proportions in the United States. Opioid physical withdrawal is a major driver of compulsive drug-taking behavior, triggering short-term relapse of opioid addiction. Early pharmacological evidence shows that midbrain periaqueductal gray (PAG) plays an important role in morphine withdrawal (MW). However, we still know few details about the underlying molecular mechanisms. Improving our understanding of such mechanisms will enable increasingly safe and effective treatments for patients with OUD. Here, MW was induced by the naloxone precipitation after chronic intraperitoneal administration of morphine for a period of 5 days in Sprague-Dawley male rats. MW increased phosphorylation of cAMP response element binding protein (pCREB, a primary marker of CREB functional activation), NMDA glutamate receptor 2B subunit (NR2B), and mitochondrial calcium uniporter (MCU) within the ventrolateral PAG (vlPAG). Inhibition of pCREB, NR2B, or MCU within this brain region reduced the severity of MW. Chromatin immunoprecipitation (ChIP) assay and luciferase report assay demonstrated that pCREB mediated the transcription of theGrin2b(glutamate ionotropic receptor NMDA type subunit 2B, encoding NR2B) andCcdc109a(encoding MCU) genes. These findings describe the role of pCREB inGrin2bandCcdc109a genetranscription levels in the vlPAG during MW. The study may provide a novel therapeutic approach for OUD.Significant StatementDependence on opioids is a part of OUD symptoms. Evidence shows that the midbrain periaqueductal gray (PAG) plays an important role in morphine withdrawal (MW). However, we still know few details about the exact molecular mechanisms of MW. Here we found that naloxone-precipitated MW increased the levels of pCREB, NR2B, and MCU in the vlPAG. ChIP and luciferase report assays demonstrated that pCREB mediated the expression of theGrin2b(glutamate ionotropic receptor NMDA type subunit 2B, encoding NR2B) andCcdc109a(encoding MCU) genes on the transcriptional level in the vlPAG.
Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN), similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task in male mice. Conversely, inhibiting CRHPVNneurons during stress reduces stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRHPVNneurons activate neurons in the lateral hypothalamus (LH), and that CRHPVNprojections to the LH regulate stress-induced memory deficits and sleep disruptions. Our results suggest that CRHPVNneuronal pathways regulate the adverse effects of stress on memory and sleep - an important step toward improving sleep and ameliorating cognitive deficits associated with stress-related disorders.Significance statementStress significantly affects both sleep and memory, with spatial memory being particularly vulnerable. In this study, we combine acute restraint stress with optogenetic manipulations and a spatial object recognition task to investigate how corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN), and their projections to the lateral hypothalamus (LH), influence memory performance and sleep-wake states following stress. Our findings reveal that activating CRHPVNneurons impairs memory performance and increases wakefulness, whereas inhibiting CRHPVNneurons during stress improves memory and sleep. Inhibiting CRHPVNneuronal projections to the LH similarly improves memory performance and sleep. This work highlights the role of CRHPVNneurons and their projections to the LH in modulating stress-induced alterations in memory and sleep-wake states.
Autapses are self-synapses formed by a single neuron. They selectively form in a subpopulation of neocortical glutamatergic pyramidal cells (PCs) where autaptic transmission provides strong feedback regulation of self-activity in individual neurons. PCs in the hippocampal formation (HPF) possess morphological and electrophysiological characteristics similar to neocortical PCs, it remains unclear, however, whether they form functional autapses. We performed whole-cell recording from HPF PCs in acute slices obtained from mice of either sex and found surprisingly that none of the recorded PCs in CA1, CA2 and CA3 show autaptic responses, only a subpopulation of PCs (∼50%) in the subiculum form functional autapses, particularly those targeting to the nucleus accumbens. Further experiments reveal that the autaptic responses in subicular PCs are mediated solely by AMPA receptors but not NMDA receptors, and occur much earlier than those of the medial prefrontal cortex (mPFC) during early development. Together, the results indicate that functional autapses selectively form in a considerable subset of subicular PCs, but are completely absent from PCs in the hippocampus proper, suggesting a key role of autapses in regulating the self-activity of subicular PCs and thus the main output signals of the hippocampus.Significance StatementNeurons of HPF wire together through synapses to form circuits critical for high-order brain functions. Unlike conventional synapses formed by two neurons, autapses are self-synapses providing feedback regulation of a neuron’s own activity. We find that autapses selectively form in a subpopulation of subicular PCs, but are entirely absent from other HPF PCs, suggesting a key role of autapses in regulating the self-activity of individual subicular PCs and thereby the primary output of HPF. Additionally, autapses of subicular PCs emerge earlier than those in mPFC, and their time course correlates well with developmental changes in neuronal morphology. Therefore, the selective and early formation of autapses in subicular PCs may play a vital role in early-life cognitive functions.
We often mistake visual noise for meaningful images, which sometimes appear as convincing as veridical percepts. This suggests considerable overlap between the mechanisms that underlie false and veridical perception. Yet, false percepts must arise at least in part from internally generated signals. Here, we apply multivariate analyses to human MEG data to study the overlap between veridical and false perception across two aspects of perceptual inference: discrimination of content (what did I see?) and detection (did I see something?). Male and female participants performed a visual discrimination task requiring them to indicate the orientation of a noisy grating, as well as their confidence in having seen a grating. Importantly, on 50% of trials only a noise patch was presented. To exclude external signals driving false percepts, noise patches were carefully designed not to contain orientation signal. Still, participants occasionally confidently reported seeing a grating on noise-only trials, dubbed here false percepts. Decoding analyses revealed a sensory signal reflecting the content of these false percepts, despite no such grating being physically presented. Uniquely, high confidence false, but not veridical, percepts were associated with increased pre-stimulus high alpha/low beta [11-14Hz] power, potentially reflecting enhanced reliance on top-down signalling on false percept trials. Later on, a shared neural code reflecting confidence in stimulus presence emerged for both false and veridical percepts. These findings suggest that false percepts arise through neural signals reflecting both sensory content and detection, similar to veridical percepts, with an increase in pre-stimulus alpha/beta power uniquely contributing to false percepts.Significance statementThe neural mechanisms underlying false percepts are likely different from those that underlie veridical perception, as the former are generated endogenously, whereas the latter are the result of an external stimulus. Yet, false percepts often get confused for veridical perception, suggesting a converging mechanism. This study explores the extent to which the mechanisms diverge and converge. We found that both high confidence false and veridical percepts were accompanied by content-specific stimulus-like orientation signals, as well as a shared signal reflecting perceptual confidence. In contrast, we found that false, but not veridical, percepts were preceded by increased high alpha/low beta [11-14 Hz] power, possibly reflecting a reliance on endogenous signals.
The circadian rhythm shapes behavioral processes by providing temporal cues for molecular regulation and adaptation in the hypothalamus of the brain. Deeper yet in the striatum of the brain, circadian rhythm also exerts an impact, conditioning diurnal patterns in neurodegenerative-related motor dysfunction. While motor properties are clearly linked to striatal dopamine, the interplay between the circadian rhythm with the key circadian transcription factor Bmal1 and dopamine signal decoding remains unknown. Here, we utilized both sexes of global and local striatal Bmal1 knockout mice to investigate changes in dopamine-mediated cAMP signaling and motor behavior. By conducting a 24-hour time-course study, we first established Bmal1-dependent molecular signatures in striatal dopamine signaling machinery that correlated with cAMP levels. Next, recording real-time signal transduction with a 2-photon FRET biosensor in brain slices revealed diminished efficacy of dopamine signaling in the absence of Bmal1. As a final functional outcome, we then found that striatal Bmal1 was necessary for motor learning in mice. Altogether, our data support a strong connection between striatal Bmal1 and dopamine signaling with potential impact in brain-related motor function.Significance StatementHuman physiology is intertwined with the circadian rhythm to orchestrates neuronal activity over a 24-hour period. Interruptions to the circadian rhythm are often met with anomalies in motor behavior, which are processes shaped by dopaminergic signaling. Understanding how dopamine transfers information between neurons remains one of the most important areas of neuroscience research. Yet it remains unclear how regulatory proteins that shape circadian rhythm coordinate decoding of dopamine neurotransmission. By examining the dopamine signaling cascade throughout the day in mice, we found that oscillations in the second messenger cAMP depend on the circadian transcription factor Bmal1. Additionally, disruptions to Bmal1 modulate motor learning. This work provides a strong case that Bmal1 greatly influences encoding of dopamine signals in the striatum.
To build an understanding of our world, we make inferences about the connections between our actions, experiences, and the environment. This process,state inference, requires an agent to guess the current state of the world given a set of observations. During value-based decision-making, a growing body of evidence implicates the orbitofrontal cortex (OFC) and the hippocampus (HPC) in the process of contextualizing information and identifying links between stimuli, actions, and outcomes. However, the neural mechanisms driving these processes in primates remain unknown. To investigate how OFC and HPC contribute to state inference, we recorded simultaneously from both regions while two male monkeys (Macaca mulatta) performed a probabilistic reversal learning task, where reward contingencies could be captured by two task states. Using population-level decoding, we found neural representations of task state in both OFC and HPC that remained stable within each trial but strengthened with learning as monkeys adapted to reversals. Subjects also appeared to use their understanding of task structure to anticipate reversals, evidenced by anticipatory neural representations of the upcoming task state.Significance StatementDuring value-based decision-making, a growing body of evidence implicates the orbitofrontal cortex (OFC) and the hippocampus (HPC) in the process of contextualizing information and identifying links between stimuli, actions, and outcomes. However, limited work has been done in nonhuman primates to bridge the gap between rodent and human models. In this study, we show that task state is represented in both OFC and HPC in nonhuman primates. These representations remain stable within each trial, but evolve with learning and anticipate upcoming task changes, equipping subjects to adapt their choice preferences to reversals in reward contingencies. Our results support the theory that OFC-HPC interactions are important for flexible, goal-directed decision making, and provide insight into how the OFC and HPC participate in decision making when information is not explicitly provided, but must instead be inferred.
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Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of these neurons co-transmit glutamate and GABA (VGluT2+VGaT+ neurons), transmit glutamate without GABA (VGluT2+VGaT- neurons), or co-transmit glutamate and dopamine (VGluT2+TH+ neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified in male and female mice that VGluT2+ subpopulations are sensitive to reward value in unique ways. VGluT2+VGaT+ neurons increased activity magnitude with increased sucrose concentration, whereas VGluT2+VGaT- neurons increased magnitude and sustained activity with increased sucrose concentration, and VGluT2+TH+ neurons increased sustained but not maximum activity with increased sucrose concentration. VGluT2+ subpopulations also uniquely signaled signaled consumption of sweet/non-caloric (saccharine) and non-sweet/high calorie rewards (fat). VGluT2+VGaT+ neurons uniquely signaled lower-calorie sucrose over fat whereas both VGluT2+VGaT- neurons and VGluT2+TH+ neurons showed a signaling preference for higher-calorie fat over sucrose, but in temporally distinct ways. Further experiments suggested that VGluT2+VGaT+ consummatory reward-related activity was related to sweetness, partially modulated by pre-feeding, and not dependent on caloric content. Additionally, aversive stimuli increased activity for each VGluT2+ subpopulation but VGluT2+VGaT+ neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2+VGaT+ neurons during low intensity footshock enhanced fear-related behavior without inducing place preference or aversion. About half of VGluT2+VGaT+ sucrose-sensitive neurons were transcriptionally activated by footshock. We interpret these data such that VTA glutamatergic subpopulations signal different elements of rewarding and aversive experiences and highlight the unique role of VTA VGluT2+VGaT+ neurons in enhancing salience.Significance StatementVentral tegmental area glutamate neurons play a role in reward and aversion-based motivated behaviors. We identify that genetically-distinct ventral tegmental area glutamatergic subpopulations show differences in their signaling of consummatory rewards and aversive experiences. While all glutamatergic subpopulations signaled rewarding and aversive experiences, glutamatergic subtypes differed in their phasic magnitude and sustained activity profiles in response to the value of consummatory rewards, comparisons between multiple present rewards, and the value of aversive stimuli. VGluT2+VGaT+ neurons showed unique profiles related to both rewarding and aversive events. Based on these results we hypothesize that VTA VGluT2+VGaT+ neurons have a role in signaling the general salience of positive and negatively valenced behavioral experiences.
Previous studies on animal models suggested that visual areas involved in motion processing could undergo important cortical reorganizations following retinal damages. This could have major implications for patients suffering from macular degeneration (MD), one leading cause of vision loss. Here, we performed fMRI recordings in a group of maculopathy patients (N=7, 3 women, including individuals suffering from age-related macular degeneration or from Stargardt’s Disease) and a control group to characterize the motion processing cortical network in MD patients and determine whether this network is modified following the onset of the scotoma. We used an experimental protocol based on random-dot kinematograms (RDKs) classically employed to characterize motion-selective areas in the brain. To ensure that the visual information processed by the two groups was equivalent, the visual field in each control participant was masked using an artificial scotoma directly derived from clinical measurements in their paired patient. We found that in MD patients, translational motion elicited significant and robust activations in a restricted cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas (V1, V2 and V3) connected to peripheral vision. Importantly, the same patterns of responses were also observed in control participants. Moreover, the extent and strength of activation within these motion-selective areas did not differ significantly between the two groups. Altogether, these results suggest that in humans, the motion-selective network does not undergo significant large-scale cortical reorganizations following the onset of MD.Significance statementMotion processing in the visual cortex of patients with macular degeneration has never been characterized. Here, we performed fMRI recordings in 7 maculopathy patients and found robust motion-selective activations in a cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas connected to peripheral vision. These activations closely align with those reported in participants with normal vision in the literature and do not significantly differ from those measured in a group of age and gender-matched control participants who viewed the motion stimuli with a matched artificial scotoma. Altogether, our results suggest that the motion-selective network does not undergo significant large-scale reorganizations in maculopathy patients following the onset of the scotoma.
Altered function of peripheral sensory neurons is an emerging mechanism for symptoms of autism spectrum disorders. Visual sensitivities are common in autism, but whether differences in the retina might underlie these sensitivities is not well understood. This includes Fragile X syndrome, which is the most common syndromic cause of autism. We explored retinal function in the Fmr1 knockout mouse model of Fragile X syndrome. We focused on a specific type of retinal neuron homologous with primate ganglion cells, the “sustained On alpha” retinal ganglion cell, which plays roles in contrast sensing and binocular vision in mice. We found that these cells exhibit changes in dendritic structure and dampened responses to light in male Fmr1 knockout mice. We show that decreased light sensitivity is due to increased inhibitory input and reduced E-I balance. The change in E-I balance supports maintenance of circuit excitability similar to what has been observed in cortex. However, this maintenance also reshapes the tuning of this retinal ganglion cell type. These results show that loss of Fmr1 in the mouse retina affects sensory function of one retinal neuron type. As other retinal cell types also express Fmr1, Fragile X syndrome may affect the tuning of retinal cells more broadly. Our findings suggest that the retina may be relevant for understanding visual function in Fragile X syndrome.Significance statementAtypical sensory processing underlies some symptoms and experiences of people with autism spectrum disorders. These symptoms may include differences in vision, audition and sense of touch. In recent years, evidence has emerged that these differences start with atypical function of neurons in the periphery. However, not much is known about how ASD affects the function of the retina. Here, we explored retinal function in a mouse model of a disease strongly linked to ASD, Fragile X syndrome. Our experiments demonstrate that a cell type in the retina has dampened responses to light in the mouse model of Fragile X syndrome. Our work suggests that atypical processing in the retina may contribute to sensory symptoms in Fragile X syndrome.
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Accumulating evidence suggests that, in addition to dopamine, the neurotransmitter norepinephrine may play an important role in Parkinson disease (PD). The norepinephrine transporter (NET) regulates noradrenergic signaling and can serve as an index of noradrenergic innervation in neuroimaging studies. ThePink1-/-rat model, which exhibits many signs similar to PD, notably in the non-motor domain, has exhibited abnormal noradrenergic markers. In this work, we sought to (1) implement reference region pharmacokinetic modeling of positron emission tomography (PET) imaging with the novel NET ligand [18F]NS12137, (2) validate the resulting indices of NET concentration, and (3) characterize NET in thePink1-/-model. Long-EvansPink1-/-male rats were imaged by PET with [18F]NS12137 at 9 and 11 months and compared to wildtype (WT) controls. An additional group of WT rats of both sexes were imaged with [18F]NS12137 PET after pretreatment with the specific and selective NET ligand nisoxetine. Binding in locus coeruleus (LC), thalamus (Thal), and prelimbic area (PrL), regions rich in NET, were analyzed by a two-tissue compartment reversible binding model using a cerebellar reference region. [18F]NS12137 binding exhibited moderate test-retest reproducibility in LC, Thal, and PrL. Nisoxetine blockade yielded substantial reductions of [18F]NS12137 binding in LC. Compared to WT controls,Pink1-/-rats exhibited reduced binding in Thal and PrL. In conclusion, pharmacokinetic analysis of [18F]NS12137 PET provides a reproducible and specific measure of NET binding and indicates reduced NET in important brain regions inPink1-/-rats. Non-invasive in vivo [18F]NS12137 PET imaging is therefore a promising method for the study of potential therapies in thePink1-/-rat model of PD with translational potential for human PD studies.Significance StatementMany signs of Parkinson disease (PD), particularly non-motor ones, are associated with dysfunction of the noradrenergic system. However, pharmacological and behavioral therapies that target norepinephrine are not well developed for PD. It is important therefore to apply new tools for evaluating the noradrenergic effects of interventions in animal models of PD. In this work, we validated positron emission tomography (PET) neuroimaging in rats with the novel norepinephrine transporter (NET) radiotracer [18F]NS12137. We also found reduced NET expression in important brain regions (thalamus and prelimbic area) in thePink1-/-rat model of PD. [18F]NS12137 PET is therefore a promising tool for trials of interventions in thePink1-/-rat, and such work may lead to improved treatments for PD.
Early dorsal telencephalon development is coordinated by an interplay of transcription factors that exhibit a graded expression pattern in neural progenitors. How they function together to orchestrate cortical development remains largely unknown. TheEmx2andDmrta2genes encode TFs that are expressed in a similar caudomedialhigh/ rostrolaterallowgradient in the ventricular zone of the developing dorsal telencephalon with, in the medial pallium,Dmrta2but notEmx2expressed in the developing choroid plexus. Their constitutive loss has been shown to impart similar cortical abnormalities, and their combined deletion exacerbates the phenotypes, suggesting possible cooperation during cortex development. In this study, using embryos of both sexes, we utilized molecular and genetic approaches to dissect how Emx2 functions with Dmrta2 during mouse cortical development. Our results show that while they regulate a similar set of genes, their common direct targets are limited but include key regulators of cortical development. The identification of the interaction partners of Emx2 suggests that it coordinates with the LIM-domain binding protein Ldb1 to execute the activation and repression of some of its downstream targets. Finally, whileEmx2is known to suppress choroid plexus development, we also provide evidence thatDmrta2is, in contrast, required for choroid plexus since in its absence in medial telencephalic progenitors, mice develop hydrocephalus postnatally, a phenotype that appears to be due to a compromised cytoarchitecture. Together, these data indicate that Emx2 and Dmrta2 have similar but also distinct functions in telencephalon development and provide the first insights into Emx2 mechanism of action.Significance statementEmx2andDmrta2encode transcription factors that generate similar phenotypes upon their loss in the developing cortex suggesting possible cooperation. Here we explored how Emx2 functions with Dmrta2 during cortical development. Results obtained indicate that Emx2 directly regulates with Dmrta2 only a few genes, some coding for key cortical determinants and that Emx2 utilizes the Ldb1 cofactor for the regulation of some of its targets. Results also suggest that, unlike Emx2 which suppresses choroid plexus development, Dmrta2 is required for choroid plexus as its loss in medial telencephalic progenitors leads to hydrocephalus. Together, our results reveal that Emx2 and Dmrta2 have similar but also distinct functions during telencephalon development and provide novel insights into the mechanism of action of Emx2.
Cocaine is an addictive psychostimulant, and the risk of developing cocaine use disorder (CUD) is highly heritable. Little is known about the specific genes and mechanisms that lead to the development of CUD, and there are currently no FDA-approved pharmacotherapies that can treat it.Drosophilahas proven an effective model organism to identify genes and mechanisms underlying addiction, especially alcohol use disorder. While flies exposed to cocaine display features of acute intoxication like those observed in mammals, including hyperactivity and reduced sleep, to date, there is no model of preferential cocaine self-administration in flies. Here, we assayed cocaine consumption inDrosophilamales, as well as preference in a two-choice paradigm. We also investigated mechanisms involved in cocaine taste sensing using genetic and imaging tools. We show that cocaine is innately aversive to flies and that this avoidance depends on bitter sensing. Gustatory sensory neurons expressing the Gr66a bitter receptor are activated upon exposure to cocaine. Silencing of these bitter-sensing neurons or mutation ofGr66areduces cocaine avoidance. In a longitudinal choice assay, these flies develop preference for cocaine-containing solutions within 12-18 h, whereas control flies do not. Our findings show that bitter sensation protects flies from developing cocaine self-administration preference. Conversely, silencing bitter perception enables us to useDrosophilaas a model for experience-dependent cocaine self-administration preference. This opens the door to testing human variants associated with CUD for their causative role in cocaine self-administration in this highly tractable model organism.Significance statementCocaine use disorder (CUD) is a highly heritable condition for which there are no effective treatments. Testing the many human genetic variants linked to CUD requires a cost-effective, genetically tractable model. Here, we show that bitter-sensing neurons prevent cocaine self-administration inDrosophila. Furthermore, we demonstrate that disruptingDrosophilabitter perception enables a model for experience-dependent cocaine preference. Our findings underscore the potential ofDrosophilaas a crucial tool for identifying the genetic mechanisms underlying CUD, aiding in the discovery of new therapeutic targets, and contributing to the development of effective treatments for this highly heritable disease.
Visual information consists of static and dynamic properties. How is their representation organized in the visual system? Static information has been associated with ventral temporal regions and dynamic information with lateral and dorsal regions. Investigating the representation of static and dynamic information is complicated by the correlation between static and dynamic information within continuous visual input. Here, we used two-stream deep convolutional neural networks (DCNNs) to separate static and dynamic features in quasi-naturalistic videos and to investigate their neural representations. One DCNN stream was trained to represent static features by recognizing action labels using individual video frames. The second DCNN stream was trained to encode dynamic features by recognizing actions from optic flow information that describes changes across different frames. To investigate the representation of these different types of features in the visual system, we used representational similarity analysis (RSA) to compare the neural network models to the neural responses in different visual pathways of 14 human participants (6 females). First, we found that both static and dynamic features are encoded across all visual pathways. Second, we found that distinct visual pathways represent overlapping as well as unique static and dynamic visual information. Finally, multivariate analysis revealed that ventral and dorsal visual pathways share a similar posterior-to-anterior gradient in the representation of static and dynamic visual features.Significance statementHow does the human cortex represent static and dynamic visual features? Investigating the representation of static and dynamic information in realistic stimuli is difficult: separating static and dynamic features requires specially designed artificial stimuli. We tackled this challenge by using neural networks and investigated separately the representation of static and dynamic information in quasi-naturalistic videos. Our results challenge the common belief that associates static features with the ventral visual pathway and dynamic features with the dorsal pathway. We found that different visual pathways represent unique as well as overlapping static and dynamic features. We also identified a gradient in the representational pattern of static and dynamic visual features from posterior to anterior regions, spanning both ventral and dorsal visual pathways.
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AbstractHow listeners cognitively process speech during natural conversation remains poorly understood, particularly in terms of the role of the speaker’s and listener’s subjective mental states and empathic traits. This study examined relationships between these psychological factors and listener’s cognitive processing of speech. We simultaneously recorded electroencephalograms from 20 romantic couples during natural face-to-face conversations. We identified the onset times of content words using morphological analysis of the speech data. Using multivariate temporal response functions (a method to estimate stimulus-related neural responses), we analyzed each listener’s event-related brain activity in response to their partner’s speech. We found positive associations between the speaker’s interest levels and the listener’s early attentional processing, as reflected in the P2 amplitude. Higher levels of personal distress, an empathic trait, corresponded with greater sustained attention among listeners, as indexed by the late positive potential. Moreover, by using brain activities along with behavioral measures of turn-taking, a support vector machine successfully distinguished between mutually satisfying and not mutually satisfying conversations. The observed associations between the cognitive processing of speech and both the speaker’s mental states and the listener’s empathic traits demonstrate that understanding speech processing in natural conversation requires consideration of factors from both participants not just from either the speaker or the listener.
AbstractNegative symptoms and social cognition (SC) are intertwined in schizophrenia spectrum disorders (SSD) but the structure of this interaction is not yet fully understood. We employed cluster analyses to advance our understanding of the relationship between negative symptom severity and SC. We sought to identify discrete groups of patients as a function of two factors of negative symptoms—Motivation and Pleasure (MAP) and Expressivity (EXP) – and two domains of SC: emotion recognition (ER) and theory of mind (ToM). We conducted two cluster analyses to determine data-driven subgroups using two independent samples of SSD participants. The first conducted with an open dataset (n = 296) and the second with a local sample (n = 138), to assess replicability. The first cluster analysis revealed a 3-cluster solution. Both analyses highlighted distinct profiles: a ‘Relatively Preserved’ Profile; a ‘Combined Impairment’ profile, with high negative symptoms and impaired ER and ToM; and a ‘MAP’ profile, with high MAP symptoms, some EXP symptoms, and slightly to moderately impaired ER and ToM. Reducing the heterogeneity in clinical presentations of SSD patients on these dimensions of negative symptoms and social cognition provides relevant information that could contribute to a more effective selection of interventions.
AbstractSocial touch serves as a pivotal element in stress reduction and cultivation of social bonds. The COVID-19 pandemic's constraints greatly affected social behavior and may have reshaped human responses to such stimuli. We investigated the impact of COVID-19 on perceptions of interpersonal touch by comparing behavioral and electrophysiological data from pre- and peri-pandemic cohorts. Based on the vigilance-avoidance theory, we hypothesized that prolonged threat context of the pandemic would lead to reduced attentional and emotional engagement with social touch. Specifically, we expected that participants tested during the pandemic would rate social touch images as less pleasant and show lower amplitudes and longer latency in the P1 and lower amplitudes in the late positive potential (LPP) EEG components—markers of early attention and emotional processing—compared to pre-pandemic. Ninety participants rated the pleasantness of images showing human and inanimate touch or non-touch. As predicted, peri-pandemic participants rated social touch images as less pleasant than pre-pandemic participants. EEG analysis revealed a shift in P1 responses: while pre-pandemic participants showed higher P1 amplitudes for touch than non-touch stimuli, this distinction disappeared during the pandemic. No significant differences were found in LPP or P1. Results suggest that social distancing reduced the salience of interpersonal touch.
AbstractSocial exclusion impairs decision-making, affecting social functioning. This study examines how social exclusion, in both immediate, experimentally-induced, and self-reported chronic forms, influences intertemporal decision-making, and whether transcranial direct current stimulation (tDCS) over the right ventrolateral prefrontal cortex (vlPFC) can mitigate these negative effects. Experiment 1 (n = 123) found that immediately excluded individuals favored immediate rewards. Experiment 2 (n = 59) demonstrated that applying anodal tDCS over the right vlPFC reduced this preference. Self-reported chronic exclusion also led to a preference for immediate rewards (Experiment 3, n = 144), but multiple anodal tDCS sessions, again, exhibited an immediate remediation effect (Experiment 4, n = 36). We discuss how self-control mediates the link between exclusion and intertemporal decision-making. We further demonstrate the underlying role of the right vlPFC in social exclusion and intertemporal decision-making, and highlight tDCS as a potential therapeutic tool for increasing resilience and coping with negative situations such as social exclusion.
AbstractTheoretical accounts propose that people update their feedback expectations asymmetrically, with stronger updating after positive than negative feedback and self-relevant than irrelevant feedback. Further, attributions to the senders influence neuronal responses toward social evaluative feedback. In this study, we examined how both attributed self-relevance and acquired sender valence through their feedback behavior impact learning about and ERP responses toward the social evaluative feedback. We investigated these questions in an Event-Related Potential (ERP) study (N = 40), where participants received either constant positive or negative feedback from senders, either self-relevant or directed to an unknown person. Participants first indicated their feedback expectations and were then exposed to the feedback and the sender's face. Feedback expectations changed according to sender behavior over time, while surprisingly, expectations changed stronger for negative senders in general and positive self-irrelevant senders. For feedback, increased P1 responses to worse-than-expected feedback were observed, while mid-latency (Early Posterior Negativity, EPN; Feedback Related Negativity, FRN) and late components (Late Positive Potential, LPP) to feedback were increased by feedback self-relevance. The FRN was additionally affected by sender valence and expectedness. Our findings thereby reveal different facets of behavioral and neuronal effects of attributed sender self-relevance and acquired sender valence.
AbstractThis study explores the dual pathways of dishonesty—conformity-driven and self-interest-driven dishonesty—by examining the role of oxytocin (IN-OT) in modulating these behaviors. Through a placebo-controlled, double-blind experiment, we investigated how IN-OT impacts dishonesty under competitive and non-competitive contexts across genders. Results show that oxytocin significantly enhances conformity-driven dishonesty, particularly among males in non-competitive settings, aligning with the social salience hypothesis that oxytocin amplifies social cues. In contrast, self-interest-driven dishonesty remained unaffected by oxytocin, indicating its stability as an intrinsic trait. These findings reveal the context-dependent nature of oxytocin’s influence on moral behavior, highlighting how social factors and biological mechanisms intersect in dishonest actions. This study underscores the importance of distinguishing motivations behind dishonesty and offers insights into neurochemical interventions that could influence ethical behavior within social and organizational settings.
AbstractContemporary affective neuroscience perspectives consider possible trade-offs of neural attunement to social cues for adolescent development. Integrating these perspectives with interpersonal theories emphasizing robust belonging needs during adolescence, this study examined whether exposure to naturally occurring interpersonal stressors was differentially associated with loneliness and depression contingent on adolescent girls’ neural sensitivity to cues indicating social threat (non-belonging) vs. reward (belonging). Eighty-six adolescent girls (M age = 16.31, SD = .84; 66.3% White) completed a social feedback task during an fMRI scan and reported on their loneliness and depression. Elevated interpersonal stress exposure was associated with more depression in girls who showed dampened but not heightened activation in the salience and social processing networks in response to threat (vs. reward). In the context of low interpersonal stress, however, dampened activation to threat (vs. reward) was associated with particularly low levels of depression. These effects were partially accounted for by self-reported loneliness. This research supports current trends toward developing a more refined perspective on the adaptational value of neural attunement to social cues for adolescent development, suggesting that the balance of social threat vs. reward sensitivity can confer emotional risks or benefits by shaping how adolescent girls navigate diverse social contexts.
AbstractLong, naturalistic stimuli are effective in evoking meaningfully differential neural response patterns between groups. However, the resulting timeseries data often have a high number of features compared to a limited sample size, increasing the likelihood of overfitting and reducing predictive power. This paper introduces multi-timepoint pattern analysis (MTPA) as a temporal dimension reduction approach for improving prediction accuracy when building models with long neural timeseries data. Using feature selection with elastic net regression, MTPA identifies predictive neural patterns while preserving the temporal structure and interpretability of the data. Across two experiments with distinct populations and objectives, MTPA demonstrated consistent advantages over approaches using principal component analysis, windowed averaging, and no dimension reduction. Experiment 1 predicted persistent work-related psychological states in business professionals, achieving accuracies up to 79.1%. Experiment 2 predicted cognitive load and narrative context during video viewing in undergraduates, with accuracies up to 66.5%. These findings suggest that MTPA may be a useful tool for analyzing neural data from extended naturalistic designs, enabling researchers to improve prediction accuracy across diverse outcomes and obtain new insights into the temporal dynamics of neural responses.
AbstractCooperation and competition represent two fundamental modes of social interaction, yet their underlying neural mechanisms remain incompletely understood. Functional near-infrared spectroscopy (fNIRS) hyperscanning, enabling simultaneous measurement of hemodynamic activity across individuals, offers unique insights into the neural substrates underlying naturalistic interactions. Using this technique, we investigated cross-channel inter-brain coupling (IBC) between interacting individuals during cooperative and competitive play in a motion-sensing tennis game. Compared to resting-state and solo gameplay with observation, both conditions elicit significantly enhanced not only IBC between the dyads’ sensorimotor regions, but also cross-regional coupling between one participant’s sensorimotor cortex and the other’s dorsolateral prefrontal cortex (DLPFC) as well as temporoparietal junction (TPJ), suggesting the contribution of high-order cognition networks to the observed IBC. Notably, competitive interactions produce stronger cross-reginal IBC between DLPFC and sensorimotor regions than cooperative ones, implying intensified demand of cognitive control during competition. Conversely, cooperation enhances neural coupling between teammates within their prefrontal cortices which could reflect shared goal representations. Behavioral cooperation performance is negatively correlated with the DLPFC-sensorimotor IBC. These spatially distinct patterns of condition-dependent neural coupling advance our understanding of the neural underpinning of naturalistic social interactions.
AbstractRecent research reveals that human occipito-temporal “social brain” regions that are selective for images of individual faces and bodies, are also sensitive to visual cues of social interaction. Earlier studies mainly contrasted observing dyadic interactions with non-interactive controls, emphasizing the interacting/non-interacting distinction to observers, and lacking the variety seen in natural settings. To address these limitations, we analyzed a 7 T fMRI data set in which participants viewed many naturalistic images while performing a memory task. We focused on 182 scenes containing at least two individuals, and used localisers to identify face- and body-selective regions of interest (ROIs). Brain responses to each image were measured, and the depiction of social interaction was rated by independent observers. Control measures were gathered, per image, for the number of people, their surface area and distribution, and their implied animatedness. Linear and generalised additive modelling revealed that social interaction predicted a greater BOLD response in all ROIs, beyond the effects of the control variables. Face- and body-selective regions in both hemispheres showed heightened sensitivity to social interaction in natural scenes, even during an orthogonal task. These findings expand our understanding of “social vision” areas beyond individual person perception to include multi-person social interactions.
AbstractWhile bacterial motility has been well characterized in uniform liquids, only little is known about how bacteria propagate through complex environments, such as gel-like materials or porous media that are typically encountered in tissue or soil. Here, we study bacterial swimming in polysaccharide matrices formed by different concentrations of agar. We focus on the soil bacteriumPseudomonas putida(P. putida) that is known for its multimode swimming pattern, where a polar bundle of flagella may push, pull, or wrap around the cell body. In the gel matrix,P. putidacells display run-and-turn motility with exponentially distributed run times and intermittent turning phases that follow a dwell time distribution with power-law decay. An analysis of the turn angle distribution suggests that both, flagella mediated turning as well as mechanical trapping in the agar matrix are part of the overall swimming pattern. We compare these results to knockout mutants which differ from the wild-type in their swimming speed and show altered probabilities for the occurrence of the three swimming modes. Their run length distributions in the agar matrix are, however, identical demonstrating that run episodes of bacterial swimmers in a gel matrix are primarily determined by the surrounding geometry. We propose a minimal active particle model providing analytical solutions that quantitatively explain the observed time dependence of the mean squared displacement in the gel based on the experimentally observed motility pattern and the measured waiting-time distributions.
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AbstractIn this study, the integration of PbO2into a borosilicate glass system was investigated for enhanced radiation shielding performance. Several glasses with varying PbO2concentrations (31, 33, 35 and 37 mol%) were prepared using the melt-quenching method. The density of the glasses increases from 4.579 to 5.044 g/cm3as a result of increase the PbO2content. The radiation attenuation factors were experimentally determined at 0.059, 0.662, 1.173 and 1.333 MeV, using HPGe detector. The results indicate that increasing PbO2content notably influences the mass attenuation coefficient and the effective atomic number. The tenth value layer (TVL) increased significantly with rising energy levels. For the glass sample containing 31 mol% PbO₂, the TVL increased from 0.177 cm at 0.059 MeV to 5.325 cm at 0.662 MeV, and to 9.094 cm at 1.333 MeV. Similarly, for the glass with 37 mol% PbO₂, the TVL increased from 0.146 cm at 0.059 MeV to 4.733 cm at 0.662 MeV, and to 8.231 cm at 1.333 MeV. The results also showed that PbO₂ has an inverse effect on the TVL, where adding more PbO₂ leads to a decrease in the TVL. At 0.662 MeV, increasing the PbO₂ content from 31 to 37 mol% reduces the TVL by approximately 11.12%. The transmission factor (TF) for the glass with a thickness of 2 cm was investigated, and results showed that the TF is nearly 0 at 0.059 MeV, indicating that the glass provides complete shielding at this low energy. The TF increases with rising energy, reaching 37.8–42.11% at 0.662 MeV, indicating that more photons penetrate the glass as the energy increases.
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AbstractThe Red Sea’s near-shore zones are considered nurseries and grazing grounds for the various economic fish species. To illustrate the relation between human health and seafloor sediments, the geological and geochemical properties of seafloor sediments were investigated in near-shore zones at Marsa Alam and Hurghada cities along the Red Sea. The obtained data illustrated that the sediment nature at Hurghada is primarily of biogenic origin, as indicated by the high carbonate contents; however, the sediment nature at Marsa Alam is attributed mainly to the terrigenous origin. Accordingly, the studied heavy metals at both localities showed different feeding sources; Marsa Alam sites showed high levels of Fe, Mn, Zn, Ni, and Cu attributed to terrigenous inputs; however, the high averages of Cd and Pb at Hurghada indicating influence from land-based and anthropogenic activities. The calculated risk assessment parameters and carcinogenic risk (ILCR) do not indicate any significant risk. Geochemically and as indicated by the statistical parameters: correlation coefficient, PCA, and Geo-accumulation (Igeo); Mn, Zn, Cu, and Ni were found to be mainly associated with Fe in the same source of accumulation and similar geochemical forms. However, the adsorption over sediment particles and/or assimilation inside the carbonate lattices are possible occurrences of Cd, Pb, and partially Ni. The calculated risk assessment parameters and carcinogenic risk (ILCR) do not indicate any significant risk to marine organisms and human consumption.
AbstractAromatic plants produce essential oils (EOs) with diverse phytochemicals and biological applications. This study investigated three eco-friendly nanoemulsions of Lemon peel (LPO), Turmeric (TO), and Black seed (BSO) oils loaded into nanochitosan (NCh) for their antifungal activity against resistant fungal strains. Phytochemical analysis identified oxygenated/non-oxygenated hydrocarbons and saturated/unsaturated fatty acids in the EOs. Physicochemical characterization using FTIR, DLS, and HR-TEM showed stable nanoemulsions and nanochitosan with homogeneous particle size distributions in the nanoscale range. Notably, the essential oil nanoemulsions exhibited potent antifungal activity againstMucor racemosus,Rhizopus microsporus, andLichtheimia corymbifera, resistant to commercial antifungal drugs. The nanoemulsions loaded with 1–3% chitosan showed inhibition zones ranging from 17 to 23 mm, outperforming the synthetic antifungal treatments. These findings highlight the potential of plant-derived essential oil nanoemulsions loaded into biocompatible nanochitosan as a promising, sustainable alternative to combat the growing threat of invasive fungal infections and drug resistance. Incorporating natural, eco-friendly materials enhances the stability, bioavailability, and targeted delivery of the active phytochemicals, contributing to the antifungal solution’s overall efficacy and safety profile.
AbstractThe insecticidal furan-2-carbaldehyde thiosemicarbazone(1)as staring compound underwent a nucleophilic substitution reaction with different reagents, chloroacetyl chloride, chloroacetic acid. 1,4-dibromobutane-2,3-dione and also, with different activated reagents 2-cyanoacetohydrazide, phthalic anhydride, and 2-chloroquinoline-3-carbaldehyde as good yields. The structures of these compounds were confirmed by elemental and spectral analyses. The majority of the synthesized compounds were assessed for their insecticidal activity towards three insects,Cryptoblabes gnidiella,Retithrips syriacusandSpodoptera frugiperdaunder laboratory conditions and promising results were obtained, with encouraging outcomes observed. Compounds5, 7, 9, 11and15were found to the most effective than other compounds on all insects. Also,R. syriacusinsects are more affected thanC. gnidiellaandS. frugiperdaafter one day of treatment with LC50values 15.68, 18.90, 58.04, 17.81, and 42.21 μg/mL respectively, comparing with positive control LC50, 8.90 μg/mL. Furthermore, biochemical parameters of five enzymes ofS. frugiperda; Acid Phosphatase, alkaline phosphatase, aspartate transferase, alanine transaminase, and acetylcholinesterase enzymes were conducted at LC50value of the highly toxic compounds. Density functional theory calculations were employed to optimize the molecular geometry and compute the electrostatic potential, complemented by molecular docking to predict the most acceptable score and root mean square deviation and affinities of the synthesized compounds.
AbstractPatients with virus encephalitis, such as herpes simplex encephalitis and Japanese encephalitis frequently relapse with autoimmune encephalitides associated with neural autoantibodies. It has been hypothesized that the infection-induced damage to the central nervous system results in shedding of neural autoantigens, their presentation to the peripheral immune system, and initiation of a secondary autoimmune encephalitis that targets these autoantigens. To test this hypothesis, we utilized a transgenic mouse model of virus-like but sterile encephalitis. After induction of acute neuronal death in the hippocampus, we monitored the mice for encephalitis-like symptoms for up to 10 months, evaluated the degree of neuroinflammation at several time points and screened their plasma for autoantibodies against 49 different autoimmune disease-associated brain autoantibodies. Throughout the study period, we did not detect any symptoms of severe autoimmune encephalitis, like hyperactivity, circling, seizures, lethargy. Evaluation of microglia numbers and morphology revealed pronounced microgliosis 1-week after initial encephalitis induction, which decreased over time. Scattered lymphocyte infiltration was present at all times in hippocampi of encephalitis mice, and did not increase over time. Perivascular cuffs were not detected. Infiltrating lymphocytes mainly consisted of CD8+ T cells. B cell infiltration was rare and did not differ from healthy control mice. High-parameter immunophenotyping of peripheral blood leukocytes did not reveal any changes associated with an autoimmune response. Testing all plasma samples (n = 30/group) at a dilution of 1:100 for autoantibodies against 49 neural autoantigens gave only two positive results, namely one healthy control with anti-CASPR2 autoantibodies (IgG) and one post-encephalitis mouse with anti-homer-3 autoantibodies (IgM). Overall, these findings suggest that acute neuronal cell death and neuroinflammation per se are not sufficient to trigger downstream autoimmune encephalitis relapses in mice.
AbstractBiallelic variants in the adenosine deaminase tRNA specific 3(ADAT3)gene are associated with a distinct neurodevelopmental disorder characterized by dysmorphic facies, poor growth, cognitive impairment, and variable brain anomalies. We describe 24 patients from 16 unrelated Egyptian families withADAT3-related neurodevelopmental disorder. All patients presented with developmental delay, growth retardation, cognitive impairment, and the characteristic facial features of the disorder, which appears to be more recognizable in older patients. Seizures were noted in 20% of patients and showed favorable responses to treatment. Brain imaging showed corpus callosum abnormalities in most patients (91.6%), followed by delayed myelination and cortical atrophy. Exome sequencing identified threeADAT3variants, including the Saudi founder variant c.430G > A (p.Val144Met), which was detected in 17 patients (70%). In addition, two novel variants were identified, c.319G > A (p.Glu107Lys) and c.1013_1018dup (p.Arg338_Ile339dup). The c.319G > A (p.Glu107Lys) was recurrent in 6 patients (25%) who shared a similar haplotype, suggesting a likely founder effect in our population. On the other hand, the c.1013_1018dup (p.Arg338_Ile339dup) was identified in a single patient. Our study reports a large cohort of patients withADAT3-related neurodevelopmental disorder from Egypt and reinforces the clinical and brain imaging characteristics of the disorder. The high prevalence of the c.430G > A (p.Val144Met) in our population strongly suggests the existence of a founder effect of this variant in the Middle East and Arab region. In addition, we report a new founder variant expanding the mutational spectrum of this rare disorder.
AbstractThis study is focused on the Menes oil field, located on the western flank of Shushan Basin in Egypt’s northern Western Desert (NWD). The primary oil-bearing reservoir in this area is the Lower Cretaceous Alam El Bueib (AEB) Formation (Fm), that extends through the Barremian to Aptian stages. This formation is characterized by thick, massive, argillaceous, and calcareous sandstones interbedded with shale and carbonate layers. 2D seismic profiles are interpreted to delineate the structural features of the subsurface. The well to seismic tie via synthetic seismograms and check-shot data are utilized for mapping the formation tops of Alamein dolomite, as well as the AEB units (1, 3 A, 3 C, and 3D), and the Paleozoic strata. Electrical wireline logs from four wells in Menes oil field were analyzed to estimate key petrophysical parameters, including porosity and hydrocarbon saturation for reservoir characterization. Finally 3D structural model was developed to enhance subsurface visualization, enabling a more precise characterization of the AEB reservoirs. This model also aims to reduce exploration risks and improve field development strategies in the study area. These findings provide crucial insights into the subsurface characteristics and hydrocarbon prospects of this formation, offering valuable information that can inform strategic decision-making in both exploration and production activities within Shushan basin. The comprehensive understanding gained from these results serves as a key contribution to optimizing future exploration efforts and enhancing the development of hydrocarbon resources in the near by regions.
AbstractThe adoption of advanced and practical technologies to boost plant productivity and improve quality under challenging environmental conditions, such as salinity, has become an essential need in modern agriculture. Plasma technology can significantly improve the seed’s resistance to stress factors like high salinity and dry environments. Thus, the current work aimed to improve the yield and quality of cowpea as an important forage crop grown in saline soil using a plasma coating approach. The seeds of cowpea were treated with three plasma doses expressed in different times of exposure (0.0, 1.0 and 2.0 min) and planted (for two seasons of 2022 and 2023) in three soil salinity levels expressed in electrical conductivity, EC (normal, 0.3 dS m−1, moderate salinity 5.5 dS m−1, and high salinity, 7.0 dS m−1, abbreviated as EC3.0, EC5.5 and EC7.0, respectively). The electron micrographs and elemental detection revealed that 2.0 min treatment resulted in deep cracking and topographical modulation with the best enhancements in cowpea seed surface nutrients. The agronomic findings revealed that compared to the corresponding check treatment (without plasma, 0.0 min), the exposure to plasma for 2.0 min in the first season was the efficient for enhancing forage yield under normal (1.37-fold increase) and medium salinity (1.79-fold increase). The in vitro data showed plasma-treated seeds for 2.0 min displayed higher acid detergent fiber content under EC3.0 or EC5.5 compared to the other treatments. Plants grown from seeds treated with plasma for 1.0 min showed higher dry matter degradability levels at EC7.0 compared to the other treatments. At EC7.0 the highest ammonia concentration was recorded in plants grown plasma-treated seeds for 1.0 min, while the lowest value was observed in 2.0-min. 2.0-min plasma-treated seeds produced the highest total volatile fatty acids across different salinity conditions, particularly at EC7.0. Plasma treatment, as a safe and innovative seed priming method, validates substantial potential in improving cowpea productivity under saline conditions. This study revealed that exposing cowpea seeds to a 2-min plasma treatment before sowing enhanced seed germination rate, and overall yield, even under challenging saline environments. Moreover, enhanced feed quality resulting from plasma-treated seeds offers direct benefits to livestock nutrition, supporting both human and animal food chains.
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AbstractGregarious desert locusts produce stage-specific pheromones that facilitate cohesive behavior in juveniles and synchronize maturation and mating in sexually mature adults. During locust outbreaks, merging populations result in cross-stage interactions, yet their impact on locust biology remains poorly understood. This study tested the hypothesis that cross-stage interactions influence juvenile cohesion and physiological traits. Using behavioral assays and gas chromatography-mass spectrometry, we examined short- and long-term interactions between juvenile and adult desert locusts. In short-term (24 h) cage assays, the presence of adults did not significantly affect grouping behavior in gregarious 3rd instar nymphs, as measured by the mean distance between individuals. Likewise, overall, juvenile pheromone emissions, based on previously identified nymphal components, showed no significant differences regardless of adult presence. Cross-stage interactions also had no measurable effect on the development time of 3rd instar nymphs. In contrast, long-term assays showed that 1st instar nymphs grouped with adults matured faster and grew heavier than older nymphal instars and fledglings, and, as mature males, released higher levels of phenylacetonitrile (PAN). Additionally, adult females emerging from these interactions oviposited earlier and laid more eggs than those not exposed to adults as juveniles. These findings indicate that cross-stage interactions impact development uniquely across different gregarious locust stages. Additionally, they offer important insights into desert locust behavior and chemical ecology, which could aid in developing more effective management strategies.
AbstractAntimicrobial agents produced byXenorhabdusspp. may hold the answer to novel antimicrobial agents. Antibacterial activity of some bacterial strains isolated from different Egyptian archaeological sites was evaluated. The most potent organism that reported high antibacterial activity was identified asXenorhabdus nematophila. The produced bioactive compound was identified as xenortide using LC–MS and NMR studies. Optimization of xenortide’s production was assessed using a central composite statistical design. The most effective fermentation factors were identified as carbon, nitrogen source concentrations and pH levels. Nano-xenortide was synthesized using the ball milling method, followed by its characterization and evaluation for its anticipated antibacterial and anticancer properties. Statistical analysis of the findings indicated that the produced nano-xenortide exhibited superior antibacterial efficacy. Furthermore, the assessment of its cytotoxicity revealed that nano-xenortide is a promising, safe candidate that can be used as an antibacterial and anti-colorectal-carcinoma agent.
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AbstractThe novel ligand (H2L), N’-(2-cyanoacetyl)isonicotinohydrazide, has been synthesizedviareacting the isonicotinic hydrazide with 1-cyanoacetyl-3,5-dimethylpyrazole. The keto-form of the free ligand has been evoked from its spectral data. Based on elemental analyses and mass spectra, the ligand formed 1:1 (M: L) metal complexes with the acetate salts of Cu(II), Co(II), Ni(II) and Zn(II). The complexes’ spectral analyses revealed that the ligand behaved as a mononegative bidentateviathe hydrazonyl N1and deprotonated enolized acetyl oxygen. Moreover, the DFT quantum chemical calculations revealed that the ligand had higher HOMO and lower LUMO energies than metal complexes, implying an electron donating character. Furthermore, the in vitro anticancer activity against HepG2 and HCT-116 cell lines displayed that the ligand was more potent than doxorubicin against both cell lines, although the metal complexes displayed lower efficacy.
AbstractThe present research was set out to delineate the protective and therapeutic potency of hesperidin (Hesp) versus cisplatin (Cis) against the deleterious consequences of Ehrlich ascites carcinoma (EAC) on the liver and the prospective mitigative effect of Hesp against Cis-mediated hepatotoxic side-effects. A total of 70 female mice were randomly assigned into control, Hesp, EAC, Hesp-protected, Hesp-treated, Cis-treated, and Cis + Hesp-treated groups. Mice inoculated with EAC cells exhibited significant reductions in the serum total protein and albumin levels, along with significant elevations of the serum aminotransferases, lactate dehydrogenase, amylase, and lipase activities, and alpha-fetoprotein level. A significant increment in malondialdehyde level concomitantly with significant declines in reduced glutathione concentration and catalase activity were also observed in the liver of EAC-bearing mice. Additionally, marked hepatic pathological changes as well as a strong Ki-67 expression and a weak caspase-3 expression in the neoplastic cells infiltrating hepatocytes were observed. In contrast, the administration of Hesp and/or Cis to the EAC-bearing mice reversed, to varying degrees, the cytotoxic effects of EAC. Besides, Hesp minimized the harmful hepatic chemotherapeutic side-effects of Cis. Overall, Hesp could be a promising phytochemical against EAC-induced cytotoxicity with its potential to improve the antitumor efficacy of chemotherapeutic drugs and minimize their hepatic adverse side-effects.
AbstractExcessive fibroblast proliferation and metabolic reprogramming are hallmarks of pathological cardiac remodeling, contributing significantly to impaired cardiac function. This study investigates the role of circular RNAs (circRNAs) in fibroblast metabolic reprogramming, an unexplored area with potential therapeutic implications. Through deep circRNA sequencing of cardiac tissue from heart failure (HF) patients and healthy individuals, we identified circIGF1R (hsa_circ_0005035), which exhibited dysregulation specifically in isolated cardiac fibroblasts derived from failing hearts. Silencing circIGF1R in patient-derived human cardiac fibroblasts (HCFs) led to accelerated proliferation, enhanced glycolytic activity, altered glucose trafficking, and increased glucose import. Conversely, administering recombinant circIGF1R inhibited the accelerated proliferation and enhanced glycolytic activity observed in HCFs from HF patients. Mechanistically, RNA pulldown assays and in silico analyses identified AZGP1 as a potential interaction partner facilitating the glycolysis-inhibitory and anti-proliferative functions of circIGF1R. Our findings identify circIGF1R as a pivotal regulator of fibroblast proliferation via metabolic reprogramming, particularly by glycolysis inhibition. Overexpression of circIGF1R demonstrated significant anti-fibrotic effects in cardiac fibroblasts derived from heart failure patients. These results underscore the therapeutic potential of circIGF1R in attenuating cardiac fibrosis by directly targeting fibroblast metabolism in the context of pathological cardiac remodeling.
AbstractAcute dyspnoea is one of the most common presenting symptoms in the emergency department (ED) and has a variety of underlying causes. Calprotectin is a neutrophil activation marker associated with adverse outcomes in acute cardiovascular and infectious diseases. However, the usefulness of calprotectin in the risk stratification of patients with acute dyspnoea is unknown. The objectives were to, in unselected patients presenting to the ED with acute dyspnoea, investigate the association between (1) calprotectin and 90-day mortality, (2) calprotectin and 90-mortality in subgroups of patients with cardiovascular disease or pneumonia, and (3) calprotectin and illness severity. Single-centre observational cohort study from a university hospital in southern Sweden. A total of 1186 patients from the original Acute Dyspnoea Study, were included. Patients were followed for discharge diagnosis and mortality. Calprotectin concentration was measured in plasma samples collected at the ED. Mean age was 72 years and 56% were women. During follow-up, 143 patients died. In multivariate Cox regression for 90-day mortality, calprotectin in the highest quartile (> 0.96 mg/L) compared to the lowest quartile (< 0.27 mg/L) was associated with a hazard ratio of 2.71 (95% confidence interval 1.39–5.26,p< 0.01). The association with mortality remained significant in the subgroup of patients with acute cardiovascular disease (N= 205,p< 0.01). There was no statistically significant difference in median calprotectin values between survivors and non-survivors with pneumonia (1.62 vs. 1.31,p= 0.155). Multivariate linear regression showed a strong positive correlation between calprotectin and illness severity (respiratory rate ≥ 29 or oxygen saturation ≤ 90%,p< 0.001). In conclusion, calprotectin was associated with 90-day mortality and correlated strongly with illness severity. This indicates that measurement of calprotectin at admission could improve clinical risk stratification of the acute dyspnoeic ED patient.Clinical trial number: Not applicable.
AbstractWe studied the characteristics and survival of patients with sorafenib-treated HCC and impact of underlying etiology on outcomes. This retrospective multicenter study recruited patients with sorafenib-treated advanced HCC (12/2016 to 4/2023) till death or the study end (2/2024). Time to progression (TTP) and overall survival (OS) were recorded. We evaluated; Clinico-laboratory and imaging predictors of OS, The impact of underlying etiology on tumor variables, outcomes and tolerance for sorafenib > 6 months. This study included 706 patients. Median duration of Sorafenib therapy was 240.00 (90.00–360.00) days. Median OS was 314.00(146.00–601.00) days. Median TTP was 180.00(90.00–330.00) days. COX regression revealed that the independent factors of mortality were baseline AST, Tumor size, hepatic vein thrombosis (HVT), development of jaundice and shifting to Regorafenib. Advanced HCCs were more common on top of non-cirrhotic non-viral and HBV-related liver disease. Adverse events, TTP and tumor response didn’t differ with the underlying etiology. Median OS was lower in non-viral-related HCC than HCV-related HCC (218.00 versus 326.50 days,P-value = 0.048). Patients who continued sorafenib > 6 months had lower AFP, HVT, adverse effects and better tumor response after 3 months. OS is lower in non-viral Sorafenib-treated HCC compared with viral-related HCC and Sorafenib was well-tolerated among different HCC etiologies.
AbstractSleep inertia is the post-awakening transitional state of lowered arousal, characterized by increased low-frequency activity in the electroencephalogram (EEG) and impaired cognition. While some theories consider arousal holistically, recent research questions whether these findings apply to situations requiring immediate critical action post-awakening, such as for pilots, emergency responders, or future drivers of automated vehicles. This study compared self-reported, cortical, and physiological arousal in such a scenario. Twenty-four participants completed four drives in a driving simulator. In three drives, participants were instructed to sleep for 20, 40, and 60 min during automated driving before being prompted to resume control. The sleep stage prior to the takeover request served as a quasi-experimental independent variable. Regression analyses showed that cortical arousal was low following awakenings from N2 or N3, indicated by increased delta, theta, and alpha activity. However, beta activity and heart rate also increased, suggesting elevated physiological arousal. Significant positive correlations were found between delta activity, heart rate and self-reported sleepiness. This “arousal paradox” is not in line with the idea of arousal as a holistic concept. We hypothesize that the heightened physiological response under sleep inertia may be attributed to stress in demanding situations under sleep inertia. We conclude that forced awakenings from N2 or N3 should be avoided. If someone is nevertheless awakened from N2 or N3, they should be given sufficient time between awakening and taking over duties for arousal to normalize.
AbstractSoil-transmitted helminths primarily compriseAscaris lumbricoides,Trichuris trichiura, and hookworms, infecting more than 600 million people globally, particularly in underserved communities. Manual microscopy of Kato-Katz thick smears is a widely used diagnostic method in monitoring and control programs, but is time-consuming, requires on-site experts and has low sensitivity, especially for light intensity infections. In this study, portable whole-slide scanners and deep learning-based artificial intelligence (AI) were deployed in a primary healthcare setting in Kenya. Stool samples (n= 965) were collected from school children and Kato-Katz thick smears were digitized for AI-based detection. Light-intensity infections accounted for 96.7% of cases. Three diagnostic methods - manual microscopy, autonomous AI and human expert-verified AI - were compared to a composite reference standard, which combined expert-verified helminth eggs in physical and digital smears. Sensitivity forA. lumbricoides,T. trichiuraand hookworms was 50.0%, 31.2%, and 77.8% for manual microscopy; 50.0%, 84.4%, and 87.4% for the autonomous AI; and 100%, 93.8%, and 92.2% for expert-verified AI in smears suitable for analysis (n= 704). Specificity exceeded 97% across all methods. The expert-verified AI had higher sensitivity than the other methods while maintaining high specificity for the detection of soil-transmitted helminths in Kato-Katz thick smears, especially in light-intensity infections.
AbstractDespite the advent of advanced molecular prognostic tools, it is still difficult to predict the course of disease for cancer patients at the individual level. This lack of predictability is also reflected in many experimental cancer model systems, begging the question of whether certain biological aspects of cancer (eg. growth, evolution etc.) can ever be anticipated or if there remains an inherent unpredictability to cancer, similar to other complex biological systems. We demonstrate by a combination of agent-based mathematical modelling, analysis of patient-derived xenograft model systems from multiple cancer types, and in-vitro culture that certain conditions increase stochasticity of the clonal landscape of cancer growth. Our findings indicate that under those conditions, the cancer genome may behave as a complex dynamic system, making its long-term evolution inherently unpredictable.
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AbstractPlant-parasitic nematodes (PPNs) pose a significant problem for farmers worldwide, leading to yield losses. Several conventional strategies, such as artificial nematocides, have been used in the past to control PPNs in pepper plants. In an in vivo trial aimed at reducing root-knot nematodes, (RKNs)Meloidogyne incognitacommunities in soil and root infestation, certain plant seed cake (PSC) was evaluated for its potential use. In this study, four PSCs were used to manage PPNs: black seed, jojoba, olive, and jatropha. These PSCs relatively inhibited nematode reproduction and promoted pepper plant health. Notably, black seed and jojoba were the most effective toxic PSC against RKNs,M. incognita, especially targeting the second-stage J2s in soil. For example, treatment with black seed at both 15 and 30 g rates, as well as jojoba at 15 g rate, was consistently effective in reducing the final nematode population. Growth parameters, including shoot and root weight and length, as well as the number of leaves, were measured. The results showed that black seed at 30 g and jojoba at 15 g significantly increased shoot weight, followed by black seed at 15 g, with corresponding values of 75.89 g, 47.86 g, and 45.9 g, respectively. According to GC-MS analysis, the mode of action of these PSC may involve natural active compounds capable of killing or inhibiting nematode communities. The GC-MS analysis of jatropha seeds cake showed remarkable bioactive compounds, including D-Psicofuranose, pentakis (trimethylsilyl) ether (isomer 2); 9,12-Octadecadienoic acid; 2-((2-Methyl-1-oxa-4-azaspiro [4.4]non-4yl) carbonyl) cyclopropane carboxylic acid and 1 H-Indene, 2,3-dihydro-4-propyl. These compounds have antimicrobial, insecticidal, anti-nematodal, and antiviral activities confirming their potential as natural biopesticides.
AbstractCurrent staple crops such as rice, wheat, and maize dominate food systems but lack climate resilience, necessitating a shift toward nutrient-rich, sustainable alternatives.Chenopodium quinoa, (C. quinoa) has gained global recognition for its adaptability and nutritional value. However, while quinoa grains have been extensively studied, young green quinoa (YGQ) leaves remain underexplored despite their potential to enhance both agricultural sustainability and human health. This study investigates the anti-inflammatory properties of YGQ leaves extracts from eight quinoa accessions cultivated during the summer. Using lipopolysaccharide (LPS)-activated mouse macrophage cells (RAW264.7), we assessed the inhibition of key pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and Interleukin (IL)-6. Four types of extracts—Ethanol:Water (70:30) (ETDW), Ethanol (ET), Ethyl Acetate (EA), and Hexane (HE) were prepared, revealing significant and specific IL-6 inhibition, with ETDW exhibiting the highest suppressive effect (73–100%). LC–MS/MS analysis identified flavonoids as the likely bioactive compounds responsible for this activity. Importantly, toxicity assays confirmed the extracts’ safety. These findings position YGQ leaves as a valuable natural source of bioactive compounds with potential applications in functional foods, which offer health benefits beyond basic nutrition by targeting the prevention of noncommunicable diseases and chronic inflammatory conditions. Furthermore, integrating YGQ leaves into food systems could support sustainable agriculture, as quinoa is a climate-resilient crop, providing dual benefits for public health and food security.
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AbstractEmotions mediate a wide range of cognitive functions, including memory, attention, and decision making. Studies of emotion in non-human animals have typically focused on negative emotions—like fear—that have clear behavioral correlates (e.g., freezing or retreating). To address this one-sided treatment of affect, we used a cognitive bias test to ask whether vocalizations associated with positive affect lead apes to expect positive future outcomes. All great apes produce laughter-like vocalizations during play that likely evolved from a shared ancestral form of laughter. We primed bonobos with conspecific laughter and then asked whether they were more likely to treat an ambiguous stimulus as if it were positive. Subjects (n= 4) were first trained to approach rewarded (black) stimuli and skip unrewarded (white) stimuli. We then presented occasional ambiguous (grey) stimuli. Bonobos approached ambiguous stimuli to search for rewards more often after hearing laughter. Our results suggest that hearing laughter induces positive emotions and may thus bias bonobos’ decision making, including foraging or search behavior. While only apes produce human-like laughter, several other non-human animals have contagious play vocalizations. These vocalizations may lead other animals to anticipate positive outcomes, revealing commonalities in the role of positive emotion in behavior and cognition across species.
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AbstractUltra-high-performance fiber-reinforced concrete (UHPFRC) is an exceptional type of cementitious composite with superior mechanical and durability performances. Achieving these properties involves maintaining a low water-to-cement ratio, optimizing aggregate size distribution, and integrating fiber reinforcement. Recently, there has been a notable trend in the development and application of UHPFRCs. However, there is still a requirement for artificial intelligence (AI) methods to predict the early-age compressive strength (CS) of UHPFRC and to define the key input factors for optimal mix design with appropriate proportions. Therefore, five AI models were chosen to assess the predictive accuracy of early-age CS in the current study. These models include support vector regression (SVR), random forest (RF), artificial neural network (ANN), gradient boosting (GB), and Gaussian Process Regression (GPR). As part of evaluating model performance and conducting error analysis, this study investigated differences in prediction accuracy among five models across training and testing datasets. Additionally, feature importance analysis was implemented to explore the influence of the input variables on the early-age CS. Results indicate that GPR and SVR models with high predictive accuracy (R2> 0.90) outperformed ANN, RF, and GB models. Water, superplasticizer, curing temperature, and fiber content emerged as the most significant controlling parameters affecting early-age CS. The analysis of the interaction among the significant input variables and early-age CS suggests recommended inclusion levels for optimal performance. Specifically, it is recommended that the water content be maintained between 145 and 155 kg/m2, the superplasticizer content between 30 and 40 kg/m2, and the fiber content exceed 200 kg/m2. These recommendations are aimed at achieving desirable early-age CS characteristics. The overall findings reveal that the AI models can effectively improve the monitoring of early-age CS of UHPFRC.
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AbstractThere is strong evidence that ceramides play a significant role in the pathology of inflammatory bowel disease (IBD) and chronic liver injury. Long-chain (LC) and very long-chain (VLC) ceramides have opposing functions, yet the associations of circulating levels of ceramide species in patients with IBD and primary sclerosing cholangitis (PSC)—as inflammatory biliary-hepatic disease closely linked to IBD— with disease severity remain poorly studied. This study investigates whether serum levels of ceramide (Cer) and hexosylceramide, a glycated ceramide derivative, are associated with disease severity in these conditions. Serum levels of eight ceramide and five hexosylceramide species were measured in 16 healthy controls, 57 patients with IBD, 7 patients with PSC, and 13 patients with PSC-IBD. Lipid levels were determined using direct flow injection analysis with a triple quadrupole mass spectrometer. Patients with IBD exhibited higher levels of Cer 18:1;O2/16:0 and Cer 18:1;O2/18:0 compared to controls. Their LC/VLC ceramide ratio was elevated and positively correlated with C-reactive protein and fecal calprotectin. However, ceramide and hexosylceramide levels were not associated with stool consistency, disease localization, or extra-intestinal manifestations. Patients with PSC and PSC-IBD also had increased LC/VLC ceramide ratios, primarily due to a decline in VLC ceramide species. In PSC-IBD, this ratio correlated positively with cholestasis markers. Additionally, serum hexosylceramide 18:1;O2/16:0 and 24:1 levels were specifically elevated in PSC. This study demonstrates that an altered LC/VLC ceramide balance is associated with disease severity in IBD, PSC-IBD, and PSC, highlighting its potential as a biomarker for IBD, PSC-IBD, and PSC. As our PSC cohorts were small, a confirmatory study is required.
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AbstractPristine PEDOT: PSS is a p-type material with salient features. However, studies have revealed that the electrical property of pristine PEDOT: PSS can be switched to n-type by solvent treatment. Notwithstanding that this method is simple, it performs inconsistently and primarily affects the samples’ surfaces due to the migration of the solvent molecules into the polymer network. These solvents are also hazardous and unfavourable to the environment. In this work, we report solvent-free switching electrical characteristics of pristine PEDOT: PSS to n-type using a spray coating technique. The obtained n-PEDOT: PSS exhibits excellent optical and electrical characteristics. In addition, high Seebeck coefficient of – 1320.06 ± 38.42 µVK−1and power factor of 4.32 ± 0.25 µWm−1K−2were found. The obtained n-PEDOT: PSS was used in the fabrication of a homojunction diode. The I-V curve showed rectification characteristics with rectification ratio and barrier height of 17.2 and 0.047 eV, respectively, which is one of the best reported values in the literature for all PEDOT: PSS-based diode.
AbstractSepsis is associated with substantial mortality rates. Traditional treatment strategies often fail to address the underlying dysregulation in immune response, necessitating novel therapeutic approaches. Ozone (O3) is an inorganic molecule with no evident function in the body. We investigated the properties of ozone, using a system of extracorporeal ozone blood treatment inPseudomonas aeruginosaseptic shock. We hypothesized that extracorporeal ozonation would decrease bacteria in blood, have immunomodulating properties, and improve organ function. In this 4-h sepsis model swine were allocated toP. aeruginosa(PA-103, ATCC 29260, CCUG31589) infusion and ozone treatment (n = 7) orP. aeruginosainfusion and no ozone treatment (n = 6). Bacteria were infused in a peripheral vein. Mean (SD) duration of ozone treatment was 134 (67) min. A single pass through the system decreased viableP. aeruginosaby 53%, mean 2193 to 1023 colony forming units/mL, mean of differences -1170 (95% CI − 1689 to − 651,P< 0.0001). No difference in viable bacterial concentration was detected in peripheral venous blood between groups (P= 0.68). IL-1β, IL-4, IL-6, IL-8 and IFN-γ decreased by ozonation. Classical and alternative complement pathways were not affected. Blood hemoglobin, hematocrit and noradrenaline doses decreased in the treatment group. Breathing frequency and pulmonary peak airway pressure decreased in the ozone treatment group. Median survival in ozone treatment was 134 min and no treatment 159 min, with no statistical difference. Extracorporeal ozone blood treatment modulated the immune response inP. aeruginosaseptic shock, which decreased mostly proinflammatory cytokines and was associated with indications of decreased vascular permeability and improved lung function and warrants further investigation for potential use in clinical settings.
AbstractDiabetes mellitus (DM) represents a multifactorial condition linked to hyperglycemia, which, can lead to damage across multiple organs, including the lungs. Nod-like receptor protein-3 (NLRP3)- mediated pyroptosis could contribute to the onset of DM consequences. Several approaches have been established aimed to minimizing the complications associated with DM. Among these, linagliptin and vildagliptin, di-peptidyl peptidase-4 (DPP-4) inhibitors, are known to exert not only antihyperglycemic effects but also additional beneficial biological activities. The current study investigated the impact of linagliptin and vildagliptin on pulmonary function, oxidative stress, and NLRP3-induced pyroptosis in rats. Thirty-two male Sprague Dawley rats were given a 7-day acclimatization period. A single intraperitoneal injection of freshly produced STZ (60 mg/kg) was utilized to develop DM type-1 in rats. Following STZ treatment, all rats were given a 5% glucose solution overnight. Blood glucose levels were monitored in overnight fasted rats 72 h later, with a threshold of 250 mg/dL or higher confirming the onset of DM. The diabetic rats were randomly allocated to treated daily with either vildagliptin (5 mg/kg/p.o.) or linagliptin (5 mg/kg/p.o.) for 30 days. Additionally, the typical control group received merely the vehicle. The findings revealed that vildagliptin improves pulmonary dysfunctions associated with DM by restoring glucose homeostasis, insulin, redox marker levels, and inflammatory indices. Additionally, the NLRP3-pyroptosis-mediated IL-1β was suppressed. Vildagliptin has been shown to mitigate the detrimental effects of diabetes mellitus (DM) on the lungs, as evidenced by a reduction in pathological lung alterations and a decrease in Caspase 3 expression, which is indicative of immunohistochemical changes. In conclusion, pyroptosis triggered by the NLRP3 inflammasome possibly exacerbate diabetic pulmonary injury in rats. Vildagliptin is superior to linagliptin in ameliorating diabetes-induced lung injury primarily via targeting the NLRP3 inflammasome pathway.
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AbstractHybrid fiber-reinforced polymer (FRP) and steel reinforced concrete (hybrid FRP-steel RC) beams have gained recognition for their exceptional flexural performance, surpassing that of beams reinforced exclusively with FRP bars (FRP-RC). However, current design guidelines, such as ACI 440.11–22, fail to accurately predict the flexural strength of these hybrid systems. This study aims to enhance the predictive accuracy and interpretability of flexural strength models by applying advanced computational approaches—specifically, machine learning (ML) techniques and symbolic regression. A robust dataset of 134 experimental data points was utilized to develop predictive models. The prediction results showed that both ML and symbolic regression models significantly outperformed the ACI 440.11–22 equations, achieving lower errors (MAE, MAPE, RMSE) and higher accuracy (R2). The results demonstrate that the ML models—Gaussian process regression (GPR), NGBoost, and CatBoost—achieved high predictive accuracy, with mean R2values approaching 1.0 and MAPE% as low as 5.19 (training) and 11.51 (testing) for GPR. Furthermore, symbolic regression yielded a transparent mathematical expression with a mean prediction ratio (µ) of 1.003, a CoV of 0.139, and a MAPE% of 11.08. These findings highlight the practical and technical advantages of symbolic regression in developing reliable, interpretable, and efficient design equations for hybrid FRP-steel RC beams.
AbstractAcute and chronic alcohol abuse are common among burn patients and may be associated with chronic liver injury, a potential factor influencing outcomes. This study evaluates the predictive power of the blood alcohol concentration (BAC) and non-invasive liver fibrosis scores and their applicability in burn patients. A retrospective analysis was conducted on patients admitted to a high-volume supraregional burn center in Northern Germany between 2007 and 2024. Patients were categorized based on their BAC at admission: low (< 100 mg/dL) vs. high (≥ 100 mg/dL). Data collected included demographics, comorbidities, and outcomes. Non-invasive liver fibrosis markers such as the Fibrosis-4 (FIB-4) score, aspartate transaminase-to-platelet ratio index (APRI) and non-alcoholic fatty liver disease (NAFLD) fibrosis score were applied to both groups. Among 121 large-surface burn patients (mean total body surface area: 16.4%), no significant differences were observed between BAC groups in demographics, comorbidities, or ICU admission rates. The serum ethanol concentration showed no significant predictive value for mortality (AUC = 0.515). In contrast, the FIB-4 score (AUC = 0.781) and APRI (AUC = 0.736) demonstrated strong prognostic accuracy. In multivariate analysis, the Abbreviated Burn Severity Index (OR = 2.42;p= 0.001), serum albumin (OR = 0.29;p= 0.016), and FIB-4 score (OR = 1.50;p= 0.033) emerged as independent predictors of mortality. Propensity score matching analysis confirmed that BAC was not associated with increased mortality after adjustment for burn depth and extent. Non-invasive liver fibrosis markers, such as FIB-4 score, provide valuable prognostic insights in burn patients, independent of acute alcohol intoxication and should be considered a routine screening tool for large surface burn patients. Incorporating chronic liver dysfunction into existing burn severity models may enhance risk stratification and outcome prediction.
AbstractEmerging tick-borne infections pose public health challenges and may complicate treatment decisions. The EMBio study, a multicenter observational study, aims to describe erythema migrans (EM), an early localized manifestation ofBorrelia burgdorferi sensu lato(s.l.) infection, and investigate the occurrence of tick-borne co-infections among patients presenting with this skin lesion. Additionally, the study seeks to determine relations between EM morphology, other clinical manifestations, specific pathogens, and disease prognosis. Clinical characteristics, skin biopsies, and blood samples were analyzed from 26 patients to assess co-infections, quantity,Borreliaspecies, and spirochete load.BorreliaDNA was detected in 88% of EM skin lesions, withBorrelia afzeliias the predominant species. Two cases of co-infections were identified, one involving twoBorreliaspecies and one involvingBorrelia afzelii andthe intracellular bacteriumNeoehrlichia mikurensis. Notably, homogeneous EM lesions harbored significantly higher spirochete quantities in the central zone compared to annular lesions, suggesting that lesion morphology reflects local bacterial density. This supports the value of molecular diagnostics in detecting mixed infections and supports morphology-guided biopsy strategies in the clinical assessment of cutaneous infections. This study contributes to a better understanding of co-infection dynamics and may improve diagnostic accuracy and patient management in endemic settings.
AbstractA novel application of light rare earth elements (LREEs) was explored for their biological activity as potential eco-friendly molluscicides and antimicrobials onTheba pisana(Müller, 1774) and their feeding behavior, and microorganisms likeCandida albicans,Bacillus cereus,Aspergillus niger,Staphylococcus aureus, andEscherichia coli. Our data showed increased snail mortality with higher element concentrations till 500 mg/L. LC25and LC50values after ten days of exposure were 513.70 and 3012.72 mg/L, respectively, lower survival rates than the control. As treatment concentration and exposure duration increased, the ingested leaf area and daily consumption rates of treated lettuce leaves declined. On day one, consumption dropped from 60.00 ± 0.00 cm² (control) to 30.25 ± 6.13 cm² at 500 mg/L, further decreasing to 31.25 ± 0.76 cm² and 14.00 ± 1.46 cm² by day four at the same concentrations. Low concentrations had minimal impact on snail feeding, while higher levels significantly reduced appetite, consumption and freshness of leaves. LREEs-based formulations exhibited marked antimicrobial activity against all tested pathogens by the measured inhibition zones. Results highlight the promising application of LREEs in integrated pest and microbial disease management. However, these findings warrant further investigation to optimize their safe and practical use in the field.
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AbstractProstate cancer (PCa) incidence has steadily increased in Sweden, more steeply in the mid-1990s caused by increased opportunistic prostate-specific antigen (PSA) testing. Tallness, normal weight, and non-smoking are associated with more PSA testing, which increases detection of low-risk and localised PCa. We investigated time trends of height, body mass index (BMI), and smoking with PCa risk in 171,889 men in Sweden aged 50–64 years at baseline, who were linked to nationwide cancer registers during follow-up. Cox regression determined the association of these factors assessed before 1980, 1980–1994, and 1995–2004 with PCa risk. During 15 follow-up years, 8,049 men were diagnosed with PCa. The association of height with PCa was weakly positive across all calendar periods. For obesity (BMI ≥30 kg/m2) vs. normal weight (BMI 18.5–24.9 kg/m2) and current vs. never smoking, the associations changed from null before 1980 (HR 1.03, 95% CI 0.86–1.23, and 1.11, 95% CI 0.97–1.27) to negative in 1995–2004 (HR 0.83, 95% CI 0.74–0.93, and 0.86, 95% CI 0.79–0.93; pinteractionbetween periods = 0.05 and 0.001). In men with clinical characteristics available, height was positively associated with both aggressive and non-aggressive PCa whilst obesity and smoking showed negative associations only with non-aggressive PCa. These findings likely reflect differences in PSA testing by BMI and smoking habits and contribute important knowledge for etiological studies of PCa.
AbstractThis study aimed to explore the development of eco-friendly antimicrobial coatings by combining antimicrobial nanocomposites with waterborne resins. Novel nanocomposites, such as nano-ZnO/silica fume and nano-CuO/silica fume, were synthesized using the solution combustion method, along with pure nano-ZnO and nano-CuO. The nanocomposites consist of a thin layer of nanometal oxide on silica fume, aiming to enhance antimicrobial activity. These nanocomposites were incorporated into acrylic waterborne resin at two concentrations (0.4 and 0.8 wt%) to provide cost-effective alternatives to imported and expensive antimicrobial agents. Antimicrobial effectiveness was evaluated againstStaphylococcus aureus,Micrococcus luteus,and Candida albicansusing disc diffusion and shake flask methods. Besides, the mechanical and physical properties of the coatings were compared to the properties of a commercial coating. The findings showed that the commercial coating offered inhibition zones ranging from 16 to 21 mm. While the disc containing 0.8% nano-ZnO/silica fume offered the greatest antimicrobial activity, with inhibitory zones ranging from 17 to 26.6 mm. Additionally, the results demonstrated that discs containing nano-ZnO were better than discs containing nano-CuO. The mechanical properties indicated that the hardness of coatings with either nano-ZnO or nano-CuO is similar to the commercial coatings in group I. However, coatings with nano-ZnO/silica fume and nano-CuO/silica fume exhibited slightly higher hardness. In group II, higher ratios of nano-ZnO, nano-CuO, and their silica fume composites significantly increase hardness compared to the commercial coatings, attributed to the formation of a more compact film. Moreover, the results showed that coatings with a high ratio of pigments (0.8%) adhered better than those with 0.4% of pigments.
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AbstractMethicillin-resistantStaphylococcus aureus(MRSA) represents a significant global health challenge due to acquired resistance mechanisms, primarily involving penicillin-binding protein 2a (PBP2a), necessitating novel therapeutic strategies. This study explores the potential of amoxicillin-conjugated magnetic nanoparticles (Amox-MNPs) as a means to overcome resistance by targeting the alternative essential protein, PBP1a. Fe₃O₄@SiO₂ core-shell MNPs were synthesized via controlled co-precipitation followed by a silica coating using the Stöber method, and subsequently conjugated with amoxicillin. Physicochemical characterization confirmed nanoparticle formation and successful conjugation. In vitro antibacterial assays againstS. aureusATCC 43,300 (MRSA) revealed that Amox-MNPs exhibited a mean inhibition zone diameter of 26.0 ± 0.82 mm, approximately double that of free amoxicillin (13.5 ± 1.12 mm) at equivalent concentrations (p< 0.05), indicating significantly enhanced antibacterial efficacy. Integrated computational modeling, including molecular docking and dynamics simulations, elucidated the favorable binding (−8.64 kcal/mol docking score;−32.65 kcal/mol MM-PBSA energy) and stable interaction dynamics between amoxicillin and PBP1a, identifying key stabilizing residues. These findings highlight the potential of MNP-mediated delivery to enhance amoxicillin’s efficacy against MRSA by targeting PBP1a, offering a promising preclinical strategy requiring further validation in animal models for combating resistant bacterial infections.
AbstractIn inflammatory bowel disease (IBD) the pathogenetic process is characterized by dysbiosis, increased permeability, translocation, and immune activation. The aim of the present study was to assess the presence of viable bacteria in the blood of patients with IBD and to correlate the findings with clinical characteristics. The study included 28 patients with Crohn’s disease (CD) (median age 38 years, 50% female, biological treatment in 71%) and 19 patients with ulcerative colitis (UC) (median age 45 years, 33% female, biological treatment in 84%). Identification of viable bacteria in the blood was evaluated by optimized cultivation and Sanger sequencing and for quantification real-time PCR was performed. Viable Gram-positive bacteria were detected in 34 IBD patients (72.3%). There were no associations between the presence of bacteria and gender, antibiotic treatment, intake of alcohol, use of PPI, steroids, or biological treatment. The number of bacterial copies was correlated with higher C-reactive protein (CRP) (p= 0.013). In ¾ of the patients, viable bacteria were identified in the blood despite treatment with biologicals, which indicates a vast barrier defect. This observation also indicates that the disease is still active. To obtain a true deep mucosal healing an intact barrier function is required.
AbstractAdverting biodiversity loss is one of the most urgent challenges of our time. The ongoing amphibian extinction crisis is the result of a multitude of factors, with emerging infectious diseases having played a key role. While extensive contributions have been made to study chytrid fungi and ranaviruses in the last two decades, other amphibian pathogens have remained largely unstudied. Here, we evaluated the spatiotemporal distribution of Bufonid herpesvirus 1 (BfHV1) in Europe, a pathogen capable infecting true toads (family Bufonidae). Using molecular detection and histology, we identified seven new BfHV1 positive sites in Germany and a first record for Luxembourg. Phylogenetic analysis of samples from these sites revealed a monophyletic cluster with the known BfHV1 reference sequences. Through additional systematic examination of photographic records from citizen scientists, we identified 229 BfHV1 cases (62 positive, 167 suspicious) in the genusBufo(B. bufo,B. spinosus), with suspicious cases being widespread across Europe and dating back until at least 2007. As such, this first continental assessment suggests that BfHV1 has been rather overlooked than being recently emerging. Yet, in view of increasing observations of population declines in bufonids across Europe, additional research is warranted to assess its effects on amphibian populations.
AbstractTheodolites and drones are key instruments for observing small whales in coastal areas. This study compared their performance while observing the harbour porpoise (Phocoena phocoena) in the western Baltic Sea. The methods were used simultaneously providing information on location, behaviour and group size during a field campaign in 2022. Theodolite observers were able to detect surfacing positions during 80.5% of porpoise sightings while a drone collected data during 50.7% of total sightings detected by plain eye. The drone footage quality was poor during 47.3% of these sightings. An in-depth analysis of 75:36 h of good quality footage resulted in 16:55 h (22.4%) of cetacean appearance. The determination of group size was significantly more precise using drone footage while the theodolite was more accurate in determining the start/end of a sighting. The accuracy of locations was modelled using the distance (Dt-d) between recorded theodolite and drone coordinates of the same surfacing porpoise. Dt-dvaried significantly based on the point quality. Sea state and porpoise to theodolite observer distance did not influence Dt-d. Both methods complement each other and should ideally be used simultaneously to obtain both accurate and detailed information on harbour porpoises and other marine mammals during land-based observation studies.
AbstractCardiovascular failure has been recognized as the predominant cause of perioperative mortality in small animals, particularly dogs. This study was designed to evaluate the effectiveness of adding intravenous atracurium to a ketofol infusion during anesthesia in dogs. Thirty male mongrel dogs were premedicated with an intramuscular injection containing 0.02 mg/kg of acepromazine and 0.2 mg/kg of methadone. Thirty minutes later, the dogs were equally and randomly divided into two groups (n = 15): the Ketofol Group (KFG), in which anesthesia was induced using IV administration of 0.5 ml/kg of ketofol, and the atracurium/ketofol Group (AKFG), in which anesthesia was induced using IV administration of 0.25 mg/kg of atracurium with 0.5 ml/kg of ketofol. Following intubation, anesthesia was maintained by a variable intravenous infusion at 0.2 ml/kg/min in KFG or a combination of 0.01 mg/kg/min atracurium and 0.2 ml/kg/min ketofol in AKFG. Respiratory frequency (fR), mean arterial pressure (MAP), heart rate (HR), oxygen saturation of hemoglobin (SpO2), end-tidal carbon dioxide concentration (EtCO2), rectal temperature (RT), the quality of induction, intubation, recovery period, ejection fraction percentage (EF%), fractional shortening percentage (FS%), and stroke volume (SV) were recorded. The ketofol doses were significantly lower,P≤ 0.01, in the AKFG group (4.2 ± 0.44 mg/kg) than in the KFG group (2.27 ± 0.6 mg/kg). There were statistically significant increases in RR, HR, MAP, EtCO2, and echocardiography parameters in the AKFG group compared to the KFG group. Additionally, the AKFG group exhibited a significant reduction in induction, intubation, and recovery scores compared to the KFG group. Adding atracurium to ketofol during dog anesthesia positively impacts the hemodynamic and cardiac parameters and improves the quality of induction, intubation, and recovery.
AbstractThis study explores the influence of the polarization angle on the formation of Laser-Induced Periodic Surface Structures (LIPSS) during Direct Laser Interference Patterning (DLIP) and its impact on ablation efficiency in stainless steel and aluminum 2024 substrates. Two pulse durations, 12 ps and 70 ps, with a laser wavelength of 1064 nm, are employed at varying accumulated fluences to evaluate their effects on the surface structuring process. The results demonstrate that the Low Spatial Frequency LIPSS (LSFL) orientation with respect to the line-like structures produced by two-beam DLIP is strongly influenced by the polarization angle and the alignment of DLIP features. In addition, the spatial period of LSFL in stainless steel remained relatively stable regardless of the polarization angle (~ 900–1000 nm), whereas in aluminum 2024, it exhibited significant variation, decreasing from approximately 920 nm to 506 nm as the LSFL rotated. The polarization angle also affected the reached structure depth at constant irradiation conditions, particularly in stainless steel, where greater depths were achieved when the LSFL aligned perpendicularly to DLIP lines (over 50% variation). These findings provide valuable insights for optimizing laser-based surface processing techniques for metallic substrates.
AbstractThe exact cause for no pain, local pain and referred pain groups according to the upper cervical palpation test (UPT) and whether neck pain in migraine patients is caused due to pain sensitization or influenced by perceived neck-related disability, is not fully understood. The aim was to determine whether upper cervical spine sensitivity tested by the UPT is associated with neck-related disability or increased pain sensitization in patients with migraine. Forty-two patients with episodic migraine were examined regarding mechanical and pressure pain thresholds, central sensitization (CSI), allodynia (ASC-12) and neck-related disability (NDI), and sub-grouped according to the UPT. An ANOVA analysis was performed for group differences. Exploratory regression and correlation analyses were performed with NDI and CSI as dependent variables to understand which factors are related and contribute to either subgroup allocation. No significant differences were found in UPT subgroups regarding CSI and NDI. The UPT subgroups could not be determined by any evaluated variable. The NDI was explained in 43.6% by the CSI and neck pain intensity. CSI results were explained to 49.4% by a model including ASC-12 and NDI. In conclusion, UPT subgroups were neither explained by differences in CSI, mechanical or pressure threshold testing or NDI.
AbstractNeem is a plant used both as food and in traditional medicine. Its many active components, such as Carotenoids, Saponins, Triterpenoids and Nimbidin, may render it a beneficial feed additive for rabbits. Healthy weaned rabbits from breed V-line (VL) were selected to examine the effect of neem (Azadirachta indica) on growth performance, carcass traits, morphology, and blood parameters responses. Thirty-two V-line rabbits (45 days old) were randomly assigned to four groups (n= 8 per group): a control group (G1) receiving a basal diet, and three treatment groups (G2, G3, G4) receiving the basal diet supplemented with 5%, 10%, and 15% neem leaf powder, respectively. Neem leaf supplementation had no significant effect on the rabbits’ growth performance, live body weight, carcass weight, lungs and abdominal fat, dressing percentage and liver. There was a significant (P< 0.05) increase in intestine length in G4. Nevertheless, the cecum considerably shrank (P< 0.05) in G3 and G4, which might have a more negative impact on growth performance. Certain biochemical measures (albumin, globulin, triglycerides, LDL, total protein, cholesterol, glucose, AST, and ALT) did not exhibit significant variations. However, a significant (P< 0.01) drop in blood urea occurred after the higher concentration. A significant (P< 0.05) rise in HDL after neem supplementation. Histologically, the liver showed signs of hepatotoxicity in the group supplemented with neem leaves, such as abnormal hepatocytes’ nuclear membranes, pyknotic nuclei, karyorrhexis and karyolysis. Additionally, the portal and central veins were congested, and a greater number of Kupffer cells were seen. In conclusion, the findings suggest that dietary neem leaf supplementation may have adverse effects on rabbit health and performance, particularly at higher concentrations.
AbstractInstructional videos need to maintain learners’ attention to foster learning, therefore, a fine-grained measurement of attention is required. Existing gaze measures like inter-subject correlation (ISC) assume a singular focal point deemed meaningful for indicating attention. We argue that multiple meaningful foci can exist and propose an automatically generated gaze measure labeled gaze cluster membership (GCM). By applying the density-based clustering in spatial databases (DBSCAN) algorithm to gaze position data from over 100 participants, we categorize viewers as attentive when they are part of a cluster and as inattentive when they are not. Using two videos, we demonstrate that our settings of DBSCAN generate meaningful clusters. We show that low ISC values (neuronal and eye tracking data) during multiple meaningful foci do not necessarily indicate a lack of attention. Additionally, GCM predicts participants’ self-reported mental effort and their tested knowledge. Our innovative approach is of high value for assessing learner attention and designing instructional videos.
AbstractCisplatin is a well-established drug for the treatment of solid tumors. One of the most common side effects is neurotoxicity and peripheral neuropathy, which affects patients’ quality of life. In previous studies, a protective effect of nimodipine on neuronal cell stress was demonstrated. Therefore, the objective of this study was to examine the impact of nimodipine on cisplatin-treated Schwann cells, neuronal cells, and tumor cells. Schwann and neuronal cells were used to investigate the neuroprotective effect of nimodipine, as well as the cancer cell lines A549, SAS and SKOV-3 to determine the effect on tumor cells. Cell death was measured using extracellular lactate dehydrogenase activity and propidium iodide staining. In addition, the protein level of the LIM-domain only four protein and the activation of known interacting anti-apoptotic pathways were analyzed. The cytotoxic effect of cisplatin was reduced by up to 23.6% in neuronal cells (p≤ 0.0001) and up to 30.6% in Schwann cells (p≤ 0.05) by nimodipine pre-treatment. However, no decrease in apoptosis could be shown in the cancer cells. Nimodipine-dependent activation of anti-apoptotic signaling pathways was detectable in Schwann cells and neuronal cells, whereas the opposite effect could be demonstrated in the cancer cells. In conclusion, the treatment with nimodipine may represent a new approach against neurotoxically side effects in cisplatin chemotherapy.
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AbstractLorazepam is extensively used to treat anxiety disorders and anxiety associated with depression. This study evaluates the safety of lorazepam based on real-world data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Data were collected from January 2004 to June 2024. After standardizing the data, we quantified signals using four algorithms, including the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Multi-Item Gamma Poisson Shrinker (MGPS) to quantize the signal by Bayesian analysis and disproportionation analysis. AE signals were predominantly involved psychiatric disorders, nervous system disorders, injury, poisoning and procedural complications, and cardiac disorders. Notably, new potential AE signals of clinical value were identified in this study, including tachycardia, rhabdomyolysis, neologism, phagophobia, pancreatic fibrosis, and pneumonia. Sex-stratified analysis showed that the risk of poisoning was more pronounced in females and the AEs of sedation were more pronounced in males. Age-stratified analysis demonstrated variations in AEs across different age groups.The findings of this study were consistent with clinical trials, and identified several new potential AE signals. In addition, there are gender and age differences in some AEs. These findings provide valuable insights into lorazepam in clinical practice.
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AbstractThe biomass filtrate of marine actinobacterium,Streptomyces vinaceusdrappusAMG31, was utilized as a biocompatible and biocatalyst for titanium dioxide nanoparticles (TiO₂-NPs) synthesis. Characterization revealed well-dispersed, spherical structures with high crystallinity in the anatase phase, with sizes from 10 to 50 nm. The biosynthesized TiO₂-NPs demonstrated potent antioxidant activity with maximum DPPH and ABTS radical scavenging percentages of 94.6% and 88.2% at 1000 µg/ml, with IC₅₀ values of 11.1 and 14.36 µg/ml, respectively. TiO₂-NPs exhibited moderate wound healing activity with 66.6% wound closure compared to controls (62.6%) after 48 h. The hemocompatibility assessment revealed minimal hemolytic activity (1.9% at 1000 µg/ml) and modest anticoagulant effects in PT (14.2 s) and PTT (43 s) at 75 µg/ml. Moreover, TiO₂-NPs displayed selective cytotoxicity towards cancer cells (Caco-2 and PANC-1) with IC₅₀ values of 74.1 ± 0.7 and 71.04 ± 1.2 µg/ml, respectively, while showing lower toxicity towards normal WI38 cells (IC₅₀ 153.1 ± 1.01 µg/ml). The nanoparticles demonstrated significant antidiabetic potential through α-amylase and α-glucosidase inhibition (IC₅₀ 69.3 and 40.81 µg/ml, respectively). Notably, TiO₂-NPs exhibited potent antibacterial activity against Gram-positive bacteria, particularlyEnterococcus faecalis(37 ± 0.1 mm inhibition zone vs. 28 ± 0.1 mm for gentamicin) and Gram-negative bacteria, especiallyE. coli(29 ± 0.1 mm vs. 22 ± 0.2 mm for gentamicin), with low MIC/MBC values (12.5/25 µg/ml for Gram-positive and 6.25/12.5 µg/ml forE. coli). The nanoparticles demonstrated superior antifungal activity compared to fluconazole againstPenicillium glabrum(45 ± 0.1 mm vs. 38 ± 0.1 mm),Aspergillusniger(37 ± 0.2 mm vs. 36 ± 0.1 mm), andCandida albicans(30 ± 0.3 mm vs. 26 ± 0.3 mm). Furthermore, TiO₂-NPs showed remarkable antibiofilm activity against bacterial (90.8–98.2% inhibition) and fungal (97.3% inhibition forC. albicans) biofilms at 75% MBC/MFC concentrations. The actinobacterial TiO₂-NPs’ biological activity profile, in conjunction with their biocompatibility, selective cytotoxicity, and minimal hemolytic activity, positions the actinobacterial TiO₂-NPs as promising candidates for various biomedical applications.
AbstractThroughout every day, we perform actions, and action information has been suggested to inform scene categorization. Here we hypothesise that actions also drive the hierarchical structure of many scenes, where anchor objects (e.g., stoves) predict the presence and position of local objects (e.g., pots) by dividing a scene in functionally distinct ‘phrases’. Specifically, we test whether the presence of anchor objects informs scene function understanding. In Experiment 1, participants matched an action word and a scene from which we either removed an action-related anchor object (REL), an action-unrelated anchor (UNREL) or a non-anchor object (RAND). Matching performance was impaired in REL compared to UNREL and RAND. Experiment 2 measured scene function activation more implicitly by priming a lexical decision task (LDT) on action words with the same stimuli (including an inconsistent condition: INCON, e.g., “cooking” in a bathroom). LDT performance was impaired after INCON and REL compared to RAND and UNREL primes. A control experiment showed that this effect was partly but not solely due to scene categorization. The results imply that understanding scene function is most closely tied to anchor objects directly relevant for actions whereas contextual scene information is not always sufficient to give rise to this understanding.
AbstractThe impact of orthostatic regulation during exercise, particularly resistance training, is not fully understood. This study investigates the acute cardiopulmonary responses of intensity-matched resistance exercises, targeting similar muscle groups but performed in different body positions in young trained females. Fourteen healthy females (21.6 ± 2.0 years) performed a 3-repetition Maximum test (3-RM) for the squat movement in the Smith machine (SM) and the leg press (LP). During two subsequent visits, they randomly completed two training sessions in SM and LP (two sets of ten repetitions at 50% 3-RM). Blood pressure (vascular unloading technique) and cardiopulmonary parameters (impedance cardiography, spirometry) were measured continuously. At baseline, there was a significant difference in heart rate and stroke volume between the SM and LP conditions. During training sessions, the SM condition showed higher ground reaction force (986.9 ± 93.3 vs. 811.2 ± 71.6 N;p< .01), systolic blood pressure (156 ± 15 vs. 141 ± 10 mmHg;p< .01), diastolic blood pressure (111 ± 11 vs. 96 ± 8 mmHg;p< .01), HR (123 ± 11 vs. 97 ± 7 bpm;p< .01), and oxygen uptake (901 ± 104 vs. 623 ± 65 ml/min;p< .01) compared to the LP condition. Total peripheral resistance (TPR) was similar. Significant different post-exercise changes could be detected in mean arterial pressure (-20.9 ± 9.9 vs. 3.3 ± 11.0 mmHg;p< .01) and TPR (-2.3 ± 1.7 vs. 0.7 ± 1.7 mmHg⋅ l⋅min-1;p< .01). Squats in the SM require greater cardiovascular and pulmonary effort than matched exercising in LP due to orthostatic stress and higher muscle activation. Conversely, the risk of blood pressure peaks is much lower with LP. Future analysis should focus on the effects of body position on patient responses.
Abstract30/70 wt.% poly (vinyl chloride-co-vinyl acetate-co-2-hydroxypropyl acrylate) (PVVH) / poly (vinylidene fluoride-co-trifluoroethylene) P(VDF-TrFE) polymer blend (PB) are prepared and doped with various content of Zinc oxide nanoparticle (ZnO NPs) using casting technique. X-ray diffraction (XRD), Fourier transform infrared (FT-IR), Transmission electron microscopy (TEM), UV–Vis and Thermogravimetric analysis (TGA) are used for structural, optical and thermal properties investigation. XRD results revealed that the crystallinity degree of PB is enhanced from 83.8 to 92.3% upon increasing the ZnO NPs. FTIR analysis showed a shift in position of some characteristic bands, confirming the complexation between ZnO NPs and functional groups of PB. UV–Vis analysis showed that both direct and indirect energy gaps (Edg/Eig) are reduced from (4.08/2.34) for PB to (3.65/1.99) eV for 1.25 wt% ZnO/PB nanocomposite. Thermally stimulated depolarization current (TSDC) measurements demonstrated that the phase transition from ferroelectric to paraelectric phase occurred at 343 K for PB and increased to 350 K after embedding ZnO NPs. Thermal sampling (TS) technique is applied and thermodynamic parameters are estimated. Piezoelectric coefficient (d33) is optimized from 12.8 pC/N for PB sample to 23.7 pC/N for 1wt.% ZnO/PB nanocomposite at 6.24 × 105Pa. Our results give a prediction for new piezoelectric material design capable for various energy harvesting applications.
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AbstractPerceived stress is prevalent in industrial societies, negatively impacting mental health. Smartphone-based stress management interventions provide accessible alternatives to traditional methods, but their efficacy remains modest, potentially due to limited integration of smartphone sensor technology. The primary aim of this study was to evaluate the efficacy of an 18-day smartphone-based stress management intervention,MT-StressLesswith integrated heart rate (HR)-based biofeedback using built-in accelerometer sensors, compared to a waitlist control (WLC) condition. Secondary outcomes included emotion regulation skills, depressive symptoms, overall well-being, usbiality and usage data. As exploratory aims, we investigated whether theMT-StressLessversion without HR-based biofeedback was also superior to the WLC condition, and whether the version with HR-based biofeedback provided additional benefits compared to the version without. In a three-arm randomized controlled trial, 166 participants were assigned toMT-StressLesswith HR-based biofeedback,MT-StressLess, or the WLC condition. Linear mixed-effects models were used to analyze intervention effects over time (baseline, postintervention, and 1-month follow-up). At postintervention,MT-StressLesswith HR-based biofeedback showed significantly greater reductions in perceived stress compared to the WLC condition (d= 0.41, 95% CI [0.03, 0.79]), whereas the version without biofeedback did not differ significantly (d= 0.14, 95% CI [−0.24, 0.51]). No significant differences were observed between the two active conditions (d= 0.29, 95% CI [−0.08, 0.66]). Both active conditions, however, led to significant improvements in the secondary outcomes of emotion regulation skills and well-being compared to the WLC (allds= −0.58 to −0.27). These patterns persisted at the 1-month follow-up. Usability ratings were high, but overall adherence was moderate. The findings in the main comparison may reflect increased interoceptive awareness and self-regulation. Yet, the limited effects of the core intervention and the biofeedback component also suggest the influence of non-specific factors, such as placebo effects, outcome expectancy and user engagement, which highlights the need to better understand optimal intervention duration, motivation, reinforcement, and more individualized approaches to stress reactivity. Overall, the findings provide preliminary support for the potential of a smartphone-based intervention that includes HR-based biofeedback to reduce perceived stress compared to no intervention. As these interventions are still in their early stages, future research should explore how personalization driven by artificial intelligence and real-time physiological tracking can enhance engagement and efficacy.
AbstractSea cucumber represents a potential marine source of high value compounds with medicinal properties especially its anti-cancer activity. Sea cucumbers contain numerous biomolecules, including sulfated polysaccharides (Ps) which have enormous therapeutic and nutraceutical potential. This study aimed to investigate anticancer effect of Ps extracted from sea cucumbers on hepatocellular carcinoma. This study was in vitro study conducted on HepG-2 cells and normal wish cells that were divided into four groups: Group I including untreated cells, Group II including cells treated with different concentrations of 5-FU, Group III including cells treated with various concentrations of Ps extract. Group IV including cells treated with different concentrations of combined 5-FU and Ps extract. The extracted Ps were characterized using FT-IR, HPLC, and GC–MS. The anticancer effect of Ps extract was determined using cytotoxicity MTT assay, DNA fragmentation assay, wound healing assay, colony formation and soft agar assay. Also, the effect of Ps extract onVEGF,survivin,BAXandBIDgene expression was determined by qRT-PCR and its effect on Bcl2 and BAK protein level was determined by western blotting technique. The results indicated that sea cucumber Ps extract either alone or in combination with 5-FU reduced HepG-2 and wish cell viability with higher selectivity index. Also, it inhibited both adherent and non-adherent colony forming ability and cell migration of HepG-2 cells. Moreover, it was significantly downregulatedVEGF,survivinand Bcl2 while, it was significantly upregulatedBAX, BAK andBID. In conclusion, sea cucumber Ps extract may be an effective chemotherapeutic agent against HCC.
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AbstractHigh salinity impairs offspring production in Florida red tilapia (FRT)Oreochromissp. A total of 624 FRT broodstock (1:1 ratio of ♂: ♀) were divided into 16 groups, with 4 males and 4 females housed separately at two salinity levels (18 ppt and 32 ppt). Fish were fed four different levels ofMoringa oleiferaleaf extract (MOLE) supplementation (0, 5, 10, and 15 g MOLE kg−1diet) for two months. Following the initial feeding period, males and females receiving the same MOLE level under the same salinity conditions were transferred to 24 spawning concrete tanks. The experiment consisted of eight groups, each containing 3♂ and 6♀, with triplicate setups (four groups at 18 ppt and four groups at 32 ppt). Fish were fed at 1% of their body weight for four months. The results revealed significant (p< 0.05) improvements in water quality (lower ammonium and nitrite), growth parameters, feed conversion ratio, carcass protein content, digestive enzymes, liver enzymes, cortisol level, innate immunity, antioxidants, testosterone and progesterone hormones, and reproductive function (♂ and ♀) with MOLE-fed broodstock in both salinities. MOLE at 10–15 g/kg can improve FRT performance, welfare, fertility (♀), and reproduction under high salinity conditions (32 ppt).
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AbstractGesture recognition plays a vital role in computer vision, especially for interpreting sign language and enabling human–computer interaction. Many existing methods struggle with challenges like heavy computational demands, difficulty in understanding long-range relationships, sensitivity to background noise, and poor performance in varied environments. While CNNs excel at capturing local details, they often miss the bigger picture. Vision Transformers, on the other hand, are better at modeling global context but usually require significantly more computational resources, limiting their use in real-time systems. To tackle these issues, we propose a Hybrid Transformer-CNN model that combines the strengths of both architectures. Our approach begins with CNN layers that extract detailed local features from both the overall hand and specific hand regions. These CNN features are then refined by a Vision Transformer module, which captures long-range dependencies and global contextual information within the gesture. This integration allows the model to effectively recognize subtle hand movements while maintaining computational efficiency. Tested on the ASL Alphabet dataset, our model achieves a high accuracy of 99.97%, runs at 110 frames per second, and requires only 5.0 GFLOPs—much less than traditional Vision Transformer models, which need over twice the computational power. Central to this success is our feature fusion strategy using element-wise multiplication, which helps the model focus on important gesture details while suppressing background noise. Additionally, we employ advanced data augmentation techniques and a training approach incorporating contrastive learning and domain adaptation to boost robustness. Overall, this work offers a practical and powerful solution for gesture recognition, striking an optimal balance between accuracy, speed, and efficiency—an important step toward real-world applications.
AbstractBackground and aim: The Albumin Platelet Product (APP) has emerged as a promising non-invasive biomarker for fibrosis staging in chronic liver disease (CLD). This cross-sectional study aims to evaluate the effectiveness of APP compared to established non-invasive markers of fibrosis in an Egyptian cohort with HCV-related CLD. Methods: 580 participants were assessed across different fibrosis stages (F0-F4) to analyze the relationship between APP and liver fibrosis. APP was compared with FIB-4 and APRI scores for diagnostic performance. Results: The study included 580 patients with HCV-related CLD (mean age: 37.6 ± 9.66 years; 74.3% males). APP proved superiority in identifying liver cirrhosis (F4) at Cut-off values ≤ 0.59 with 81% sensitivity, 63.6% specificity (p< 0.001). APP showed a significant correlation with fibrosis stages, with an AUC of 0.920 (95% CI: 0.888–0.953) for distinguishing F4 from F0-F3 surpassing both FIB4 and APRI scores. However, FIB-4 proved superiority in distinguishing advanced fibrosis (F ≥ 3) with AUC of 0.899 (95% CI: 0.871–0.927) compared to APP with AUC of 0.87 (95% CI: 0.84–0.90), respectively. Multivariate analysis confirmed APP as an independent predictor of fibrosis (OR: 0.997, 95% CI: 0.995–0.998;p< 0.001). Conclusion: APP showed the highest performance in predicting cirrhosis, suggesting its potential as a simple, non-invasive marker for identifying patients with advanced liver disease. Its integration into clinical practice may enhance early detection and risk stratification in chronic HCV-related fibrosis. However, further multicenter, longitudinal studies are required to validate its efficacy across diverse populations and other liver disease etiologies.
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AbstractThe classical approach of using adjacent pieces of fresh-frozen tissue for various omics analysis from the same sample possesses a risk of biological mismatch between arising from intrinsic tissue heterogeneity. We propose an alternative approach of tissue cryogenic pulverization and lyophilization before distribution for omics studies for a more reliable analysis. Here, we compare individual omics layer readouts from fresh-frozen adjacent tissue pieces and homogenized powder in mouse brain, kidney, and liver. Genomics, transcriptomics, proteomics, and metabolomics analyses showed comparable RNA integrity, DNA methylation, and coverage of transcripts, proteins, and metabolites across both methods. Moreover, the homogenized-lyophilized powder usage led to reduced heterogeneity between biological replicates. We conclude that the cryogenically pulverized-lyophilized tissue approach not only maintains a critical molecular feature coverage and quality but also provides a homogenous basis for various omics analysis enhancing reproducibility, sample transport, storage and enabling multi omics base on one and the same tissue aliquot.
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AbstractThe global pandemic caused by SARS-CoV-2 has underscored the critical necessity for effective antiviral therapies. The viral main protease (Mpro), crucial for viral replication, has emerged as a promising therapeutic target. In the present study, the inhibitory potential of ten drug-like compounds (KL1-KL10), designed as derivatives of the parent inhibitor K36, against Mpro, has been computationally investigated. To elucidate the binding affinities and interactions of the suggested drugs with the Mpro active site, molecular docking and molecular dynamics (MD) simulations till 500 nanoseconds have been applied. Our results revealed that many suggested inhibitors exhibited enhanced binding affinities compared to the parent inhibitor K36. Among these, KL7 displayed the most favourable binding characteristics, with a docking score of -13.54 and MM-PBSA binding energy of -34.57 kJ/mol, surpassing that of K36. Molecular dynamics simulations demonstrated persistent binding of these compounds to Mpro, with RMSD values ranging from 0.5 to 2.0 nm, suggesting their potential as effective inhibitors. These findings suggest that the proposed ligands hold promise as potential scaffolds for developing potent antiviral drugs against COVID-19.
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AbstractThe existence of transgenerational effects of radiation exposure on the human germline remains controversial. Evidence for transgenerational biomarkers are of particular interest for populations, who have been exposed to higher than average levels of ionizing radiation (IR). This study investigated signatures of parental exposure to IR in offspring of former German radar operators and Chernobyl cleanup workers, focusing on clustered de novo mutations (cDNMs), defined as multiple de novo mutations (DNMs) within 20 bp. We recruited 110 offspring of former German radar operators, who were likely to have been exposed to IR (Radar cohort, exposure = 0–353 mGy), and reanalyzed sequencing data of 130 offspring of Chernobyl cleanup workers (CRU, exposure = 0–4080 mGy) from Yeager, et al. In addition, we analyzed whole genome trio data of 1275 offspring from unexposed families (Inova cohort). We observed on average 2.65 cDNMs (0.61 adjusted for the positive predictive value (PPV)) per offspring in the CRU cohort, 1.48 (0.34 PPV) in the Radar cohort and 0.88 (0.20 PPV) in the Inova cohort. Although under the condition that the proportion of true mutations is low in this analysis, this represented a significant increase ($$\:p<0.005$$) of cDNMs counts, that scaled with paternal exposure to IR ($$\:p<0.001$$). Our findings corroborate that cDNMs are a potential transgenerational biomarker of paternal IR exposure.
AbstractRecently, men with overactive bladder have been prescribed mirabegron and tamsulosin for the treatment of benign prostatic hyperplasia. Highly efficient and environmentally sustainable spectrophotometric methods have been developed for the accurate determination of mirabegron and tamsulosin in their pure forms as well as within pharmaceutical formulations. This study presents three effective and simple spectrophotometric methods for the simultaneous quantification of mirabegron and tamsulosin. The current protocols have demonstrated validation for linearity across concentration ranges of 3–20 µg/mL for mirabegron and 2–40 µg/mL for tamsulosin, utilizing dual wavelength, ratio difference, and derivative ratio techniques. The coefficients of determination exceeded 0.999. The validation of these methodologies was conducted in accordance with the guidelines set forth by the International council for Harmonization (ICH). Quality control laboratories may utilize existing techniques to identify the binary combination because of their high accuracy and cheap cost. The evaluation of the environmental sustainability of the established approaches was conducted using AGREE, GAPI, MOGAPI and whiteness revealing their notable eco-friendliness. The proposed method was deemed practical after the evaluation carried out with the Blue Applicability Grade Index (BAGI) assessment.
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AbstractChronic low back pain (cLBP) is a leading cause of disability worldwide, however, the influence of age on electromyography (EMG) during lifting tasks is not well understood. This study examined the effects of age and pain on EMG and kinematics in 102 participants. They were divided into no low back pain (no-BP) (n= 42; mean age: 41.86) and cLBP groups (n= 60; mean age: 43.41) and further categorized by age: 44 under 40 years (mean age: 31.14) and 58 over 40 years (mean age: 51.38). Two lifting tasks from the ground to the hip height were performed: lifting a 10 kg box in front of the body (Task 1) and two 5 kg dumbbells beside the body (Task 2), with EMG and flexion angles recorded. Older participants showed significantly higher EMG amplitudes (p< 0.05), particularly in Task 1 while holding the weight at hip height. No significant EMG differences were found between cLBP and no-BP groups after adjusting for age, sex, and body mass index (BMI) (p> 0.05). Task 1 showed higher back muscle activation than Task 2 (p< 0.05). These findings suggest that age, rather than pain, may play a more critical role in muscle activation, highlighting the need for age-specific interventions in cLBP rehabilitation.
AbstractRecently, meta-heuristic optimization algorithms have enhanced resource efficiency, facilitated informed decision-making, and addressed complex problems involving multiple variables and constraints in engineering and science fields. However, numerous handicaps are reported on the performance of a quite number of these optimizers, such as local solution trapping, slow convergence and the requirements for elevated storage and computation capability. This article proposes a novel, simple, and elaborate remedy for the reported deficiencies of meta-heuristic optimizers. This deficiency is accomplished by proposing a hybrid optimizer composed of an ambiguous optimizer and Artificial Intelligence (AI). The performance of the proposed technique is evaluated using four different meta-heuristic optimizers: Genetic Algorithm (GA), Particle Swarm Optimization (PSO), Teaching–Learning-Based Optimization (TLBO), and Artificial Gorilla Troops Optimization (AGTO). These optimizers range from the mature to the recently evolved. These meta-heuristic optimizers validate the proposed solver and confirm its applicability to any meta-heuristic optimization algorithm. Economic Dispatch (ED) of the IEEE 30-bus system is utilized to evaluate the performance of the proposed solver. The comprehensive results demonstrate the superiority, reliability, and adequacy of the proposed technique. It consistently converges to the global optimum solution, achieving the minimum energy cost of the system under concern while requiring the fewest iterations and minimal computational requirements.
AbstractLittle documented studies regarding analysis of macular telangiectasia type 2 in Egyptian patients. This prospective study included 24 eyes with MacTel-2, and 24 control eyes. Spectral-domain optical coherence tomography Angiography (OCT-A) was performed. Staging of eyes with MacTel-2, quantification of Foveal and parafoveal vascular density and full retinal thickness were performed. In MacTel-2 eyes, the superficial capillary vessel density was significantly decreased in the temporal, superior and inferior para-foveal area (p-value = 0.004, < 0.001 and 0.002 respectively). Only temporal parafoveal deep vessel density showed significant decrease in the MacTel-2 group as compared with the normal control group (49.6% versus 54.01%, p value = 0.010). There was a statistically significant decrease in the foveal and all the para-foveal thickness as compared with normal control group (P< 0.001). One-fourth of cases were classified as stage 4 MacTel-2. The patterns of neovessels were sea-fan, tangled or dead tree network, equally distributed among the six affected eyes. A significant reduction in both foveal density and visual acuity was documented with disease progression. This study emphasizes the role of OCT-A in diagnosis, staging and identification of neovascular pattern of MacTel-2. Furethermore, this study is considered one of the few Egyptian studies in staging the disease providing correlation to visual acuity, macular thickness and vessel density affection.
AbstractThe global outbreak of the novel coronavirus (COVID-19) has highlighted the urgent need for innovative therapeutic solutions. Remdesivir (REM) was the first drug granted approval by the US FDA for treating hospitalized COVID-19 patients. A selective and sensitive derivative spectrofluorimetric method has been developed and validated for the determination of Remdesivir (REM) in presence of its Alkaline-induced degradation product (AKDP), which is also known to be its metabolite (GS-441524). The method utilized the intrinsic fluorescence properties of REM, achieving a linear response within the range of 3.0–120.0 ng/mL at 428.3 nm using first-order derivative. Methodological parameters were optimized to ensure high sensitivity, with detection and quantification limits of 1.12 and 3.67 ng/mL, respectively. This approach successfully quantified REM in pure form, intravenous infusions, and spiked human plasma. Recovery rates in plasma were satisfactory at 97.64 ± 1.87, confirming the method’s suitability for therapeutic drug monitoring (TDM) in COVID-19 patients. Additionally, the environmental sustainability of the method was evaluated using GAPI, AGREE, and RGB12 metrics, underscoring its green and eco-friendly characteristics.
AbstractPhytogenic feed additives are increasingly used to improve animal health and productivity. This study compared the effect of supplementation with tannin to an herbal mixture consisting of ginger, garlic, artemisia, and turmeric on the performance, intestinal parasites, blood metabolites, carcass characteristics, and histology of muscles and intestine of goats. Twenty-seven Shami male goats were assigned to three treatments (n = 9): non-supplemented goats fed a control diet (CC); goats supplemented with 10g /animal/day of quebracho tannins as a source of condensed tannin (TT); and goats supplemented with 10g/animal/day of an herbal mixture (HM). All the animals received a basal diet consisted of concentrate feed mixture and alfalfa hay. The supplementation improved growth performance, nutrients digestibility, and serum immunoglobulins concentration (P< 0.05). The supplementation decreased fecal parasite counts, blood cholesterol, and glutamic-pyruvic transaminase (GPT) enzyme and improved blood glucose (P< 0.05). The supplementation decreased renal and meat fat, and group HM revealed higher polyunsaturated fatty acids and α-Linolenic acid in meat (P< 0.05). Tannin supplementation (TT group) negatively affected the histology of muscles and intestines. The results provide evidence for the beneficial use of an herbal mixture in the diet to improve animal performance, health status, and meat quality in goats.
AbstractTemporal contiguity between conditioned (CS) and unconditioned stimuli (US) is a crucial factor in Pavlovian learning, yet little is known about its role in appetitive conditioning and extinction. In a within-subject design, 60 participants underwent both a delay (DC) and trace conditioning (TC) session with partial reinforcement (75%) by monetary rewards (US) and varying interval between CS offset and US onset (DC: 0s; TC: 4s). In addition to self-report indices (reward expectancy, arousal, valence), psychophysiological markers (pupil dilation, heart-period and startle reflex modulation) were recorded during acquisition and extinction training. For most measures, significant differential conditioned responses emerged, irrespective of temporal contiguity, with no major differences observed between TC and DC during acquisition (except for potentially diminished startle attenuation in TC). Despite overall similar patterns in conditioned responding (with small to moderate effects on physiological measures), there was no intraindividual concordance between sessions, yet evidence for differential TC effects on extinction learning. Specifically, smaller reductions in differential reward expectancy, heart-period deceleration and startle modulation after extinction in TC suggested relatively diminished extinction learning. Conditioned pupil dilation (0–2 s after CS onset) remained comparatively stable. Taken together, our findings extend evidence of differences in underlying learning mechanisms between TC and DC to the context of reward learning.
AbstractEvaporation represents a fundamental hydrological cycle process that demands dependable methods to quantify its fluctuation to ascertain sustainable agriculture, irrigation systems, and overall water resource management. Meteorological variables such as relative humidity, temperature, wind speed, and sunshine hours affect evaporation non-linearly, resulting in challenges while developing prediction models. To combat this, the study aimed to develop robust models for estimating evaporation in semi-arid environments by applying machine learning techniques. Daily meteorological datasets (from January 2000 to December 2010) for the above variables (input) were collected from the Sidi Yakoub meteorological station in the Wadi Sly basin, Algeria. Conventional deep neural network (DNN) coupled with support vector machine (SVM), Bayesian additive regression trees (BART), random subspace (RSS), M5 pruned, and random forest (RF) were used for developing prediction models using various input variable combinations. Model performances were compared using mean absolute error (MAE), root mean square error (RMSE), determination coefficient (R2), Nash–Sutcliffe efficiency (NSE) coefficient, and percentage bias (PBIAS). Results indicated comparatively better performance for hybrid models (DNN-SVM, DNN-BART, DNN-RSS, DNN-M5 pruned, and DNN-RF) than conventional models (standalone DNN). Among hybrid models, the DNN-SVM model outperformed others with high accuracy and performance and fewer statistical errors in the daily pan evaporation prediction during the testing phase (R²=0.65, RMSE = 3.00 mm, MAE = 2.13, NSE = 0.65, and PBIAS = 3.54). DNN-RF was in the second rank for the prediction with R2of 0.64, RMSE of 3.00 mm, MAE of 2.16, NSE of 0.64, and PBIAS = 0.41. While the standalone DNN model gave the lowest results with MAE of 4.87, RMSE of 5.00 mm, and NRMSE of 0.65. The present framework’s success in Algeria’s Wadi Sly basin highlights its potential for scalable adoption in irrigation scheduling and drought resilience strategies, yielding implementable steps for policymakers, addressing climate-driven water scarcity. Future research should explore integrating real-time climate projections and socio-hydrological variables to improve predictive adaptability across diverse agroecological zones.
AbstractRewetting of peatlands requires the development of new biomass utilization pathways. The supply of strategic elements with key importance for the development of priority technologies, such as germanium (Ge), silicon (Si) and rare earth elements, from fenland plants is one option. To provide a first estimation of the potential, concentrations of strategic elements were determined in nine biomass samples covering typical fenland vegetation in northeast Germany. Subsequently, a simplified estimation of potential revenue from strategic element recovery was made. The analysed plant species can be classified as high or intermediate Si plant accumulators with highest contents of more than 16.0 g Si kg−1dry mass (DM) in sedges and common reeds. Ge concentrations were lower with reed canary grass containing the highest amounts of 465.3 µg Ge kg−1DM. Simultaneous acquisition of Ge and Si could provide higher total element yields and revenues of up to 500 $ ha−1. In contrast, the potentials for supplying rare earth elements appeared to be very low, with common reed containing the highest sum of rare earth elements of 437.4 µg kg−1DM. Biomass from rewetted fenlands is capable of accumulating strategic elements. More knowledge is required to understand the factors affecting their accumulation.
AbstractThis was a retrospective cross-sectional study evaluating the aetiology and antibiotic susceptibility in patients treated for suspected bacterial keratitis at Skåne University Hospital during 2019. Inclusion criteria: eyes with bacterial keratitis. Exclusion criteria: co-infection with other microbes. Primary outcome parameters: predisposing factors, causative pathogens and antibiotic susceptibility. Secondary outcome parameter: antibiotic treatment. A total of 255 cases met the inclusion criteria. Of these, 149 (58%) occurred in contact lens wearers. Corneal cultures, when performed, were positive in 51% of cases. For eyes which had received antibiotic treatment prior to corneal culture (n = 36), the proportion of positive cultures was 50%. Ulcers < 1 mm were less likely to yield a positive culture than those ≥ 1 mm. The most frequently isolated bacteria were coagulase-negative staphylococci (48%). Antibiotic resistance rates were lowest to levofloxacin (0%), ciprofloxacin (2%) and chloramphenicol (4%), and highest to fusidic acid (47%) and clindamycin (19%). The low proportion of positive cultures from small ulcers suggests that these warrant a different diagnostic approach. Furthermore, corneal cultures from eyes with ongoing antibiotic treatment were positive to the same extent as those from untreated eyes, suggesting that discontinuation of antibiotic treatment before re-culturing might not be necessary.
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AbstractGentamicin (GET), a widely utilized aminoglycoside antibiotic for severe bacterial infections, is associated with significant hepatorenal toxicity. These adverse effects are frequently exacerbated by GET-induced oxidative stress and inflammation. This study aimed to evaluate the potential protective efficacy of vincamine (VIN) against GET-induced hepatic and renal damage. 4 groups of adult male rats were assigned: normal control (received CMC), GET (100 mg/kg, i.p.), VIN (40 mg/kg, p.o.), and GET/VIN (received both VIN and GET) for 7 days. Liver and kidney function tests were performed. Serum total antioxidant capacity (TAC) and tissue malondialdehyde (MDA) were quantified. To assess apoptosis,BaxandBcl-2mRNA levels were quantified using real-time polymerase chain reaction (RT-PCR), while cleaved caspase-3 protein levels were measured using ELISA. Histopathological alterations were also examined. The implication of autophagy was assessed by detecting AMPK, beclin-1, LC3 and mTOR proteins. Our results indicated that VIN significantly attenuated GET-induced hepatotoxicity and nephrotoxicity by mitigating oxidative stress and apoptosis. Mechanistically, VIN modulated apoptotic pathways by upregulating the anti-apoptoticBcl-2gene and downregulating the pro-apoptoticBaxgene. Notably, VIN potently enhanced autophagy through modulation of the AMPK/mTOR signaling pathway, evidenced by the upregulation of beclin1 and LC3 levels. Histopathological analysis further corroborated these findings, demonstrating that VIN markedly reduced the tissue damage associated with GET administration. VIN demonstrates potential as a cytoprotective agent against GET-induced hepatorenal toxicity. The protective effect of VIN may be attributed to its capacity to modulate the Bax/Bcl-2/Caspase-3-dependent apoptotic pathway and the AMPK/mTOR-mediated autophagy pathway.
AbstractGene doping is known as the manipulation of congenital traits by gene therapeutic approaches with the intent of illicit athletic performance enhancement. A panel prototype suitable for multiplex gene doping detection by combining multiplex Polymerase Chain Reaction (PCR)-amplification with Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis was developed and examined for its specificity and sensitivity, and its applicability in human sports drug testing programs was assessed. The panel comprises 20 assays for exon-exon-junction detection of seven human transgenes (EPO, FST, GH1, IGF1, MSTN(propeptide),VEGFA, VEGFD), which have been considered as material to routine doping controls, in one reaction. Alongside, a suitable reference material (RM) was designed and tested for its utility. An estimated LOD95of 1,500 cp / mL or 30 copies (cp) per reaction of the panel and 500 cp / mL or 10 cp per reaction of the RM was determined in plasmid-spiked human whole blood samples. The specificity and applicability of the panel and the RM was further determined by testing equine plasma samples obtained from an animal that received rAAV-delivered human transgenicEPOas well as 111 native human doping control samples.
AbstractIdentifying the direction of fault is an essential mission of the transmission line protective scheme. This paper discusses a direction protective technique based on a positive impedance approach. The samples of the instantaneous positive sequence voltage component and the instantaneous positive sequence current component are used to determine the impedance approach and complete the Z matrix values. The fault direction can be determine using Z matrix values. Different configurations of the power system are utilized to examine the proposed protective scheme. Software ATP-EMTP (Simulation experiments) verified the feasibility of the presented scheme. To verify the capability and accuracy of presented scheme, it is examined by many fault scenarios such as high fault resistance, far end fault, cross-country fault, power flow change, single pole tripping, CT saturation and noise impact. In addition, the validity of the presented scheme is compared with other protection directional schemes.
AbstractThe increase in infections caused by multi-resistant Gram-negative bacteria, likeStenotrophomonas maltophilia, has become a growing health crisis worldwide.S. maltophiliaposes a risk because of its tendency to opportunistically infecting patience for example through colonization of catheters in hospital environments using its intrinsic resistance against multiple antibiotics. Through the COVID-19 pandemic it gained more prominence by being a key pathogen in respiratory co-infections. This study will present a structural analysis of StmPr1,S. maltophilia’s main virulence factor, an excreted serine protease. Our study outline structure and functional aspects of StmPr1, revealing a unique autoproteolytic activity resulting in a shortened version of the active enzyme. We also investigated the potential of two groups of peptide-based inhibitors, one being acetyl- and the other being boron-based inhibitors. The focus here lies on Bortezomib, a boron-based serine protease inhibitor, and its potential therapeutic use againstS. maltophilia.We provide a structure-function analysis which includes X-ray crystallography data with resolutions ranging from 1.64 to 2.08 Å, molecular dynamic simulations and small-angle X-ray scattering (SAXS) experiments. These data provide a deeper understanding of StmPr1’s resilience and mechanisms, while highlighting the relevance of StmPr1’s C-terminal extension for correct folding and its stability. Moreover, it also shows that StmPr1 is promising target for further drug discovery investigations to identify compounds and drugs to treatS. maltophiliainfections.
AbstractThe aim of this study is to explore the association between grandparental socioeconomic disadvantages and grandchild psychiatric disorders, the role of parental socioeconomic and psychosocial factors in this association, as well as potential gender differences. We utilized a cohort study design using data from the Stockholm Birth Cohort Multigenerational Study, including 11,299 individuals born in 1953 (parental generation), their 22,598 parents (grandparental generation), and 24,707 adult children (grandchild generation). Grandparental and parental socioeconomic disadvantages, respectively, included low income, non-employment, and overcrowding. Parental psychosocial disadvantages included single parenthood, psychiatric disorders, and criminality. Psychiatric disorders in the grandchildren were reflected by hospitalizations due to mental and behavioral disorders from age 18 to 30 (1986–2019). Analyses were performed within the Structural Equation Modeling framework. We found an association between grandparental socioeconomic disadvantages and grandchild psychiatric disorders (standardized total effect 0.155, 95% confidence interval [CI] 0.099–0.211), which was mediated through parental psychosocial disadvantages (standardized mediating effect 0.101, 95% CI 0.073–0.130). The mediation was more pronounced via psychosocial disadvantages among mothers than fathers. These findings indicate that psychosocial disadvantages among parents, especially mothers, reflect an important mediating mechanism, and addressing such disadvantages may help mitigate social inequalities in mental health across generations.
AbstractThis study explores the potential of six novel thiophene derivative thin films (THIOs) for reducing cancer cell adhesion and enhancing controlled drug release on inert glass substrates. Thiophene derivatives3a–cand5a–cwere synthesized and characterized using IR,1H NMR,13C NMR, and elemental analysis before being spin-coated onto glass to form thin films. SEM analysis and roughness measurements were used to assess their structural and functional properties. Biological evaluations demonstrated that the films significantly reduced HepG2 liver cancer cell adhesion (~ 78% decrease vs. control) and enabled controlled drug release, validated through the Korsmeyer-Peppas model (R2> 0.99). Theoretical studies, including in-silico target prediction, molecular docking with JAK1 (PDB: 4E4L), and DFT calculations, provided insights into the electronic properties and chemical reactivity of these compounds. Notably, compound5bexhibited the best binding energy (-7.59 kcal/mol) within the JAK1 pocket, aligning with its observed apoptotic behavior in cell culture. DFT calculations further revealed that5bhad the lowest calculated energy values; -4.89 eV (HOMO) and − 3.22 eV (LUMO), and the energy gap was found to be 1.66 eV, supporting its role in JAK1 inhibition and cancer cell adhesion reduction. These findings underscore the promise of thiophene derivatives in biomedical applications, potentially leading to safer surgical procedures and more effective localized drug delivery systems.
AbstractDuring the breeding season, the male stickleback proximal tubule of the kidney undergoes hypertrophy. This is due to the synthesis of the nest building protein spiggin, in response to increased levels of 11-ketotestosterone. The increased protein synthesis that is initiated during breeding alters the kidney function and the ability to secrete excess water, to osmoregulate, in fresh water. It has earlier been shown that there exist organ specific differences in transport proteins between mature and non-mature three-spined stickleback. To understand the molecular mechanisms compensating for kidney functions, this study examined transport genes responsible for functional changes between the kidney and intestine. RNA sequencing was performed on castrated and 11-ketoandrostenedione (11KA)-treated male stickleback. Results showed organ-specific responses: 2,549 differentially expressed genes (DEGs) in the kidney and 885 in the posterior intestine, with 210 shared between the organs. Solute transporters, aquaporin 10a and cadherin-17, were upregulated in the posterior intestine but downregulated in the kidney in 11KA treated males. Enrichment analysis revealed distinct biological processes, primarily involving solute transporters, indicating functional adaptation. While amino acid and ion transport were downregulated in the kidney, compensatory transport was observed in the posterior intestine. However, cellular hexose transporters were downregulated in both organs, suggesting a reduction in glucose absorption and passive water diffusion. The present study shows that androgens alter the expression of cellular transporters and redirect functions of the kidney to the posterior intestine. The results also indicate reduced glucose absorption in breeding, male three-spined stickleback.
AbstractStudies investigating psychological safety in sports and non-sports contexts have mostly utilized the universal Team Psychological Safety Scale (TPSS) aimed for performance development in professional teams. The Sport Psychological Safety Inventory (SPSI) has recently been introduced for psychological safety measurement specifically in sports. The aim of this study was to compare the psychometric properties of the TPSS and the SPSI within an elite sport context. A cross-sectional survey was used to collect data for assessment of the internal consistency, factorial validity, construct validity and measurement invariance of the TPSS and the SPSI. Complete data sets were provided by 371 elite Athletics athletes (track and field) and orienteers. Both the TPSS (ω = 0.72) and the SPSI subscales (range: ω = 0.81-0.88) showed acceptable internal consistency. Confirmatory factor analyses indicated a mediocre to good model fit for the TPSS and the SPSI three-factor correlated structure. The TPSS and the SPSI subscale ‘mentally healthy environment’ showed a moderate correlation. Measurement invariance tests suggested the TPSS to be fully invariant across genders, while the SPSI was found non-invariant. The study shows that the TPSS appears sound for assessing psychological safety in elite sports, while caution is needed when using the SPSI.
AbstractManganese, an essential nutrient for male reproductive health, exerts dose-dependent effects, with excessive exposure—particularly to manganese dioxide nanoparticles (MnO2-NPs) from environmental or industrial sources inducing gonadal damage via oxidative stress, hormonal disruption, and impaired steroidogenesis. This study evaluated rosemary essential oil (REO) againstMnO2-NP-induced reproductive dysfunction in male rats. Seventy-two Sprague–Dawley rats (130 ± 10 g) were divided into six groups (n= 12): Group I (deionized water), Group II (saline), Group III (MnO2-NP, 100 mg/kg bw/day), Group IV (REO, 250 mg/kg/day), Protective Group V (REOpre-treatment +MnO2-NPs), and Therapeutic Group VI (MnO2-NPs + REOco-treatment) for 56 days.MnO2-NPexposure caused testicular injury, marked by elevated lipid peroxidation (↑malondialdehyde, ↑nitric oxide), suppressed antioxidants (↓total antioxidant capacity, ↓catalase, ↓glutathione), impaired sperm parameters (motility, count, morphology), and altered serum hormone levels (follicle-stimulating hormone, luteinizing hormone, testosterone). These effects correlated with downregulated steroidogenesis genes (StAR,HSD-3β,CYP11A1). Both Protective and Therapeutic REO treatment mitigatedMnO2-NPsoxidative stress, restored hormonal balance, and normalized gene expression. Histopathology revealed reduced seminiferous tubule degeneration and enhanced spermatogenesis inREOgroups. Findings demonstrateREO’sefficacy in alleviatingMnO2-NPsinduced reproductive toxicity via antioxidant and steroidogenic modulation, positioningREOas a promising therapeutic against nanomaterial-induced gonadotoxicity.
AbstractThe Nile Delta coastal area surface sediments were evaluated for twenty-five elements. Inductively coupled plasma-mass spectroscopy (ICP-MS method) was used to analyze the digested solutions, previously filtered using discrete 0.2 μm PTFE syringe filters according to USEPA protocols. Potentially toxic elements (PTEs) and pollution levels were estimated using several indices. Pollution guides such as the enrichment factor (EF), contamination degree (Cd), geoaccumulation index (Igeo), and pollution load index (PLI) are mainly determined by actually toxic elements such as Cr, Co, Cd, Hg and Pb, while Principal component analysis (PCA), concerned with the distribution of all elements in sediment to determine the sources of elements. The following is the order of the EF values: Mn < Cu < Zn < Ni < Pb < Cr. The areas under investigation showed no pollution with Cr, Cu, Mn, Ni, Pb, or Zn, as indicated by their (Igeo≤0) values andCd(< 1.5). Significant connections between Mn, Fe, Cr, Co, and Ni values were observed, indicating comparable origins. In the current study, the children’s Hazard Quotient (HQ) results for the dermal exposure pathway are low, but adult values are 3–4 times higher. The chronic daily intake(CDIDermal) and carcinogenic risk (CRDermal) through dermal absorption were also investigated.
AbstractTherd10mouse is a widely used model for degenerative retinal diseases such as retinitis pigmentosa (RP). Its retina shows rhythmic spontaneous activity at a frequency of three to seven Hz, and the retinal ganglion cells (RGCs) are less electrically excitable. We hypothesize that the electrical excitability can be improved by suppressing the oscillations using the neuroprotective drugs 2-aminoethanesulphonic acid (taurine), brimonidine and betaxolol. These are involved in calcium homeostasis and may play a crucial role in neuroprotection and excitotoxicity by preventing Ca2+overload. Spontaneous activity and responses to electrical stimulation of isolated retinas from 3- to 4-month-oldrd10mice were recorded using multielectrode arrays. At defined times, the neuroprotectants were repeatedly added to the medium according to a standardized protocol to analyze the reproducibility and reversibility of their effects. Taurine and betaxolol significantly reduced oscillations and bursting behavior and ameliorated electrical efficiency. Brimonidine only reduced the frequency of oscillations. The effects on oscillation, spontaneous firing frequency, bursting behavior and stimulation efficiency were reproducible and reversible. The drugs tested appear to be promising therapeutic candidates for improving the residual function of RGCs. They will be further investigated and combined with other RP treatments, such as retinal prostheses, in the future.
AbstractData Harmonization is an important yet time-consuming process. With the recent popularity of applications using Language Models (LMs) due to their high capabilities in text understanding, we investigated whether LMs could facilitate data harmonization for clinical use cases. To evaluate this, we created PASSIONATE, a novel Parkinson’s disease (PD) variable mapping schema as a ground truth source for pairwise cohort harmonization using LLMs. Additionally, we extended our investigation using an existing Alzheimer’s disease (AD) CDM. We computed text embeddings based on two language models to perform automated cohort harmonization for both AD and PD. We additionally compared the results to a baseline method using fuzzy string matching to determine the degree to which the semantic capabilities of language models can be utilized for automated cohort harmonization. We found that mappings based on text embeddings performed significantly better than those generated by fuzzy string matching, reaching an average accuracy of over 80% for almost all tested PD cohorts. When extended to a further neighborhood of possible matches, the accuracy could be improved to up to 96%. Our results suggest that language models can be used for automated harmonization with a high accuracy that can potentially be improved in the future by applying domain-trained models.
AbstractCOVID-19 has been linked to acute and long-term cognitive impairments, including memory and concentration deficits, as well as neuropsychiatric symptoms such as anxiety and depression. However, the neuropathophysiological mechanisms underlying these cognitive and affective changes remain poorly understood. Accumulating evidence points towards neuroinflammation as a potential driver of most acute and post-acute neurofunctional symptoms. In this study, we aimed to comprehensively characterize cognitive impairment associated with COVID-19 using a large online cohort of over 1400 participants, including individuals reporting a previous SARS-CoV-2 infection and individuals who had never been tested positive. Our cognitive test battery covered alertness, executive functions, and episodic long-term memory. Our results demonstrate a pronounced and selective impairment of individuals previously infected in a mnemonic discrimination task known to engage hippocampus-dependent pattern separation. This impairment remained statistically significant after controlling for potential confounding factors (i.e., age, gender, education, depressiveness, anxiety, and stress). This finding, derived indirectly from behavioral performance, suggests compromised hippocampal neurogenesis following infection, which may contribute to COVID-related memory deficits. Our study has important implications for understanding the neurofunctional consequences of COVID-19 and highlights the potential significance of neuroinflammation in the manifestation of cognitive impairments.
AbstractRunning performance from sprint to long distance is largely determined by the interplay between basic speed and endurance. Existing power-law, physiological, and theoretical models describe and explain the characteristic decline in pace with increasing distance. However, normative and statistically validated measures that capture both the average and variability of pace decline across standard track distances remain incomplete. To address this gap, we analysed over 14,000 race times from competitive male runners and introduce the coefficient of special endurance (KsA), a novel metric that quantifies relative pace loss between adjacent race distances, from 100/200 to 5000/10,000 m. The KsA values obtained for seven distance pairs are nearly constant over decades in national runners, show low variability, and predict race times with less than one percent. The KsA-based reference ranges allow performance to be evaluated from the international to the regional level. This provides specific insight into runners’ strengths, weaknesses and progression for individualizing training, selecting the most promising race distance, and identifying and developing talent. Overall, we provide empirically derived KsA values that serve as statistical norms for pace loss from 100 m to 10,000 m to evaluate running performance of males. The current approach should also be applicable to women, juniors, and road runners.
AbstractLyme neuroborreliosis (LNB) is the most common form of disseminated Lyme borreliosis in Europe and North America. There are limitations in existing LNB diagnostics and a lack of reliable objective markers for disease-course. Here, extensive protein profiling with two panels of 184 proteins, was done in the search for new clinically useful diagnostic and prognostic candidate biomarkers. Cerebrospinal fluid (CSF) was collected from patients with definite LNB (n= 13) at the time of diagnosis before initiating antibiotic treatment, and at a follow-up one month later. When symptoms were evaluated at a six-month follow-up, six patients had recovered with no persistent symptoms (NPS), and seven experienced delayed recovery with persistent post-treatment symptoms (PS). Orthopedic patients (n= 60) served as controls. With the panels used, no protein biomarkers able to differentiate between PS and NPS were identified. However, from a diagnostic perspective, we identified multiple proteins that were differentially expressed between LNB and controls. The majority of them were downregulated following antibiotic treatment, at the one-month follow-up. IL10, TNF, and CCL8 were considered examples of potentially useful candidate biomarkers in both the early diagnostics and in monitoring of treatment response. These markers merit further investigation to understand their utility in relation to other neurological manifestations.
AbstractThe current research discuss in detail the tourmaline distribution in Sikait leucogranites in order to deduce its genesis and type. We conduct new detailed geological, petrographical, mineralogical, and geochemical examinations to understand the Arabian Nubian Shield development by investigation of such the examined leucogranites. Tourmaline occurs as disseminated or cluster nodular within coarse-grained leucogranites. Geochemically, the examined leucogranites have high contents of SiO2(69.44–75.87 wt%), and total alkalis (mean > 7) with low mean CaO (0.4 wt%), Fe2O3(1.93 wt%), and Mg# (14.59) values. They share features of calc-alkaline, strongly peraluminous (A/CNK > 1.1), with high contents of Zn (av. 266.68 ppm), Pb (av. 29.13 ppm), Rb/Sr (av. 22), Al2O3/TiO2(av. 832.6), FeO/MgO (av. 12.24). They are remarkably enriched in semi-volatile elements (Pb = 12–235 ppm), and LILEs (Rb = 192–679 ppm) relative to HFSEs (e.g. Zr, U and Nb) with notable strong Ba, Sr and Ti negative anomalies. They are depleted in ∑REEs (av. 19.1 ppm) and reveal parallel, uniform patterns slightly notable depletion of HREEs in comparison with LREEs. They reveal extreme pronounced Eu (av. Eu/Eu*= 0.02) negative and Ce/Ce* (0.76–1.12) positive anomalies. The examined rocks have prominent tetrad effect (M-type) as indicated by Irber and Lambda methods. Based up on conventional geochemical diagrams, the examined rocks are post-collisional S-type granites derived by partial degree of the clay-rich pelite rocks melting followed by extreme fractional crystallization processes during post-collisional extension episode at temperatures (663 –786 °C) based on saturation temperature of zircon. The investigated tourmaline nodules are of alkali group and foitite end-member.
AbstractAttenuated interpersonal synchrony (IPS) has been shown between autistic individuals and their interaction partners; however, the mechanisms of this attenuation remain unclear. One possibility could lie in perceiving the timing of others’ behaviors. The present study aimed to relate the behavioral production of IPS with the perception of temporal dynamics of social interactions and event timing perception in autistic and non-autistic adults. Autistic and non-autistic participants engaged in naturalistic conversations with a non-autistic stranger, who was naïve to the participant’s diagnostic status. Behavioral IPS was computed using automatic video-based analysis. Participants reported their experiences of perceived IPS with the partner, as a measure of the perceived temporal dynamics of the social interaction. A perceptual simultaneity task measured the perception of event timing in a nonsocial context. Bayesian linear mixed models were used to evaluate the effects of perceived IPS ratings and simultaneity thresholds on behavioral IPS. Expectedly, behavioral IPS was reduced for dyads including an autistic adult. Neither perceived IPS ratings, nor simultaneity thresholds, were associated with reduced behavioral IPS for dyads with or without an autistic adult. These findings hint that attenuated behavioral IPS may not result from atypical perceived timing of others’ behaviors or event timing perception.
AbstractThis article presents several innovative methods to mitigate frequency deviations in hybrid renewable power grids (HRPGs) with high penetration of renewable energy sources (RESs). Two models of the HRPGs are considered: the first model is a two-area power grid that combines three conventional power plants and two RESs in each area, while the second model is the IEEE 39-bus system. The tie-line is connected in series with a unified power flow controller (UPFC). The first method introduces an approach in the secondary control loop (SCL), where a fuzzy logic controller is cascaded with an Integral-Tilt-Derivative (I-TD) controller (Fuzzy I-TD). Additionally, the performance of the Fuzzy I-TD controller is compared with other approaches, such as Fuzzy Proportional-Integral-Derivative (Fuzzy-PID) and Fuzzy Integral-Proportional-Derivative (Fuzzy I-PD). The second strategy integrates the Fuzzy I-TD controller in the SCL along with controlled energy storage systems (ESSs), such as plug-in electric vehicles (PEVs). The parameters of the strategies are optimized using a recent metaheuristic algorithm known as the Sea Horse Optimizer (SHO) under different operating conditions. A comprehensive investigation is conducted to validate the effectiveness of the Fuzzy I-TD controller and the Fuzzy I-TD controller with PEVs in HRPGs. The Fuzzy I-TD controller significantly reduces frequency and tie-line deviations in the SCL by 82.7% and 97.01%, respectively, when compared to the Fuzzy I-PD and Fuzzy-PID controllers. Moreover, the Fuzzy I-TD with PEVs reduces frequency fluctuations by 40% compared to the Fuzzy I-TD alone in the SCL. The results demonstrate that the presented strategy is efficient and effective for HRPGs.
AbstractThe current investigation evaluated the impact of the dietary addition of commercial bile acids (BAs) on growth, nutrient assimilation, immunity, antioxidant status, intestinal and hepatic histomorphometry, and gene expression of lipid metabolism in Nile tilapia (Oreochromis niloticus). In a study conducted for seventy days, 180 healthy fingerlings weighing 9 ± 0.5 g were divided into 18 hapas measuring 0.7 × 0.7 × 1.0 m. The fish were fed on six meals enriched with varied amounts of BAs: 0.0 (D1), 0.1 (D2), 0.2 (D3), 0.3 (D4), 0.4 (D5), and 0.5 (D6) g/kg diet. Nile tilapia fed the D3 diet exhibited significantly enhanced growth performance, with a specific growth rate of 1.89%/day and had the greatest feed conversion ratio (1.25), protein productive value, and energy utilization (33.28%). Fish fed the D3 exhibited significantly the highest crude protein content (64.50%). Energy content varied significantly, with D1 showing the lowest value (533.34 Kcal/100 g) and D3 the highest (604.27 Kcal/100 g). D3 improved biochemical indicators, immunological parameters, and digestive enzymes ofO. niloticus. Histological analysis revealed notable liver and intestinal integrity enhancements among fish receiving BA-enriched diets, especially D3. Additionally, gene expression related to lipid metabolism in liver, peritoneal fat, and muscle tissues was upregulated in the treatment groups, especially 0.2 g/kg BAs compared to the control group. Results illustrate significant modulation of lipid metabolism gene expression parameters (Adipose triglyceride lipase; ATGL, Hormone-sensitive lipase; HSL, Peroxisome proliferator-activated receptor α; PPARα, Fatty acid synthase; FAS) by BAs treatments and were upregulated in BA-fed groups (D2–D6). Conversely, Carnitine palmitoyl transferase 1; CPT-1and Insulin-like growth factor-II; Igf-IIexpression declined, particularly when the BAs dose was increased. Accordingly, dietary 0.2 g/kg BAs supplementation positively influences on physiological, biochemical parameters, and lipid metabolic of Nile tilapia, making it a promising feed additive for aquaculture.
AbstractAmorphous calcium carbonate (ACC) plays an important role in the crystallization pathways of calcite and its polymorphs influencing many natural and anthropogenic processes, such as carbon sequestration. Characterizing the dissolution rate of ACC in presence of additives of contaminants in favor of crystalline phases is challenging as such reactions occur readily in bulk solution. Droplet microfluidics offers a solution by confining ACC within a droplet, enabling a quantification of the transformation rate of ACC into crystalline phases. However, accurate quantification of this transformation requires analyzing more than thousands of droplets identifying the different polymorphs of calcium carbonate during an experiment, which is labor-intensive. Here we develop a visual-based machine learning method, combining cascading U-Net and K-Means clustering, to allow efficient analysis of droplet microfluidics experiment results. Using our method, we accurately inspect 11,288 droplets over 6 hours of experimental time to identify the polymorphs, using a CPU core in a laptop for only 42 minutes. This is achieved with manual labeling of 11 experimental microscopy images before augmentations. From our analyses the transformation rate of ACC into its crystalline phases can be inferred. The transformation rate indicates an increasing stability of the ACC phase in confinement. Our method is generalizable and can be applied to different setups of droplet microfluidics experiments, facilitating efficient experimentation and analysis of complex crystallization processes.
AbstractPosterior fossa (PF) tumors are the most common neoplastic entity in pediatric neurosurgery. Children suffering from PF tumors regularly present with hydrocephalus and CSF diversion is a crucial point of treatment. There is an ongoing debate about external ventricular drainage (EVD) management before surgery and its influence on ongoing hydrocephalus treatment afterwards. Beyond onco-surgical aspects, the prevention of shunt-dependency is an important goal in posterior fossa surgery. Various predictors for shunt-dependency after posterior fossa surgery in children have been suggested. Because these predictors may only apply to small subsets of children, and their reliability has been questioned, we evaluated a straightforward, potentially automated, and unbiased method for shunt prediction. In this retrospective radiomic study we analyzed 60 pediatric patients with posterior fossa tumors. Exclusion criteria were age under two years, missing MRI data, tumor location non-exclusive to the PF, traumatic brain injury and less than 6 months follow-up. Ultimately, 36 children met the inclusion criteria. We performed a volumetric assessment of various skull and brain compartments before and after surgery focused on ventricle-brain ratio (VBR). We dichotomized for potential predictors and performed ROC analyses. We evaluated the prognostic parameters for shunt dependency, including supratentorial transependymal edema and VBR, as well as pre- and postoperative radiomic measurements as early prognostic tools. The cutoff in ventricle volume for CSF diversion was 60.9 ml (AUC 0.788,p= 0.001). The radiomic-based prediction of shunt dependency with VBR-scoring showed an AUC of 0.783. Postoperative reduction in ventricle size, depicted by the deltaVBR scoring, showed an AUC of 0.719 in predicting shunt-free survival. Perioperative CSF diversion did correlate with postoperative persistent HCP, whereas the odd’s ratio for shunting was decreased, but not significantly lower, when CSF diversion was undertaken perioperatively (AUC = 0.618, OR = 0.273, CI = 0.029–2.577). Ventricle-brain ratio may be a potential predictor for the necessity of CSF diversion. In our cohort, radiomic predictors performed better than hydrocephalus categorization, modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) or transependymal edema alone. VBR pre- and deltaVBR postoperatively may be potential tools to predict the need for shunting in pediatric posterior fossa tumor patients. The decision for pre- or intraoperative CSF diversion showed no correlation and no influence on persistent hydrocephalus.
AbstractAir temperature plays a critical role in estimating agricultural water requirements, hydrological processes, and the climate change impacts. This study aims to identify the most accurate forecasting model for daily minimum (Tmin) and maximum (Tmax) temperatures in a semi-arid environment. Five machine learning models—linear regression (LR), additive regression (AR), support vector machine (SVM), random subspace (RSS), and M5 pruned (M5P)—were compared for Tmaxand Tminforecasting in Gharbia Governorate, Egypt, using data from 1979 to 2014. The dataset was divided into 75% for training and 25% for testing. Model input combinations were selected based on best subset regression analysis, result shows the best combination was Tmin(t−1), Tmin(t−3), Tmin(t−4), Tmin(t−5), Tmin(t−6), Tmin(t−7), Tmin(t−8)and Tmax (t−1), Tmax (t−2), Tmax (t−3), Tmax (t−4), Tmax (t−5), Tmax (t−6), Tmax (t−8)for daily minimum maximum air temperature forecasting, respectively. The M5P model outperformed the other models in predicting both Tmaxand Tmin. For Tmin, the M5P model achieved the lowest root mean square error (RMSE) of 2.4881 °C, mean absolute error (MAE) of 1.9515, and relative absolute error (RAE) of 40.4887, alongside the highest Nash-Sutcliffe efficiency (NSE) of 0.8048 and Pearson correlation coefficient (PCC) of 0.8971. In Tmaxforecasting, M5P showed a lower RMSE of 2.7696 °C, MAE of 1.9867, RAE of 29.5440, and higher NSE of 0.8720 and R² of 0.8720. These results suggest that M5P is a robust and precise model for temperature forecasting, significantly outperforming LR, AR, RSS, and SVM models. The findings provide valuable insights for improving decision-making in areas such as water resource management, irrigation systems, and agricultural productivity, offering a reliable tool for enhancing operational efficiency and sustainability in semi-arid regions. The Friedman ANOVA and Dunn’s test confirm significant differences among temperature forecasting models. Additive Regression overestimates, while Linear Regression and SVM align closely with actual values. Random Subspace and M5P exhibit high variability, with SVM differing significantly. For maximum temperature, Random Subspace and M5P perform similarly, while SVM remains distinct.
AbstractOptical Coherence Tomography Angiography (OCTA) has become an essential non-invasive imaging technique for high-resolution visualization of retinal microvasculature. This study evaluates the performance of a novel Swept-Source OCTA device, Intalight DREAM, compared to established systems: Heidelberg Spectralis, Topcon Triton, and Zeiss Cirrus. We assessed acquisition time and microvascular parameters in the superficial (SCP) and deep (DCP) capillary plexuses using the OCTA Vascular Analyser algorithm for standardized image analysis across devices on 30 eyes from 15 healthy participants. In the SCP, DREAM demonstrated a higher median vessel length (47 μm) and greater fractal dimension (mean: 1.999) than the other devices, indicating enhanced continuity and network complexity. In the DCP, DREAM showed a smaller foveal avascular zone (median: 0.339 mm2) compared to Spectralis (0.51 mm2), Triton (0.5935 mm2), and Cirrus (0.9145 mm2), along with a smaller vessel diameter (median: 23 μm) compared to Triton and Cirrus. With a median imaging time of 9.1 s, DREAM was significantly faster than the Spectralis system (23.3 s) while providing largely comparable image quality, enhancing patient comfort, and potentially minimizing motion artifacts. These findings suggest that DREAM OCT is a promising tool for deep retinal imaging, with strong potential for clinical application and research.
AbstractBenign prostatic hyperplasia (BPH) is a prevalent progressive age-related disorder in men, yet its etiopathophysiology remains poorly understood. Current treatments like finasteride (Fin) have limited long-term efficacy, necessitating alternative therapies. Hydroxychloroquine (HCQ), a safe antimalarial agent, possesses anti-inflammatory, immunomodulatory, and antiproliferative activities, however, its therapeutic effect in BPH has not been investigated. Accordingly, we examined its therapeutic potential and underlying mechanisms, alone or combined with Fin, in testosterone-induced BPH in rats. In BPH-induced rats, HCQ markedly reduced prostate weight and index, and PSA, testosterone, dihydrotestosterone, pro-inflammatory cytokines (TNF-α, κ and IL-6), and the transcription factor “NF-κB” levels, while improving histological abnormalities in epithelial and stromal tissues. HCQ reduced the mRNA expression of AR and ERK1/2, and decreased the protein levels of EGFR and STAT3. Additionally, HCQ increased the mRNA expression of FOXO1 and promoted apoptosis through both intrinsic and TRAIL-mediated pathways. This was evidenced by the upregulation of pro-apoptotic Bax and the downregulation of anti-apoptotic Bcl-2 and Bcl-XL levels in the intrinsic pathway, as well as the reduction in mRNA expression of DR4 and DR5 in the TRAIL-mediated pathway. Notably, combining HCQ with Fin enhanced these effects. Molecular docking revealed HCQ’s strong interactions with androgen receptor (AR), EGFR, ERK1/2, FOXO, and TRAIL death receptors (DR4/DR5), comparable to Fin except for STAT3. Our findings suggest that HCQ modulates BPH progression by targeting STAT3/FOXO1/TRAIL and EGFR/ERK/AR pathways, offering a promising therapeutic strategy for BPH, either alone or in combination with Fin.
AbstractThe aim of this study was monitoring health status of mastitic Barki ewes using candidate gene approach, gene expression and serum profile of inflammatory and antioxidant markers. A total of 70 ewes were allocated into two equal-sized groups: healthy and ewes have a history of mastitis. DNA sequencing ofIFN-γ(365-bp),IL-4(285-bp),TNF-α(273-bp),MYD88(660-bp),CCL5(360-bp),TLR4(256-bp),TLR9(414-bp),LTF(299-bp),PRLR(891-bp),CAT(300-bp),GPX1(221-bp),Keap1(360-bp),OXSR1(357-bp),ATOX1(433-bp),GST(480-bp) andNrf2(340-bp) revealed single nucleotide polymorphisms (SNPs) between healthy and mastitic ewes. Levels ofIFN-γ,IL-4,TNF-α,MYD88,CCL5,TLR4,TLR9,LTF,PRLR,Keap1andOXSR1genes expression were significantly up-regulated in ewes affected with mastitis than resistant ones. MeanwhileCAT,GPX1,ATOX1,GST, andNrf2genes elicited an opposite trend. There is a significant elevation of activity of AST, LDH, Hp, CP, SAA, IgG, MDA, and NO levels (P< 0.05), along with reduction of total protein, albumin, GSH, GPx, catalase and SOD (P< 0.05) in mastitic ewes. The findings of this study supported the hypothesis that SNPs in immune and antioxidant genes could be important genetic markers for mastitis susceptibility or resistance in Barki ewes. The examined genes’ gene expression profiles may also be utilized as surrogate biomarkers to establish an efficient management regimen and forecast the period of time at which a disease is most likely to manifest.
AbstractUltrasound shear wave elastography (SWE) is broadly used to quantify muscle stiffness. Currently, most stiffness measures are retrieved from manually placed small measurement zones, which is an operator-dependent and laborious procedure of questionable reliability. Automated time-series measurements over the full visible muscle are expected to improve measurement validity, robustness, and efficiency in larger studies. This study aimed to develop and validate a semi-automated algorithm for analyzing SWE clips of muscle tissue using the single-image, manufacturer-provided manual measurements in every image of the corresponding clips as reference. SWE clips of the relaxed and activated upper trapezius muscle of 52 healthy participants were analyzed manually and with the algorithm for the muscle’s Young’s modulus (kPa) and shear wave velocity (SWV). Results demonstrated excellent correlation between manual and algorithm measurements, Spearman’sρ> 0.99,p< 0.001. Bland–Altman analyses indicated good method agreement with proportional biases of + 0.747 kPa and − 0.068 m/s for Young’s modulus and SWV, respectively, and widths of the limits of agreement of 8.653 kPa and 0.500 m/s, respectively. The proportional bias is within the minimal detectable change and therefore clinically negligible. These results support the algorithm as a tool enabling valid SWE time-series measurements in muscle tissue and an improved workflow.
AbstractBalance control requires the continuous integration of feedback signals from several sensory organs with feedforward estimates about the state of the body. Such feedback signals are important for standing upright, as shown in increased and more variable sway patterns when sensory feedback is compromised, for instance when standing with eyes closed or on unstable surfaces that make cutaneous signals from the foot less reliable. Poorer sensory processing is also considered to arise during healthy aging due to a decrease of the reliability and transmission rate of feedback signals. Here, we are interested in how processing of tactile signals from the lower leg is modulated when balance control is challenged and how this interacts with age-related sensorimotor changes. We examined tactile sensitivity on the lower leg during sitting, standing on stable ground, and standing on unstable ground (foam). We quantified the center of pressure during the two standing conditions by determining the area of a 95% confidence interval ellipse as well as the total displacement of the center of pressure. Tactile sensitivity was assessed by asking participants to detect brief vibrotactile probes of various intensities to the lower leg. As expected, postural sway increased when standing on foam than stable ground for both age groups. When postural demands were minimal (sitting), tactile sensitivity was overall poorer in older than younger adults. Tactile perception was also poorer when standing on foam than on the stable ground, for both age groups. We conclude that increased postural demands reduce reliance on tactile signals from the lower limb in both young and older adults.
AbstractRecent research has shown that cognitive reserve is associated with better cognitive abilities in ALS/MND, and that a slow brain ageing speed is associated with intact cognition in ALS. This study compares the effects of cognitive reserve and the predicted brain age difference (PAD) on the risk of being diagnosed with ALS, the risk of having cognitive or behavioral impairment, or even fronto-temporal dementia, and on disease duration.Our results indicated that neither PAD nor cognitive reserve was associated with an increased risk of ALS, but that higher PAD was associated with an increased risk of cognitive impairments and FTD, as well as a shortened disease duration. Higher cognitive reserve on the other hand was associated with a lower risk of cognitive impairment and a longer disease duration.Brain age as a proxy of brain reserve influences disease progression and presentation more strongly than cognitive reserve.
AbstractMagnetomyography (MMG) can be used as a contactless modality to study the neuromuscular system. On the one hand, being contactless is a practical advantage as there is no need to prepare skin or attach electrodes as in electromyography (EMG). On the other hand, it is also a disadvantage because the magnetic field decays with increasing distance. However, the effect of sensor-to-source distance in MMG has not been systematically studied. Comparative in vivo and in silico experiments of the effect of sensor-to-source distance were performed. In vivo, muscle activity was recorded using simultaneous surface EMG and one triaxial optically pumped magnetometer (OPM). For the simulations, an established multiscale muscle model was used to predict how distance affects the signal-to-noise ratio (SNR) and the signal’s spectral content. Given an environmental noise level of 0.5–1 pT root-mean-square (RMS) from 10 to 350 Hz, it was impossible to robustly detect muscle activity of one finger flexor muscle beyond a distance of two centimeters using OPM technology. In silico experiments showed a high SNR between 8 and 29 for MMG at 0.5 cm distance. Increasing the distance increases the MMG’s median frequency content. The simulations uncovered that this is due to the effect of noise. For distances greater than two centimeters, measuring MMG of voluntary contractions in medium-sized muscles with current OPM technology and conventional magnetic shielding cannot be recommended.
AbstractGlobal warming affects the Earth system in complex ways, often preventing a functional understanding of the underlying processes. Disentangling these processes between abiotic drivers and single species or entire communities is, however, essential for an in-depth understanding of the impacts of climate change on the ecosystem. Using a high-resolution time series on heat waves and cold spells in an Arctic fjord system, we demonstrate that AI-supported digital data processing, which is based on state-of-the-art observatory technology, has the potential to provide new insights into the effects of abiotic factors on biotic communities, which would not be possible with traditional expedition-based sampling methods. Furthermore, our study shows that short-term, event-driven anomalies in key ocean variables not only alter a system’s hydrography but also have the potential to impact the entire community across the trophic chain from benthos and zooplankton to fish. We found a significant positive correlation between hydrographic temperature anomalies and biota abundance, with high biota abundances linked to ‘Atlantic’ phases with frequent heat waves and low biota abundances correlated with ‘Arctic’ phases dominated by cold spells. The study also revealed that hydrographic anomalies can not only influence overall biota abundance in an area but also trigger complex shifts in species composition. This leads to fluctuating interannual abundance peaks in specific biotic groups, such as jellyfish, fish, or chaetognaths, depending on trigger factors that are not yet fully understood.
AbstractEye tracking is a widely used tool to study infant development, but creating diverse stimuli while maintaining high control over confounding variables can be challenging. In this proof-of-concept study, we examined an innovative way to generate ecologically valid stimuli using AI technology, in order to create videos that can be used in culturally diverse settings. Using the eye-mouth-index (EMI), a commonly used paradigm in infant eye tracking, we examined the consistency of eye tracking measures across original videos and two types of AI-manipulated videos in a sample of 46 infants aged 12–14 months. We found a very strong correlation of the EMI across original and AI videos (r= 0.873–0.874), and there were no statistically significant differences between mean EMI in the original and AI conditions. Additionally, we created culturally diverse videos to measure gaze following, and found that children followed the gaze of the people in the AI-manipulated videos in an expected manner. In conclusion, AI technology provides promising tools to create ecologically valid and culturally diverse stimuli, that can be used to conduct studies in a wide range of settings and to examine the generalizability of earlier findings in the field of developmental psychology.
AbstractThis study presents a novel hardware and software architecture combining capacitive sensors, quantum-inspired algorithms, and deep learning applied to the detection of Essential Tremor. At the core of this architecture are graphene-printed capacitive sensors, which provide a cost-effective and efficient solution for tremor data acquisition. These sensors, known for their flexibility and precision, are specifically calibrated to monitor tremor movements across various fingers. A distinctive feature of this study is the incorporation of quantum-inspired computational filters—namely,QuantvolutionandQuantClass—into the deep learning framework. This integration offers improved processing capabilities, facilitating a more nuanced analysis of tremor patterns. Initial findings indicate greater stability in loss variability; however, further research is necessary to confirm these effects across broader datasets and clinical environments. The approach highlights a promising application of quantum-inspired methods within healthcare diagnostics.
AbstractCirculating cell-free (cf) DNA in blood plasma is considered a diagnostic and prognostic biomarker of tissue damage and could be a driver of chronic inflammation by stimulating the innate immune response via activation of inflammasomes. Increased AIM2-inflammasome activity in the aortic wall is associated with abdominal aortic aneurysm (AAA). We here hypothesized that cfDNAs are elevated in the plasma of AAA patients and are associated with chronic inflammation. Single strand (ss)DNA, double strand (ds)DNA and mitochondrial (mt)DNA levels were explored in plasma and leucocytes from 93 AAA patients, 89 controls (non-AAA patients) and 10 healthy subjects, using fluorescence-based quantification and real-time qPCR, respectively. To analyse inflammasome activation by cfDNA, differentiated THP-1 macrophages were primed with lipopolysaccharide (LPS) and then stimulated for one, six or 24 h with DNA extracted from peripheral blood mononuclear cells (PBMC) of AAA patients. Our analysis revealed significantly increased levels of ssDNA, dsDNA and mtDNA levels in plasma from AAA patients compared with non-AAA patients and healthy subjects. In addition, the mtDNA copy number was significantly higher in PBMC from AAA patients. Stimulation of THP-1 cells with PBMC-DNA resulted in increased expression of inflammasome genes, especially the DNA sensorsAIM2andIFI16. At early time points, PBMC-DNA stimulated THP-1 showed significantly increased apoptosis-associated speck-like protein with a CARD (ASC) and Pro-Interleukin-1β protein levels compared to untreated or only LPS-primed cells, resulting in the formation of significantly more ASC specks after 24 h, a sign of inflammasome activation. We conclude from our data that cfDNA of AAA patients triggers a proinflammatory response in macrophages by activating the AIM2 inflammasome and thus could be a driving force for the chronic inflammation observed in these patients.
AbstractEven though non-invasive prediction of endometriosis may seem technically feasible using sophisticated machine learning algorithms, a standard clinical use case for non-surgical diagnosis of endometriosis has not yet been established. In the present paper, we assess the potential of the inflammatory serum markers hepcidin, soluble urokinase-type plasminogen activator receptor (suPar), and interleukin-6 (IL-6) in a cohort of 87 patients. Hereby, 59 patients were histologically diagnosed with endometriosis, whereas other 28 patients served as our non-endometriosis control group. An initial exploratory univariate statistical analysis (Mann-Whitney test) revealed the diagnostic potential of different serum levels of suPar (p= 0.024) and IL-6 (p< 0.001) between both groups; the formation of a distinct training data set (n= 77) subsequently allowed to train a supervised machine learning analysis (tree classifier) employing serum levels of suPar, hepcidin, and IL-6 as predictor variables. Based on an internal 5-fold cross validation, the classifier performance was initially assessed using standard metrics such as sensitivity, positive predictive value, and AUROC curve. Additionally, the algorithm was tested on an external validation (holdout) data set (n= 10), showing sufficient overall accuracy of 80% without tendencies of overfitting. In conclusion, our data demonstrates the diagnostic potential of IL-6 and suPar as pro-inflammatory serum biomarkers in endometriosis. Using a decision tree-based supervised learning approach, we additionally present a straight-forward way of a potential clinical employment, aiming at less invasive (non-surgical) diagnosis.
AbstractIn this study, polypyrrole/carbon black (PPy/C) filler with different amounts (5, 10, 15, and 20 wt%) was immobilized in a polymer blend consisting of chitosan/polyethylene glycol (CS/PEG) to produce conductive and dye adsorbent films. The study employed various distinctive techniques, including X-ray diffraction, Fourier transform infrared, and high-resolution scanning electron microscope, indicating that composites have high complexity and good interaction. Through the implementation of the UV-Vis technique, it has been observed that the reflectance of composites experiences enhancement with an increase in PPy/C content. The discussion covers the optical constants, such as the composites’ refractive index and optical conductivity. Notably, the uniform dispersion of PPy/C has caused a significant rise in the electrical conductivity of the pristine blend from 1.182 × 10−8(Ω.cm)−1to 1.42 × 10−5(Ω.cm)−1when 15% PPy/C was added. This increased conductivity is attributable to correlated barrier-hopping mechanisms. The effects of increasing PPy/C quantity, contact time (0–260 min), initial MO dye concentration (20–120 mg/L), adsorbent film dosage (0.1, 0.25, 0.5, 0.75, and 1 g/L), and the initial pH (4–10) were examined. Incorporating PPy/C up to 10% improved the removal effectiveness of the composite film. The 10% PPy/C film exhibited the maximum removal effectiveness relative to other films. Langmuir showed better conventionality than the Freundlich isotherm model with R2of 0.999. The maximal adsorption capacity observed in monolayer adsorption was determined to be 217 mg/g. The adsorption of MO by the 10% PPy/C film is a chemisorption process, according to the parameters of the kinetic studies. (CS/PEG)- (PPy/C) films could be assigned to the synergistic dye adsorption effect of PPy/C filler and CS/PEG polymer-making material, ensuring excellent adsorption efficiency. Because of these appealing characteristics, PPy/C has the potential to be an environmentally friendly adsorbent in the treatment of dye wastewater.
AbstractHeavy metals in wastewater represent a main source of environmental contamination for the ecosystem and aquatic system. Herein, the in situ polymerization method was used to prepare a novel nanocomposite polyaniline/muscovite (PANI/Msc) using ammonium persulphate as an oxidizing agent and HCl as a catalyst. The combination of muscovite with polyaniline (PANI) creates a hybrid material that leverages the strengths of both components. PANI/Msc nanocomposite was characterized using XRD, TEM, FT-IR, SEM, and surface area analyzer. Crystalline size of the prepared nanocomposite found in the range 15.6 – 45 nm , while its surface area was 208.6 m2/g. The resulting nanocomposite was used for Cd2+and Pb2+adsorption from their solution. Up to 75.6 and 72.6% of Cd2+and Pb2+, respectively, were removed in the optimized conditions of metal concentration 75 ppm, pH 6 and 7 for Pb2+and Cd2+, adsorbent dose 0.1 g, 25 °C solution temperature, and 60 min contact time. Kinetic and adsorption studies clearly demonstrated that the results of the adsorption process followed the pseudo-second order (qe32.8 and 33.1 mg g−1) and Langmuir models (Q036.1 and 61 mg g−1) for Cd2+and Pb2+, respectively. The thermodynamic indicated favorable, spontaneous and exothermic process. Electrostatic interaction and ion exchange mechanisms were responsible for the adsorption of Cd2+and Pb2+by PANI/Msc as demonstrated by FTIR spectroscopy and pH studies. This study ended with the cost- effective preparation of PANI/Msc nanocomposite that offers a promising solution for the removal of heavy metals from contaminated water source. In addition, the capability study regarding Pb2+and Cd2+ion adsorption over the PANI/Msc nanocomposite clearly revealed that our method is suitable for large- scale application.
AbstractAlternate bearing (AB) is a major challenge for citrus orchards. Increasing yield in one season (On year) leads to more seeds (fruits) as a supplier of gibberellins, which delay harvesting with low fruit quality and also decreases flowering and fruiting in the next season (Off year). So, the aim of this study is improving Balady mandarin fruit quality as well as accelerating fruit harvesting during the On year via foliar nourishments with potassium citrate (KC) or nitrate (KN) at 0.5% incorporated with either methionine (M) at 0.2% or sulphur (S) at 0.3%, twice two months before harvest (at flower bud induction time). The results indicated that, during On year, all treatments accelerate harvesting date, improve fruit weight, yield, fruit quality with a highly significant effect for KC + M treatment compared to the control. Moreover, this treatment increased fruit yield by 20.72% and 33.74%, for the first and the second On years, respectively. The most promising effect for KC + M is decreasing gibberellins levels during December (flower bud induction) in On year by 7& 19.4% and during January (before flowering) in Off year by 19.4% and 17.44%. Moreover, it increased both salicylic acid and auxin in the following Off year (before flowering) by 17.44%, 42.9 and 40%, respectively. This findings led to increase fruit number by 272.64% and 267.94%, and fruit yield by 251.3% and 289.65% for the following two off-year as well as decreasing AB by 61.7% and 61.67%. This study highlights the efficiency role of KC as a key for improving fruit quality during On year where heavy fruit load, as well as M application for overcoming AB as anti-gibberellins agent via accelerating harvesting in On year and enhances flowering in the following Off year via hormonal control.
AbstractThe reservoir compartment is a major uncertainty at South Abu El Naga gas field, onshore Nile Delta, Egypt. The objective of this study is to detect Abu Madi gas sand reservoir using different pre-stack inversion techniques such as AVO reflectivity attributes, impedance methods, and lambda-mu-rho (LMR) analysis. The Messinian sandstone gas reservoir at the study area was effectively characterized using these three techniques. Well logs, 2D partial angle stack, and full angle stack seismic sections are the available dataset used to derive several seismic pre-stack inversion attributes. The results of these attributes show that the gas sand bodies are clearly separated from shale and detect the gas channel lateral edges from the cutting mud filled channel. These findings determine the utility of integrating AVO reflectivity attributes and impedance methods in enhancing geophysical interpretation, reducing uncertainty, aiding exploration and support more accurate compartment delineation in data-limited settings and provide a convenient workflow applicable to other areas facing similar exploration and challenges.
AbstractMetal–organic frameworks (MOFs) have recently garnered attention as promising candidates for the effective removal of sulfur-containing compounds from liquid fuels. In this study, the potential of employing Al-MIL-53 as an adsorbent for liquid fuel desulfurization is demonstrated. Material analysis through SEM, XRD, and FTIR studies was conducted. Equilibrium between in the solution and on the adsorbent surface was successfully achieved within 1 h. Optimal operational parameters for 99% Sulfur removal were identified as a 60-min adsorption time, 50 ppm initial thiophene concentration, and 2 g adsorbent dosage. The equilibrium adsorption data is adequately represented by Freundlich isotherm (R2= 0.97). The adsorption kinetics of DBT by Al-MOF followed pseudo first-order model (R2= 0.99). The equilibrium (qm) of the prepared Al-MOF = 11 (mg/g).
AbstractThis paper aims to evaluate the bond performance of basalt FRP bars under severe conditions such as salts, alkaline, and water. Specimens were tested under direct pull-out tensile load. The specimens were exposed to aggressive solutions at an elevated temperature of 60 °C to accelerate the degradation process. The parameters were the concrete compressive strength (CCS) (25, 45, and 60 MPa), the exposure condition (water, salts, and alkaline), and the exposure duration (30, 60, and 90 days). Seventy-two specimens were investigated in terms of bond strength, failure mechanism, and stress-slippage response. The most detrimental environment was the alkaline environment, while the salt environment had an insignificant effect on the bond strength. After 90 days of conditioning in the alkaline solution, the normalized bond strength had reduced by 17.29%, 12.74%, and 8.72% for specimens of concrete compressive strength (CCS) of 25 MPa, 45 MPa, and 60 MPa, respectively.
AbstractThe textile industry exposes people to various harmful and allergenic compounds, with dye wastewater being a significant source of persistent organic pollutants (chemical substances accumulate in living organisms and pose risks to human health and ecosystems) in the environment. This study aimed to measure the activity concentrations of radionuclides, specifically238U,226Ra,232Th, and40K, in different types of textile dyes (disperse, direct, and reactive) and dye wastewater from the cities of Abour and Badr, using gamma spectrometry with a Hyper Pure Germanium detector. Additionally, heavy metal concentrations (Zn, Cd, Fe, Pb, Co, and K) were analyzed through Atomic Absorption Spectroscopy. The results indicated that the average specific activities of238U,226Ra,232Th, and40K were higher in disperse dyes compared to direct and reactive dyes. Potential radiation hazards were evaluated, revealing detectable levels of radioactivity in some textile dyes. This underscores the need for safety protocols and preventive measures for workers in the textile industry and those handling these dyes.
AbstractStability indicating RP-HPLC method was developed and validated for the estimation of finerenone (FIN) in pure and in new tablet dosage form. The proposed approach was applied and validated for determination of (FIN) related substances. Stability studies of (FIN) was carried out using five stress conditions; acid, alkali, oxidation, photodegradation and heat degradation. The chromatographic analysis of (FIN) was based on using mobile phase consist of filtered and degassed mixture of 450mL water, 550mL acetonitrile and 10mL triethylamine with pH adjusted to 7. Phenomenex (C18, 4.6 × 250 mm, 5 μm) column was used with 0.8 mL/min flow rate and 40 °C column temperature. The UV detection was set at 252 nm with injection volume (10µL). The (FIN) retention time was 4.437 ± 0.05 min. The proposed technique was validated according to ICH guidelines with good linearity in ranges (8–30 µg/mL) for assay of (FIN) and (0.2–1.4 µg/mL) for determination of (FIN) unspecified impurities. The found mean percentage recoveries were 99.74% for (FIN) assay and 99.11% for (FIN) related substance determination which indicate good trueness. The developed approach was successfully applied for the determination of (FIN) in Nexifinerenone®film coated tablet dosage form. Good agreement was established when assay results using the validated RP-HPLC method were compared statistically to those obtained using the reported method. For the greenness assessment Complex GAPI, Complex MoGAPI and AGREE methods were applied.
AbstractHigh-power, short-duration (HP-SD) ablation is a well-established radiofrequency (RF) ablation protocol in cardiac electrophysiology. Recently, very high-power, short-duration (vHP-SD) ablation has emerged as an alternative. This study compares lesion metrics between vHP-SD and HP-SD ablation protocols using the latest irrigated RF catheter with temperature-based power regulation, considering the impact of contact force (CF). RF ablations were performed in a porcine ex vivo model using myocardial preparations in a circulating saline bath. Three protocols were applied: vHP-SD (90 W for 4s), HP-SD-4 (50 W for 4s) and HP-SD-15 (50 W for 15s). A total of 360 lesions in 12 hearts were analyzed (vHP-SD: 120; HP-SD-4: 120, HP-SD-15: 120). The HP-SD-4 protocol produced the lowest mean lesion depth (2.42 ± 0.61 mm vs. 3.16 ± 0.41 mm vs. 4.49 ± 0.66 mm,p< 0.001), mean maximum lesion diameter (6.02 ± 1.00 mm vs. 7.34 ± 0.92 mm vs. 9.13 ± 1.59 mm), and mean lesion volume (52.0 ± 22.5 mm³ vs. 96.4 ± 28.8 mm³ vs. 211.4 ± 95.3 mm³,p< 0.001), followed by the vHP-SD protocol. In contrast, the HP-SD-15 protocol resulted in the highest values across all three parameters. Lesion depth, maximum lesion diameter, and lesion volume increased significantly with higher contact force (p< 0.001,p= 0.002, andp= 0.003, respectively). However, the absolute changes in these lesion dimensions were relatively small compared to those observed with power-controlled RF catheters, likely due to the effect of temperature-based power regulation.
AbstractAnimal research show that a novel exploration task performed shortly before a learning episode can strengthen hippocampal memory consolidation through behavioural tagging mechanisms. The aim of the present study was to conceptually translate behavioural tagging results to humans using a novel exploration task in virtual reality. Mimicking conditions for animal research, sixty participants underwent a context conditioning task in virtual reality to create a hippocampal-dependent fear memory. Twenty-four hours later, half of the participants performed a novel exploration task in virtual reality shortly before extinction learning the next day, and the other half performed a visual control task. Twenty-four hours after extinction learning, remaining fear responses were evaluated by a reinstatement procedure. Results showed that participants acquired context conditioning, but no effect of the novel exploration procedure on fear responses during reinstatement could be noted. Thus, the study did not conceptually translate the rodent results to humans; possible reasons for this, as well as future directions, are discussed.
AbstractThe complexity and diversity of bioscientific research laboratories, creates significant challenges for automation. Their varying workflows, personnel, and instruments, often hinder smaller research laboratories to benefit from automated processes, as existing systems seem unsuitable due to low flexibility. Therefore, we developed a versatile robotic system designed to automate a broad range of bioscience laboratory processes. Central to our system and novel, compared to all other kinds of laboratory automation concepts, is a multifunctional end effector, inspired by the Swiss-army-knife, capable of executing multiple tasks, including an operating finger, a camera system, a gripper, and a pipette. This end effector is mounted on a 6-axis robotic arm, supported by a mobile base, enabling easy transport across different bioanalytical laboratory environments. Utilizing windows manipulating scripting routines, allows the automation of diverse software programs including software-based laboratory devices. We demonstrate the capabilities of the Laboratory Automation Robotic System (LARS) by automating the pH buffer adjustments, showcasing its potential to improve efficiency and reproducibility in bioscience research. The resulting prototype allows the integration of any laboratory instrument into a desired automation routine without limitations concerning device interfaces, while using a highly flexible multifunctional end-effector as a replacement of the human hand and eye.
AbstractReinforced Concrete (RC) slabs are widely used in structural applications due to their ability to withstand heavy loads. However, under impact loading conditions such as falling objects or debris, their brittle nature makes them prone to cracking and damage. To address this, Expanded Polystyrene (EPS) has been explored as an energy-absorbing material capable of reducing the severity of impact forces. Traditionally used as an insulating material, EPS possesses favorable mechanical properties—lightweight, high deformability, and cushioning capacity—that have led to its application in civil infrastructure as geofoam and lightweight fill. Despite its growing use, the potential of EPS as a protective surface layer for RC slabs under impact loading remains underexplored. This study investigates the effectiveness of a surface-mounted EPS layer in reducing the impact response of RC slabs. Six full-scale RC slab specimens were tested under vertical impact from a 90 kg steel ball dropped from a height of 1 m. Half of the specimens were cast as control slabs, while the other half included a 5 cm thick EPS layer atop the concrete. Accelerometers were used to capture dynamic responses, and a detailed finite element model was developed in ABAQUS, incorporating experimentally measured material properties and contact interaction at the EPS–concrete interface. The model accounted for separation and frictional behavior between the two materials. Experimental and numerical results showed that the EPS layer significantly reduced the maximum acceleration, displacement, and energy dissipation within the concrete slab compared to the control specimens. While control slabs absorbed more energy through cracking and damage, the EPS slabs exhibited reduced structural deterioration, indicating more efficient impact mitigation. These findings highlight the potential of EPS as a cost-effective solution to enhance the impact resistance of RC slabs. Future work will focus on parametric studies involving EPS thickness, EPS density, steel reinforcement ratio, intensity of impact load and concrete material properties to generalize the results for broader applications.
AbstractScarring and its long-term sequelae, contribute significantly to morbidity following burn injuries. Factors associated with less favourable scar outcomes include the depth of burn, younger age, pigmented skin types and prolonged healing times. The aim of primary burn surgery is to debride non-viable tissue, to enable healing. However, international consensus regarding the optimal timing for debridement and grafting in pediatric patients with burns is lacking. Delayed wound healing is thought to increase the risk of poor scar quality, however, the evidence for this is weak with few studies investigating long-term outcomes in pediatric patients. The aim of this study, therefore, was to investigate the effect of patient and treatment factors on scar quality, one year after skin grafting in pediatric patients with burns. Patient factors included age, skin type, and site of burn, while treatment factors included timing of surgery, type of surgery, and healing times. Pediatric patients (age < 18 years) presenting to a National Burn Unit from 2011 until 2020, inclusive were considered for inclusion in the study. Burn injuries between 1% and 14.9% total body surface area (TBSA) and who required skin grafting for the primary treatment of their burn, were included. Patients who failed to attend their 12-month follow-up visit were excluded. Standardised clinical photographs were assessed using a modified version of the Patient and Observer Scar Assessment Scale, version 2.0 (POSAS). Thirty children (median age 3.9 years) were included. Factors with an independent effect on higher (worse) POSAS scores were younger age at the time of injury (p< 0.001), body site of the trunk (p< 0.002), or the lower extremity (p< 0.001) and a longer duration of healing time after skin grafting (p= 0.003). The duration of time between injury and surgery was not an independent factor for POSAS scores (p= 0.56). We had insufficient numbers to discriminate differences in scar quality for different graft types; meshed versus non-meshed. In this study, we found that long-term scar outcomes in pediatric burn patients after skin grafting were worse for those injured at a younger age, with burns on the trunk or lower extremity, or with prolonged healing time after grafting. The robustness of this conclusion is limited by the small sample size of the study cohort and by our use of photographic scar assessment .
AbstractComputed Tomography (CT)-derived body composition parameters of cardiac adipose tissue (CAT), as well as abdominal adipose and muscle tissue are surrogates for the patient’s clinical condition and have prognostic implications. However, associations between the compositions of these diverse tissue compartments remain poorly investigated. This study aimed to investigate the associations between CT-derived parameters of CAT and abdominal adipose and muscle tissues. Retrospective analysis of CT scans from 842 patients was conducted, with measurements of CAT taken at the aortic valve level and abdominal tissues assessed at the L3/L4 intervertebral disc space. Area and density were calculated for each tissue compartment using single-slice images. Strong positive correlations were found between CAT area and visceral adipose tissue (VAT) area (R= .755,P< .001), as well as moderate correlations between CAT density and VAT density (R= .521,P< .001). Additionally, skeletal muscle (SM) area exhibited modest positive correlations with VAT area (R= .370,P< .001), CAT area (R= .300,P< .001), and SM density (R= .356,P< .001). No significant differences were observed between genders in the correlation strengths of these associations. These findings indicate a systematic pattern of body composition alterations, advocating for the inclusion of comprehensive body composition analysis in future studies and emphasizing the need for a deeper understanding of the underlying systemic processes influencing body composition.
AbstractDental implant-associated infections increase the risk of implant failure, presenting significant challenges in modern dentistry. The host-microbe interaction plays a crucial role in the development of implant-associated infections. To gain a deeper understanding of the underlying mechanisms, numerous studies have been conducted using in vitro co-culture models of bacteria and human cells or in situ samples. Due to the complexity of the images generated throughout these studies, however, the analysis by means of classical image processing techniques is challenging. This study proposes a workflow—based on two custom Cellpose models—that, for the first time, allows the analysis of microbial surface coverage in microscopy images of fluorescent-stained and co-localized microorganisms and human cells with substantial background signals. The first Cellpose model demonstrated its efficacy in the analysis of individual bacteria within images derived from an 3D implant-tissue-oral biofilm in vitro co-culture model. In combination with the second custom model, which was trained to recognize microcolonies, images obtained from an in situ study could also be automatically segmented. The model’s segmentation accuracy could be further enhanced by acquiring additional training images and improving image quality, making the proposed workflow now valuable for a range of dental implant-related and other co-culture images.
AbstractDocetaxel resistance, particularly post-androgen-receptor targeted therapy (ART), undermines its clinical utility in metastatic castration-resistant prostate cancer (mCRPC). This study explores the impact of docetaxel plus carboplatin (DC) chemotherapy on serum testosterone levels in metastatic docetaxel-resistant prostate cancer (mDRPC) patients. 123 mDRPC patients were categorized into three groups: (1) no previous ART (n= 65), (2) previous ART with serum free testosterone (FT) > detection limit (DL) at baseline (n= 31), and (3) previous ART with FT < DL at baseline (n= 27). Salvage DC chemotherapy led to significant reductions in FT and total testosterone (TT) levels in groups 1 and 2 (p< 0.05). Group 1 saw FT decrease from 0.85 pg/mL to below the DL (< 0.18 pg/mL) with 54.3% achieving complete reduction (CR); group 2 showed FT decrease from 0.28 pg/mL to below the DL with 67.7% achieving CR; group 3 had baseline FT values already below the DL with 96.3% maintaining this level. TT reductions to below the DL occurred in all groups. Low FT was an independent predictor for better PFS and for improved OS in groups 1 and 2. Our data indicate that adding carboplatin may improve the therapeutic effects of docetaxel in a castration-dependent setting.
AbstractThe pulsed nature of laser-driven ion sources and their relative large emission angles result in the production of secondary, undesired, pulsed neutron (and photon) radiation. Conventional neutron monitors struggle to accurately measure in such environments, yet characterizing these fields is crucial for applications like hadron therapy. Parasitic neutron dose measurements were performed at the Petawatt beam of the Dresden Laser Acceleration Source (DRACO) employing laser energies from 4.5 to 18 J. An active extended-range neutron REM counter specifically developed for pulsed neutron fields, the LUPIN-II, was employed, as well as a passive extended-range neutron REM counter, the Passive LINUS. Neutron doses were recorded on a single-bunch level with values up to about 260 nSv per proton bunch characterized by a proton cutoff energy of about 60 MeV at about 2 m from the DRACO vacuum chamber, confirming the expected pulsed nature of the neutron field. Results of passive measurements were compared to the LUPIN-II results, integrated over the same period, and showed a reasonable agreement, confirming the presence of pulsed neutron radiation in the proximity of the DRACO ion source. These results demonstrate for the first time that this kind of radiation can be monitored, in terms of H*(10) on a single-shot basis by using the LUPIN-II neutron REM counter.
AbstractCardiovascular magnetic resonance (CMR) evaluation of valvular heart disease is an important diagnostic tool when echocardiography is inconclusive. Phase contrast flow quantification is usually performed during breath hold (BH), which can be challenging in patients suffering from dyspnea and heart failure. The purpose of the present study is to compare a free-breathing (FB) with the conventional BH approach for flow quantification in the aortic, pulmonary and tricuspid valves in 20 healthy subjects (HS) and 25 patients with tricuspid regurgitation (TR). Aortic (AoFF) and pulmonary forward flow volume (PuFF), and tricuspid inflow volume (TrIF) were evaluated. Mean, standard deviation (SD) and limits of agreement (LoA) were calculated. There were good agreements between phase contrast flow volumes obtained by FB and BH approach. Mean difference ± SD / LoA for AoFF during BH versus FB were 1 ± 6 / -10 to 13 ml. The corresponding for PuFF were 1 ± 6 / -11 to 13 ml, and for TrIF − 3 ± 6 / -15 to 9 ml, respectively. Thus, free-breathing CMR flow acquisition can be an important alternative in the assessment of stroke volume, valvular regurgitant volume and be useful in all patients with difficulties to hold their breath.
AbstractLaboratory automation has transformed bioanalytical research, yet smaller research laboratories face challenges in adopting such technologies due to limited resources, time, and technical expertise, while already facing complex bioanalytical methods. To address these barriers, we developed a robotic-arm-based camera detection system featuring two software applications designed to simplify laboratory automation. Both applications use fiducial markers (Augmented Reality University of Cordoba (ArUco)), for object detection. The first application creates a 3D digital model of the robot’s environment using ArUco markers and a Python-based Open Computer Vision (OpenCV) simulated stereo vision setup, enabling automated computer-aided design (CAD) in FreeCAD. This facilitates safe and efficient robot arm navigation. The second application integrates a deep learning neural network for automated digital display recognition, achieving an in-house error rate of 1.69%, comparable to manual readings. By leveraging low-cost hardware and open-source software available on GitHub, the system is accessible to smaller research facilities, reducing programming complexity and enabling broader adoption of laboratory automation in bioanalytical workflows. This work demonstrates an affordable and effective solution for integrating robotic arms into scientific workflows, enhancing reproducibility and efficiency in bioanalytical research.
AbstractPotential properties of astaxanthin include immunomodulation, antioxidant, and anti-inflammatory effects. In diabetic rats, we examined the potential impacts and underlying mechanisms of astaxanthin on hippocampal DNA, cognition, and glycemic status. Rats were divided into five equal groups: non-diabetic, and diabetic (non-treated, metformin treated, astaxanthin treated, and treated with a combination of metformin and astaxanthin). Both spatial and non-spatial memory and learning were assessed. IL-6, malondialdehyde, total antioxidant capacity, lipid profile, and glycemic status were assessed. Phosphorylated tau expression level was measured, and H&E section analysis was used to evaluate the hippocampal tissue. DNA fragmentation, intact DNA, and hippocampal RNA were evaluated. Induction of diabetes led to a reduction in cognitive abilities along with significant hyperglycemia, dyslipidemia, oxidative stress, hyperphosphorylation of tau, and DNA fragmentation. Astaxanthin as monotherapy or in combination with metformin improved cognitive functions with reduction of hyperglycemia, dyslipidemia, oxidative stress, hyperphosphorylation of tau, and DNA fragmentation.
AbstractBiogeochemical soil processes are closely linked to the structure of soil. In particular, nutrient transport depends on diffusivity and permeability within the soil’s pore network. A deeper understanding of the relationship between microscopic soil structure and such effective macroscopic properties can be obtained by tomographic imaging combined with a quantitative analysis of soil morphology and numerical simulations of effective macroscopic properties. In a previous work it has been shown that different parametric regression formulas can be used to predict these relations for finely sieved soils of loam and sand. In the present paper, we validate these formulas and further extend their applicability to structured soils. In particular, 3D CT data of a total of six samples, consisting of three loam and three sand samples, are used as the basis for an extensive structural analysis. As expected, the performance of most regression formulas can be improved by specifically adjusting their parameters for the considered soil structures. However, it turns out that some regression formulas based on, e.g., tortuosity which were fitted for finely sieved soils still reliably predict diffusion for structured soils without adjusting their parameters. For additional validation and improvement of the considered regression formulas, artificially generated soil structures can be utilized. Therefore, a method for the generation of such structures via samples drawn from a parametric stochastic 3D microstructure model is outlined which may serve as a basis for further work.
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AbstractMany pyridopyrimidine moieties linked to the coumarin ring were synthesized by the reaction of malononitrile with 7-hydroxy-4-methyl-2-oxo-2 H-chromene-8-carbaldehyde(2)directly in the presence of ammonium acetate and different ketones and studied the effect of other basic catalysis, ratio of reactants and the effect of the solvent. The newly synthesized compounds were evaluated for their cytotoxic activity against four cell lines namely HepG2, WI-38, VERO, and MCF-7. The cytotoxic activity showed that compounds8,9,10, and7have the highest activity against the studied cell lines. Focusing on the binding affinity and interactions between the five synthesized derivatives with the highest anticancer activity and specific amino acids of4HJOresidues over the molecular docking analysis. Derivative10recorded the highest energy score with good RMSD compared to the rest of the derivatives.
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AbstractThis study evaluated the functional relevance of relative ellipsoid zone reflectivity (rEZR) on spectral-domain optical coherence tomography as a structural biomarker for retinal integrity, focusing on its association with retinal function. Participants with age-related macular degeneration (AMD) and controls from the MACUSTAR study underwent functional testing, including mesopic fundus-controlled perimetry, best-corrected visual acuity, low-luminance visual acuity, low-luminance deficit, Moorfields Acuity Test, and Pelli-Robson contrast sensitivity, along with spectral-domain optical coherence tomography imaging. Structural and functional data were analyzed globally and spatially aligned for topographic analysis. Linear-mixed effects models, adjusted for age, sex, and eccentricity of the rEZR, assessed associations between rEZR and functional metrics. A total of 275 eyes (early AMD, n = 34; intermediate AMD, n = 152; late AMD, n = 36; controls, n = 53) from 275 participants (mean ± standard deviation age: 71.1 ± 7.2 years; 63.3% female) were included. In global analyses, rEZR was associated with the mean average threshold in mesopic fundus-controlled perimetry (coefficient estimate 0.0492, 95% confidence interval 0.0190–0.0794, p = 0.0015), low-luminance visual acuity (coefficient estimate − 0.0015, 95% confidence interval − 0.0026 to − 0.0004, p = 0.0092), Moorfields Acuity Test (coefficient estimate 0.0092, 95% confidence interval − 0.0022 to − 0.0001, p = 0.0285), and Pelli-Robson contrast sensitivity (coefficient estimate 0.0030, 95% confidence interval 0.0015–0.0045, p = 0.0001). Topographic analysis further revealed an association of rEZR with mesopic retinal sensitivity (coefficient estimate 0.0065, 95% confidence interval 0.0026–0.0104, p < 0.0001). Higher outer retinal reflectivity is linked to better retinal function in AMD and controls, supporting its potential as a biomarker for retinal integrity and function.
AbstractThe root knot nematodesMeloidogyne incognitaare the most serious threats affecting eggplant,Solanum melongenaL. Chemical nematicides are commonly used against plant-parasitic nematodes, but due to their negative impact on health and the environment, safe and environmentally friendly alternatives have become increasingly important. Biological control using rhizospheric bacteria metabolites, and plant substances have, emerged as important alternatives to the use of agrochemicals. Recently, nanotechnology has revolutionized nematode management and its effectiveness in biological control. The aim of this study is to evaluate the efficiency ofBacillus cereusNem 212 supernatant and garlic essential oil in their regular and nanoscale forms againstM. incognitainfecting eggplants CV. Baladi and investigate their impact on plant growth parameters under field conditions. All nano formulations produced higher nematicidal activities compared to their respective original extracts. Garlic oil nano emulsion and garlic oil emulsion were more effective as natural nematicides onM. incognita, and in enhancing eggplant growth parameters, followed by bio- silver nanoparticles synthesized byB. cereusNem 212 filtrate. These formulations are promising and environmentally friendly alternatives for controlling root knot nematode and have the potential to reduce reliance on hazardous agrochemicals. In addition, these techniques increase vegetative plant growth and yield production.
AbstractCocopeat is among the most frequently utilized substrates in soilless farming. Nonetheless, the extraction of Cocopeat generates a detrimental carbon footprint, highlighting the necessity for alternative, sustainable substrate options. To tackle this issue, we examined the effects of substituting Cocopeat with a blend of various Rice straw, Sawdust, and compost on cucumber growth and yield over two growing seasons, 2021–2022 and 2022–2023. The treatments included Cocopeat 100% (control), sawdust 100%, rice straw 100%, compost 100%, combinations of Cocopeat and sawdust (1:1, v/v), combinations of Cocopeat and sawdust (3:1, v/v), combinations of Cocopeat and rice straw (1:1, v/v), combinations of Cocopeat and rice straw (3:1, v/v), combinations of Cocopeat and compost (1:1, v/v), and combinations of Cocopeat and compost (3:1, v/v). The highest yield was recorded with rice straw at 100.55 ton ha− 1, followed by the Coco 50%: Compost 50% treatment yielding 74.32 ton ha-1 and 69.26 ton ha− 1, respectively, while the lowest yield was noted for sawdust at 22.23 ton ha− 1. Across both growth seasons, rice straw achieved the highest irrigation water productivity (IWP) of 51.56 and 51.91 kg m− 3, respectively, followed by Coco 50%: Rice straw 50% at 38.08 and 38.37 kg m− 3, whereas sawdust resulted in the lowest IWPs of 6.93 and 11.48 kg m− 3. In both growing seasons, the rice straw showed the greatest rate of photosynthesis, with readings of 23.34 µmol m–2s–1and 22.14 µmol m–2s–1, respectively. Conversely, the lowest photosynthesis rates during both growing seasons were observed with the Coco 75%: Compost 25% treatment, at 3.23 µmol m–2s–1and 3.03 µmol m–2s–1, respectively. The treated rice straw substrate media ranked as the most profitable and resilient option in terms of net present value (NPV) and benefit-cost (B/C) ratio metrics, followed closely by the compost treatment. It seems that treated rice straw-based media is a promising substrate in soilless culture systems as a viable alternative substrate for cucumber cultivation instead of Cocopeat substrate.
AbstractInhibition of Smoothened (SMO), a key protein in the Hedgehog signaling pathway, is effective for locally advanced basal cell carcinoma (BCC), but is not yet used for sebaceous carcinoma (SEB) or squamous cell carcinoma (SCC). This study quantified SMO expression and its relationship to proliferative activity in non-nodular periocular BCC, SEB and SCC. Tumor samples from 47 patients (17 BCC, 15 SCC, and 15 SEB) were immunostained and analyzed digitally to assess SMO optical density and Ki67 hot-spot index. SMO expression was significantly higher in all tumor types than in surrounding stroma, with no inter-tumor differences. SMO correlated with mitotic count in BCC but not in SCC or SEB, whereas higher SMO consistently paralleled a higher Ki67 index across all three carcinomas. These findings indicate that SMO expression and proliferative activity are closely linked and suggest that Hedgehog inhibitors, proven in BCC, warrant clinical evaluation as adjuvant or neoadjuvant therapy for periocular SEB and SCC.
AbstractThis research uses the third edition of the Gaia Data Release (DR3) to re-investigate the open star cluster NGC 2158. We employed the pyUPMASK Python package and HDBSCAN algorithms to identify the cluster member stars. The key focus of this investigation is our new method of evaluating membership probability based on the radius of each shell in the studied cluster, rather than applying a single probability value to the entire cluster. We calculated all astrophysical parameters of NGC 2158-including center, cluster radius, radial density distribution, color-magnitude diagram, distance, age, and reddening-using the photometric and astrometric data from Gaia DR3. The cluster’s relaxation time, total mass, luminosity, and mass functions are computed. The components of the proper motions ($$\mu$$$$_{\alpha }$$cos$$\delta$$,$$\mu$$$$_{\delta }$$), and the trigonometric parallax ($$\varpi$$) are found to be$$-$$0.196$$\pm$$0.03 ,$$-$$1.984$$\pm$$0.21 mas/yr and 0.21$$\pm$$0.044 mas, respectively. According to the King model and pyUPMASK membership, we obtained 3067$$\pm$$69.84 stars with a total mass of 3216.4$$\pm$$59.50$$M_{\odot }$$. Using the PARSEC stellar isochrones fit, the mean cluster age and its relaxation time are 1.95$$\pm$$0.28 Gyr and 89.0$$\pm$$12.54 Myr, respectively. The cluster distance modulus and reddening are estimated to be 12.86$$\pm$$0.080 , and 0.66$$\pm$$0.040 mag, resulting in a distance of 3.733$$\pm$$0.36 kpc. The mass function MF for the cluster under study has been constructed using a step function with two power lows,$$\alpha _1$$and$$\alpha _2$$, rather than the single power low suggested by Salpeter. In this cluster, the$$\alpha _1$$and$$\alpha _2$$are found to be$$-$$3.2$$\pm$$0.3 and 2.52$$\pm$$0.1 , respectively. The Gaia archive contains 17 stars flagged for variability, detecting 11 stars classified as eclipsing binaries. Additionally, we identified 62 member stars as blue stragglers. We utilized the galpy Python package to obtain the cluster’s kinematics and the Galactic orbital parameters using 126 stars which have radial velocities data in Gaia DR3 archive, with average value 26.1$$\pm$$2.3 km/s.
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AbstractHuman observers perceive natural and man-made environments differently, a distinction measurable through image statistics. However, limited evidence exists on how architectural style influences these statistics and, consequently, visual perception. Understanding this relationship is essential, as architectural design shapes both our visual and psychological experiences of built environments. The amplitude spectrum slope quantifies sharpness and detail in an image, with values closer to 1 typically found in photographs of natural scenes. Image entropy, reflecting unpredictability, also plays a role in visual attention—images with higher entropy are more likely to capture interest. In this study, we analyzed photographs of buildings designed by Antoni Gaudí, renowned for his nature-inspired architecture. Our findings reveal that Gaudí’s buildings display an amplitude spectrum slope more similar to that of natural scenes than contemporary structures from the same area, alongside higher image entropy. Effect size measures indicated that the observed differences in slope constant and entropy between images of Gaudí buildings and contemporary buildings were medium and large in magnitude. The presence of trees in front of contemporary buildings shifts their image statistics toward naturalistic values. These results suggest that incorporating naturalistic design elements into architecture can alter image statistics, potentially influencing perception and aesthetic experience. In contemporary architecture, where minimalist and geometric styles are prevalent, these insights highlight the potential benefits of reintroducing complexity and naturalistic aesthetics to create more engaging and psychologically restorative built environments.
AbstractCystic pancreatic lesions (CPL) pose a diagnostic challenge due to their morphological diversity and malignant potential. Given the limited study data, transabdominal ultrasound (TAUS) is currently not established for either primary diagnostics or CPL monitoring. This study compared the diagnostic accuracy of TAUS in the assessment of CPL to that of the reference method, endoscopic ultrasound (EUS), to identify patient subgroups suitable for TAUS monitoring. In a monocentric, retrospective analysis, patients with CPL who underwent EUS and TAUS within six months from 01/2016 to 06/2022 were included. Univariate and multiple logistic regression analyses were used to identify determinants for the detection of CPL via TAUS. Cross-method morphological assessments were analysed, and a patient-specific algorithm for selecting the appropriate monitoring method was developed. Among 105 patients, CPL were detected by both EUS and TAUS in 90 patients (86%). Patients with “TAUS negative” CPL (n= 15) exhibited greater body mass indices (BMI,p= 0.002) and smaller CPL diameters (p= 0.043). The final multivariate model (BMI, age, CPL diameter) yielded an 85% accuracy in predicting CPL detectability by TAUS. TAUS could be a cost-effective and patient-friendly imaging method for the surveillance of CPL in selected patients.
AbstractIn this work, an azo dye ligand of 2,6-dichloroaniline with nitroxoline (CPAQ), and its Zn(II), Cu(II), Cd(II), Ni(II) and Co(II) complexes have been synthesized. The structures of the synthesized compounds have been elucidated applying analytical and spectral tools. According to these results, all complexes proved to have a tetrahedral structure, except Ni(II) complex, which has an octahedral geometry. Analytical results also inferred the formation of Co(II) and Ni(II) complexes in the molar ratio 1M:1L and the remaining complexes in 1M:2L molar ratio. For further insight into the complexes’ geometry, bond lengths, bond angles, and electronic characteristics with respect to the organic ligand were assigned in addition to DFT calculations. HOMO and LOMO calculations show the Co(II) complex is more reactive. The interactions of the target compounds with theMus musculusADA enzyme structure (PDB ID: 1a4m) were estimated by applying molecular docking studies. The inhibitory effect of the synthesized compounds on adenosine deaminase enzyme (ADA) activity was tested in-vitro, showing the Co(II) to be the most active.
AbstractInduction motors (IMs) are vital in industrial applications. Although all motor faults can disrupt its operation significantly, stator turn to turn faults (ITFs) are the most challenging one due to their detection difficulties. This paper introduces an AI-based approach to detect ITFs and assess their severity. A simulation based on an accurate mathematical model of the IM under ITFs is employed to generate the training data. Recognizing that ITFs directly affect the motor’s current balance, complex current unbalance coefficient is identified and used as the key feature for detecting ITFs. Since unbalanced supply voltage (USV) can also disrupt current balance, the AI models are trained to account for USV by incorporating complex voltage unbalance coefficient that helps to distinguish between ITF-induced and voltage-induced imbalances. After feature extraction, the AI models are trained and validated with simulation data. The approach’s effectiveness is further tested using an experimental setup, where measurements from motors under various fault conditions, including USV scenarios, are considered. The results indicate that the gradient boosting model outperforms other ML models in detecting ITFs in IMs and assessing their severity. In the pursuit of achieving highest possible performance, DNN is tested and compared with ML models. The study reveals that DNN demonstrates superior performance in all tested scenarios including USV making DNN the top performer that to be used in the proposed approach. The proposed AI-based approach based on DNN offers high accuracy in fault detection and can effectively distinguish between ITFs and USV-induced anomalies, maintaining low estimation errors and robust performance across different operational conditions.
AbstractLinear repetitive construction projects present unique challenges in optimizing both completion time and cost performance. Traditional scheduling techniques often struggle to effectively address these complexities. This paper aims to enhance project optimization by introducing a metaheuristic-based Time-Cost Trade-off (TCT) framework specifically designed for repetitive project environments. Unlike previous studies that focus solely on single-algorithm applications, this research evaluates two metaheuristic optimization strategies—Genetic Algorithm (GA) and Particle Swarm Optimization (PSO)—within a consistent problem setting. The framework employs both algorithms, which are independently assessed for their effectiveness in tackling the Linear Repetitive Project Time-Cost Trade-off (LRPTCT) problem. The methodology utilizes task decomposition alongside the Line of Balance (LOB) scheduling technique, facilitating a more detailed and adaptable planning process. Each sub-task is systematically evaluated to identify the optimal construction method based on cost-time trade-offs, with scheduling constraints integrated into the fitness functions of both GA and PSO. Results from an in-depth case study reveal significant improvements in project efficiency. Specifically, GA achieved approximately a 3.25% reduction in direct costs, a 20% reduction in indirect costs, and a 7% reduction in total construction costs. In comparison, PSO demonstrated slightly superior cost performance, with a 4% reduction in direct costs and comparable reductions in indirect costs, along with a 20% decrease in total project duration. These findings highlight practical gains in resource utilization and scheduling efficiency. This study presents a structured, comparative analysis of GA and PSO within the LOB-based TCT framework, providing a replicable methodology for optimizing schedules in linear repetitive projects. By bridging the gap between traditional scheduling techniques and advanced optimization algorithms, this research contributes valuable insights for enhancing operational efficiency and informed decision-making in construction project management.
AbstractAcute myocardial infarction (MI), a serious manifestation of ischemic heart disease, remains the culprit for mortality among coronary heart disease patients. Astaxanthin has demonstrated the ability to alleviate inflammation-induced myocardial damage while maintaining a balance between oxidants and antioxidants. This study investigates the cardioprotective potential of astaxanthin (ASX), particularly when encapsulated in nanostructured lipid carriers (NLCs), in isoprenaline (ISO)-induced myocardial infarction in rats. The study involved 48 rats separated into 6 groups. ASX and Nano-ASX (5 mg/kg) were administrated orally for 21 days before MI induction (isoprenaline, 85 mg/kg, subcutaneously). Blood and cardiac tissue samples were taken 24 h following the last isoprenaline injection for biochemical and histopathological investigation. The findings reveal that nano-formulated ASX significantly reduces oxidative stress and cardiac injury markers, including CK-MB, Troponin-I, and LDH. Additionally, it enhances antioxidant enzyme activities (GSH, GPx, and GSH-RD) and decreases inflammatory markers (COX-2 and VEGF). The study further demonstrates that nano-ASX stimulates autophagy by upregulating critical genes such as Beclin-1, ULK1, and LC3B, which are vital for cardiac protection and repair. Histological analysis confirms these biochemical outcomes, showing reduced myocardial damage and inflammation in the nano-ASX-treated groups. This study concludes the potential of ASX nano-formulations as an advanced therapeutic approach for myocardial infarction, leveraging improved bioavailability and targeting oxidative stress, inflammation, and autophagic mechanisms.
AbstractIntestinal epithelial overexpression of the Th17 cell chemoattractant CCL20 is implicated in inflammatory bowel disease and influenced byNOD2mutations in Crohn’s disease. Vitamin D metabolites have been shown to ameliorate inflammatory bowel disease. ConsideringNOD2mutations in Crohn’s disease, we investigated whether Vitamin D deficiency (serum 25-hydroxyvitamin D concentration < 20 ng/mL) increases circulating CCL20 levels in inflammatory bowel disease patients and healthy controls and whether active 1,25-dihydroxyvitamin D (calcitriol) downregulates systemic and intestinal CCL20 expression. In a cross-sectional study, serum concentrations of CCL20, 25-hydroxyvitamin D, and calcitriol were measured in 170NOD2-genotyped Crohn’s disease patients, 80 ulcerative colitis patients, and 60 healthy controls. Additionally, the effect of calcitriol on experimentally induced CCL20 expression was examined using human intestinal epithelial HT-29 cells. Multivariable linear regression analyses revealed that both the diagnosis of inflammatory bowel disease and vitamin D deficiency were independently associated with elevated CCL20 levels. Compared to healthy controls, Crohn’s disease patients and ulcerative colitis patients exhibited significantly higher circulating CCL20 levels. Unlike in Crohn’s disease patients, vitamin D deficiency was associated with higher CCL20 levels in healthy controls and ulcerative colitis patients, whereas the calcitriol/25-hydroxyvitamin D activation ratios were negatively correlated with serum CCL20 levels in healthy controls and ulcerative colitis patients with sufficient serum 25-hydroxyvitamin D status. Furthermore, calcitriol markedly inhibited intestinal epithelial induction of CCL20. In Crohn’s disease patients, cholecalciferol supplementation was associated with lower serum CCL20 levels, which were unaffected byNOD2mutations. These findings suggest that although vitamin D metabolites may downregulate CCL20 expression in healthy controls and ulcerative colitis patients, this regulatory effect appears to be impaired in Crohn’s disease patients.
AbstractThis research explores the use of kraft lignin (KL), derived from pulping black liquor waste, as a supportive medium for Ag3PO4@ZnO (AZ-NC) p-n heterojunction and design a new cost-effective ternary KL-Ag3PO4@ZnO nanocomposite (AZKL). The aim is to improve its photocatalytic efficiency in treating textile wastewater while tackling environmental issues such as chemical stability, charge carrier separation, and the production of secondary waste during the photocatalytic process. The response surface methodology (RSM) analysis shows that AZKL is highly effective catalyst for methylene blue (MB: 10 - 25 mg/L) dye mineralization, achieving a rapid decolorization (> 98.2% within 40 min) under visible light at a near-neutral pH (7.48) with maintained high catalytic activity across four consecutive cycles. This outstanding performance is driven by the synergistic interplay of AZKL-based photocatalysis and advanced oxidation process using 0.03% H2O2co-catalyst. Gas chromatography-mass spectrometry analysis reveals that MB dye degrades stepwise into intermediates such as N, N-dimethyl-p-phenylenediamine, hydroquinone, and formic acid, ultimately mineralizing completely into CO₂ and H₂O. The dominant reactive oxygen species driven this multi-step process are identified as hydroxyl radicals (•OH) and photogenerated holes (h⁺), with H₂O₂ and superoxide radicals (•O₂⁻) playing secondary roles. The data also highlights the multifunctional role of KL support, which enhances charge carrier separation, captures dye molecules, and prevents Zn2+/Ag+ion leaching (less than 0.2 ppm) into the treated water during photocatalysis. This is facilitated by the electron-donating polyphenolic hydroxyl groups on the KL surface, which reduce Ag⁺ to metallic silver and stabilize AZ-NC heterojunction under light irradiation, creating Schottky junctions that improve charge transfer efficiency while reducing secondary contamination risks. A practical case study further illustrates the effectiveness of AZKL in treating real textile effluents, as evidenced by the improved biodegradability of residual organic matter, indicated by changes in chemical/biological oxygen demands (COD/BOD) ratios from 2.62 to 1.47 and inhibition tests against E. coli, meeting wastewater discharge standards. The findings emphasize that the AZKL composite could serve as an effective and adaptable photocatalyst for breaking down organic pollutants and treating intricate wastewater systems.
AbstractDespite extensive research on reinforced concrete (RC) pile caps, the influence of column and pile configuration and dimensions on their shear performance remains unexplored. This study investigates the structural behavior of RC pile caps through experimental and numerical analyses, focusing on how variations in column and pile geometry affect shear capacity. Two pile cap specimens (700 mm long × 300 mm wide) with heights of 250 mm (SB1) and 350 mm (SB2) were tested under shear-dominated conditions. Both were supported by two square piles (200 × 200 mm) and loaded centrally via a square column (200 × 200 mm). The study reports crack patterns, ultimate shear load, load-displacement behavior, elastic stiffness, and energy absorption capacity. A validated 3D finite element model was developed to parametrically analyze rectangular/circular columns and piles with dimensions ranging from 0.2d to d (where d = pile cap width). The findings indicate that failure modes were consistently shear-dominated and remained unaffected by variations in column or pile configuration and size. Increasing the rectangular column length from 0.2d to d enhanced the ultimate load capacity by 108% and energy absorption by 100%. Similarly, increasing the circular column diameter from 0.2d to d improved these metrics by 348% and 373%, respectively. Widening the rectangular pile from 0.2d to d resulted in a 34% increase in ultimate load capacity. Overall, the study demonstrates that larger column and pile dimensions significantly enhance shear performance, with circular configurations yielding superior improvements. These insights offer practical guidance for optimizing pile cap design.
AbstractThe challenge of optimizing battery operating revenue while mitigating aging costs remains inadequately addressed in current literature. This paper introduces a novel cost–benefit approach for scheduling battery energy storage systems (BESS) within microgrids (MGs) that features smart grid attributes. The proposed comprehensive approach accounts for fluctuations of real-time pricing, demand charge tariffs, and battery degradation cost. Using the dynamic programming technique, a novel high-speed BESS scheduling optimization algorithm that incorporates a LiFePO4 battery degradation cost model is developed, achieving substantial monthly operational cost savings for the MG with a fine-grained sampling interval of nine minutes and execution time under one minute. The algorithm utilizes day-ahead forecasts for MG load profiles and photovoltaic output power, enabling the prediction of BESS’s optimal power profile a day in advance. The algorithm’s rapid execution enables real-time adaptability, allowing BESS scheduling to dynamically respond to grid fluctuations. The proposed approach outperforms existing methods in the literature, delivering MG operational cost savings ranging from 33.6% to 94.8% across various scenarios. Consequently, this approach enhances MG operational efficiency and provides significant cost savings.
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AbstractIndustrial activities, especially textiles and cosmetics, release harmful wastewater, threatening the environment and human health. Photocatalysis has emerged as an effective, eco-friendly solution for these issues, particularly using metal-organic frameworks (MOFs) for water treatment. This study explores the performance, computational analysis, and mechanistic behavior of a novel magnetically responsive cellulose-based metal-organic framework (MOF) nanocomposite, DAC@PdA@FM, for the simultaneous photocatalytic degradation of Toluidine Blue O (TBO), Crystal Violet (CV), and Sunset Yellow FCF (E110) dyes. The material was synthesized using a controlled oxidation method and characterized using FTIR, XRD, EDX, SEM, TGA techniques and PPPS saturation magnetization properties. The uptake capacity of DAC@PdA@FM toward organic dyes as TBO, CV, and E110 from water, achieving reductions of 988.75, 1242.5, and 497 mg/g, respectively, within short time frames.The kinetic and isotherm studies were best fitted by PSO and the Langmuir models due to the higher correlation coefficient (R2≥ 0.999) and the lower error functions. The nanocomposite exhibited enhanced reusability and separation efficiency due to its superparamagnetic nature. Density functional theory (DFT) calculations confirmed the electronic structure and charge transfer mechanisms. Comparative analysis with previous studies confirmed superior degradation efficiency. The results also suggest that the MOF: DAC@PdA@FM nanocomposite possesses notable antimicrobial activity, particularly against gram-ve bacteria. These findings suggest that the MOF: DAC@PdA@FM nanocomposite is a promising applicant for wastewater treatment applications. The catalytic degradation mechanism for dyes on the prepared MOF:DAC@PdA@FM nanocomposite involves various interactions, including electrostatic attraction, pore-filling, π–π stacking, and hydrogen bonding. Also, The results suggest that utilizing pre-prepared MOF:DAC@PdA@FM nanocomposite could serve as a potent and efficient antimicrobial agent.
AbstractIndoor air pollution may harm child health. Indoor air pollution inequalities among children and adolescents is under-researched. We analyzed associations between equivalized disposable income, socioeconomic status, and history of migration with benzene, toluene, xylene, limonene, and formaldehyde among children and adolescents in Germany. Using pooled data from the German Environmental Survey (GerES IV, GerES V) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Baseline, KiGGS Wave 2) (N = 1117, aged 3–14 years), six out of fifteen random intercept models revealed statistically significant findings. An increase of one standard deviation in equivalized disposable income was associated with 5% lower benzene concentrations (exp(ß): 0.95, 95% confidence interval [CI] 0.91, 0.99). Higher socioeconomic status was associated with a 10% decrease in benzene (exp(ß): 0.90, 95% CI 0.87, 0.94) and a 6% decrease in toluene (exp(ß): 0.94, 95% CI 0.89, 0.99). Having a parental history of migration was associated with 24% higher concentrations of formaldehyde (exp(ß): 1.24, 95% CI 1.07, 1.43) and 102% increased limonene concentrations (exp(ß): 2.02, 95% CI 1.61, 2.55). Subgroup analysis from urban municipalities showed only slight differences. Although results varied, they highlight that indoor air pollution is unequally distributed among children and adolescents in Germany.
AbstractA growing number of studies have compared human and AI creative performance. These studies differ in AI chatbots, human populations, creativity tasks, and creativity indicators (e.g., originality, usefulness, elaboration). They mostly neglect psychological research on determinants of creative performance such as instructions or processing time. The present study contributes to the theoretical foundation and replicates a study comparing humans’ and AI’s creative output in the Alternate Uses Task. Building on established knowledge of creativity determinants, we modified the Alternate Uses Task’s instructions (call for quality AND quantity), provided more time for the human participants, and added a second task (Remote Associates Task). The Alternate Uses Task output was scored in two ways: the mean and maximum scores of each Alternate Uses Task item, both in terms of semantic distances and in terms of human rating scores. The result shows that AI’s mean scores were significantly higher in the original and modified Alternate Uses Task condition, maximum scores in the original Alternate Uses Task condition, and in the Remote Associates Task. No significant differences between humans and AI were found for the maximum scores in the modified Alternate Uses Task. We mainly replicated the original studies’ findings. Our study provides initial clues that the evaluation of creative performances depends on creativity indicators and approaches (instructions and time).
AbstractThree novel morpholinium-cationic surfactants (coded: DCSM-8, DCSM-10, and DCSM-12) with chemical structure confirmed via FT-IR, HNMR, and mass analysis were applied for carbon steel (CS) corrosion control in acidic 4 M HCl solution. The investigated compounds decreased water surface tension (72 mN.m-1) to 19.85 mN.m-1after the addition of DCSM-12. The surfactants mitigation performance was assessed via weight loss (WL), potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS). The synthesized surfactants protectedCSefficiently with higher inhibition efficiencies up to 97.029% at 1 × 10–3M for DCSM-12 using PDP which also indicated that, the prepared surfactants inhibited bothCSanodic and cathodic sites with cathodic dominant. EIS data showed higherCSresistance from 35.24 Ω.cm2to 1245.54 Ω.cm2after addition of 1 × 10–3M for DCSM-12 with mitigation potency 97.17% which can be attributed to their adsorption process overCSsurface forming a protective film layer that followed Langmuir adsorption isotherm reflecting the chemical adsorption affinity of the prepared mitigators with higher adsorption energy (ΔG*ads) values (> -40 kJ.mol-1). Also, the protection effect of the prepared inhibitor (DCSM-12) was confirmed using SEM (scanning electron microscopy) and EDX (energy-dispersive X-ray) showing improvement inCSsurface morphology. The reactivity of the prepared surfactants and their mitigation role inCSdeterioration were confirmed theoretically using DFT (density functional theory) and MCs (Monte Carlo simulations).
AbstractThis study investigated the effects of astaxanthin (ASTA) on diabetic cardiomyopathy (DCM) and nephropathy (DN) in rats. Type 2 diabetes was induced through a high-fat/high-fructose (HF/HFr) diet followed by a sub-diabetogenic dose streptozotocin injection. Diabetic rats were treated with ASTA at a dose of 100 mg/kg for four weeks. Serum markers of renal and cardiac function, oxidative stress parameters, and electrocardiographic (ECG) measurements were assessed. Diabetic control rats exhibited significant impairment in renal and cardiac functions, heightened oxidative stress, and altered ECG parameters. Treatment with ASTA (100 mg/kg) markedly improved these conditions, proven by reduction in serum urea, creatinine, cardiac creatine phosphokinase-MB (CK-MB), and LDH levels. Additionally, oxidative stress markers such as MDA, GSH, SOD, and NOX4 were restored in both heart and kidney tissues. Furthermore, ASTA was able to increase the cardiac and renal Fractalkine chemokine as well as attenuate the elevated Nrf2 and AP-1. ECG abnormalities were partially reversed, with enhancements in the QTc interval and ST segment height. The histopathological examination of cardiac and renal tissues confirmed these results. Finally, the forementioned promising observations suggest that ASTA may offer therapeutic potential in mitigating DCM and DN via modulation of NOX4, Fractalkine, Nrf2, and AP-1 Pathway, warranting further research into its mechanisms and clinical applicability.
AbstractUltrashort XUV pulses of the Free-Electron-LASer in Hamburg (FLASH) were used to investigate laser-induced fragmentation patterns of the prototypical chiral molecule 1-iodo-2-methyl-butane ($$\hbox {C}_5$$$$\hbox {H}_{11}$$I) in a pump-probe scheme. Ion velocity-map images and mass spectra of optical-laser-induced fragmentation were obtained for subsequent FEL exposure with photon energies of 63 eV and 75 eV. These energies specifically address the iodine 4d edge of neutral and singly charged iodine, respectively. The presented ion spectra for two optical pump-laser wavelengths, i.e., 800 nm and 267 nm, reveal substantially different cationic fragment yields in dependence on the wavelength and intensity. For the case of 800-nm-initiated fragmentation, the molecule dissociates notably slower than for the 267 nm pump. The results underscore the importance of considering optical-laser wavelength and intensity in the dissociation dynamics of this prototypical chiral molecule that is a promising candidate for future studies of its asymmetric nature.
AbstractThe current study investigates the development and characterization of sustainable activated carbons (ACs) via chemo-thermal activation from the hull and core of sugarcane bagasse as a viable and renewable substitute for commercial ACs. Characterize ACs using XRD, FTIR, SEM, etc. The sorption kinetics of methylene blue (MB) onto AC(H) were well described by a pseudo-second-order model. Also, the controlling step in the MB sorption process was related to several intervening diffusion sorts, including intra-particle ones. The MB equilibrium data were also analyzed using linear and non-linear forms of Langmuir, Freundlich, and Temkin isotherms, revealing a better fit of Langmuir, with R2values > 0.97 in both modes. With adsorption capacities (qmax= 357.14 and 389.4 mg/g) in linear and non-linear modes, orderly. The activation energy (EDR) of 550.8 and 2500 J/mol in non-linear and linear further supports the dominance of chemisorption, implying the formation of chemical bonds between the MB and the functional groups present in the sorbent material. The spontaneous and exothermic nature of the MB sorption process at 291–323 K was confirmed by the thermodynamic parameters ΔH°, ΔS°, and ΔG°. The design expert program suggested 17 numerical possibilities for the maximum dye removal at the 99% desirability level using ANOVA within the experimental parameter range. The total cost of producing 1.0 g of AC(H) is estimated at 0.041 USD. These findings underscore the potential of AC(H) as a highly efficient adsorbent for MB removal, positioning it as a strong candidate for wastewater treatment applications.
AbstractShunt faults may cause significant fluctuations in the electrical output of the Synchronous Generators (SGs), leading to a loss of synchronization with the remaining power network. Electrical power analysis and the Durbin Watson (DW) statistic can be manipulated to diagnose the instability of the power quality parameters, and to discern between synchronous and asynchronous running of the generator. In this research, the computational techniques serve as a proper foundation of intelligent relay to anticipate and detect the generator Out-of-Step (OOS) situation following the fault presence. The protection strategy can identify sudden variations in several electrical waves in the OOS conditions, such as phase voltage, current, active power, reactive power, and power angle. To verify the performance of the method, a power model with real parameter data of its components is built using the software package of the Alternative Transient Program (ATP). The advanced algorithm is carried out and analyzed using the MATLAB application. Simulation results and analysis show that the protection plan has the ability to recognize the OOS events upon which the protective relay emits a tripping signal to both the annunciation panel and the generator circuit breakers. Whereas, it remains idle under acceptable synchronization conditions. As a consequence, the OOS is rapidly announced before the second pole-slipping occurrence. Furthermore, the algorithm is robust during the stable power swings, and the property of the protection redundancy is provided in this strategy. Additionally, it has the capability of estimating both the instability time and the frequency rate of the unstable power swings.
AbstractPhotoinduced intramolecular electron transfer (ET) is essential for understanding charge transport in biological and synthetic systems. This study examines ET in peptide His-Glu-Tyr-Gly (1) and the conjugate His-Gln(BP)-Tyr-Gly (2) with benzophenone (BP) as a photoactive electron acceptor and His or Tyr as donors. Time-resolved and field-dependent chemically induced dynamic nuclear polarization (CIDNP) techniques were employed to investigate ET mechanisms and kinetics. Peptide 1 with 3,3’,4,4’-tetracarboxy benzophenone as a photosensitizer initially forms two types of radical with radical center at either His or Tyr residue, the consequent intra- and intermolecular ET electron transfer from Tyr residue to the His radical takes place with rate constants ke(intra)=(1.5±0.5)×105s− 1and ke(inter)=(1.3±0.4)×107M− 1s− 1at pH 8.8. Conjugate 2 forms two types of biradicals under irradiation: with radical centers at Tyr and BP across the entire pH range, and with radical centers at His and BP at slightly basic pH. Field-dependent CIDNP revealed nonzero electronic exchange interaction (2Jex= − 8.78 mT) at acidic pH, indicating proximity between BP and Tyr radicals. Low-field CIDNP spectra showed strong emissive polarization patterns, with pH-dependent exchange interaction and biradical geometry. Notably, no electron transfer from tyrosine to histidine radicals was observed in the conjugate 2, distinguishing its behavior from peptide 1.
AbstractThe worldwide prevalence of type 2 diabetes mellitus (T2DM) is increasing swiftly.Cymbopogon proximus(C. proximus) is a wild herbaceous plant utilized as a potent remedy in Egyptian folk medicine, sometimes referred to as “Halfabar.” This study examined the hypoglycemic, hypolipidemic, and antioxidant properties of the methanolic extract from the aerial parts ofC. proximus, as well as its impact on pancreatic tumour necrosis factor-α (TNF-α) and Glucose Transporter-4 (GLUT4) in skeletal muscles within an experimental model of insulin resistance. Additionally, bioactive metabolites in the extract were analyzed via liquid chromatography-mass spectrometry (LC/MS) technology. Insulin resistance was induced by administering 1 mg/kg of dexamethasone to rats over a period of 14 days. The rats received two doses of the extract: a low dose of 100 mg/kg body weight and a high dose of 200 mg/kg body weight, along with the reference drug; Metformin (M) at a dose of 40 mg/kg body weight, supplied once daily by gastric tube for 14 days. The treatment of dexamethasone led to a significant (P< 0.05) elevation in serum fasting glucose, fasting insulin, HOMA-IR, and pancreatic TNF-α, along with a significant (P< 0.05) reduction in GLUT4 expression in skeletal muscles. Both extract and reference treatments significantly (P< 0.05) mitigated these abnormalities. The highest dose of the extract exhibited a significantly (P< 0.05) greater antioxidant impact, a more pronounced reduction in insulin levels and HOMA-IR, as well as an enhanced rise in GLUT4 expression and insulin sensitivity index compared to the lowest dose and the M. Histopathological and immunohistochemical analyses corroborate the biochemical results. The LC–ESI–MS/MS profiling resulted in the characterization and tentative identification of 95 metabolites’ structures. Identified substances purported to possess anti-diabetic effect include apigenin, luteolin, tricin flavone glycosides, cyanidin, malvidin anthocyanin glycosides, and caffeic acid. These findings suggest thatC. proximuscan mitigate insulin resistance. Additional clinical trials are necessary to validate these findings and assess the extract’s effectiveness in human insulin resistance.
AbstractThis study investigates the electronic properties of a proposed composite structure consisting of SiO2, Pb3O4, Bi2O3, and graphene oxide (GO) for glutamic acid (Glu) biosensing applications in aqueous media. Using Density Functional Theory (DFT) at B3LYP functional and SDD basis set, we examine the reactivity and electronic properties of the combination of these structures under weak and complex interaction scenarios with Glu. The study focuses on studying total dipole moments (TDM), HOMO/LUMO bandgaps, molecular electrostatic potential (MEP) maps, reactivity descriptors, and the density of states (DOS) for the proposed model molecules. The calculated TDMs and HOMO/LUMO bandgap energies highlight the highly reactive nature of the 3SiO2/GO/Pb3O4/Bi2O3“complex” structure toward the surrounding species. This is because it has the highest TDM (up to 35.1 Debye) and the lowest bandgap energy (decline significantly to 0.158 eV). The MEP maps for the interaction between 3SiO2/GO/Pb3O4/Bi2O3and Glu under the two proposed scenarios display markedly different MEP profiles, underscoring the substantial impact of the interaction type. Additionally, the interaction between 3SiO2/GO/Pb3O4/Bi2O3“complex” structure and Glu exhibits the highest ionization potential, electron affinity, and electronegativity. The plotted DOS curves of the interaction between the proposed composite structure (both weak and complex forms) and the target analyte reveal that the unoccupied states begin to emerge slightly below − 4.0 eV and − 5.0 eV, then extend towards 0.0 eV, indicating potential excitation energies for electrons. These findings boost the potential of the proposed 3SiO2/GO/Pb3O4/Bi2O3structure as a promising candidate for tailoring novel electrode materials for Glu biosensing applications, thereby advancing the development of effective biosensors.
AbstractMonosodium glutamate (MSG)-induced excitotoxicity is a major factor contributing to cognitive decline and neurodegeneration. Given the well-established roles of vitamin D (Vit D) and omega-3 polyunsaturated fatty acids (N-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in neuroprotection, the present study aimed at analyzing their possible neuroprotective efficacy against MSG-induced neurotoxicity in rats, concerning the behavioral performance, hippocampal histological integrity, and pathological protein accumulation, along with determination of the inflammatory marker levels and mRNA expression of vitamin D receptors (VDR) and other neurodegeneration-related genes. Fifty male Sprague Dawley rats were randomly allocated to a control, an MSG, and three treatment groups that received MSG and either Vit D or N-3 PUFA supplements in combinations or alone for 4 weeks. At the end of the study, five behavioral tests were conducted to assess cognitive functions, motor activity, and anxiety-related behaviors, and hippocampal tissues were analyzed for tau pathology, neuroinflammation, expression of VDR, and neurodegeneration-related markers. The results demonstrated that supplementation with Vit D (1 mcg/kg) and N-3 PUFAs (300 mg/kg EPA + DHA) profoundly attenuated MSG-induced neurodegeneration. The combined therapy decreased neuronal damage caused by MSG by 87% and tau pathology by 83%. The combined treatment further suppressed pro-inflammatory cytokines (TNF-α: 52%; IL-6: 65%) and elevated anti-inflammatory IL-10 by 2.8-fold, demonstrating a dual anti-inflammatory action. A major upregulation of hippocampal VDR by 4.6-fold was noted, with stabilization of calcium homeostasis and normalization of caspase-3 and α-synuclein expression. Our findings confirm that Vit D and N-3 PUFAs exhibit substantial synergistic neuroprotective abilities that might be mediated through synergistic VDR upregulation, providing a promising dietary intervention against MSG-induced excitotoxicity and highlighting their broader implications for supporting cognitive health and mitigating the adverse effects of other neurotoxins.
AbstractIndividuals with chronic low back pain (cLBP) may self-report about impairment of their back shape and function. As classical clinical diagnostic modalities seem to provide limited information on the pathogenesis of cLBP, interest has shifted to a more comprehensive approach of diagnosing cLBP. Self-reported outcome measurements in the form of either questionnaires or as part of clinical interview have gained interest. In theory, these self-reported assessments on one’s LBP provide the clinician with substantial information regarding the dominance of specific factors in a rather complex bio-psycho-social interplay of factors leading to cLBP. In order to analyze how well self-reported impairment (SRI) corresponds with objective measures, we evaluated the association between SRI and objectively measured back shape and function. In a cross-sectional study, we included 914 participants (207 asymptomatic, 480 non-chronic LBP (ncLBP), 227 cLBP). Participants were categorized into three groups: asymptomatic participants did not report back pain. Participants with back pain lasting for 12 weeks or more were categorized as cLBP patients, while participants with back pain for less than 12 weeks were classified as non-chronic LBP patients (ncLBP). Back function was quantified using finger-to-floor distance (FFD), Ott and Schober test, and 30 s sit-to-stand test (STS). Back shape and function were measured in standing position using a computer-assisted medical device. SRI was quantified during a clinical interview using a numerical 10–score-scale (1: unrestricted, 10: severely restricted). Higher SRI was associated with worse performance in every clinical test. Effect estimates ranged from small (Ott test: β = −0.05, CI −0.09–0.00, η2= 0.01; p = 0.05; Schober test: β = 0.08, CI −0.13 −0.04, η2= 0.01, p < 0.01) to moderate (FFD: β = 1.66, CI 1.27–2.19, η2= 0.05, p = 0.05; STS: β = −0.08, CI −0.82, CI −1.06–−0.59, η2= p < 0.01) in participants with ncLBP and cLBP. Higher SRI was associated with pathological back shape (hyperkyphosis, β = −0.03, CI = −0.29–0.51, η2= 0.01; p = 0.58 and hyperlordosis, β = 0.35, CI 0.04–0.65, η2= 0.02, p = 0.03) as well as attenuation of range of motion in the frontal and sagittal planes in every direction except for the thoracic range of extension. Effect sizes were small (η2= 0.01–0.04). This study demonstrated an association of SRI with objective back shape and function. Participants with ncLBP seem to have the highest correspondence between objective evaluation and SRI of back shape an function. In the future, these associations can be used to further personalize both diagnostic and therapeutic modalities for individuals suffering from LBP rather than generalizing treatment options.
AbstractTraditional restorative materials often fail to integrate seamlessly with natural tooth structures due to differences in chemical composition, leading to microleakage and related clinical problems. This study aims to create a material entirely composed of calcium phosphates, the main component of dental enamel, to repair minor enamel cavities. Inspired by the biomineralization process and employing the inorganic ionic polymerization strategy, a cohesive calcium phosphate mass was developed to repair minor enamel cavities. Calcium phosphate ionic clusters (CPICs) and three types of calcium phosphate powder were utilized; (bone-derived and synthetic hydroxyapatite; (BHA and SHA), and dried CPICs. Two different techniques, namely layer by layer (LbL) and premixing (PM), were employed to mix CPICs with one type of calcium phosphate powder to form a cohesive mass. Different analysis techniques were used including FTIR, XRD, SEM and TEM. Among the tested approaches, the mass formed by mixing BHA with CPICs using the PM technique demonstrated superior integration with enamel walls and infiltration of calcium phosphate particles into enamel. To the best of our knowledge, repairing cavitated enamel defects using a bioinspired approach with a material composed entirely of calcium phosphate has not yet been achieved.
AbstractThe negative impact of alcohol consumption on cancer development and progression is well-established in oncologic research, yet it receives surprisingly little attention from patients with cancer, the public, and even oncology professionals. A cancer diagnosis can lead to significant psychological distress, including high levels of depression and anxiety. For patients with cancer experiencing high levels of psychological burden, psycho-oncological care is available to help manage these symptoms and the overall impact of their condition. Alcohol consumption can serve as a coping mechanism for psychological stress. However, there is limited knowledge about the alcohol consumption patterns among this particularly vulnerable group of patients with cancer, as well as the patient- and disease-related factors associated with drinking. Patients with cancer are particularly susceptible to the harmful effects of alcohol. The aim of this study is to investigate the prevalence of potentially risky alcohol consumption among patients with cancer receiving psycho-oncological care over a six-month period and to identify sociodemographic, health-related, and psychosocial factors that may predict alcohol consumption after a cancer diagnosis. We conducted a secondary analysis using data from 300 patients with cancer (72 % female, mean age 52.74 years) treated at the outpatient clinic of the University Medical Center Hamburg-Eppendorf in Germany. Between 2013 and 2021 demographic, medical, and psychosocial information was collected using self-report questionnaires. A generalized longitudinal linear mixed model was used to determine the prevalence of risky and potentially harmful drinking behavior (AUDIT-C ≥ 2 for women and ≥ 3 for men) among patients with cancer as well as to identify patient characteristics associated with alcohol consumption. The results show that approximately 70% of the patients continued drinking after their cancer diagnosis, despite the known detrimental effects of alcohol on prognosis. At both time points, around 40 to 50% of female and male patients reported potentially harmful drinking behaviors (T0 (beginning of psychosocial treatment): 49.1% of female, 38.1% of male patients; T1 (6 months later): 41.2% of female and 42.9% of male patients). A higher number of comorbidities (OR = 0.707; 95% CI: 0.567–0.883), older age (OR = 0.983, 95% CI: 0.967–0.999, and higher levels of depressive symptoms (OR = 0.952, 95% CI: 0.907–0.998) were significantly associated with lower odds of risky alcohol consumption over the six-month period. In contrast, higher anxiety levels (OR = 1.075, 95% CI: 1.021–1.132) were associated with an increased likelihood of risky drinking. The significant proportion of patients with cancer consuming alcohol at levels that may worsen their cancer prognosis highlights the need for improved patient education and guidelines. The results can help identify high-risk patients who require close monitoring of their drinking behaviors during their survival period, and inform the implementation of better alcohol control measures in cancer care. By understanding alcohol consumption patterns and associated factors, we aim to promote healthier behaviors and improve treatment outcomes for patients with cancer in psycho-oncological care.
AbstractDue to the rise in power consumption in recent years, the rated capacity of the power system has increased, resulting in an increase in the presence of Distributed Generators (DGs) in electrical networks. As a result, short-circuit currents surge when shunt faults occur. Fault Current Limiters (FCLs) are an effective way to suppress fault currents in the power systems. On the other hand, FCLs have an impact on the response speed of the protective devices, such as over-current relays (OCRs), which increase the relay operating time, raising the electrical and mechanical stresses on the system equipment. This paper presents an adaptive OCR algorithm considering the FCLs effect without any delay time. The proposed algorithm includes two modules: (1) a Z-score algorithm based on both the mean and the standard deviation values of the input current data, which is used to detect fault conditions, and (2) tripping characteristic curves based on the current Mean Ratio, which are applied to estimate the appropriate operating time of the adaptive OCR. To verify the method performance, a power system with real parameters is simulated on the Alternative Transient Program platform, and the algorithm procedure is implemented in the MATLAB program. Extensive simulation studies of load changes and various fault types are conducted, encompassing a wide range of fault initiation angles, fault resistances, and fault zones. The quantitative findings of these studies are analyzed in the presence and absence of FCLs/DGs. The simulation results indicate that the proposed algorithm can operate online and adjust its operating time settings automatically. As a consequence, it is able to detect fault instances upon which the relay sends a tripping flag, yet remains inactive under normal operating conditions. The algorithm speed and sensitivity are controllable using a moving data window size. Moreover, it is characterized by being easy to use, reliable, and accurate. Furthermore, the Z-score of the phase current can be used to identify the faulty phase and classify the fault type. In addition, the algorithm can be integrated with other digital protection and automation systems to be applied in conventional and smart grids.
AbstractThe demand for gluten-free products for people suffering from a gluten allergy is increasing. Therefore, the aim of this study was to produce high-quality gluten-free pasta from brown rice flour (BRF), quinoa flour (QF) and chickpea flour (CPF), semolina flour (S) was used as control sample. The chemical composition of the raw materials showed the higher protein, carbohydrate and fat content of CPF, S and QF, respectively. In addition, the content of Ca, K, and Fe was higher in CPF. The total concentration of essential amino acids in CPF, BRF and QF was between 38.9 and 34.04%. Pasta was prepared with different levels of CPF, BRF, and QF. The quality of the pasta was evaluated chemically and physically. The chemical analysis showed that the formula (BRQ5) had the highest protein, fat, ash and fiber content. The color analysis showed that the darkness of the pasta increased with increasing QF. The overall acceptability of the different pasta showed that the control (S) had the highest acceptability, followed by BR and BRQ1. The analysis of the texture profile showed that the hardness of the uncooked control pasta was the highest. In summary, it can be recommended to produce gluten-free pasta with the BRQ1 formula.
AbstractThis study aimed to analyze the antibiotic resistance patterns and virulence profiles ofKlebsiella pneumoniae, a prevalent gram-negative pathogen linked to CLABSI patients globally. Of a total of 185 microbial isolates, 51 (27.5%) wereK.pneumoniaeisolates. The results of antimicrobial susceptibility testing using the disk diffusion method were compared to those of the VITEK-2. Phenotypic analysis revealed that 88.3% were biofilm producers and 50.9% were extended-spectrum beta-lactamase (ESBL) producers. Enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) revealed a discriminatory power of 0.7111 between ten selected isolates. The PCR detection of the virulence genes, includingFimH,rmpA,iutA, andfyuA, revealed that the ten selected isolates harbored all these genes, except one without thefyuAgene. The presence of thermpAand theiutAgenes confirmed them as hypervirulent (hv)K.pneumoniae. The genes (EAST-1,CNF-1) were present in 20% and 60% of the isolates, respectively. All isolates had theblaTEMandblaSHVresistance genes, while 50% had theblaNDMcarbapenemase resistance gene. In conclusion, all selectedK.pneumoniaeisolates were proven to be ESBL producers and carbapenem-resistant, highlighting significant multidrug resistance. We found a strong correlation between biofilm formation and multidrug resistance, as well as between phenotypic and genotypic detection of various virulence factors. Infections from hyKp strains represent a growing public threat. Our findings aim to enhance therapeutic options for patients and help reduce complications and mortality.
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ABSTRACTThere is increasing evidence that white matter fibres play an important role in tinnitus. A directed bilateral Mendelian randomization (MR) analysis based on genome‐wide association studies (GWAS) has been implemented to explore the impact of idiopathic tinnitus on the brain white matter (WM) integrity of different severity and stages at a causal level. The tinnitus‐related GWAS is derived from the research of 117,882 European participants, which contains accounts of tinnitus at different severities and stages. WM diffusion indices, which come from GWAS of 3144 brain imaging phenotypes from the UK Biobank, based on tract‐based spatial statistics and neurite orientation dispersion and density imaging, represent its integrity in this study. The primary estimate was inverse‐variance weighted, with heterogeneity and pleiotropy detected using MR Pleiotropy Residual Sum and Outlier and MR‐Egger. This study revealed a significant causal relationship between tinnitus and brain WM microstructural alterations, including changes primarily within the thalamic and acoustic radiation, limbic‐related fibre bundles, as well as fibres along the transmission pathways of auditory information from peripheral to central. Interestingly, we found that individuals exhibiting WM changes in the internal capsule, corticospinal tract and tapetum might have previously experienced tinnitus. Furthermore, moderate tinnitus patients exhibit the most pronounced WM integrity changes. This study substantiates that tinnitus can instigate substantial WM microstructural alterations mainly within the auditory‐thalamic‐limbic system and the auditory information transmission pathway from peripheral to central, while the reciprocal causality is not supported. Moreover, the data underscores that WM integrity changes vary depending on the severity and stages, and moderate tinnitus precipitates the most significant. Alterations in several specific WM fibre bundles indicate a history of tinnitus.
ABSTRACTExternalizing behaviors are particularly pronounced in the context of psychopathy. Recent neurobiological models suggest that psychopathy may be associated with abnormalities in brain network connectivity, which could contribute to its development and its links to externalizing behaviors. However, the specific structural networks contributing to psychopathy and its relation to externalizing behaviors remain poorly understood. In this study, we investigated the structural connectivity associated with psychopathy and its relation to externalizing behaviors in 82 young adults from the MPI Leipzig Mind‐Brain–Body dataset. A structural connectome–based prediction model with leave‐one‐out cross‐validation identified both positive and negative networks associated with psychopathy. Specifically, the positive network involved regions related to social‐affective processing, language, and reward systems, while the negative network was associated with regions involved in attention modulation. Furthermore, mediation analyses revealed two potential neural pathways from psychopathic traits to externalizing behaviors via emotional processing and attention modulation networks. These findings suggest that alterations in structural connectivity play a significant role in psychopathy and may underlie the externalizing behaviors observed in individuals with the disorder.
ABSTRACTLow‐frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) was shown to impair short‐term consolidation of a balance task, emphasizing the importance of M1 in balance skill consolidation. However, the disruptive mechanisms of rTMS on neural consolidation processes and their persistence across multiple balance acquisition sessions remain unclear. GABAergic processes are crucial for motor consolidation and, at the same time, are up‐regulated when learning balance skills. Therefore, this study investigated the impact of rTMS on GABA‐mediated short‐interval intracortical inhibition (SICI) and consolidation of balance performance. Participants (n= 31) underwent six balance acquisition sessions on a rocker board, each followed by rTMS (n= 15) or sham‐rTMS (n= 16). In the PRE‐measurement, SICI was assessed at baseline and after balance acquisition with subsequent rTMS/sham‐rTMS. In the POST‐measurement, this procedure was repeated to assess the influence of motor memory reactivation on SICI. In addition, SICI‐PRE and SICI‐POST were compared to assess longer‐term processes. Both groups achieved similar improvements within the balance acquisition sessions. However, they did not consolidate equally well, indicated by significant declines in performance for the rTMS group (p= 0.003) in the subsequent sessions. Adaptations in SICI were affected by rTMS (p= 0.024): while the sham‐rTMS group up‐regulated SICI, rTMS led to reductions in inhibition. The interfering effect of rTMS on both balance consolidation and up‐regulation of SICI suggests that increased intracortical inhibition is an important factor to protect and consolidate the newly acquired motor memory.
ABSTRACTEnsuring equitable access to research funding is crucial for fostering diversity, innovation and excellence in science. Despite progress, significant disparities remain, with underrepresented researchers—including women, racial and ethnic minorities, LGBTQIA+ individuals and those with disabilities—continuing to receive disproportionately less funding. These disparities not only hinder individual careers but also limit the breadth of perspectives that drive scientific discovery. Through discussions with major funding agencies, including the Dana Foundation, European Research Council (ERC) and ERA‐NET NEURON, we examine how equity, diversity and inclusion (EDI) are integrated into research funding allocation. We focus on three key areas: (1) How EDI is defined and prioritised (2) metrics for assessing and tracking progress and (3) strategies for mitigating bias in selection procedures. While agencies have implemented initiatives such as demographic data transparency, targeted funding mechanisms and bias‐awareness training, systemic challenges remain. Variability in data collection practices, barriers in peer review processes and limitations of interventions like double‐blind reviews highlight the need for ongoing reform. As EDI policies face growing political scrutiny and active efforts to dismantle existing frameworks, reinforcing and expanding strategies to ensure equitable funding distribution has never been more critical. The scientific community must continue advocating for evidence‐based approaches that improve transparency, accountability and fairness in research funding. Without sustained commitment, the progress made over the past decades is at risk of being reversed, undermining the diversity of thought and innovation essential to scientific advancement.
ABSTRACTRat whiskers comprise an “active sensing” system involving two functional subdivisions: long whiskers for object localization and short whiskers for object recognition. To explore their respective roles in orientation, rats were trained in a reaching–grasping task. Specifically, four consecutive salient frames were identified in control rats: (i) whisker touch (Wt), the long whiskers came into contact with the front wall; (ii) first nose touch (Fnt), the rat brought the nose into contact with the wall; (iii) poke (Pk), the rat inserted its nose through the slot and placed short whiskers on the shelf, exploring it until the pellet was detected; and (iv) nose elevation (Nel), the rat raised its nose until reach start. These frames were used to subdivide orientation behavior into three specific phases: Wt–Fnt, Fnt–Pk, and Pk–Nel. To determine their respective roles in orientation, the rats performed the task after either long whiskers trimming or short whiskers shaving. Data evidenced a temporary loss of orientation followed by a recovery specific to each experimental group. Trimmed rats presented incomplete trials with loss of invariance, longer Fnt–Pk duration, and an increased number of nose touches. Shaved rats displayed longer trial duration and longer Pk–Nel interval. This duality is explainable by a consecutive use of the two kinds of whiskers and confirms their different roles in the multisensory integration necessary for each orientation phase. The data suggest that the long whiskers can be viewed as a spatial orientation system acting as a precision mechanism guiding head position in the context of coherent behavior.
ABSTRACTLinguistic, motor, cognitive, and social‐behavioral functions are fundamental facets of a child's neurodevelopment and are influenced by both genetic factors and environmental factors, such as the home environment, including the parents' mental health. However, the nature of these influences remains largely unknown. Using a genotyped cohort of 391 7‐year‐old children with comprehensive phenotype data on linguistic, motor, cognitive, and social‐behavioral performance as well as data on parental mental health and the home environment, we performed regression analyses for the individual neurodevelopmental domains and principal components (PCs) capturing the variance across all domains simultaneously, where these outcomes were regressed on a polygenic score for educational attainment (PGS for EA) as a proxy for genetic factors and the Home Observation for Measurement of the Environment (HOME) as a proxy for environmental factors. HOME was significantly associated with all domains; the PGS for EA was nominally significantly associated (p≤ 0.05) with cognitive function only. In the principal component analysis, PC1 and PC2 captured 52.57% and 20.73% of the variance in our phenotypic data, respectively. HOME was significantly associated only with PC1, while the PGS for EA was significantly associated only with PC2. Significant differences between familial risk groups were observed for PC1. Our results suggest an important role for potentially modifiable environmental factors on child neurodevelopment across multiple domains. We identified two orthogonal dimensions capturing parts of phenotypic variance that were associated with either environmental or genetic factors, but not both, providing insight into the interplay between genes and the environment in neurodevelopment.
ABSTRACTThe structural model predicts the laminar patterns and strength of corticocortical connections. Here, we addressed whether the structural model extends to connections between the thalamus and prefrontal cortices, which are connected with the mediodorsal (MD) nucleus and with other thalamic nuclei. The prefrontal cortex is composed of a series of areas ranging from caudal orbital and medial limbic areas that have the simplest trilaminar architecture through successive areas that show increasing elaboration into six delineated layers. Here, we compiled detailed, quantitative tract‐tracing data from connectivity studies of the thalamus and cortex in macaques, which revealed that the structural model extends to thalamocortical connections. The phylogenetically ancient limbic areas were more diffusely connected with thalamic nuclei, projected to the thalamus from canonical Layer VI, and also substantially from Layer V, and were innervated more broadly by thalamic pathways that terminated in the middle and other layers. The pattern of thalamocortical connections became increasingly sharper for prefrontal areas with progressive laminar differentiation, with decreasing contribution of thalamic nuclei besides MD, sharpening of thalamic terminations to the middle cortical layers, gradual decreasing contribution by Layer V, and increased projection from canonical Layer VI to the thalamus. These findings support the hypothesis that the structural model can be extended to the broad thalamic connections and laminar‐specific interactions with the thalamus, tested in a series of prefrontal cortices with a gradual increase in laminar complexity.
ABSTRACTMounting evidence suggests that individuals with chronic low back pain exhibit changes in brain activity. However, changes in brain activity during the performance of salient motor tasks have not been fully described. Therefore, the purpose of this study was to investigate the differences in cortical activation and functional connectivity between individuals with and without chronic low back pain while performing condition‐specific motor tasks. Twenty‐three individuals with chronic low back pain and 19 asymptomatic individuals participated in this study. Whole brain activity and functional connectivity were measured, whereas participants performed three lumbopelvic motor tasks: modified bilateral bridge, left unilateral bridge, and right unilateral bridge. Whole‐brain analysis revealed no significant differences in brain activation between the groups when performing lumbopelvic motor tasks. An exploratory region of interest analysis demonstrated that individuals with chronic low back pain had significantly higher activation in the left insular‐opercular cortex, left midcingulate gyrus, right insular‐opercular cortex, right midcingulate gyrus, and right putamen. Functional connectivity analysis revealed significantly higher connectivity between the midcingulate gyrus, putamen, and insular‐opercular cortex in those with chronic low back pain compared to asymptomatic participants. Taken together, this study helps build on the existing literature by providing unique insights into the changes that occur during the performance of salient motor tasks in individuals with chronic low back pain.
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ABSTRACTSeemingly simple actions, like reaching for and lifting an object, involve the coordination of distinct neural pathways within the dorsal and ventral streams. These components can be differentially affected by repetition‐induced anterograde interference, where extensive practice on one task impairs performance on subsequent tasks. Repetition leads to rigid movement patterns, making it harder to adapt flexibly to new situations, especially in tasks with sensory uncertainty that require the brain to rely more on past experiences (i.e., sensorimotor memories). To explore this, we tested whether object‐use tasks, which depend on the ventral stream, are more affected by this interference than a simpler reach‐to‐button task with helpful visual cues. Participants completed two tasks: a reach‐to‐button task involving pressing buttons on either side of a symmetrical object and an object‐use task where the same object had a hidden, asymmetric center of mass (CoM). To measure interference, we manipulated how many times participants lifted the object with the weight on one side before switching it to the other side. Our results showed that interference was strongest in the object‐use task, where uncertain visual information forced participants to rely on sensorimotor memories. In contrast, the reach‐to‐button task, supported by helpful visual cues, showed no significant interference. This suggests that tasks relying on the ventral stream are more vulnerable to interference, particularly when sensory feedback is unclear. Our findings highlight how repetition affects different movement types and emphasize the need for a balance between repetition and flexibility in motor learning.
ABSTRACTNeurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid‐β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α‐synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood–brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.
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ABSTRACTAmong the various forms of exploration, rearing—where rodents stand on their hind legs—reflects the animal's processing of spatial information and response to environmental novelty. Here, we investigated the developmental trajectory of rearing in response to spatial novelty in a standard object–place recognition (OPR) task, with the OPR retrieval phase allowing for a direct comparison of measures of rearing, object exploration, and locomotion as indicators of spatial novelty and memory. Groups of male rats were tested on postnatal day (PD) 25, PD31, PD38, PD48, and at adulthood (PD84). The OPR task comprised a 5‐min encoding phase with the rat exposed to an arena with two identical objects and, 3 h later, a 5‐min retrieval phase in the same arena with one object being displaced to another arena zone. Rearing increased in response to spatial novelty (i.e., the displaced object) at retrieval relative to encoding, with this increase occurring first on PD31, and thus later than preferential object exploration‐based responses emerging already on PD25. Importantly, zone‐specific analyses during retrieval revealed an increase in rearing events in the (now empty) zone where the displaced object is used to be at encoding. This increase was only observed in adult rats (PD84) and likely indicates the presence of specific object–place associations in memory. These findings evidence rearing as behavior covering aspects of spatial novelty complementary to those of object exploration, thereby enabling a more comprehensive characterization of the emergence of spatial episodic memory during early life.
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ABSTRACTThe paraventricular nucleus of the thalamus (PVT) is a central node in brain networks controlling motivated behaviors. It processes inputs from cerebral cortex, brainstem, and hypothalamus and has efferents that project to a wide range of structures, including the nucleus accumbens (nAcc). It is known that PVT neurons projecting to the nAcc show c‐Fos activation in response to reward‐related cues, in well‐trained animals. We previously found that c‐Fos expression is also increased early in the conditioning process, during the first session of learning a new cue‐reward association in rats, but neurons with projections to nAcc were not identified in that study. Here, we tested the hypothesis that nAcc‐projecting PVT neurons would show this enhanced c‐Fos expression following first exposure to the association of a visual cue with a subsequent food reward. Male rats were stereotaxically injected in the nAcc with a retrogradely transported adeno‐associated virus construct leading to green fluorescent protein (GFP) expression in cell bodies of afferents from PVT. Following a single session of cue‐reward training, processing of the brains with dual immunohistochemistry for c‐Fos and GFP showed significantly higher density of double labelled neurons in the conditioned group, compared to controls in which the same number of cues and rewards were delivered at random intervals with respect to each other. Such activation of immediate early gene expression in PVT to nAcc projecting neurons very early in paired associative reward learning may have a role in modulating plasticity in the nAcc.
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ABSTRACTWhen encountering a potential threat, humans and animals engage in different strategic behaviours, such as orienting and defence, depending on the perceived threat imminence. Orienting has been associated with attentional immobility and heightened ‘stimulus intake’, while defence is linked to action preparation and ‘sensory rejection’. First, we replicated previous findings showing that humans exhibit either heart rate (HR) acceleration or deceleration in response to the same threat‐related picture content. Second, we provide direct evidence that orienting, as indexed by increased HR deceleration, leads to enhanced visuocortical processing of threat‐related images, as measured by steady‐state visual evoked potentials (ssVEPs). Excitation of motor‐relevant cortical circuits, assessed by beta‐band desynchronization, was reduced in relation to HR deceleration. Conversely, HR acceleration was associated with a reversed pattern: reduced visual processing and increased excitation of cortical motor circuits, as reflected in ssVEP and beta‐band modulations. While self‐reported measures of state and trait anxiety, along with valence, arousal and dominance ratings, did not account for variations in HR response patterns, shorter self‐paced viewing time of looming threat pictures was linked to defensive HR changes, whereas orienting‐like HR responses were associated with longer avoidance latencies.
ABSTRACTEstrogen deficiency after menopause contributes to various neurological disorders, including stress, anxiety, depression, and memory impairment. Hormone replacement therapy (HRT) is commonly used to mitigate menopausal symptoms, but its use is associated with significant adverse effects. As a result, phytoestrogens, plant‐derived estrogens structurally similar to HRTs, are preferred alternatives due to their lack of side effects associated with synthetic HRTs. Among these phytoestrogens, red clover (RC) has emerged as a potent medicinal herb used for the treatment of menopausal symptoms. Thus, the aim of the current study was to evaluate the effects of RC on neurological disorders in estrogen‐deficient rats subjected to chronic unpredictable mild stress (CUMS). Ovariectomy (OVX) was performed to induce estrogen deficiency, a condition that closely mimics menopause in females. CUMS, a model of chronic stress, was employed to mimic the stress and anxiety that commonly accompany menopause. Significant changes in physiological, neurobehavioral, biochemical, molecular, and histopathological alterations in the brain hippocampal region were observed in OVX, CUMS, and OVX + CUMS group rats, indicating enhanced neuronal deficits compared with control group rats. Treatment with RC supplementation, 17‐β estradiol (E2), and fluoxetine (Flx) significantly restored the pathological alterations caused by both CUMS and estrogen deficiency toward normal. E2 and Flx were included in the study to serve as established treatments for postmenopausal symptoms and stress‐related disorders, providing a basis for comparison with RC. In conclusion, our study demonstrated the immense potential of RC in alleviating neurological disorders associated with estrogen deficiency and chronic stress.
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ABSTRACTMotor imagery (MI) engages higher cognitive functions such as memory, attention, and the transformation of sensory information in various ways, depending on the current goal. MI can be used to reproduce in the mind a possibly exact copy of an earlier motor experience (isomorphic motor imagery [IMI]) or to transform earlier experiences into new mental representations (transmorphic motor imagery [TMI]). Our study aimed to identify electroencephalographic (EEG) patterns of brain oscillations that can distinguish these two types of MI focused on differences in the frontal midline theta (FMΘ), central parietal beta (CPβ), and sensorimotor rhythms (SMR). Twenty subjects (14F; 18–25 years) participated in the study. Experimental stimuli were generated using a haptic interface to stimulate force feedback during hand clamping. The subjects had to squeeze the interface handle, memorizing the sensations associated with this movement. Then, they mentally reproduced the action they had just performed (IMI) or imagined stronger/weaker sensations (TMI). The study findings demonstrate significant differences in FMΘ and CPβ oscillation activity when comparing IMI and TMI. The IMI condition exhibits similar brain rhythm activity to working memory, probably due to its function of reproducing a previous motor experience. In contrast, oscillation patterns during TMI resemble introspective activity typical of multimodal sensory transformations. Additionally, we observed differences in the parietal delta and theta, in line with prior research on actual movement. Results may suggest that controlling movement kinematic parameters is critical when MI replicates sensory experiences, whereas creating new representations from experiences may require less stringent control.
ABSTRACTUnderstanding the neural correlates of short‐term memory is crucial, particularly in the context of aging. In this electroencephalography (EEG) study, we investigated the impact of aging on the brain activity underlying short‐term memory and perception of dissimilarity of auditory sequences. Fifty‐four participants were divided into two groups: (i) 29 young adults (20–30 years old) and (ii) 25 older adults (60–80 years old). We used a variation of the same/different task employing pairs of tone sequences and asking participants to rate the degree of dissimilarity of the second sequence in comparison to the first one. Sequences could be either identical (same), totally different, or with transposed tones. Behavioral results showed a lower level of perceived dissimilarity in different sequences in older compared to young adults. The memory task induced a fronto‐central negative slow wave (NSW) that was significantly higher in the 20–30 group for all three conditions. NSW was higher in the same than in the different and transposed conditions but only in young adults. In transposed sequences, NSW amplitude was modulated by the perception of dissimilarity. The P50 component to first sound of the second sequence was significantly higher in older adults. The N1 was more negative in the same than in the different and transposed conditions. The P2 was higher in the same than in the transposed condition.
ABSTRACTDysregulation of the mesolimbic reward circuitry is implicated in the pathophysiology of stress‐related illnesses such as depression and anxiety. These disorders are more frequently diagnosed in females, and sex differences in the response to stress are likely to be one factor that leads to enhanced vulnerability of females. In this study, we use subchronic variable stress (SCVS), a model in which male and female mice exhibit distinct behavioral, transcriptional, and immunological alterations, to investigate sexually divergent mechanisms of regulation of the ventral tegmental area by stress. Using slice electrophysiology, we find that female, but not male, mice have a reduction in the ex vivo firing rate of VTA dopaminergic neurons following SCVS. Surprisingly, both male and female animals show an increase in inhibitory tone onto VTA dopaminergic neurons and an increase in the firing rate of VTA GABAergic neurons. In males, however, this is accompanied by a robust increase in excitatory synaptic tone onto VTA dopamine neurons. This supports a model by which SCVS recruits VTA GABA neurons to inhibit dopaminergic neurons in both male and female mice, but males are protected from diminished functioning of the dopaminergic system by upregulation of excitatory synapses. Thus, SCVS leads to both shared and disparate changes in the organization of the VTA in males and females.
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ABSTRACTThe degree to which motor imagery engages the motor system or relies on perceptual/cognitive processes is a continuing debate. Here, we used the size weight illusion to create dissociation between perception and action to address the nature of motor imagery. Participants alternated lifting bricks of equal mass but where one brick was larger than the other, resulting in a perceptual illusion. Fifty‐seven participants were divided into three groups differing in the modality used for training (motor imagery, MI; and overt execution, OE) and exposure to the size weight illusion pretraining, one (MI‐2) and five (MI‐10 and OE) lifts of each brick. We hypothesized that the MI groups would use lifting dynamics post‐training consistent with the illusion, whereas the OE group would maintain accurate lifting forces. Contrary to our hypothesis, the OE and MI‐10 groups maintained the effect of the illusion post‐training. In the MI‐2 group, perception of the bricks' weight changed to reflect the participant's belief that large objects are heavy, and they correspondingly adjusted their lifting force post‐training. These results demonstrate that perceptual and motor processes are engaged during motor imagery and that the simulation of the motor component of the movement during motor imagery guides the performed action.
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In the Drosophila olfactory system most odorants are encoded in the antennal lobe in a combinatory way, activating several glomerular circuits. However, odorants of particular ecological role for the fly are encoded through activation of a single specialized olfactory pathway. Comparative analyses of densely reconstructed connectomes of one broadly tuned glomerulus (DL5) and one narrowly tuned glomerulus (DA2) gained detailed insight into the variations of synaptic circuitries of glomeruli with different computational tasks. Our approach combined laser-branding of glomeruli of interest with volume based focused ion beam-scanning electron microscopy (FIB-SEM) to enable precise targeting and analysis of the two glomeruli. We discovered differences in their neuronal innervation, synaptic composition and specific circuit diagrams of their major cell types: olfactory sensory neurons (OSNs), uniglomerular projection neurons (uPNs) and multiglomerular neurons (MGNs). By comparing our data with a previously mapped narrowly tuned glomerulus (VA1v), we identified putative generic features of narrowly tuned glomerular circuits, including higher density of neuronal fibers and synapses, lower degree of OSN lateralization, stronger axo-axonic connections between OSNs, dendro-dendritic connections between many uPNs, and lower degree of presynaptic input on OSN axons. In addition, this work revealed that the dendrites of the single uPN in DL5 contain a substantial amount of autapses interconnecting distant regions of the dendritic tree. The comparative analysis of glomeruli allows to formulate synaptic motifs implemented in olfactory circuits with different computational demands.
The detection and localization of signals rely on arrays of receptors, and their spatial organization plays a key role in determining the accuracy of the system. Weakly electric ghost knifefish rely on a distributed array of electroreceptors to detect spatially diffuse electric signals from conspecifics. While we know that spatial resolution for small objects, such as prey, is enhanced near the head due to a high receptor density, it is not clear how receptor organization influences the processing of global and diffuse signals from conspecifics. Using spatially realistic modeling, we quantified how receptor density influences detection and localization accuracy for conspecific signals across varying distances. Our main result demonstrates that receptor density markedly enhances detection accuracy in frontal regions at intermediate distances (35-50 cm) yet surprisingly contributes minimally to improving localization accuracy. This highlights a fundamental principle: receptor convergence primarily benefits signal detection when dealing with spatially diffuse stimuli, even though higher receptor density can enhance localization accuracy for spatially delineated signals. Our findings extend beyond the electrosensory modality, drawing parallels with other sensory systems, and offer broader insights into spatial processing principles.
The detection and localization of signals rely on arrays of receptors, and their spatial organization plays a key role in determining the accuracy of the system. Weakly electric ghost knifefish rely on a distributed array of electroreceptors to detect spatially diffuse electric signals from conspecifics. While we know that spatial resolution for small objects, such as prey, is enhanced near the head due to a high receptor density, it is not clear how receptor organization influences the processing of global and diffuse signals from conspecifics. Using spatially realistic modeling, we quantified how receptor density influences detection and localization accuracy for conspecific signals across varying distances. Our main result demonstrates that receptor density markedly enhances detection accuracy in frontal regions at intermediate distances (35-50 cm) yet surprisingly contributes minimally to improving localization accuracy. This highlights a fundamental principle: receptor convergence primarily benefits signal detection when dealing with spatially diffuse stimuli, even though higher receptor density can enhance localization accuracy for spatially delineated signals. Our findings extend beyond the electrosensory modality, drawing parallels with other sensory systems, and offer broader insights into spatial processing principles.
Dreams incorporate recent experiences, and memory-related brain activity is reactivated during sleep, suggesting that dreaming, memory consolidation and reactivation are tightly linked. We devised a paradigm to investigate whether memory reprocessing during sleep contributes to dreaming. Participants listened to different audiobooks before falling asleep, introducing dissimilar experiences to be processed at night. We show that audiobook content was reprocessed at the neural level using multivariate pattern analyses. Brain activity during rapid eye movement sleep, particularly in the beta range, carried information about the audiobook. While the amount of neural reinstatement did not correlate with memory retention, global beta power during REM sleep was associated with better memory performance. Moreover, blind raters could determine which audiobook participants had studied based on dream reports. Participants who dreamt of the audiobook also showed stronger neural reinstatement. Reprocessing of pre-sleep experiences during sleep may thus shape our brain activity, our dreams, and our memories.
Beta band rhythms often appear as brief bursts, but how variations in burst properties impact neural function is unclear. We probed beta burst heterogeneity by developing two complementary detection algorithms. One isolates brief high amplitude events (bursts of power, BoP) and another that identifies consistent oscillations that span multiple cycles (bursts of consistency, BoC). Examining frontal LFP and ECoG recordings from mice and macaques, these two burst types occupied the same 15 to 30 Hz frequency band yet showed minimal temporal overlap, indicating independent phenomena probably with distinct neural generators. Crucially, when task demands shifted between high and low cognitive control states, BoC bursts were enriched during demanding phases, whereas BoP bursts dominated routine phases. These results demonstrate that frontal beta activity comprises at least two rhythmically distinct regimes linked to different levels of cognitive control. Our dual mode framework refines mechanistic models of transient oscillations and underscores the significance of burst waveform diversity for flexible brain function.
Cognitive decline associated with healthy ageing is multifactorial: brain-based and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing models of neurocognitive ageing such as compensation, maintenance, or reserve, we explore how various known brain-based and cardiorespiratory fitness factors intersect to better understand cognitive decline. In a pre-registered study (https://osf.io/6fqg7), we tested 73 healthy older adults aged 60--81 (M = 65.51, SD = 4.94) and collected neuroimaging (functional, structural, and perfusion MRI), cardiorespiratory fitness, and cognitive data to investigate a prominent challenge for older adults: word-finding failures. fMRI signal was recorded while participants responded to a definition-based tip-of-the-tongue task, T1-weighted imaging estimated grey matter volume, and cerebral blood flow was indexed using multi-delay pseudo-continuous arterial spin labelling. Commonality analyses were used to analyse these multi-domain data (neuroimaging, cardiorespiratory fitness, language skills, demographic characteristics) and uncover associations between predictors in explaining age-related tip-of-the-tongue rates. Commonality analyses revealed that functional activation of language networks associated with tip-of-the-tongue states is in part linked with age and, interestingly, cardiorespiratory fitness: the combination of higher cardiorespiratory fitness and functional recruitment in some older adults offsets part of the age-related variance in tip-of-the-tongues. Moreover, age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongues. Our findings can be interpreted in the context of the classic models of neurocognitive ageing, suggesting compensation. Brain health indices in concordance with cardiorespiratory fitness can provide a more holistic explanation of individual differences in age-related cognitive decline. HighlightsO_LIWord-finding problems are linked to brain health and cardiorespiratory fitness (CRF) C_LIO_LIBrain activity linked to word-finding failures is modulated by CRF and age C_LIO_LIDistinct contribution of structure and perfusion also associated with word-finding C_LIO_LILinking brain and CRF factors provides better account of age-related cognitive decline C_LI
With advancing age, the distinctiveness of neural representations of information declines. While the finding of this so-called age-related neural dedifferentiation in category-selective neural regions is well-described, how neural dedifferentiation manifests at the level of large-scale functional networks is less understood. Furthermore, the relationship between age-related changes in network organization and dedifferentiation is unknown. Here, we investigated age-related neural dedifferentiation of category-selective regions as well as whole-brain functional networks. We additionally examined age differences in connectivity of category-selective regions to the rest of the brain. Younger and older adults viewed blocks of face and house stimuli while performing memory encoding and retrieval in the fMRI scanner. We found an age-related decline in neural distinctiveness for faces in the fusiform gyrus (FG) and for houses in the parahippocampal gyrus (PHG). Functional connectivity analyses revealed age-related dedifferentiation of global network structure as well as age differences in the connectivity profiles to category-selective regions. Together, our findings suggest that age-related neural dedifferentiation manifests both in regional categorical representations as well as in whole- brain functional networks. HighlightsO_LICategory representations are less distinctive, or dedifferentiated, in older adults C_LIO_LIFunctional networks are less segregated in older adults C_LIO_LIOlder adults reveal less connectivity between fusiform gyrus and visual cortices C_LI
Synchronous neuronal ensembles play a pivotal role in the consolidation of long-term memory in the hippocampus. However, their organization during the acquisition of spatial memory remains less clear. In this study, we used neuronal population voltage imaging to investigate the synchronization patterns of CA1 pyramidal neuronal ensembles during the exploration of a new environment, a critical phase for spatial memory acquisition. We found synchronous ensembles comprising approximately 40% of CA1 pyramidal neurons, firing simultaneously in brief windows ([~]25ms) during immobility and locomotion in novel exploration. Notably, these synchronous ensembles were not associated with contralateral ripple oscillations but were instead phase-locked to theta waves recorded in the contralateral CA1 region. Moreover, the subthreshold membrane potentials of neurons exhibited coherent intracellular theta oscillations with a depolarizing peak at the moment of synchrony. Among newly formed place cells, pairs with more robust synchronization during locomotion displayed more distinct place-specific activities. These findings underscore the role of synchronous ensembles in coordinating place cells of different place fields.
Cortical activity shows the ability to recover from distractions. We analyzed neural activity from the prefrontal cortex (PFC) of monkeys performing working memory tasks with mid-memory-delay distractions (a cued gaze shift or an irrelevant visual input). After distraction there were state-space rotational dynamics that returned spiking to population patterns similar to those pre-disruption. In fact, rotations were fuller when the task was performed correctly versus when errors were made. We found a correspondence between state-space rotations and traveling waves across the surface of the PFC. This suggests a role for emergent dynamics like state-space rotations and traveling waves in recovery from distractions.
Estimating dynamic network communication is attracting increased attention, spurred by rapid advancements in multi-site neural recording technologies and efforts to better understand cognitive processes. Yet, traditional methods, which infer communication from statistical dependencies among distributed neural recordings, face core limitations: they do not incorporate possible mechanisms of neural communication, neglect spatial information from the recording setup, and yield predominantly static estimates that cannot capture rapid changes in the brain. To address these issues, we introduce the graph diffusion autoregressive model. Designed for distributed field potential recordings, our model combines vector autoregression with a network communication process to produce a high-resolution communication signal. We successfully validated the model on simulated neural activity and recordings from subdural and intracortical micro-electrode arrays placed in macaque sensorimotor cortex demonstrating its ability to describe rapid communication dynamics induced by optogenetic stimulation, changes in resting state communication, and neural correlates of behavior during a reach task.
Although hippocampal place cells replay nonlocal trajectories, the computational function of these events remains controversial. One hypothesis, formalized in a prominent reinforcement learning account, holds that replay plans routes to current goals. However, recent puzzling data appear to contradict this perspective by showing that replayed destinations lag current goals. These results may support an alternative hypothesis that replay updates route information to build a "cognitive map." Yet no similar theory exists to formalize this view, it is unclear how such a map is represented or what role replay plays in computing it. We address these gaps by introducing a theory of replay that learns a map of routes to candidate goals, before reward is available or when its location may change. Replay is then focused on current goals (as with planning) and/or potential future goals (like a map), depending on the animal's expectations about future goal switching. Our work thus generalizes the planning account to capture a general map-building function for replay, reconciling it with data, and revealing an unexpected relationship between the seemingly distinct hypotheses. The theory offers a unifying explanation why data from tasks with different goal dynamics have seemingly supported different hypotheses for the function of replay, and suggests new predictions for experiments testing these effects.
The superior colliculus (SC) is traditionally considered a brain region that functions as an interface between processing visual inputs and generating eye movement outputs. Although its role as a primary reflex center is thought to be conserved across vertebrate species, evidence suggests that the SC has evolved to support higher-order cognitive functions including spatial attention. When it comes to oculomotor areas such as the SC, it is critical that high precision fixation and eye movements are maintained even in the presence of signals related to ongoing changes in cognition and brain state, both of which have the potential to interfere with eye position encoding and movement generation. In this study, we recorded spiking responses of neuronal populations in the SC while monkeys performed a memory-guided saccade task and found that the activity of some of the neurons fluctuated over tens of minutes. By leveraging the statistical power afforded by high-dimensional neuronal recordings, we were able to identify a low-dimensional pattern of activity that was correlated with the subjects' arousal levels. Importantly, we found that the spiking responses of deep-layer SC neurons were less correlated with this brain-wide arousal signal, and that neural activity associated with changes in pupil size and saccade tuning did not overlap in population activity space with movement initiation signals. Taken together, these findings provide a framework for understanding how signals related to cognition and arousal can be embedded in the population activity of oculomotor structures without compromising the fidelity of the motor output.
Humans routinely anticipate upcoming language, but whether such predictions come at a cognitive cost remains debated. In this study, we demonstrate the resource-dependent nature of predictive mechanisms in language comprehension across the lifespan: Experimentally limiting executive resources through a concurrent task reduces the effect of language predictability on reading time. Participants (N=175, replication N=96) read short articles presented word-by-word while completing a secondary font colour n-back task, thus varying cognitive demand. Language predictability was indexed by word surprisal as derived from a pre-trained large language model (GPT-2). Across two independent samples, our findings reveal that language predictions are not cost-free: They draw on executive control resources, and this dependency becomes more pronounced with age (18-85 years). These results help resolve the debate over cognitive demands in language comprehension and highlight prediction as a dynamic, resource-dependent process across the lifespan.
A greater understanding of the neurobiology of nicotine is needed to reduce or prevent chronic addiction, ameliorate detrimental nicotine withdrawal effects, and improve cessation rates. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), 4{beta}2 and 7. Protein kinase B-{beta} (Pkb-{beta} or Akt2) expression is restricted to astrocytes in mice and humans and is activated by nicotine. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specific Akt2 conditional knockout (cKO) and full Akt2 KO mice. For in/ex vivo studies, we examined mice exposed to chronic nicotine for two weeks in drinking water (200 g/mL) or following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 hrs. Our in vitro studies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereas Akt2 cKO mice showed enhanced acute responses and reduced area following chronic exposure. In culture, we found 100 M nicotine sufficient for morphological changes and blocking 7 or 4{beta}2 nAChRs prevented observed morphologic changes. We performed conditioned place preference (CPP) in Akt2 cKO mice, which revealed reduced nicotine preference in cKO mice compared to controls. Finally, we performed RNASeq comparing nicotine- and LPS-mediated gene expression, identifying robust differences between these two astrocytic stimuli. These findings show the importance of nAChRs and AKT2 signaling in the astrocytic response to nicotine. Main PointsO_LINicotine regulates astrocytes in vivo: acute exposure boosts complexity; chronic exposure diminishes it. C_LIO_LIAKT2, expressed in astroglia, modulates morphological changes in response to nicotine and nicotine-dependent conditioned place preference. C_LI
Time-resolved functional network connectivity (trFNC) assesses the time-resolved coupling between brain regions using functional magnetic resonance imaging (fMRI) data. This study aims to compare two techniques used to estimate trFNC, to investigate their similarities and differences when applied to fMRI data. These techniques are the sliding window Pearson correlation (SWPC), an amplitude-based approach, and phase synchronization (PS), a phase-based technique. To accomplish our objective, we used resting-state fMRI data from the Human Connectome Project (HCP) with 827 subjects (repetition time: 0.7s) and the Function Biomedical Informatics Research Network (fBIRN) with 311 subjects (repetition time: 2s), which included 151 schizophrenia patients and 160 controls. Our simulations reveal distinct strengths in two connectivity methods: SWPC captures high-magnitude, low-frequency connectivity, while PS detects low-magnitude, high-frequency connectivity. Stronger correlations between SWPC and PS align with pronounced fMRI oscillations. For fMRI data, higher correlations between SWPC and PS occur with matched frequencies and smaller SWPC window sizes ([~]30s), but larger windows ([~]88s) sacrifice clinically relevant information. Both methods identify a schizophrenia-associated brain network state but show different patterns: SWPC highlights low anti-correlations between visual, subcortical, auditory, and sensory-motor networks, while PS shows reduced positive synchronization among these networks. In sum, our findings underscore the complementary nature of SWPC and PS, elucidating their respective strengths and limitations without implying the superiority of one over the other. Impact StatementThis study demonstrates that SWPC and PS provide complementary insights into dynamic functional connectivity, revealing different aspects of brain dynamics based on signal focus. For tasks involving slow dynamics, SWPC amplitude is ideal, while the PS phase is more suitable for transient dynamics. In schizophrenia, typically associated with general dysconnectivity, we uncover a dual dysconnectivity profile depending on phase or amplitude dynamics. This novel approach offers researchers a platform to explore task-specific dysconnectivity profiles, enabling more targeted interventions. These findings will guide methodology choices, deepen understanding of brain dynamics, and support the development of precise neuropsychiatric biomarkers. HighlightsO_LITime-resolved functional network connectivity (trFNC) is widely used; here we study two approaches often pit against one another: 1) phase synchrony (PS), a phase-based method, and 2) sliding window Pearson correlation (SWPC), an amplitude-based method. C_LIO_LISWPC is sensitive to the choice of window size, while PS requires a narrow frequency band. Both can result in the loss of relevant information. C_LIO_LIWe find through simulation that SWPC better captures high-magnitude slow-varying amplitude-encoded connectivity while PS better captures low-magnitude fast-varying phase-encoded connectivity. C_LIO_LIWe find that while both SWPC and PS detect disconnected states mostly associated with schizophrenia they exhibit unique complementary patterns. C_LIO_LIWe conclude that SWPC and PS are complementary techniques, each with distinct assumptions and constraints, which should be selected based on the focus of the study. C_LI
Perceptual similarity is a cornerstone for human learning and generalization. However, in assessing the similarity between two stimuli differing in multiple dimensions, it is not well- defined which feature(s) one should focus on. The problem has accordingly been considered ill-posed. We hypothesize that similarity judgments may be, in a sense, metacognitive: The stimuli rated as subjectively similar are those that are in fact more challenging for oneself to discern in practice, in near-threshold settings (e.g., psychophysics experiments). This self- knowledge about ones own perceptual capacities provides a quasi-objective ground truth as to whether two stimuli should be judged as similar. To test this idea, we measured perceptual discrimination capacity between face pairs, and asked subjects to rank the similarity between them. We found a positive association between perceptual discrimination capacity and subjective perceptual dissimilarity, with this association being importantly specific to each individual. The results indicate that perceptual similarity judgment reflects and predicts ones own perceptual capacities, supporting our hypothesis that perceptual similarity judgment is metacognitive.
Pain is a prominent and debilitating symptom in myotonic disorders, including myotonia congenita and myotonic dystrophy type 1 (DM1). Although patients frequently report chronic pain, its underlying mechanisms remain poorly defined. In both disorders, impaired chloride conductance through voltage-gated CLC-1 chloride channels in skeletal muscle disrupts membrane repolarization, leading to delayed relaxation and persistent muscle hyperexcitability. Here, we investigated the pathophysiology of pain in mouse models of acute and chronic myotonia. In the acute model, a single intraperitoneal injection of anthracene 9 carboxylic acid (9-AC, 30 mg/kg), a selective ClC-1 antagonist, induced transient muscle stiffness, cramping, and gait abnormalities, followed by prolonged pain like behavior, including static and dynamic mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity for up to 48 hours. Whole-cell patch-clamp recordings from dorsal root ganglion neurons demonstrated increased action potential firing in small diameter sensory neurons, consistent with enhanced peripheral excitability of putative nociceptors. Compound action potentials from isolated sciatic nerves revealed that 9-AC impaired A-fiber recruitment and stimulus-response gain without affecting conduction velocity, suggesting a reduction in non-nociceptive fiber input that may disinhibit central nociceptive processing. To assess central mechanisms of sensitization, we performed in vivo fiber photometry of the parabrachial nucleus (PBN), a key supraspinal hub for pain signaling. Mice treated with 9-AC exhibited exaggerated PBN responses to normally innocuous mechanical and cold stimuli, indicative of enhanced central nociceptive transmission. Having established that acute myotonia can evoke both peripheral and central sensitization, we next examined whether chronic myotonic activity in a disease-relevant genetic model produces similar pathophysiological changes. To model chronic myotonia, we evaluated HSA LR20b mice, a transgenic model of DM1 carrying a skeletal muscle-specific CTG repeat expansion. These mice displayed persistent mechanical and thermal hypersensitivity, along with elevated dorsal root ganglia neuron excitability, supporting sustained peripheral sensitization in a genetic model of myotonic disease. Together, these findings establish robust preclinical models of myotonic pain and demonstrate that myotonia drives a prolonged nociplastic pain state through combined peripheral and central mechanisms. These results provide a foundation for future studies aimed at identifying and validating therapeutic targets for pain associated with myotonic disorders.
In the early olfactory system, adult-neurogenesis, a process of neuronal replacement results in the continuous reorganization of synaptic connections and network architecture throughout the animals life. This poses a critical challenge: How does the olfactory system maintain stable representations of odors and therefore allow for stable sensory perceptions amidst this ongoing circuit instability? Utilizing a detailed spiking network model of early olfactory circuits, we uncovered dual roles for adult-neurogenesis: one that both supports representational stability to faithfully encode odor information and also one that facilitates plasticity to allow for learning and adaptation. In the main olfactory bulb, adult-neurogenesis affects neural codes in individual mitral and tufted cells but preserves odor representations at the neuronal population level. By contrast, in the olfactory piriform cortex, both individual cell responses and overall population dynamics undergo progressive changes due to adult-neurogenesis. This leads to representational drift, a gradual alteration in sensory perception. Both processes are dynamic and depend on experience such that repeated exposure to specific odors reduces the drift due to adult-neurogenesis; thus, when the odor environment is stable over the course of adult-neurogenesis, it is neurogenesis that actually allows the representations to remain stable in piriform cortex; when those olfactory environments change, adult-neurogenesis allows the cortical representations to track environmental change. Whereas perceptual stability and plasticity due to learning are often thought of as two distinct, often contradictory processing in neuronal coding, we find that adult-neurogenesis serves as a shared mechanism for both. In this regard, adult-neurogenesis in the mammalian olfactory bulb that has been the focus of considerable study in chemosensory neuroscience may be the mechanistic underpinning behind an array of complex computations.
While we often assume that memory encoding occurs from an in-body (first-person) perspective, out-of-body experiences demonstrate that we can form memories from a third-person perspective. This phenomenon provides a distinctive opportunity to examine the interaction between embodiment and visual perspective during encoding, and how this interplay shapes the recall of past events. Participants formed memories for naturalistic events following a manipulation of their sense of embodiment from in-body and out-of-body perspectives and recalled them during functional scanning. Region of interest multivariate analyses examined how the angular gyrus, precuneus, and hippocampus reflected visual perspective, embodiment, and their interaction during remembering. Patterns of activity during retrieval in the left angular gyrus and bilateral precuneus predicted embodiment on its own separated from visual perspective. In contrast, we observed only inconclusive evidence that these posterior parietal regions predicted visual perspective independent of embodiment. While the left angular gyrus distinguished between in-body and out-of-body perspectives during the retrieval of events associated with both strong and weak embodiment, decoding accuracy predicting visual perspective was only above chance for events encoded with strong embodiment in the precuneus bilaterally. Our results suggest that the contribution of posterior parietal regions in establishing visual perspectives within memories is tightly interconnected with embodiment. Encoding events from an embodied in-body perspective compared to embodied out-of-body perspective led to higher memory accuracy following repeated retrieval. These results elucidate how fundamental feelings of being located in and experiencing the world from our own bodys perspective are integrated within memory.
Goal-directed learning arises from distributed neural circuits including the prefrontal, posterior parietal and temporal cortices. However, the role of cortico-cortical functional interactions remains unclear. To address this question, we integrated information dynamics analysis with magnetoencephalography to investigate the encoding of learning signals through neural interactions. Our findings revealed that information gain (the reduction in uncertainty about the causal relationship between actions and outcomes) is represented over the visual, parietal, lateral prefrontal and ventromedial/orbital prefrontal cortices. Cortico-cortical interactions encoded information gain synergistically at the level of pairwise and higher-order relations, such as triplets and quadruplets. Higher-order synergistic interactions were characterized by long-range relationships centered in the ventromedial and orbitofrontal cortices, which served as key receivers in the broadcast of information gain across cortical circuits. Overall, this study provides evidence that information gain is encoded through synergistic and higher-order functional interactions and is broadcast to prefrontal reward circuits.
A high degree of structural complexity arises in dynamic neuronal dendrites due to extensive branching patterns and diverse spine morphologies, which enable the nervous system to adjust function, construct complex input pathways and thereby enhance the computational power of the system. Owing to the determinant role of dendrite morphology in the functionality of the nervous system, recognition of pathological changes due to neurodegenerative disorders is of crucial importance. We show that the statistical analysis of a temporary signal generated by cargos that have diffusively passed through the complex dendritic structure yields vital information about dendrite morphology. As a feasible scenario, we propose engineering mRNA-carrying multilamellar liposomes to diffusively reach the soma and release mRNAs, which are translated into a specific protein upon encountering ribosomes. The concentration of this protein over a large population of neurons can be externally measured, as a detectable temporary signal. Using a stochastic coarse-grained approach for first-passage through dendrites, we connect the key morphological properties affected by neurodegenerative diseases--including the density and size of spines, the extent of the tree, and the segmental increase of dendrite diameter towards soma--to the characteristics of the evolving signal. Thus, we establish a direct link between the dendrite morphology and the statistical characteristics of the detectable signal. Our approach provides a fast noninvasive measurement technique to indirectly extract vital information about the morphological evolution of dendrites in the course of neurodegenerative disease progression.
Core body temperature (Tb) is defended within narrow limits through thermoregulatory behaviors like huddling, nesting, and physical activity as well as autonomic responses like brown fat thermogenesis and peripheral vasodilation. While Tb displays regulated fluctuations across different behavioral states and rest/arousal cycles, the neural control of these transitions is poorly understood. Here, we investigate the relationship between oxytocin neurons of the paraventricular hypothalamus (PVNOT) and behavioral and autonomic thermoeffector pathways across physiological states in mice. First, we show that PVNOT neurons are activated during social thermoregulation. We then demonstrate that--in both social and nonsocial contexts--in vivo PVNOT calcium dynamics align with transitions from rest to thermogenesis and behavioral arousal. Using a computer vision model to track thermoeffector pathways, we demonstrate that precisely timed stimulation of PVNOT during low-Tb resting states increases thermogenesis and behavioral arousal. We therefore suggest a model in which PVNOT neurons facilitate state-dependent transitions in thermo-behavioral states.
Unilateral spatial neglect (USN) is a common consequence of right-hemisphere stroke, traditionally attributed to structural lesions and dysfunctional attention networks. However, the brain is fundamentally a rhythmic and dynamical system, and how disrupted neural synchronization underlies USN remains unknown. We recorded steady-state visual evoked potentials (SSVEPs; 3 - 30 Hz flicker) in stroke patients with USN, without USN, and healthy controls. Only the USN group exhibited significant hemispheric asymmetry at 9 Hz, driven by exaggerated responses in the intact hemisphere rather than suppression in the lesioned hemisphere. This effect appeared only during stimulation, not at rest, indicating its specificity to sensory processing. The enhanced 9 Hz entrainment in the intact hemisphere was accompanied by increased phase-amplitude coupling (PAC) between alpha phase and gamma amplitude, reflecting systematic coordination of high-frequency activity. Transfer entropy analysis further revealed increased feedforward information flow from the right visual to the left frontal cortex, highlighting large-scale asymmetry. To explore the mechanism underlying this frequency-specific bias, we implemented a coupled-oscillator model. The model showed that the hemispheric asymmetry arises from resonance between intrinsic alpha rhythms and external input, amplified by asymmetric right-to-left interhemispheric coupling. These findings suggest that USN arises from a selective impairment of alpha-band synchrony capacity. This study offers a novel framework conceptualizing USN as a disorder of disrupted oscillatory dynamics underlying spatial attention, and points toward frequency-specific neuromodulatory intervention as a potential therapeutic approach.
Rapid and high local calcium (Ca2+) signals are essential for triggering neurotransmitter release from presynaptic terminals. In specialized bipolar ribbon synapses of the retina, these local Ca2+ signals control multiple processes, including the priming, docking, and translocation of vesicles on the ribbon before exocytosis, endocytosis, and the replenishment of release-ready vesicles to the fusion sites for sustained neurotransmission. However, our knowledge about Ca2+ signals along the axis of the ribbon active zone is limited. Here, we used fast confocal quantitative dual-color ratiometric line-scan imaging of a fluorescently labeled ribbon binding peptide and Ca2+ indicators to monitor the spatial and temporal aspects of Ca2+ transients of individual ribbon active zones in zebrafish retinal rod bipolar cells (RBCs). We observed that a Ca2+ transient elicited a much greater fluorescence amplitude when the Ca2+ indicator was conjugated to a ribeye-binding peptide than when using a soluble Ca2+ indicator, and the estimated Ca2+ levels at the ribbon active zone exceeded 26 M in response to a 10-millisecond stimulus, as measured by a ribbon-bound low-affinity Ca2+ indicator. Our quantitative modeling of Ca2+ diffusion and buffering is consistent with this estimate and provides a detailed view of the spatiotemporal [Ca2+] dynamics near the ribbon. Importantly, our data demonstrates that the local Ca2+ levels may vary between ribbons of different RBCs and within the same cells. The variation in local Ca2+ signals is found to correlate with ribbon size and active zone extent. Our serial electron microscopy results provide new information about the heterogeneity in ribbon size, shape, and area of the ribbon in contact with the plasma membrane.
Complex behavioral and cognitive functions emerge from coordinated dynamic communication between often disparate brain regions, implying a systems-level arrangement of underlying neural signals. This study introduces multivariate mixture and hidden Markov modeling approaches to analyze phase coherence networks in fMRI data, capturing macroscale dynamic functional synchronization in the human brain. We show that 1) phase coherence is inherently a complex-valued phenomenon and should beanalyzed as such, 2) statistical models for assessing complex-valued phase coherence, particularly the complex angular central gaussian (ACG) distribution, outperform amplitude and phase-amplitude methods on synthetic and task fMRI data as well as existing phase coherence modeling approaches (including LEiDA), 3) models of phase coherence should account for the inherent anisotropy of the brains interconnections by including a covariance matrix in each mixture component. We provide a Python-based toolbox ("Phase Coherence Mixture Modeling" (PCMM): github.com/anders-s-olsen/PCMM) to facilitate implementation of phase coherence models.
Connectomics is a field of neuroscience that maps the brains intricate wiring diagram. Accurate neuron segmentation from microscopy volumes is essential for automating connectome reconstruction. However, state-of-the-art algorithms use image-based convolutional neural networks limited to local neuron shape context. Thus, we introduce a new framework that reasons over global neuron shape with a novel point affinity transformer. Our framework embeds a (multi-)neuron point cloud into a fixed-length feature set from which we can decode any point pair affinities, enabling clustering neuron point clouds for automatic proofreading. We also show that the learned feature set can easily be mapped to a contrastive embedding space that enables neuron type classification using a simple classifier. Our approach excels in two demanding connectomics tasks: correcting segmentation errors and classifying neuron types. Evaluated on three benchmark datasets derived from state-of-the-art connectomes, our method outperforms point transformers, graph neural networks, and unsupervised clustering baselines.
Human walking involves tightly coordinated movements of the right and left legs. We recently developed and tested a "dynamic treadmill walking" paradigm that changes the treadmill speed within a single step to provide asymmetric training for persons with gait dysfunction. We previously demonstrated that this approach could induce changes in human gait symmetry; however, if this approach is to be used in rehabilitation, we also need to understand how movements of the legs are coordinated to produce these asymmetric gait changes. The goal of this study was to examine the temporal (phase shift) and spatial (center of oscillation difference) aspects of interlimb coordination during dynamic treadmill walking in ten young adults without gait impairment. We found that dynamic treadmill walking drove significant changes in phase shift and center of oscillation difference that were dependent on the timing of the treadmill speed change within the gait cycle. For example, slowing the treadmill during the stance phase extended the double limb support period, and these changes were strongly correlated with a phase shift between the two legs. Accelerating the treadmill late in stance led to extensions in the trailing limb angle that were strongly correlated with changes in the center of oscillation difference. Overall, dynamic treadmill walking can be configured to drive changes in many spatiotemporal, kinematic, and interlimb coordination parameters, creating a variety of options for restoring gait symmetry and targeting aspects of spatial and temporal interlimb coordination in clinical populations with heterogenous patterns of gait asymmetry.
Sexual differentiation of the nervous system drives profound neurobiological and behavioral differences between the sexes across various organisms, including Caenorhabditis elegans. Using single-nucleus RNA sequencing, we profiled and compared adult male and hermaphrodite C. elegans neurons, generating an atlas of adult male-specific and sex-shared neurons. We expanded the molecular map of male-specific neurons, and identified highly dimorphic expression of GPCRs, neuropeptides, and ion channels. Our data demonstrate sex-shared neurons exhibit substantial heterogeneity between the sexes, while sex-specific neurons repurpose conserved molecular pathways to regulate dimorphic behaviors. We show that the PHD neurons display remarkable similarity to sex-shared AWA neurons, suggesting partial repurposing of conserved pathways, and that they and the GPCR SRT-18 may play a role in pheromone sensing. We further demonstrate that the ubiquitously expressed MAPK phosphatase vhp-1 regulates both sex-specific and sex-shared behaviors. Our data provide a rich resource for discovering sex-specific transcriptomic differences and the molecular basis of sex-specific behaviors.
Neuromodulation therapies are often applied to peripheral nerves. These nerves can have physiological activity that interacts with the activity evoked by electrical stimulation, potentially influencing targeted neural output and clinical outcomes. Our goal was to quantify changes in sensory neural unit activity in response to variations in electrical stimulation frequency and amplitude. In a feline model, we applied cutaneous brushing to evoke pudendal nerve afferent activity with and without electrical stimulation via a pudendal nerve cuff electrode. We recorded neural output with microelectrode arrays implanted in ipsilateral sacral dorsal root ganglia (DRG). Combined inter-spike interval distributions for all DRG units showed ranges of flattening, increases, and shifts in response to electrical stimulation. These distributions and changes within them due to electrical stimulation were largely driven by a select few units. Mixed-effects models revealed that quicker firing units generally decreased in firing rate in response to electrical stimulation and, conversely, slower firing units increased in firing rate. A units underlying firing rate also drove the magnitude of change in mean output firing rate in response to stimulation. Further, the models reported a small, negative correlation between the output mean unit firing rate and the applied electrical stimulation frequency. These results demonstrate the potential impact of electrical stimulation on underlying neural firing activity and output. Peripheral neuromodulation may normalize abnormal firing patterns in nerves contributing to pathological disorders or alter unrelated physiological activity in off-target neurons. These factors should be considered when selecting neuromodulation settings in animal subjects and human patients.
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. The presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.
Sensory stimuli vary across a variety of dimensions, like contrast, orientation, or texture. The brain must rely on population representations to distinguish changes in one dimension from changes in another. To understand how the visual system might extract separable stimulus representations, we recorded multiunit neuronal responses to texture images varying along two dimensions: contrast, a property represented as early as the retina, and naturalistic statistical structure, a property that modulates neuronal responses in V2 and V4, but not in V1. We measured how sites in these 3 cortical areas responded to variation in both dimensions. Contrast modulated responses in all areas. In V2 and V4, the presence of naturalistic structure both modulated responses and increased contrast sensitivity. Tuning for naturalistic structure was strongest in V4; tuning in both dimensions was most heterogeneous in V4. We measured how well populations in each area could support the linear readout of both dimensions. Populations in V2 and V4 could support the linear readout of naturalistic structure, but in V4, this readout was more robust to variations in contrast. Significance StatementTo support flexible behavior, the brain must simultaneously represent different stimulus dimensions. Single neurons are typically modulated by multiple dimensions, and so cannot distinguish them - they must be extracted by decoding neural populations. We studied neuronal responses in three cortical visual areas - V1, V2, V4 - using texture images varying in both contrast and naturalistic image structure. We used population decoders to read out each dimension. In all areas, contrast was decoded independently of image structure. V1 could not decode image structure independent of contrast, and V2 could do so only poorly. Because the selectivity of individual sites for texture and contrast in V4 was more diverse than V1 or V2, only there could we extract separate representations of both dimensions.
Despite showing significant impact in cognitive preservation, the relationship between brain activity captured with functional Magnetic Resonance Imaging (fMRI) in gray matter and ventricular cerebrospinal fluid dynamics remains poorly understood. We analyzed 599 fMRI scans from 163 elderly participants at rest with varying degrees of cognitive impairment employing a unified phase coupling analysis that breaks from convention by incorporating both tissue and ventricular signal fluctuations. This whole-brain approach identified distinct brain-ventricle coupling modes that differentiate between cognitive status groups and correlate with specific cognitive abilities. Beyond the previously reported anti-phase coupling between global brain signals and ventricles--which we confirm occurs more frequently in cognitively normal controls--our analysis method uncovered additional coupling modes where signals in specific brain networks temporarily align with ventricle signals. At the cortical level, these modes reveal patterns corresponding to known resting-state networks: one overlapping with the Default Mode Network occurs significantly less frequently in Alzheimers Disease patients, while another revealing the Frontoparietal Network correlates positively with memory scores. Our findings demonstrate that different brain-ventricle coupling modes correlate with specific cognitive domains, with particular modes predicting memory, executive function, and visuospatial abilities. The coupling between signals in brain ventricles and established resting-state networks challenges our current understanding of functional network formation, suggesting an integral link with brain fluid motion. This reconceptualization of brain dynamics through the lens of fluid-tissue interactions establishes a fundamental physical basis for cognitive preservation, suggesting that therapeutic interventions targeting these interactions may prove more effective than approaches focused solely on cellular or molecular mechanisms.
Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.
A key challenge in todays fast-paced digital world is to integrate information from various sources, which differ in their reliability. Yet, little is known about how explicit probabilistic information about the likelihood that a source provides correct information is used in decision-making. Here, we investigated how such explicit reliability markers are integrated and the extent to which individuals have metacognitive insight into this process. We developed a novel paradigm where participants viewed opinions from sources of varying reliability to make a choice between two options. After each decision, they rated how much they felt a given source influenced their choice. Using computational modelling, we estimated the effective reliability participants assigned to each source and how leaky their decision process was. Overall, we found that participants acted as if sources were more informative than they actually were, inflating the reliability they were communicated. Interestingly, we show that even though sources were explicitly labelled as unreliable, these sources biased choices, as if these were treated as moderately reliable. Additionally, the presence of sources known to be lying, reliably voting for the incorrect answer, impaired performance by increasing decision leakiness. Despite these biases, participants showed some metacognitive awareness of what influenced their choices: they were generally accurate in reporting the degree to which a source influenced them and were aware of the impact unreliable sources had on their decisions. These results suggest that people make suboptimal use of explicit source reliability, but have some awareness of their suboptimal choices.
The Lateral Habenula (LHb) is a small brain structure specialized in encoding aversive signals. Bursting activity in the LHb has been consistently linked to mood regulation, with increased bursting activity proposed to promote depressive behaviors. Bursting is a complex dynamic process that has been extensively studied and modeled in other neuronal contexts. However, at the LHb this type of activity has typically been described only as transient periods of high frequency firing. Here, to provide a deeper understanding of LHb bursting, we analyzed this activity from the perspective of dynamical systems. Ex vivo, LHb neurons display a variety of bursting patterns, characterized at one extreme by a dominating square-wave type and in other by parabolic type, plus transitional forms referred to as triangular bursting. Notably, these bursting patterns, which reflect different LHb output modes, can occur within the same neuron, suggesting that they may correspond to distinct dynamic states of the same LHb neuron. To capture these complex behaviors, we propose an idealized multiple-timescale dynamical model. This model successfully reproduces the three main bursting patterns observed in experimental data. Furthermore, we identify a special point in the parameter space, termed the saddle-node homoclinic bifurcation, which acts as an organizing center demarcating the boundary between the two primary bursting patterns and around which the third pattern appear. Our model suggests that LHb bursting activity is structured around distinct dynamic states with potentially diverse and unexplored impacts on mood regulation. By providing new insights into the dynamic principles underlying LHb bursting, this framework may advance our understanding of its biological significance.
Cryopreserving the adult brain is challenging due to damage from ice formation, and traditional freezing methods fail to maintain neural architecture and function. Vitrification offers a promising alternative but has not been surveyed in the brain. Here, we demonstrate near-physiological recovery of the adult murine hippocampus after vitrification of brain slices and of the whole brain in situ. Key features of the hippocampus are preserved, including structural integrity, metabolic responsiveness, neuronal excitability, and synaptic transmission and plasticity. Notably, hippocampal long-term potentiation was well preserved, indicating that the cellular machinery of learning and memory remains operational. These findings extend known biophysical limits for cerebral hypothermic shutdown by demonstrating recovery after complete cessation of molecular mobility in the vitreous state. This suggests that the brain can be arrested in time and then reactivated, opening avenues for potential clinical applications. Significance StatementWhile the brain is considered exceptionally sensitive, we show that the hippocampus can resume normal electrophysiological activity after being rendered completely immobile in a cryogenic glass. The work extends known biophysical tolerance limits for the brain from the hypothermic to the cryogenic range and establishes a protocol for its long-term storage in a viable state.
Despite serious health and economic burden, borne more prominently by lower and lower middle-income countries, pharmacotherapy for common psychiatric disorders rely on drugs altering neurotransmission, with partial efficacies. The persistence of a chronic yet sub-threshold inflammation across the periphery and the brain is well documented in the patients and animal models of these disorders and can be investigated for augmenting pharmacotherapy. IL1{beta}, a pleiotropic cytokine and a key regulator of neuroinflammation has been of particular interest in this regard. Previous studies on rodent models of anxiogenic stress show activation of a large multiprotein complex - the NLRP3 inflammasome, which increases IL1{beta} production facilitated by caspase 1, through what is considered a canonical inflammasome activation pathway. However, there exists a second non canonical inflammasome activation pathway whose impact on IL1{beta} release, inflammation and behavioral consequences remain unclear. Using rat models of physical and psychosocial stress, we observed stress-induced sex-specific upregulation of activated caspase 11 and gasdermin D N-terminal fragments, the mediators of the non-canonical inflammasome pathway that facilitates IL1{beta} release through pore formations in the plasma membrane. This is the first report of non-canonical inflammasome pathway being activated in the brain and peripheral immune cells in response to psychosocial stress. Inhibition of caspase 11 with wedelolactone, or Gasdermin D cleavage with Disulfiram reduced stress-induced elevation of IL1{beta} levels, anxiety and fear acquisition, facilitated fear extinction and recall, and improved working memory. Combination treatments targeting both canonical (ibrutinib for pBTK/NLRP3 or MCC950 for NLRP3 inhibition) and non-canonical (wedelolactone for caspase 11 or disulfiram for gasdermin D) pathways proved more efficacious in reducing stress-mediated neuroinflammation, dendritic spine elimination in the CA3 region of the hippocampus and behavioral dysfunction. Furthermore, psychosocial stress drove peripheral inflammation, in peripheral blood mononuclear cells, which was mitigated by the combination treatment. Taken together, this study reveals a novel mechanism underlying psychosocial stress involving both canonical and non-canonical inflammasome signaling to facilitate IL1{beta} induction and behavioral changes. Our finding further suggests that combined targeting of the NLRP3 inflammasome and gasdermin D could contribute to the development of future transdiagnostic therapeutic targets for stress, anxiety, and depression.
Epileptic seizures result from abnormal synchronous neuronal firing caused by an imbalance between excitatory and inhibitory neurotransmission. While most seizures are self-limiting, those lasting over five minutes, termed status epilepticus, require medical intervention. Benzodiazepines, the first-line treatment, terminate seizures by enhancing GABAergic inhibition, but fail in approximately 36% of cases. In this paper, we employ a neural mass framework to investigate how different interventions influence brain dynamics and facilitate seizure termination. As seizures are characterized by persistent firing, we extend the classic Wilson-Cowan framework by introducing a term called sustenance which encodes factors that promote or discourage perpetual firing. The resulting model captures transitions between normal activity and seizure and provides a tractable framework for analysing diverse pathophysiological mechanisms. We first show how various dysfunctions - such as hyperexcitation, depletion of inhibitory neurotransmitters, and depolarizing GABAergic transmission - can all give rise to seizures, with overlapping but distinct dynamics. Building on this foundation, we turn to the central question of intervention: how different treatments act on these mechanisms to terminate seizures. We find that while enhancing GABAergic inhibition is generally effective, it fails when GABA becomes depolarizing. In such cases, interventions like levetiracetam that suppress sustained excitatory activity remain effective. These findings highlight the importance of aligning interventions to the specific underlying dysfunction for effective seizure termination.
Large-scale extracellular recording techniques represent a major advance in interrogating the structure and dynamics of neuronal circuits. However, methods that can resolve cell-type identity in a principled way, while simultaneously scaling to thousands of neurons, are currently lacking. Here, we introduce spikeMAP, a pipeline for the analysis of large-scale recordings of in vitro cortical activity that not only allows for the detection of spikes produced by single neurons (spike sorting), but also allows for the reliable distinction between genetically determined cell types by utilizing viral and optogenetic strategies as ground-truth validation. This approach tightly integrates the data analysis pipeline to an optogenetic, viral, and pharmacological protocol allowing for the dynamical probing of distinct cell-types while simultaneously recording from large populations. The novelty of spikeMAP is to combine a stream of well-established analysis techniques in an end-to-end fashion, creating a unified framework as follows. First, individual spike waveforms are fitted by spline interpolation to estimate their half-amplitude and peak-to-peak durations. These values are then entered in a principal component analysis with k-means clustering to identify uncorrelated signals from single channels on the array. Optimal separability of clusters is assessed by linear discriminant analysis. Finally, each channels source location is identified using spatiotemporal characteristics of spike waveforms across the array. We show that spikeMAP can resolve cell type identity in high-density arrays by analyzing activity monitored from mouse prefrontal cortex in vitro slices with an array of 4,096 closely-spaced channels. Using an optotagging functional strategy, we show an effective distinction of regular-spiking excitatory neurons from fast-spiking inhibitory interneurons using measures of action potential waveform, Fano factor, and spatially-dependent cross-correlations. In sum, the approach introduces a toolbox, validated by an experimental pipeline, that allows for a comprehensive characterization of neuronal activity obtained from different cell-types in high-density multielectrode recordings. This provides a scalable approach to investigate the interplay between distinct cell types in microcircuits of the brain.
It has not previously been possible to investigate the fundamental relationship between axonal structure - which dictates action potential transmission - and human neuronal function in vivo. Here, we introduce a novel metric of axonal signal speed, estimated axonal latency (EAL), derived from the relationship between axonal diameter, myelination, and length measured via MRI. We validate EAL along two pathways of the face processing network by relating it to N170 latency, an electrophysiological marker of face processing speed measured via EEG. Our results show that EAL along these pathways predicts N170 latency specifically during face processing. Moreover, we demonstrate that individuals with and without autism rely upon different pathways, potentially providing a structural account for autism-related face processing differences. By establishing this relationship between EEG-based electrical function and MRI-based axonal microstructure, we provide a non-invasive, spatially detailed estimate of neuronal processing speed that can inform our understanding of brain function, development, and disorder. TeaserEstimated axonal latency is a non-invasive, spatially detailed measure of neuronal speed to inform brain function and disorder.
Tool use is a complex motor planning problem. Prior research suggests that planning to use tools involves resolving competition between different tool-related action representations. We therefore reasoned that competition may also be exacerbated with tools for which the motions of the tool and the hand are incongruent (e.g., pinching the fingers to open a clothespin). If this hypothesis is correct, we should observe marked deficits in planning the use of incongruent as compared to congruent tools in individuals with limb apraxia following left-hemisphere stroke (LCVA), a disorder associated with abnormal action competition. We asked 34 individuals with chronic LCVA (14 females) and 16 matched neurotypical controls (8 females) to use novel tools in which the correspondence between the motions of the hand and tool-tip were either congruent or incongruent. Individuals with LCVA also completed background assessments to quantify apraxia severity. We observed increased planning time for incongruent as compared to congruent tools as a function of apraxia severity. Further analysis revealed that this impairment predominantly occurred early in the task when the tools were first introduced. Lesion-symptom mapping analyses revealed that lesions to posterior temporal and inferior parietal areas were associated with impaired planning for incongruent tools. A second experiment on the same individuals with LCVA revealed that the ability to gesture the use of conventional tools was impaired for tools rated as more incongruent by a normative sample. These findings suggest that tool-hand incongruence evokes action competition and influences the tool-use difficulties experienced by people with apraxia. Significance StatementPrior research indicates that competition between different representations associated with moving or using tools must be resolved to enable tool use. We demonstrated that competition may be exacerbated when tool and hand motions are incongruent (e.g., pinching the hand opens a clothespin), resulting in tool-use impairments particularly for individuals with greater severity of limb apraxia, a disorder known to be associated with action competition abnormalities. Lesions in posterior portions of the brains tool use network were associated with impairments in planning incongruent tool actions. This study thus demonstrates that tool-hand incongruence may invoke competition between motions of the hand and tool-tip, which individuals with limb apraxia have difficulty resolving to properly use tools.
Neurofibromatosis Type 1 (NF1) is a rare, single-gene neurodevelopmental disorder. Atypical brain activation patterns have been linked to working memory difficulties in individuals with NF1. The present work investigates if NF1 has increased inhibitory activity in the frontoparietal network during working memory tasks compared to neurotypical controls. Forty-three adolescents with NF1 and twenty-six age-matched neurotypical controls completed functional magnetic resonance imaging scans during a verbal working memory task. Dynamic causal models (DCMs) were estimated for bilateral frontoparietal network (dorsolateral and ventrolateral prefrontal cortices (dlPFC and vlPFC), superior and inferior parietal gyri (SPG and IPG)). The parametric empirical Bayes approach with Bayesian model reduction was used to test the hypothesis that NF1 diagnosis would be characterised by greater inhibitory self-connections (intrinsic connectivity). Leave-one-out cross-validation (LOO-CV) was performed to test the generalisability of group differences. NF1 participants demonstrated greater average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC. The DCM that best explained effects of working memory showed that NF1 group has increased intrinsic connectivity of left vlPFC, but weaker intrinsic connectivity of right vlPFC and left dlPFC. The parameters of these connections showed a modest but positive predictive correlation of r = 0.19 (p = 0.055) with diagnosis status, suggesting a trend toward predictive value. Overall, increased average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC in NF1, suggests reduced overall sensitivity of these regions to inputs. Working memory evoked different patterns of input processing in NF1, that cannot be characterised by increased inhibition alone. Instead, modulatory connectivity related to working memory showed less inhibitory self-connectivity of left dlPFC and left vlPFC, and more inhibitory intrinsic connectivity of right vlPFC in NF1. This discrepancy between average and modulatory connectivity suggests that overall NF1 participants are responsive to cognitive task-related inputs but may show atypical adaptation to the task demands of working memory.
AO_SCPLOWBSTRACTC_SCPLOWGrid cells in the medial entorhinal cortex (MEC) fire when an animal is located at the vertices of a hexagonal grid that extends across the environment. The population activity of grid cells serves as an allocentric representation of the current location of the animal. Recent studies have identified a class of grid cells that represent locations ahead of the animal. How do these predictive representations emerge from the wetware of the MEC? To address this question, we developed a detailed conductance-based model of the MEC network, constrained by existing data on the biophysical properties of stellate cells and the topology of the MEC network. Our model revealed two mechanisms underlying the emergence of a predictive code in the MEC. The first relied on a time scale associated with the HCN conductance. The other depended on the degree of asymmetry in the topology of the MEC network. The former mechanism was sufficient to explain predictive coding in layer II grid cells that represented locations shifted ahead of the current location. The shift was equivalent to [~]5% of the diameter of a grid field. The latter mechanism was required to model predictive representations in layer III grid cells that were shifted forward by a distance of [~]25% of the diameter of a grid field. A corollary of our model, that the extent of the predictive code changes monotonically along the dorsoventral axis of the MEC following observed changes in the properties of the HCN conductance, is borne out by recent experiments.
The olfactory bulb (OB) contains multiple, parallel projection neurons to relay the nature of a stimulus. In a mouse ex vivo slice preparation, we used patch-clamp electrophysiology to measure intrinsic properties, excitability, action potential (AP) shape, voltage-activated conductances, and neuromodulation in the newly-categorized superficial tufted cells (sTCs) compared with those of mitral cells (MCs). We propose that a marked difference in voltage- dependent current represents distinct ion channel populations that affect the kinetics of action potentials, and evokes an increase in sTC firing frequency, albeit both types of projection neurons having similar AP spiking activity. Triple-colored immunofluorescence and RNA scope were used to detect co-localization of the Kv1.3 ion channel and the insulin receptor in sTCs, with [~]73% of sTCs expressing both. The sTCs were modulated by bath application of insulin - increasing AP firing frequency by 97%, attributable to an 8% decrease in the intraburst interval, and a reduction of the latency to first spike by 37%. We conclude that there may be a range of neuromodulators of sTCs that may alter excitability and fine-tune olfactory information processing or metabolic balance. SUMMARY STATEMENTSuperficial tufted cells, as output neurons of the olfactory bulb, were electrophysiologically studied to be insulin sensitive. Brain insulin signaling represents a manner in which olfactory and metabolic circuitry are intertwined.
Vestibular hair cells (HCs) convert gravitational and head motion cues into neural signals through mechanotransduction, mediated by the hair bundle--a mechanically integrated organelle composed of stereocilia and a kinocilium. The kinocilium, a specialized form of primary cilium, remains incompletely defined in structure, molecular composition, and function. To elucidate its characteristics, we conducted single-cell RNA sequencing of adult vestibular and cochlear HCs, uncovering a selective enrichment of primary and motile cilia-associated genes in vestibular HCs, particularly those related to the axonemal repeat complex. This enrichment of orthologous axonemal-related genes was conserved in zebrafish and human vestibular HCs, indicating a shared molecular architecture. Immunostaining validated the expression of key motile cilia markers in vestibular kinocilia. Moreover, live imaging of bullfrog and mouse HCs from crista ampullaris revealed spontaneous kinociliary motion. Together, these findings define the kinocilium as a unique organelle with molecular features of primary and motile cilia and support its previously unknown role as an active, force-generating element within the hair bundle.
During infections, vertebrates develop stereotypic symptoms such as elevated body temperature, reduced appetite, and lethargy. These changes, collectively known as sickness syndrome, are orchestrated by the brain in response to immune mediators released during systemic inflammation. While the roles of subcortical regions, including the hypothalamus and brainstem nuclei, in regulating sickness symptoms are well established, the contribution of the neocortex to the encoding and modulation of the sick state remains less well understood. We examined the neuronal correlates of sickness in the neocortex of awake mice following a single intracerebroventricular (i.c.v.) injection of prostaglandin E2 (PGE2), a well-characterized mediator of sickness. Behavioral analysis revealed that PGE2 elicited a rapid and robust sickness response, characterized by fever, slower locomotion, quiescence, anorexia, and eye squinting. Whole-brain Fos mapping showed that PGE2 generates a distinct neural activation pattern encompassing much of the interoceptive network. Electrophysiological recordings using Neuropixel probes in awake mice together with dimensionality reduction and decoding analysis revealed that neuronal population dynamics in the insular cortex (IC) and the primary somatosensory cortex (SSp), two regions involved in body state representation, encode sickness-related information, such as body temperature, walking velocity, grooming, and eye squinting. However, unlike SSp, ongoing neuronal activity in IC exhibited a better decoding performance for an integrated measure of sickness rather than individual symptoms. Together, these results suggest that PGE2 induces a coordinated physiological and behavioral response akin to a sick state, which is preferentially encoded in the IC.
BackgroundContinuous theta-burst stimulation (cTBS) can perturb neural activity and behavior by inducing effects that persist beyond the relatively short stimulation period. Although widely used in basic research and clinical settings, there lacks an understanding of the neurophysiological and behavioural effects of cTBS. Objectives/HypothesisTwo assumptions motivating the use of cTBS are that it will i) inhibit neural activity in the targeted area, and ii) consequently disinhibit neural activity in the mirroring region in the contralateral cortex. Here, we test these assumptions in the oculomotor system of healthy rhesus macaques. MethodsIn two macaques, we delivered cTBS between blocks of trials where they performed a delayed pro-/anti-saccade task, delivered cTBS to the right PFC (areas 8Ar and 46, which includes the frontal eye fields; 32 cTBS-PFC sessions), to the air as a SHAM control (27 cTBS-SHAM sessions), or to the nearby primary motor cortex as a brain control (21 cTBS-M1 sessions). Across these different types of sessions, we compared changes in oculomotor behavior (reaction times, error rates, peak saccade velocity), and changes in neural activity recorded from the left, contralateral PFC. ResultsDespite multiple lines of evidence consistent with TMS influencing neural activity in the cTBS-PFC and cTBS-M1 sessions, we found no behavioral evidence for inhibition of the right PFC in the cTBS-PFC sessions, nor any evidence for contralateral disinhibition in the left PFC. ConclusionsOur results call into question some of the fundamental assumptions underlying the application of cTBS. HighlightsO_LIcTBS widely used in lab and clinic to rebalance activity across cortex C_LIO_LIWe tested this in a monkey model, delivering cTBS to the prefrontal cortex C_LIO_LINo behavioural evidence for inhibition of brain area targeted by cTBS C_LIO_LINo evidence for disinhibition of spiking activity in mirroring, contralateral cortex C_LIO_LIResults question key assumptions about how cTBS influences network activity C_LI
Precise modulation of brain networks responsible for tongue motor and sensory control (TMSC) is critical for restoring functions, such as speech and swallowing in neurodegenerative disease or in treatment-induced chronic cranial neuropathy. We present an individualized, AI-driven fMRI neuromodulation (iNM) platform that adaptively targets subject-specific TMSC networks in real time. To enhance iNM precision and encodability --critical for neurorehabilitation--we mapped each healthy participants individualized TMSC selectivity network, creating a subject-specific TMSC digital twin. iNM increased signal strength, spatial expansion, and consistency across motor, sensory, and attention regions, while it reduced signal variability. The bilateral inferior parietal lobule emerged as key sensorimotor integration hub, as it exhibited exclusive activation under iNM along with highest discriminability, and largest spatial expansion. iNM also significantly strengthened and expanded motor, sensory, and attention-related networks -- medial-middle frontal areas, insula-claustrum, S1, M1, basal ganglia, motor cerebellum, and inferior temporal-- supporting interoceptive and proprioceptive-motor integration. Machine learning and unsupervised hidden Markov modeling revealed that iNM enhanced the decodability and stability of TMSC-neural states, while it suppressed competing swallow-neural state interference. Notably, the iNM effects extended beyond the neuromodulation window, indicating functional persistence--a key requirement for rehabilitation. iNM reconfigured TMSC networks by strengthening cortico-subcortical connectivity and adaptive circuit dynamics. Our findings show iNM as a non-invasive, personalized intervention capable of selectively enhancing sensorimotor control with high spatiotemporal specificity. By demonstrating mechanistic network-precision and functional carryover, iNM offers a promising intervention for individuals with limited treatment options, including head and neck cancer survivors and early-stage neurodegenerative disease patients.
Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) and alternative splicing provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)--a fatal neurodegenerative disease characterized by disrupted RBP function. Here, we reveal enrichment of genes associated with ALS and other neurodegenerative diseases in the spinal cord cholinergic neuron rhythmic transcriptome. We demonstrate that there is circadian regulation of ALS-linked RBPs and rhythmic alternative splicing of genes involved in intracellular transport (Aftph and Mvb12a), microtubule cytoskeleton organization (Limch1 and Drc3), and synaptic function (Sipa1l2) in this neuronal sub-type. Further, we show that the cholinergic neuron clock regulates sporadic ALS-associated changes in cytoskeleton and neuromuscular junction synapse gene expression. Finally, we report that cell-type-specific Bmal1-deletion (i) increases lumbar spinal cord motor neuron loss and sciatic nerve axon degeneration, (ii) drives alternative splicing of genes encoding ALS-linked RBPs (Matr3 and Srsf7), and (iii) drives alternative splicing of genes associated with microtubule transport and postsynaptic organization. Our results establish a role for the cholinergic neuron circadian clock in RBP function and ALS disease phenotypes.
The relationship between structural properties of diverse neuronal populations in monkey primary visual cortex (V1) and their in vivo functional responses is not fully understood. We combined high-density Neuropixels recordings across cortical layers of macaque V1 with non-linear dimensionality reduction on waveform shape to delineate nine putative cell classes: 4 narrow-spiking (NS), 4 broad-spiking (BS) and 1 tri-phasic (TP). Using targeted analyses of laminar organization, spike amplitude, multichannel waveforms, functional properties, and network connectivity of these cell classes, we demonstrate four aspects of the V1 microcircuit predicted by anatomical studies but never fully demonstrated in vivo. First, NS neurons were concentrated in layer 4. Second, a large-amplitude NS cell class in layer 4B showed strong direction selectivity. Third, another layer 4B NS class exhibited robust bursting and orientation selectivity. Finally, cross-correlation analysis revealed functional interactions between cells in different layers. Our results highlight how high-resolution electrophysiology can reveal novel relationships between in vivo function of neurons and the underlying circuit. TeaserHigh-resolution electrophysiology used with machine learning reveals links between function and the underlying neural circuitry.
Animals respond to tactile stimulations of the body with location-appropriate behavior, such as aimed grooming. These responses are mediated by mechanosensory neurons distributed across the body, whose axons project into somatotopically organized brain regions corresponding to body location. How mechanosensory neurons interface with brain circuits to transform mechanical stimulations into location-appropriate behavior is unclear. We previously described the somatotopic organization of bristle mechanosensory neurons (BMNs) around the Drosophila head that elicit a sequence of location-aimed grooming movements (Eichler et al., 2024). Here, we use a serial section electron microscopy reconstruction of a full adult fly brain to identify nearly all of BMN pre-and postsynaptic partners, uncovering circuit pathways that control head grooming. Postsynaptic partners dominate the connectome, and are both excitatory and inhibitory. We identified an excitatory hemilineage of cholinergic interneurons (hemilineage 23b) that elicit aimed head grooming and exhibit varied connectivity to BMNs from different head locations, revealing lineage-based development of a somatotopic parallel circuit architecture. Presynaptic partners provide extensive BMN presynaptic inhibition, consistent with models of sensory gain control as a mechanism of suppressing grooming movements and controlling the sequence. This work provides the first comprehensive map of a somatotopically organized connectome, and reveals how this organization could shape grooming. It also reveals the mechanosensory interface with the brain, illuminating fundamental features of mechanosensory processing, including feedforward excitation and inhibition, feedback inhibition, somatotopic circuit organization, and developmental origins.
Predictive-coding like theories agree in describing top-down communication through the cortical hierarchy as a transmission of predictions generated by internal models of the inputs. With respect to the bottom-up connections, however, these theories differ in the neural processing strategies suggested for updating the internal model. Some theories suggest a coding strategy where unpredictable inputs, i.e., those not captured by the internal model, are passed on through the cortical hierarchy, whereas others claim that the predictable part of the inputs is passed on. Here, we addressed which neural coding strategy is employed in cortico-cortical connections using an information-theoretic approach. Our framework allows for quantifying two core aspects of both strategies, namely, predictability of inputs and information transfer, through local active information storage and local transfer entropy, respectively. A previous study on the neural processing of retinal ganglion cells connected to the lateral geniculate nucleus showed a coding for predictable information, captured by an increase in the information transfer with the predictability of inputs. Here, we further investigate predictive coding strategies at the cortical level. In particular, we analyzed LFP activity obtained from intracranial EEG recordings in humans and spike recordings from mouse cortex. We detected cortico-cortical connections with increasing information transfer with the predictability of inputs in recorded channels from frontal, parietal and temporal areas in human cortex. In the mouse visual system, we detected connections exhibiting both an increase and decrease in the information transfer with input predictability, although the former was predominant. Our evidence supports the presence of both predictive coding strategies at the cortical level, with a potential predominance of encoding for predictable information. SummaryThe ability of the brain to infer the hidden causes of sensory experiences has been conceptualized within the computational framework of predictive coding. This framework explains perceptual inference and learning as a process of constantly updating an internal model of the world. Predictive coding describes cortical activity as a communication of sensory evidence and predictions generated from prior expectations. While different views of predictive coding agree on the communication of prior expectations throughout cortex, they differ in how internal expectations are updated. One view states that, to update the internal model, the cortex propagates the mismatch between the expected neural activity and the actual neural response to sensory stimuli. In contrast, another view suggests that the cortex propagates the match between the expected neural activity and the actual neural response. In this work, we were able to tease apart these two views, both in human cortex and the mouse visual system, using information theory. We observed that the brain predominantly propagates expected information, i.e., the match between prior expectations and incoming sensory inputs.
Synapses are critical targets of Alzheimers disease (AD), a highly prevalent neurodegenerative disease associated with accumulation of extracellular amyloid-{beta} peptides. Although amyloidosis and aggregation of the 42-amino acid amyloid-{beta} (A{beta}42) have long been considered pathogenic triggers for AD, clinical evidence linking high levels of A{beta}42 with normal cognition challenges this hypothesis. To resolve this conundrum on the role of A{beta}42 in regulating synaptic activity, we used an adeno-associated viral vector approach that triggers extracellular accumulation of A{beta}42 and spatial memory impairment. We show that A{beta}42 leads to an early increase in excitatory and proximal inhibitory synaptic transmission onto hippocampal CA1 pyramidal cells, and an increased expression of the glutamate transporter GLT-1 in these cells. A{beta}42 accumulation does not cause early cognitive deficits unless accompanied by an increased neuronal GLT-1 expression, suggesting this transporter is a critical mediator of A{beta}42s effects. These findings unveil key molecular and cellular mechanisms implicated with AD pathogenesis.
Parental communication signals are transmitted through nursing and critically shape neurodevelopmental trajectories. Mirroring some well characterized effects of gestational challenges in rodents, maternal immune activation (MIA) during the lactational period disrupts maternal physiology, decreases milk quality, and is associated with adverse neurobehavioral outcomes in offspring. This occurs without MIA significantly affecting maternal care. While gestational MIA models are responsive to environmental interventions, which beneficially alter maternal milk composition and associated offspring outcomes, the milk-borne mediators underlying resilience remain poorly understood. Given their ability to transport and deposit biologically active cargos, we propose that milk-derived extracellular vesicles (MEVs) are vehicles that deliver environmental programming signals (e.g., miRNAs) from nursing mothers to their offspring. Using a rat model, we show that lactational MIA altered MEV miRNA cargo and expression of hippocampal miRNAs in offspring. Several miRNAs in MEVs were also found in the hippocampus of matching offspring. Remarkably, the miRNA dysregulation observed in MEVs and hippocampus was rescued when dams were raised in an enriched environment, suggesting environmental enrichment protected from the effects of MIA, as also observed in the behavioral phenotype. RNA-seq of adult offspring hippocampus showed long-term transcriptional changes associated with the gene targets of early-life regulated miRNAs. Our results position MEV miRNA cargos as dynamic programming signals by which maternal experience is communicated to offspring, encoding both stress-induced and protective cues that influence development. This suggests that breastfeeding interventions can regulate the genetic cargo of the milk, programming the life of developing infants.
Microglial dysregulation is increasingly recognized as a driver of Alzheimers disease (AD), yet how pathogen-specific cues sculpt microglial diversity remains unclear. Here we integrate high-dimensional single-cell cytometry in vitro with spatial proteomics in vivo to dissect the impact of two major periodontal pathogens on microglia. Using a 36-marker CyTOF panel, we exposed SIM-A9 microglia to wild-type Porphyromonas gingivalis (Pg) or Tannerella forsythia (Tf) and to gingipain-deficient or S-layer-deficient mutants, resolving 38 clusters. Virulence-factor "switches" redirected cells from homeostatic states toward i) oxidative, antigen-presenting programmes driven by Pg gingipains and ii) an immunosuppressive, exhausted-like state driven by the Tf S-layer. Complementary 37-marker imaging mass cytometry of 5xFAD x hTau knock-in mice chronically infected with Pg identified 21 microglial subclusters. The cortex--but not hippocampus--lost two Arg1/IL-10 immunoregulatory subsets (>2-fold decrease) while NADPH-oxidase-high microglia accumulated around amyloid-{beta} and tau aggregates. These data demonstrate pathogen-specific reprogramming of microglia across model systems and brain regions, linking virulence-factor activity to AD-relevant neuroinflammation. By pinpointing gingipains and the bacterial S-layer as molecular "switches," our study highlights tractable therapeutic targets for limiting infection-driven microglial dysfunction in Alzheimers disease.
The cerebral cortex operates in a state of restless activity, even in the absence of external stimuli. Collective neuronal activities, such as neural avalanches and synchronized oscillations, are also found under rest conditions, and these features have been suggested to support sensory processing, brain readiness for rapid responses, and computational efficiency. The rat barrel cortex and thalamus circuit, with its somatotopic organization for processing sensory inputs from the whiskers, provides a powerful system to explore such interplay. To characterize these resting state circuits, we perform simultaneous multi-electrode recordings in rats barrel cortex and thalamus. During spontaneous activity, oscillations with frequencies centered around 11.5 Hz are detected concomitantly with slow oscillations below 4 Hz, as well as power-law distributed avalanches. The phase of the lower-frequency oscillation appears to modulate the higher-frequency amplitude, and it has a role in gating avalanche occurrences. We then record neural activity during controlled whisker movements to confirm that the 11.5 Hz barrel circuit active at rest is indeed the one involved in response to whisker stimulation. We finally show how a thalamic-driven firing-rate model can describe the entire phenomenology observed at resting state and predict the response of the barrel cortex to controlled whisker movement.
Long axial field of view (LAFOV) PET imaging requires a high level of automation and standardization, as the large number of target tissues increases the manual workload significantly. We introduce an automated analysis pipeline (TurBO, Turku total-BOdy) for preprocessing and kinetic modelling of LAFOV [15O]H2O and [18F]FDG PET data, enabling efficient and reproducible analysis of tissue perfusion and metabolism at regional and voxel-levels. The approach employs automated processing including co-registration, motion correction, automated CT segmentation for region of interest (ROI) delineation, image-derived input determination, and region-specific kinetic modelling of PET data. MethodsWe validated the analysis pipeline using Biograph Vision Quadra (Siemens Healthineers) LAFOV PET/CT scans from 21 subjects scanned with [15O]H2O and 16 subjects scanned with [18F]FDG using six segmented CT-based ROIs (cortical brain gray matter, left iliopsoas muscle, right kidney cortex and medulla, pancreas, spleen and liver) representing different levels of blood flow and glucose metabolism. ResultsModel fits showed good quality with consistent parameter estimates at both regional and voxel-levels (R{superscript 2} > 0.83 for [15O]H2O, R{superscript 2} > 0.99 for [18F]FDG). Estimates from manual and automated input functions were in concordance (R{superscript 2} > 0.74 for [15O]H2O, and R{superscript 2} > 0.78 for [18F]FDG) with minimal bias (<4% for [15O]H2O and <10% for [18F]FDG). Manually and automatically (CT-based) extracted ROI level data showed strong agreement (R{superscript 2} > 0.82 for [15O]H2O and R{superscript 2} > 0.83 for [18F]FDG), while motion correction had little impact on parameter estimates (R{superscript 2} > 0.71 for [15O]H2O and R{superscript 2} > 0.78 for [18F]FDG) compared with uncorrected data. ConclusionOur automated analysis pipeline provides reliable and reproducible parameter estimates across different regions, with an approximate processing time of 1-1.5 h per subject. This pipeline completely automates LAFOV PET analysis, reducing manual effort and enabling reproducible studies of inter-organ blood flow and metabolism, including brain-body interactions.
Fiber photometry is a neuroscience technique that can continuously monitor in vivo fluorescence to assess population neural activity or neuropeptide/transmitter release in freely behaving animals. Despite the widespread adoption of this technique, methods to statistically analyse data in an unbiased, objective, and easily adopted manner are lacking. Various pipelines for data analysis exist, but they are often system-specific, only for pre-processing data, and/or lack usability. Current post hoc statistical approaches involve inadvertently biased user-defined time-binned averages or area under the curve analysis. To date, no post-hoc user-friendly tool with few assumptions for a standardised unbiased analysis exists, yet such a tool would improve reproducibility and statistical reliability for all users. Hence, we have developed a user-friendly post hoc statistical analysis package in Python that is easily downloaded and applied to data from any fiber photometry system. This Fiber Photometry Post Hoc Analysis (FiPhoPHA) package incorporates a variety of tools, a downsampler, bootstrapped confidence intervals (CIs) for analyzing peri-event signals between groups and compared to baseline, and permutation tests for comparing peri-event signals across comparison periods. We also include the ability to quickly and efficiently sort the data into mean time bins, if desired. This provides an open-source, user-friendly python package for unbiased and standardised post-hoc statistical analysis to improve reproducibility using data from any fiber photometry system.
Optogenetic activators with red-shifted excitation spectra, such as Chrimson, have significantly advanced Drosophila neuroscience. However, until recently, available optogenetic inhibitors required shorter activation wavelengths, which dont penetrate tissue as effectively and are stronger visual stimuli to the animal, potentially confounding behavioral results. Here, we assess the efficacy of two newly identified anion-conducting channelrhodopsins with spectral sensitivities similar to Chrimson: A1ACR and HfACR (RubyACRs). Electrophysiology and functional imaging confirmed that RubyACRs effectively hyperpolarize neurons, with stronger and faster effects than the widely used inhibitor GtACR1. Activation of RubyACRs led to circuit-specific behavioral changes in three different neuronal groups. In glutamatergic motor neurons, activating RubyACRs suppressed adult locomotor activity. In PPL1-{gamma}1pedc dopaminergic neurons, pairing odors with RubyACR activation during learning produced odor responses consistent with synaptic silencing. Finally, activation of RubyACRs in the pIP10 neuron suppressed pulse song during courtship. Together, these results demonstrate that RubyACRs are effective and reliable tools for neuronal inhibition in Drosophila, expanding the optogenetic toolkit for circuit dissection in freely behaving animals.
Human high-level visual cortex has been described in two seemingly opposed ways. A categorical view emphasizes discrete category-selective areas, while a dimensional view highlights continuous feature maps spanning across these areas. Can these divergent perspectives on cortical organization be reconciled within a unifying framework? Using data-driven decomposition of fMRI responses in face-, body-, and scene-selective areas, we identified overlapping activity patterns shared across individuals. Each area encoded multiple interpretable dimensions tuned to both finer subcategory features and coarser cross-category distinctions beyond its preferred category, even in the most category-selective voxels. These dimensions formed distinct clusters within category-selective areas but were also sparsely distributed across the broader visual cortex, supporting both locally selective, category-specific, and globally distributed, feature-based coding. Together, these findings suggest multidimensional tuning as a fundamental organizing principle that integrates feature-selective clusters, category-selective areas, and large-scale tuning maps, providing a more comprehensive understanding of category representations in human visual cortex.
Focal cortical dysplasia (FCD) is a leading cause of pharmacoresistant epilepsy in pediatric populations, although its contribution to epileptogenesis remains incompletely understood. Recent findings indicate that hyperexcitability might stem from peripheral areas that are not dysplastic, rather than from the malformation itself. However, consid-ering the significant variability associated with these malformations, it remains challenging to clarify whether this degree of disorganization contributes to changes in activity. In this study, we used the carmustine-induced animal model to investigate how varying degrees of cortical malformation influence neural dynamics. Local field potentials (LFP) were recorded using a multielectrode array (MEA) during both spontaneous activity and external perturbation. We developed a novel metric to quantify spatial heterogeneity in signal organization and evaluated its association with excitation-inhibition (E/I) balance. Our results reveal that alterations such as the aperiodic exponent value and the sparcity of clustering in signal classification are related to the extent and distribution of cortical abnormalities, underscoring the functional relevance of cytoarchitectural variability. This work advances the understanding of FCD-related network dysfunction and introduces analytical approaches with potential translational value for neuroscience research and pre-surgical evaluation.
BackgroundChlordecone (CLD) is a persistent organochloride pesticide formerly used against banana weevil. It is detectable in blood samples from a large proportion of the population in the French Caribbean Islands. Several experimental studies have demonstrated acute neurotoxicity of CLD, but the effect of a subchronic exposure to CLD remains to be studied. MethodsYoung adult male mice were injected intraperitoneally with 3 mg/kg CLD (n=34) or vehicle (n=22), twice a week, for eight weeks. Behavior, regional brain accumulation, and effects on the dopaminergic system were studied. In addition, functional ultrasound imaging (fUSi) was used to probe the visual, somatosensory and dopaminergic pathways. ResultsCLD was detected in all brain regions (5-15 mg/kg) after two-month exposure, without any marked impact on behavior (anxiety, motor coordination, memory). The dopaminergic system was mostly unaffected, despite slight decreases in the number of TH-positive neurons and the expression of VMAT2, quantified in a subset of animals. fUSi highlighted a decreased response to the visual stimulation in CLD-exposed animals, in contrast to the sensorimotor response, which was found unaltered. ConclusionThe two-month-long, systemic, exposure to an intermediate dose of CLD resulted in a mostly unaffected phenotype, with a normal behavior and a largely intact dopaminergic system. Interestingly, functional ultrasound imaging was able to detect an altered visual response, which has also been noted in Parkinsons disease. This study position functional ultrasound imaging as a promising technique to capture early signs of neurotoxicity, opening up opportunities for "toxico-fUS" in the field of neurotoxicology. HighlightsHigh CLD neurotropism confirmed in mice by LC-MS/MS. Sub-chronic chlordecone exposure suggests possible early signs of parkinsonism. Functional UltraSound reveals impairment of brain areas linked to vision and hearing.
Movement disorders, like Parkinson's disease, happen because of unusual patterns in the connections between the cortex and basal ganglia, often caused by timing issues in feedback pathways. This study uses a two-delay nonlinear dynamic model, based on the delayed the van der Pol oscillator, to examine how delays in the feedback loops of the direct and indirect basal ganglia pathways lead to unusual movement patterns and resonance. A thorough analysis of resonance looks at how the ratios of delays and the time it takes to respond affect the system's frequency, showing when internal resonance occurs and how frequency stabilizes under different conditions. We examine how stable the system is by looking at changes in its behavior and measuring the Lyapunov exponent across distinct types of nonlinear feedback setups. Simulations demonstrate transitions from stable oscillations to chaos with varying delays and saturation strength. Our results reproduce symptoms of Parkinson's disease, such as resting tremor, dyskinesia, and freezing, demonstrating how delayed inhibition or hyperactivity destabilizes motor function. The discussion supports these findings, indicating that early problems start in the striatum, with complex effects in the globus pallidus that worsen motor symptoms. This model explains the temporal evolution of Parkinson's disease symptoms and highlights the timing of feedback and saturation as key therapeutic targets. Overall, this research offers a biological explanation for motor problems caused by delays and supports novel approaches for brain stimulation using flexible methods.
Autobiographical memory (AM) retrieval involves goal-directed and reconstructive processes that unfold over time. A key feature of this process is the visual perspective adopted during remembering, which shapes subjective memory experience. Using fMRI, we cued participants to retrieve AMs from an own-eyes, observer, or natural perspective followed by an event probe. Our design dissociates preparatory (cue phase) and reconstructive (probe phase) mechanisms to isolate the neural signatures of retrieval orientation, the strategic use of cues to optimize retrieval. Whole-brain and ROI analyses revealed that the angular gyrus (AG) and precuneus support perspective-guided retrieval in distinct ways. During the cue phase, PGp showed greater activity for instructed perspectives than natural retrieval, consistent with preparatory perspective selection. During the probe phase, observer-perspective retrieval elicited greater activity in PGp and precuneus (7P), supporting sustained perspective maintenance. Brain-behavior models linked PGp and 7P activity to greater vividness and perspective stability, while precuneus (7M) activity was negatively associated with emotional intensity, especially in the observer condition. These findings reveal phase- and subregion-specific contributions of posterior parietal cortex to the subjective qualities of memory. AG subregions support goal-directed perspective selection and implementation, while precuneus subregions flexibly modulate phenomenological features during memory reconstruction.
Transcription factors are potent levers for neural repair, but systematic pipelines to uncover factors that unlock adult corticospinal regeneration are lacking. By intersecting developmental RNA-seq with ATAC-seq footprints, we pinpointed two nuclear-receptor transcription factors--NR2F1 and NR2F6, neither previously linked to CNS axon growth--as top candidates. Forced expression of either factor doubled neurite length in culture, and each proved highly effective in vivo: after unilateral pyramidotomy they drove robust midline sprouting, while after complete thoracic crush they supported long-tract CST regeneration that restored hip lift, partial swing trajectories and grip strength. Multi-omics dissection revealed complementary mechanisms: NR2F1 re-engaged chromatin-remodelling and cytoskeletal networks, whereas NR2F6, via a conserved corepressor domain, imposed a broad translational down-shift, bound predominantly to distal enhancers and re-packaged chromatin into new topologically associating domains that cluster growth genes with freshly activated regulatory hubs. These discoveries establish NR2F1 and NR2F6 as novel pro-regenerative TFs, demonstrate their potency across lesion types, and expose repression-driven translational control and enhancer-TAD reconfiguration as previously unrecognised axes of CNS repair.
Neuronal polarization is essential for functional compartmentalization, enabling dendritic synaptic integration and axonal action potential generation. While structural differences in mitochondria across compartments have been identified, their functional distinctions remain unclear. Here, we uncovered compartment-specific mitochondrial Ca2+ dynamics and their molecular determinants. In axonal mitochondria, Ca2+ uptake through MCU occurs independently of ER-stored Ca2+ release, with faster matrix Ca2+ clearance than dendritic mitochondria, where Ca2+ uptake predominantly originates from ER Ca2+. The ER-independent mitochondrial Ca2+ uptake in axonal mitochondria is mediated by enriched MCU-regulating proteins, MICU1 and MICU2, while higher NCLX expression facilitates rapid Ca2+ clearance. Moreover, NCLX knockdown, which functionally mimics a mental retardation-associated mutation, caused more significant axonal branching defects compared to dendrites in vivo, aligning with its enrichment in axons. These findings highlight fundamental Ca2+-modulating features and developmental importance of neuronal mitochondria in a compartment-specific manner and reveal the key underlying molecular mechanisms.
Neural oscillations at distinct frequency bands facilitate communication within and between neural populations. While single-frequency oscillations are well-characterized, the simultaneous emergence of slow (beta) and fast (gamma) oscillations within the same network remains unclear. Here, we demon-strate that multi-frequency oscillations naturally arise when the ratio of inhibitory-to-excitatory synaptic strength falls within a specific regime using a biologically plausible Izhikevich model. We show that this regime maximizes both information capacity and transmission efficiency, suggesting an optimal balance for neural communication. Deviations from this range lead to single-frequency oscillations and reduced communication efficiency, mirroring disruptions observed in neurological disorders. These findings provide mechanistic insight into how the brain leverages multiple oscillatory frequencies for efficient information processing and suggest a potential biomarker for impaired neural communication. 1. SIGNIFICANCE STATEMENTBeta (slow) and gamma (fast) oscillations often coexist in the brain, yet their origin and functional role remain unclear. Our study reveals that the inhibitory-to-excitatory synaptic strength ratio governs the emergence of this multifrequency state. Furthermore, we demonstrate that information capacity and transmission efficiency are maximized in this regime, leading to significantly enhanced neural communication. These findings provide mechanistic insight into how multiple oscillatory frequencies support efficient brain function and offer a potential framework for understanding disruptions in neural communication associated with neurological disorders.
Contemporary accounts of semantic cognition propose that conceptual knowledge is supported by a heteromodal conceptual store and controlled retrieval processes. However, it remains unclear how the neural basis of semantic control varies across modalities. Recent models of cortical organization suggest that control networks are distributed along a unimodal-to-heteromodal cortical gradient, with the semantic control network (SCN) located in more heteromodal cortex than the domain-general multiple demand network (MDN). We used fMRI to examine how these networks respond to semantic control demands in visual and auditory tasks. Participants judged the semantic relatedness of spoken and written word pairs. On half of the trials, a task cue specified the semantic feature to guide retrieval; on the remaining trials, no such cue was given. The SCN showed greater activation when task knowledge was available, consistent with a role in the top-down control of semantic retrieval across modalities. In contrast, the MDN showed greater activation for spoken words, likely reflecting increased demands in speech perception. These findings demonstrate a dissociation between control networks, with SCN involvement modulated by task structure and MDN activity influenced by input modality.
Climbing fiber (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum1-3. Paradoxically, CFs also excite molecular layer interneurons (MLIs)4,5, a cell-type that inhibits PCs and can restrict plasticity and learning6,7. However, two types of MLIs with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals, and suppress plasticity of granule cell to PC synapses2,6-9, whereas MLI2s inhibit MLI1s and disinhibit PCs8. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial EM reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 via more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s via glutamate spillover4,5. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s, and disinhibits PCs. In contrast, learning-related sensory stimulation produced more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted toward MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for LTD. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity.
AbstractFragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. While structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout (KO) mice, their developmental onset and contribution to early FXS pathophysiology remain unknown. In this study, we examined the postnatal maturation of SPN in the dorsomedial striatum (DMS) of Fmr1 KO mice, assessing glutamatergic synaptic inputs and intrinsic excitability. During postnatal development, Fmr1 deficient SPNs in DMS display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, SPNs of mice exhibit pronounced hyperexcitability, characterized by increased membrane resistance, reduced rheobase, and slower action potential kinetics. These perturbations affect both Dopamine 1 receptor-expressing (D1-SPN) and D2 receptor-expressing (D2-SPN) SPNs, though some action potential dynamics are selectively impaired in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for FXS-related symptoms, fails to normalize SPN excitability, highlighting its limited efficacy in addressing core SPN dysfunction. Our findings reveal a late-onset hyperexcitability in DMS SPNs of Fmr1 KO mice, suggesting a progressive emergence of striatal neuron abnormalities over development. These results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address striatal circuit dysfunction.
Metabolic collapse of retinal ganglion cells (RGCs) onsets glaucoma, yet no approved drug directly protects these neurons. Through a live-cell mitochondrial screen in human stem-cell-derived hRGCs we uncovered WAY-100635 (WAY), a clinically tested 5-HT1A antagonist, as a systemic neuroprotectant. WAY triggers a reversible cyclic-AMP surge that activates PGC-1-driven reversible mitochondrial biogenesis and suppresses apoptosis. In glaucoma associated OPTNE50K hRGCs, WAY restores mitochondrial fitness, dampens excitotoxicity, and reprograms metabolism toward aerobic glycolysis, while in progenitors WAY boosts mitochondrial cristae maturation, oxidative phosphorylation, and cell-cycle exit to accelerate RGC specification. Daily intraperitoneal dosing preserves RGC bodies, neural activity, promotes axon regeneration into the optic nerve and vision centers after optic-nerve crush, as well as shows RGC protection and maintenance of visual acuity in chronic ocular hypertension glaucoma. As the non-invasive neuroprotective therapy with a human safety profile, WAY addresses a critical gap in glaucoma care and potentially for other mitochondrial optic neuropathies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/659983v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@131ff3eorg.highwire.dtl.DTLVardef@16c4e6borg.highwire.dtl.DTLVardef@190724eorg.highwire.dtl.DTLVardef@4067e4_HPS_FORMAT_FIGEXP M_FIG C_FIG
Fear is a double-edged sword: it supports survival based on learned associations between environmental cues and potential threats, but its dysregulation can lead to anxiety disorders and PTSD. Many studies have addressed the roles of the hippocampus and basolateral amygdala in the storage of the fear engram, but the role of the anterior cingulate cortex (ACC), especially during and immediately after fear acquisition, remains poorly defined. To address this gap, we longitudinally recorded ACC neuronal activity using single-photon calcium imaging in freely behaving adult male mice subjected to fear conditioning. Subjects acquired a conditioned freezing response to a tone cue (conditioned stimulus, CS) paired with light foot shocks (unconditioned stimulus, US), and ACC activity was monitored during cue pre-exposure, fear acquisition, fear recall, and fear extinction. Consistent with known functions of the ACC, neuronal responses were modulated by the US and by the novelty of the CS and US. Critically, both the number of CS-responsive neurons and the CS-associated population activity rose during acquisition, peaked during recall, and decreased throughout extinction. Neuronal populations responsive to the CS overlapped at a rate consistent with chance, suggesting that the ACC operates as a flexible integrative hub rather than containing stable engrams. Together, these findings indicate that ACC neuronal populations, but not engrams, represent novelty, pain, and the dynamic valence of a CS. Our findings are consistent with a model in which the ACC plays a role in threat appraisal and provides a learning signal that dynamically updates fear representations in other regions.
Brain size measures are well-studied and often treated as a confound in volumetric neuroimaging analyses. Yet their relationship with body anthropometric measures and demographics remains underexplored. In this study, we examined those relationships alongside age- and sex-related differences in global brain volumes. Using brain magnetic resonance imaging (MRI) of healthy participants in the UK Biobank, we derived global measures of brain morphometry, including total intracranial volume (TIV), total brain volume (TBV), gray matter volume (GMV), white matter volume (WMV), and cerebrospinal fluid (CSF). We extracted these measures using the Computational Anatomy Toolbox (CAT) and FreeSurfer. Our analyses were structured in three approaches: across-sex analysis, sex-specific analysis, and impact of age analysis. Employing machine learning (ML), we found that TIV was strongly predicted by sex (across-sex r = 0.68), reflecting sexual dimorphism. On the other hand, TBV, GMV, WMV, and CSF were more sensitive to age, with higher prediction accuracy when age was included as a feature, highlighting age-related changes in the brain structure, such as fluid expansion. Sex-specific models showed reduced TIV prediction (r {approx} 0.25) but improved TBV accuracy (r {approx} 0.44), underscoring sex-specific body-brain relationships. Anthropometrics enhanced prediction but only subsidiary to age and sex. These findings advance our understanding of brain-body scaling relationships and underscore the necessity of accounting for age and sex in neuroimaging studies of brain morphology.
Primary mixed glial cultures are key tools to isolate and study astrocytes, microglia and oligodendrocytes. Cell-substrate adhesion is critical for neural cell survival and differentiation. Cationic polymers like poly-D-lysine (PDL) are widely used to promote cell adhesion to cell culture substrates, however, PDL is not stable long-term, with cultured cells often detaching (peeling) after 2-3 weeks. Dendritic polyglycerol amine (dPGA) is a synthetic polycationic non-protein polymer biomimetic of poly-lysine that is highly resistant to degradation by cellular proteases. Substrates coated with dPGA promote cell adhesion and improve survival in long-term neuronal cultures. Here we assessed dPGA as a substrate coating to provide long-term support for mixed glial cultures. Oligodendrocyte precursor cells (OPCs) were isolated weekly by differential adhesion from cultures grown in T75 flasks with PDL or dPGA-coated substrates. Following two "shake-off" isolations, the cell layer in most PDL-coated flasks fully detached, rendering these flasks unusable for further culture. In contrast, dPGA-coated flasks consistently yielded cells for six or more sequential isolations over seven weeks in culture. dPGA-coated flasks produced more cells, a greater percentage of O4+ cells, and maintained similar proportions of OPCs and MBP-positive cells as when isolated from a PDL-coated substrate. dPGA is cyto-compatible, functionally superior, easy to use, low cost and a stable alternative to conventional cell substrate coatings. The enhanced long-term stability of mixed glial cultures grown on a dPGA substrate has the capacity to increase cellular yield, reduce animal use, and facilitate studies of oligodendrocyte cell biology.
Establishing learned associations between rewarding stimuli and the context under which those rewards are encountered is critical for survival. Hippocampal input to the nucleus accumbens (NAc) is a key connection involved in integrating environmental information and reward processing to facilitate goal-directed behaviors. This connection consists of two independent pathways originating from the dorsal (dHipp) or ventral (vHipp) hippocampus, which have previously been considered functionally and anatomically distinct. Here, we show overlap in dHipp and vHipp terminal fields in the NAc, which led us to reconsider this view and raise new questions regarding the potential interactions between dHipp and vHipp pathways in the NAc. Using optogenetics, electrophysiology, and transsynaptic labeling in adult male and female mice, we investigated anatomical and functional convergence of dHipp and vHipp in the NAc. We identified a subpopulation of dually innervated cells in the NAc medial shell where dHipp and vHipp inputs are located near one another along dendritic branches. We independently manipulated dHipp and vHipp inputs via two-color optogenetic manipulation during whole-cell electrophysiology recordings to confirm functional dual innervation of individual neurons and revealed heterosynaptic interactions between the two pathways. Altogether, these results demonstrate that dHipp and vHipp dually innervate a subset of neurons in the NAc, suggesting integration of these inputs at the level of individual neurons. Exploring the physiological and behavioral implications of this convergence will offer new insights into how individual neurons incorporate information from distinct inputs and how this integration may shape learning. SIGNIFICANCE STATEMENTForming associations between rewards and the circumstances under which they are experienced is vital for survival. Hipp input to the NAc is essential for associating rewards with their environmental context to effectively guide motivated behaviors. This connection consists of two separate pathways originating from dHipp and vHipp that have long been considered distinct. Here, we reveal a subpopulation of neurons in the NAc shell innervated by both Hipp subregions as well as heterosynaptic interactions that occur between dHipp and vHipp synapses. These findings suggest that integration of distinct hippocampal information occurs at the single-neuron level, providing a critical mechanism underlying learning and motivated behavior while also opening new avenues for understanding how diverse contextual and reward signals shape decision-making.
BACKGROUNDPrevious studies have shown that cocaine-induced changes in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) differ based on dopamine receptor subtype expression, the sex of the animal, and for females, phase of the estrous cycle. These findings highlight the need to account for both sex and estrous cycle when studying drug-mediated alterations in neurophysiology. Whether MSNs of the nucleus accumbens core (NAcC), which serve different aspects of addiction, will exhibit similar sex and estrous cycle effects with cocaine administration was investigated. METHODSMice underwent a 5-day locomotor sensitization paradigm via daily cocaine administration (15 mg/kg, s.c.) followed by a 1-to 4-day drug-free abstinence period. We examined NAcC MSN excitability by obtaining ex vivo whole-cell recordings from differentially labeled dopamine D1-receptor expressing MSNs (D1R-MSNs) and dopamine D2-receptor expressing MSNs (D2R-MSNs) obtained from male mice or female mice that were either in estrus or diestrus. RESULTSIn this genetic background of mice, both male and female mice sensitized to cocaine in a similar manner. In males, there were no cocaine-induced changes in D1R-MSN or D2R-MSN excitability, with D2R-MSNs exhibiting greater excitability. In saline-treated females, D1R-MSN excitability fluctuated across the estrous cycle with increased excitability during estrus. Following cocaine, estrous cycle-dependent D1R-MSN excitability was arrested, fixed at an intermediate value between estrus and diestrus when compared to saline controls. D2R-MSNs did not change either across the estrous cycle or following cocaine. When comparing MSN subtypes, in diestrus, D2R-MSNs were more excitable under saline conditions, but indistinguishable from D1R-MSNs following cocaine. In contrast, during estrus, D1R-and D2R-MSN excitability was similar in saline treated animals, but with cocaine, D2R-MSNs displayed heightened excitability. CONCLUSIONSThere are fundamental sex differences in cocaine-induced changes to the excitability of D1R-MSNs in the NAcC. After cocaine exposure, female mice in diestrus exhibited a significant main effect change in MSN excitability, an inversion of what had previously been demonstrated in the NAcSh where no cocaine-induced changes were observed. These data suggest that there are distinct differences in the neuropharmacological effect of cocaine in males versus females that are shell and core specific. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/660420v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@fdb01corg.highwire.dtl.DTLVardef@1350b15org.highwire.dtl.DTLVardef@16aac03org.highwire.dtl.DTLVardef@433842_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSThere are sex-and estrous-cycle dependent changes to D1R-MSNs in the NAcC that are sensitive to cocaine exposure. In males, cocaine has no effect on D1R-or D2R-MSNs excitability. During the estrous cycle, D1R-MSNs exhibit increased excitability during estrus. This fluctuation is halted by cocaine, such that D1R-MSNs recorded in diestrus show increased excitability following cocaine exposure whereas female D1R-MSNs recorded in estrus have decreased excitability. PLAIN LANGUAGE SUMMARYThe nucleus accumbens core (NAcC) is a brain region associated with regulating motivated behavior. The primary neuronal populations of the NAcC are dopamine D1 receptor expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor expressing medium spiny neurons (D2R-MSNs). No studies exist which examine sex differences and estrous cycle effects in the NAcC following cocaine administration. Using ex vivo electrophysiology, we found inherent sex-and estrous-cycle differences in cocaine-induced changes in MSN neuroplasticity. D1R-MSN excitability was unaffected in males, increased in females recorded during the diestrus phase, and decreased in females recorded during estrus following cocaine exposure. This ran counter to estrous cycle effects under drug-naive conditions where D1R-MSN excitability was higher in estrus versus diestrus. The estrous cycle effects on D1R-MSNs were eliminated following cocaine administration. For both sexes, D2R-MSN excitability was not impacted following cocaine. These results highlight fundamental sex differences that might underpin differences in substance abuse.
Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS) is associated with language impairments despite seizures originating in the motor cortex, suggesting aberrant cross-network interactions. Here we tested whether functional connectivity in SeLECTS during language tasks predicts language performance. We recorded high-density EEG from right-handed children with SeLECTS (n=31) and age-matched controls (n=32) during verb generation, repetition, and resting tasks. Phonological awareness was assessed using the Comprehensive Test of Phonological Processing-2. Connectivity between bilateral motor cortices and language regions (the left inferior frontal and superior temporal cortices and their right hemisphere homologues) was measured using weighted Phase Lag Index (wPLI). Children with SeLECTS demonstrated significantly elevated connectivity between motor and language regions during language processing. Motor-to-frontal connectivity was higher in SeLECTS during both verb generation and repetition tasks. Frontal-to-temporal connectivity was elevated specifically during verb generation. Higher interhemispheric connectivity (between the left and right hemispheres) during language tasks strongly predicted worse phonological awareness in children with SeLECTS ({beta}= -40 to -61, all p<0.005), but not controls. Together, we found that children with SeLECTS exhibited pathologically elevated connectivity between motor and language networks that was strongly associated with impaired phonological awareness. These findings identify aberrant interhemispheric connectivity as a pathophysiological mechanism underlying language dysfunction and establish EEG-based connectivity measures as a potential biomarker for guiding targeted neuromodulation therapies to treat cognitive impairments in pediatric epilepsy.
Recent developments in acquisition and reconstruction of 3-dimensional magnetic-resonance spectroscopic imaging (3D-MRSI) enable the high-resolution mapping of multiple neurometabolites in the whole-brain, in vivo. Leveraging this capability, we created a voxel-based pipeline that corrects and spatially normalizes whole-brain maps of total N-acetylaspartate (tNAA), myo-inositol (Ins), choline compounds, glutamate + glutamine, and creatine + phosphocreatine. We examined a clinical cohort of adolescents and young adults at risk for psychosis (n= 21) --meeting DSM-5 criteria for Attenuated Psychosis Syndrome (APS)or Schizotypal Personality Disorder (SCZT)-- and age-/sex-matched healthy controls (n =13), as well as an independent non-clinical sample of adolescents (n = 61). We first aimed at assessing the reproducibility of MRSI measures across datasets and scanning sites, then validate the feasibility of a whole-brain voxel-based analyses on 3D-MRSI data and eventually test the sensitivity of this approach. Metabolite distributions showed reproducible regional variation in standard space between the two independent samples and scanning sites (r ranging from 0.82 to 0.99). Relative to controls, at-risk participants exhibited higher tNAA in frontal grey matter; the SCZT subgroup additionally displayed widespread cortical and subcortical Ins elevations compared with both APS and controls. Voxel-based analyses of structural (i.e., gray and white matter volumes or densities) and dijusion (i.e., generalized fractional anisotropy) parameters yielded no significant dijerences between risk participants and controls. These findings suggest the sensitivity of high-resolution 3D-MRSI for detecting subtle neurometabolic alterations at the group level in the early stages of psychotic disorders. Detailed brain metabolic mapping has the potential to help with early identification of young people at risk for psychosis or other mental disorders.
1Lie detection is important for government law enforcement. Current lie detection methods such as the polygraph test have been found to be unreliable (Meijer et al. 2017). New lie detection technology is currently arising that is based on fMRI; however, single subject tests have only been successful in detecting lies 88% of the time (Langleben et al., 2005; Wild, 2005). One of the main problems with most fMRI-based approaches is that they assume that various acts of deception involve common brain regions, (Ganis et al., 2003). In this work I propose a much more accurate fMRI lie detection method that does not make this assumption and is domain based. In my investigation, rather than trying to localize brain regions that are indicative of lying in general, I localize brain regions that indicate lying specifically about face recognition. In criminal investigations one frequently needs to establish familiar relations between a suspect, victim and/or witness. This type of information can be used as circumstantial evidence in a crime. In this work I propose to use fMRI to detect whether a suspect has any familiarity with an individual face. I find that activation in the left inferior frontal gyrus was a reliable discriminator for face familiarity.
To support robust behaviors in highly variable environments, animals rely on active sampling of their sensory surroundings. Here, we use tethered, flying Drosophila melanogaster and a multisensory behavioral apparatus simulating forward flight to determine how visual and mechanosensory information are integrated and control active movements of an important multimodal sensory organ, the antennae. We found that flies perform active antennal movements in response to varying airflow, and that the direction of these movements changes depending on the visual environment. Next, we found that antennal movements are amplified in the presence of visual motion, but only when the fly was flying. Through mechanical and optogenetic manipulation of mechanosensory input, we found that mechanosensory feedback is vital to antennal positioning at flight onset. Additionally, we observed unexpected changes in wingbeat frequency when the antenna was mechanically stabilized, suggesting that multiple antennal mechanosensors contribute to flight regulation. Finally, we show that integration of mechanosensory and visual cues for controlling antennal motion follows in a "winner-takes-all" paradigm dependent on the stimulus frequency, mirroring visuo-mechanosensory guided behaviors in other species. Together, these results reveal novel behavioral gating of sensory information and expand our understanding of the efferent control of active sensing.
The barcoded connectomics tool MAPseq enables highly multiplexed projection mapping of individual neurons by translating neuroanatomy into a DNA sequencing problem. Here we present MAPseq2, a user-friendly protocol with 3-4 fold increased barcode detection sensitivity and [~]10 fold decreased cost relative to the current MAPseq protocol. As MAPseq workflows are used across a range of barcoded connectomics methods, including BARseq, BRICseq, and ConnectID, all improvements in MAPseq2 directly transfer to these technologies.
The retrosplenial cortex (RSC) is a key integrative hub involved in spatial orientation, navigation, and cognitive processes. In rodents, RSC neurons carry rich sensory and navigational signals and are interconnected with sensory, motor, thalamic, and hippocampal circuits--supporting multimodal integration. However, the circuitry that supports this integration remain unclear. Here, we combined 2-photon calcium imaging in navigating mice with brain-wide retrograde tracing to investigate how visual and positional information are represented and distributed across RSC subregions. We found a clear anterior-posterior gradient: anterior RSC neurons exhibited sharper, more reliable position tuning and preferred fast-moving visual stimuli, while posterior RSC neurons showed broader tuning and preferential responses to slower motion. These functional differences were paralleled by distinct patterns of long-range input: anterior RSC received denser projections from motor, parietal, and hippocampal-associated areas--regions implicated in position encoding--whereas posterior RSC was more strongly innervated by visual cortices. Our findings reveal that the RSC contains functionally and anatomically distinct subregions specialized for processing different visuospatial features, suggesting a modular organization that supports integration of contextual and sensory information during navigation.
Many animals strongly rely on their sense of vision, as it provides information about the natural world with particularly high dimensionality. In insects, the first visual processing stage of the brain, the lamina, plays an important role in parallel processing of this complex information. Its main relay neurons, lamina monopolar cells (LMCs), receive information directly from the photoreceptors and shape the contrast, luminance, spatial and temporal tuning of the insect visual system in a cell-type specific manner. One of their best-investigated downstream targets is the motion vision pathway. However, how LMC types that feed into motion processing delineate contrast and luminance is only known from fruit flies, while the contribution of LMCs to spatial processing has only been described in hawkmoths. Here, we provide a novel characterization of hawkmoths lamina monopolar cells, to integrate the contrast, luminance and spatial processing properties of LMCs in the motion pathway. We used serial block-face scanning electron microscopy to reconstruct the anatomical fine structure of LMCs in a focal lamina cartridge, including their pre- and post-synaptic connections. Combining our novel LMC classification with intracellular recordings, we further investigated the functional role of hawkmoth L1 and L2 in terms of contrast and spatial processing. We show that unlike in flies, L1 and L2, the main relay neurons to the motion pathway, process contrast and luminance information in a similar manner. We further demonstrated that the spatial processing properties of these cells are highly similar as well, and can be explained by the density and the distribution of their synapses across different lamina layers. Based on these findings, we propose that the different lamina layers support distinct connectivity and functional roles in spatial processing.
SignificancePyruvate is a nodal intermediate in cellular metabolism, positioned at the crossroads between glycolysis and fermentative metabolism. It is exchanged between the intracellular and extracellular compartments through the proton-coupled monocarboxylate transporters and between the cytosol and mitochondria through the mitochondrial pyruvate carrier, where it serves as a primary carbon source for respiration. AimOur goal is to present a detailed protocol for quantifying cytosolic pyruvate concentration in neurons at single-cell resolution using a minimally invasive, two-point calibration approach with the FRET-based genetically-encoded fluorescent indicator Pyronic. ApproachThis protocol is based on a non-invasive pharmacological two-point calibration approach, where Pyronics dynamic range ({Delta}RMAX) is established by using trans-acceleration exchange to deplete intracellular pyruvate (RMIN), and by inducing Pyronic saturation (RMAX) through the combination of inhibition of pyruvate export, stimulation of its production, and blockade of its mitochondrial consumption. The protocol also incorporates the previously published KD values for Pyronic obtained from in vitro experiments. This procedure does not require the use of detergents to permeabilize the cells. ResultsImplementing this protocol enables the measurement of absolute cytosolic pyruvate concentrations. This quantitative parameter facilitates comparisons of pyruvate metabolism across different cells, samples and experimental batches, thereby enabling the comparison between a plethora of experimental conditions. ConclusionsThe FRET-based fluorescent indicator Pyronic can be reliably calibrated using a minimally invasive, pharmacology-based two-point calibration protocol in neurons, thus providing a robust and quantitative method to study pyruvate metabolism under various physiological and pathological scenarios.
From birth, individuals interpersonal dimension is underpinned by progressive learning of social interaction rules, their variations rooted in the temporal prediction of sensory events, and the inferences made about the organization of the social world. How this dimension is structured during infancy and articulated at the neural level is a critical question for cognitive and affective neurosciences. This systematic review aims to define the neural signatures of temporal prediction in newborns and infants and to discuss them in the context of the development of proximal cognitive and affective neural functions. Eight peer-reviewed studies were included, with 228 infants from birth to 9 months of age. Studies have evidenced that neural signatures of temporal prediction in infants present a broad cerebral localization, including the anterior and medial parts of the brain, especially in the frontal and central areas. Temporal prediction mechanisms emerge well before birth and evolve from early sensory-driven responses to complex top-down processing within the first year, shaped by both innate and experience-dependent factors, with influences like wakefulness and musical exposure that modulate neural integration across sensory and higher-order brain regions.
In natural language, word meanings are contextualized, that is, modified by meanings of nearby words. Inspired by self-attention mechanisms in transformer-based large language models (LLMs), we hypothesized that contextualization in the brain results from a weighted summation of canonical neural population responses to words with those of the words that contextualize them. We examined single unit responses in the human hippocampus while participants listened to podcasts. We first find that neurons encode the position of words within a clause, that they do so at multiple scales, and that they make use of both ordinal and frequency-domain positional encoding (which are used in some transformer models). Critically, neural responses to specific words correspond to a weighted sum of that words non-contextual embedding and the embedding of the words that contextualize it. Moreover, the relative weighting of the contextualizing words is correlated with the magnitude of the LLM-derived estimates of self-attention weighting. Finally, we show that contextualization is aligned with next-word prediction, which includes prediction of multiple possible words simultaneously. Together these results support the idea that the principles of self-attention used in LLMs overlap with the mechanisms of language processing within the human hippocampus, possibly due to similar prediction-oriented computational goals.
In natural language, word meanings are contextualized, that is, modified by meanings of nearby words. Inspired by self-attention mechanisms in transformer-based large language models (LLMs), we hypothesized that contextualization in the brain results from a weighted summation of canonical neural population responses to words with those of the words that contextualize them. We examined single unit responses in the human hippocampus while participants listened to podcasts. We first find that neurons encode the position of words within a clause, that they do so at multiple scales, and that they make use of both ordinal and frequency-domain positional encoding (which are used in some transformer models). Critically, neural responses to specific words correspond to a weighted sum of that words non-contextual embedding and the embedding of the words that contextualize it. Moreover, the relative weighting of the contextualizing words is correlated with the magnitude of the LLM-derived estimates of self-attention weighting. Finally, we show that contextualization is aligned with next-word prediction, which includes prediction of multiple possible words simultaneously. Together these results support the idea that the principles of self-attention used in LLMs overlap with the mechanisms of language processing within the human hippocampus, possibly due to similar prediction-oriented computational goals.
All-optical interrogation, based on high-resolution two-photon stimulation and imaging, has emerged as a potentially transformative approach in neuroscience, allowing for the simultaneous precise manipulation and monitoring of neuronal activity across various model organisms. However, the unintended excitation of light-gated ion channels such as channelrhodopsin (ChR) during two-photon calcium imaging with genetically encoded calcium indicators (GECIs) introduces artifactual neuronal perturbation and contaminates neural activity measurements. In this study, we propose an active pixel power control (APPC) approach, which dynamically adjusts the imaging laser power at each scanning pixel, to address the challenge. We aim to achieve simultaneous two-photon optogenetic manipulation and calcium imaging with a single femtosecond laser, while minimizing the crosstalk between manipulation and imaging. To study this technologys capabilities, we applied it to the larval zebrafish brain in vivo. Our results demonstrate that the APPC approach preserves GECI signal quality while suppressing optogenetic artifacts significantly. This enhances the accuracy of neural circuit dissection and advances the precision of all-optical interrogation, offering a robust framework for probing neural circuit dynamics and causality in vivo with high fidelity, potentially across various model organisms. Importantly, this technology can be seamlessly integrated with commonly used two-photon microscope systems in laboratories worldwide.
Adult hippocampal neurogenesis (AHN) is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to AHN impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-) signalling as a key driver of neurogenic dysregulation via a previously unrecognized type I interferon (IFN) autocrine/paracrine loop in human hippocampal progenitor cells (HPCs). Using a human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that TNF- induces a robust type I IFN response in HPCs, promoting chemokine and CXCR3-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in HPCs from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis. These findings uncover a key inflammatory checkpoint regulating human AHN and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.
Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) and electromyography (EMG) provides a unique window into instantaneous cortical and corticospinal excitability states. We investigated 50 healthy participants to determine how fluctuations in pre-stimulus brain activity influence single-trial TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs). We developed a novel automated source-level TEP extraction method using individualized spatiotemporal priors that is robust against poor single-trial signal-to-noise ratios (SNRs) and ongoing oscillations. TEP and MEP amplitudes were predicted with linear mixed-effects models based on pre-stimulation EEG band-powers (theta to gamma), while accounting for temporal drifts (within-session trends), coil control, and inter-subject differences. We found that higher pre-stimulus sensorimotor alpha, beta, and gamma power were each associated with larger TEPs, indicating a more excitable cortical state. Increases in alpha and gamma power immediately before stimulation specifically predicted larger MEPs, reflecting increased corticospinal excitability. These results reveal relationships between ongoing oscillatory brain states and TMS response amplitudes, identifying EEG biomarkers of high- and low-excitability states. In conclusion, our study demonstrates the feasibility of single-trial source-level TMS-EEG analysis and shows that spontaneous alpha-, beta-, and gamma-band oscillations modulate motor cortical and corticospinal responsiveness. These findings pave the way for EEG-informed, brain-state-dependent TMS protocols to optimize neuromodulatory interventions in clinical and research applications.
Understanding social difficulties in Autism Spectrum Disorder (ASD) remains challenging due to its neurobiological heterogeneity and the limited ecological validity of conventional neuroimaging methods in capturing dynamic social interactions. Hyperscanning analysis based on functional near-infrared spectroscopy (fNIRS), which measures inter-brain synchrony (IBS) during dyadic interaction, offers a novel avenue to address these challenges. However, prior studies on ASD have reported inconsistent findings, primarily focusing on intra-regional synchronization while overlooking cross-regional network dynamics. To bridge this gap, we proposed an interpretable graph neural network (GNN) model to systematically identify ASD-specific IBS modular network between child-caregiver dyads during naturalistic cooperative puzzle-solving and free-talking tasks. We identified distinctive key IBS sub-networks for the cooperative puzzle-solving task and free-talking task, with the frontal eye field (FEF) of caregivers, the dorsal lateral prefrontal cortex (DLPFC) and the motor region of children highlighted. Furthermore, the key IBS sub-networks were found to be able to predict multiple domains of the core ASD symptoms. By integrating hyperscanning with GNN-driven analysis, this work uncovers task-dependent inter-brain neural mechanisms underlying social difficulties in ASD. These findings advance the field by proposing a data-driven framework to identify IBS biomarkers tied to clinical profiles, paving the way for personalized interventions that integrate computational neuroscience with clinical practice.
Perceptual illusions are widely used to study brain processing, and are essential for elucidating underlying function. Successful brain models should then also be able to reproduce these illusions. Some of the most successful models for vision are several variants of Deep Neural Networks (DNNs). These models can classify images with human-level accuracy, and many behavioral and activation measurements correlate well with humans and animals. For several networks it was also shown that they can reproduce some human illusions. However, this was typically done for a limited number of networks. In addition, it remains unclear whether the presence of illusions is linked to either how accurate or brain-like the DNNs are. Here, we consider the scintillating grid illusion, to which two DNNs have been shown to respond as if they are impacted by the illusion. We develop a measure for measuring Illusion Strength based on model activation correlations, which takes into account the difference in Illusion Strength between illusion and control images. We then compare the Illusion Strength to both model performance (top-1 ImageNet), and how well the model explains brain activity (Brain-score). We show that the illusion was measurable in a wide variety of networks (41 out of 51). However, we do not find a strong correlation between Illusion Strength and Brain-Score, nor performance. Some models have strong illusion scores but not Brain-Score, or vice-versa, but no model does both well. Finally, this differs strongly between model types, particularly between convolutional and transformer-based architectures, with transformers having low illusion scores. Overall, our work shows that Illusion Strength measures an important metric to consider for assessing brain models, and that some models could still be missing out on some processing important for brain functioning.
Task context affects stimulus representations in human visual cortex, suggesting that visual representations are flexible. However, this interpretation is at odds with a major computational goal of the human visual system: creating a perceptually stable representation of the external visual environment. How does the visual system balance stability and flexibility? Here, human participants (71 percent females) categorized object images and written words according to different task rules, while brain responses were measured with fMRI. Using an ANOVA-based modeling strategy, we precisely quantified the relative contributions of stimulus, task, and their interaction in explaining representational variance across the cortical hierarchy. Our results show that stimulus effects account for the overwhelming majority of explainable representational variance across the ventral visual system: > 95 percent in V1 and V2, and > 90 percent in higher-level visual cortex. In prefrontal cortex, the relative contributions reverse: task effects dominate stimulus effects, accounting for 80 percent of explainable representational variance. In parietal cortex, contributions of stimulus and task are approximately equal. Our findings suggest that population coding in sensory cortex is optimized for representational stability to allow a consistent interpretation of the external environment. Population coding in parietal and frontal multiple-demand cortex, by contrast, is optimized for representational flexibility to accommodate changing behavioral goals and support flexible cognition and action. Significance statementStimulus representations in human visual cortex are affected by behavioral goals and are therefore thought to be flexible. However, this view is inconsistent with a major computational goal of the human visual system: creating a perceptually stable representation of the external environment. Here, we show that modulatory effects of behavioral goals on stimulus representations in visual cortex are surprisingly small. In contrast, behavioral goals strongly affect representations in parietal and frontal multiple-demand cortex. Our findings suggest that population coding in sensory cortex is optimized for stable perception, while population coding in parietal and frontal multiple-demand cortex is optimized for flexible cognition.
Botulinum neurotoxin type A1 (BoNT/A1) is an effective treatment for chronic migraine, but its direct mechanism of action on human sensory neurons has not been fully elucidated. While rodent studies on dorsal root ganglion (DRG) and trigeminal ganglion (TG) show that BoNT/A1 inhibits neurotransmission, including calcitonin gene-related peptide (CGRP) release, by cleaving SNAP-25, only one previous study has assessed its effect on human DRG neurons. The objective of this study was to understand the mechanism of action of BoNT/A1 in cultured human sensory neurons and assess, using RNA sequencing, the transcriptomic consequences of BoNT/A1 treatment. Using DRGs obtained from organ donors the expression of key targets, including SNAP25, SV2C, & CALCA, was validated by mining existing transcriptomic datasets as well as immunohistochemistry. Cultured dissociated human DRG neurons treated with BoNT/A1 were used to examine cleavage of SNAP25, release of CGRP and transcriptomic changes after BoNT/A1 treatment. SV2C was found to be widely expressed in human DRG neurons in a pattern that completely overlapped with CGRP expression. Consistent with this finding, BoNT/A1 disrupted SNARE protein complexes in human DRG neurons as demonstrated by SNAP-25 cleavage in most somatosensory neurons and a reduction in capsaicin-evoked CGRP release, indicating impaired vesicle fusion. Moreover, Bulk RNA sequencing experiments revealed downregulated expression of a large subset of genes responsible for neurotransmitter and neuropeptide release from neurons suggesting a novel mechanism through which BoNT/A regulates neurotransmission. These results provide new insight into the molecular mechanisms by which BoNT/A may exert its pain-relieving effects in humans.
BackgroundSocial stress--particularly when experienced during adolescence, can have a lasting impact on health and well-being. Among other key biological pathways, inflammatory and innate immune signaling appear to play important roles in linking stress to physical and mental health problems. Individual differences in sensitivity to social threats may leave certain people more vulnerable to stress and its harmful sequelae than others, and a growing body of research has found that stress sensitivity is reflected in neural activity throughout the threat network. However, few studies have investigated whether heightened neural sensitivity to social threats is related to acute changes in immune and neuroendocrine pathways relevant to health, particularly among those for whom the effects of stress may be especially impactful. MethodIn the current research, 52 adolescent females (MAge = 14.90, SD = 1.35) participated in a functional magnetic resonance imaging study to examine brain activity and functional connectivity during a social evaluation task. Nearly half of the sample (n = 22) were identified as having a maternal history of depression. Blood samples were collected prior to the task, as well as 35 and 65 min. after the task began, and were used for transcriptional profiling. ResultsThe primary analyses tested whether threat network activity and connectivity predicted the magnitude of change in gene expression from baseline to the follow-up time points. Results revealed robust shifts in expression of genes in innate immune pathways in response to the task (e.g., hypoxia inducible factor-1, interferon signaling). Although activity across the entire threat network was related to individual differences in gene expression, anterior cingulate cortex-insula and insula-ventromedial prefrontal cortex connectivity were most consistently related to up- and down-regulation of immune pathways, respectively. These patterns were further moderated by differences in maternal depression history. ConclusionResults demonstrate that individual differences in threat network activity may have important implications for biological responses to social threat among adolescent females. In turn, these findings both provide insights into neural signatures of social stress vulnerability and the biological pathways that may contribute to poorer health outcome among those most vulnerable to stress.
Attention plays a crucial role in maintaining precision and effectiveness in goal-directed actions. Although there is evidence that dividing attention across tasks impairs performance in various domains, the impact of attention on sensorimotor adaptation remains inconclusive, with some studies reporting deficits and others showing no effects. Because sensorimotor adaptation arises from the interaction of explicit and implicit processes, this discrepancy may reflect differential effects of attention on each process. Here, we investigate how divided attention influences implicit sensorimotor adaptation using an error-clamp paradigm, coupled with a random dot kinematogram (RDK) motion coherence discrimination task. We also assessed whether the timing of the secondary task affects error processing during sensorimotor adaptation by presenting the RDK either during the outward movement (coinciding with error feedback), or the inward movement (following error feedback). We observed that attentional manipulation influenced implicit sensorimotor adaptation only when the RDK was presented on the outward movement, not the inward movement. Remarkably, implicit sensorimotor adaptation was enhanced when attention was divided, compared to when attention was focused entirely on the adaptation task. This suggests that implicit sensorimotor adaptation is sensitive to attentional demand, particularly during the time window where error feedback is received.
Xylazine is a veterinary sedative and widespread adulterant of illicit opioids, where it is commonly combined with the highly potent synthetic {micro} opioid receptor (MOR) agonist fentanyl. Xylazine adulteration of fentanyl is associated with increased risk of lethal overdose and decreased efficacy of reversal by the MOR antagonist naloxone. Here we use whole body plethysmography in mice to show that xylazine produces profound respiratory depression at subanesthetic doses. Xylazine rapidly and dose-dependently suppressed minute ventilation, tidal volume, and respiratory frequency. These effects were dependent on -2 adrenergic receptors and were fully blocked by coadministration of the -2 adrenergic antagonist atipamezole. Atipamezole, administered alone, produced only modest reversal of fentanyl-induced respiratory depression. Xylazine, when combined with a dose of fentanyl with modest respiratory effects, suppressed breathing with greater efficacy than when administered alone. Strikingly, doses of naloxone sufficient to completely reverse fentanyl-induced respiratory depression were ineffective in reversing the respiratory suppression induced by xylazine-adulterated fentanyl. By contrast, combinations of naloxone with atipamezole rapidly and fully reversed the suppression of breathing induced by xylazine-adulterated fentanyl. Our results show that xylazine suppresses breathing via activation of -2 receptors, an effect enhanced by coadministration with the MOR agonist fentanyl. Respiratory suppression inflicted by the mixture of xylazine and fentanyl resisted reversal by naloxone but was fully reversible by subsequent coadministration of both naloxone and atipamezole. These observations have profound implications for the current opioid epidemic.
In biological systems, survival is predicated on an animal being able to perform computations quickly on a minimal energy budget. What is the energy consumption of non-equilibrium brain computation, i.e., what is the cost of cognition? Previous literature has estimated the metabolic cost using neuroimaging measures of glucose consumption but complementary to these findings, here we directly estimate the computational costs by combining the new field of stochastic thermodynamics with whole-brain modelling. We developed the COCO (COst of COgnition) framework using an analytical expression quantifying the links between energy cost, non-equilibrium and information processing for any given brain state measured with neuroimaging. Importantly, this key relationship also holds at the level of individual brain regions. We used this to quantify the benefits of information processing on the highly anatomically, interconnected hierarchical systems of the brain. Crucially, in empirical neuroimaging data we demonstrate that the human brain uses significantly less energy overall than other mammals (including non-human primates and mice), suggestive of an evolutionary optimisation of the effectiveness of computation. Focusing on the cost of cognition, using large-scale human neuroimaging data of 970 healthy human participants, we show that the resting state uses significantly less energy that seven different cognitive tasks. Furthermore, different kinds of tasks require different amounts of non-equilibrium, information processing and energy consumption. We found that tasks requiring more distributed computation also use more energy. Overall, these results directly quantify the cost of cognition, i.e., the non-equilibrium and energetic demands of information processing, allowing a deeper understanding of how the brain compute in a way that is far more energy efficient than current generations of digital computers and artificial intelligence.
In biological systems, survival is predicated on an animal being able to perform computations quickly on a minimal energy budget. What is the energy consumption of non-equilibrium brain computation, i.e., what is the cost of cognition? Previous literature has estimated the metabolic cost using neuroimaging measures of glucose consumption but complementary to these findings, here we directly estimate the computational costs by combining the new field of stochastic thermodynamics with whole-brain modelling. We developed the COCO (COst of COgnition) framework using an analytical expression quantifying the links between energy cost, non-equilibrium and information processing for any given brain state measured with neuroimaging. Importantly, this key relationship also holds at the level of individual brain regions. We used this to quantify the benefits of information processing on the highly anatomically, interconnected hierarchical systems of the brain. Crucially, in empirical neuroimaging data we demonstrate that the human brain uses significantly less energy overall than other mammals (including non-human primates and mice), suggestive of an evolutionary optimisation of the effectiveness of computation. Focusing on the cost of cognition, using large-scale human neuroimaging data of 970 healthy human participants, we show that the resting state uses significantly less energy that seven different cognitive tasks. Furthermore, different kinds of tasks require different amounts of non-equilibrium, information processing and energy consumption. We found that tasks requiring more distributed computation also use more energy. Overall, these results directly quantify the cost of cognition, i.e., the non-equilibrium and energetic demands of information processing, allowing a deeper understanding of how the brain compute in a way that is far more energy efficient than current generations of digital computers and artificial intelligence.
White matter injury (WMI) is a major cause of morbidity in premature infants, contributing to 5%-10% of cerebral palsy cases and up to 50% of cognitive and behavioral deficits in the United States. Two commonly used preclinical models, intermittent hypoxia (IH) and hypoxia-ischemia (HI) are widely employed to investigate the effects of WMI. The internal capsule (IC) and corpus callosum (CC) are major white matter tracts undergoing active myelination during the neonatal period, making them particularly vulnerable to hypoxic insults. This study aims to compare the effects of IH and HI models on myelination as well as the involvement of inflammatory cells in the IC and CC. We evaluated five oligodendrocyte (OL) subtypes, along with astrocytes, microglia, and activated microglia in IC and CC at postnatal day 12 (P12) and day 20 (P20) using spatial transcriptomics (CosMx, Novogene). For the HI model, C57BL/6 mice at P10 underwent permanent ligation of the left carotid artery followed by 45 minutes of hypoxia (8% O2 / 92% N2). For the IH model, P3 mice were exposed to 5% O2 / 95% N2, twice daily for five consecutive days. Animals were euthanized at P12 and P20, perfused transcardially, and brains were post-fixed in 4% paraformaldehyde, dehydrated in an ethanol series, embedded in paraffin, and coronally sectioned at 7 m. Slides were submitted for CosMx spatial transcriptomic analysis (NanoString Technologies), and data analysis was performed using the Seurat package in RStudio. Our results demonstrate that IH and HI models affect OL populations differently, and these effects vary by brain region. In the IC, the IH model caused earlier and more pronounced changes in OL differentiation-related gene expression compared to HI. In contrast, the CC was more affected by HI. Moreover, in the HI group, mature OL s in both regions showed reduced expression of myelination-associated genes. This was accompanied by greater activation of inflammatory cells and increased intercellular communication between these cells and mature OLs, potentially contributing to the observed hypomyelination. Overall, our study provides critical insights into how each model of neonatal hypoxia differentially impacts white matter development. This knowledge can help refine preclinical strategies and guide therapeutic research tailored to the underlying pathology of each model.
Human infants begin life with limited visual capacities, such as low acuity and poor color sensitivity, due to gradual sensory maturation. In contrast, machine learning models are trained on high-fidelity inputs from the outset, often leading to shortcut learning and overfitting to spurious correlations. Here, we show that early sensory immaturity plays a critical role in shaping bias-resistant, abstract visual representations that conventional models struggle to develop. Using neural network simulations and human psychophysics experiments, we demonstrate that gradual sensory development supports the emergence of robust and generalizable internal representations, reduces reliance on superficial cues, and promotes disentangled representations that enable compositional reconstruction and visual imagination. Comparative analyses of human and model behavior reveal shared patterns of bias resistance and adaptive generalization, including resilience to misleading information. Our findings suggest that gradual sensory maturation is not merely a developmental constraint, but rather a key mechanism that enables abstract representation learning. One sentence summaryEarly-stage sensory immaturity guides the development of abstract, bias-resistant representations that enable generalization and compositionality, providing a functional account of gradual sensory maturation. HighlightsO_LIThe essential yet overlooked role of gradual sensory maturation was explored C_LIO_LIEarly sensory immaturity promotes abstract representations resistant to shortcut learning C_LIO_LIEmergent representations support compositional reconstruction of novel visual attributes C_LIO_LIHuman and model behaviors show similar bias resistance and adaptive generalization C_LI
Singing to infants is a universal human practice that has beneficial effects on infants cognitive and affective development. Children born preterm have impaired brain development, and their perception of maternal speech is known to be affected by the atypical hospital auditory environment. Understanding how preterm infants perceive maternal singing is of critical importance, yet it remains largely unexplored. Using high-density EEG, we examined neural responses to the same melody presented through maternal singing, stranger singing, and instrument, and compared the responses in 12 preterm infants. Moreover, to examine their processing of spatialisation, auditory stimuli were presented under monaural and binaural conditions. Preterm newborns are able to discriminate the same melody when sung by their mother, a stranger, or played by an instrument. When presented monaurally, the mothers singing voice enhances widespread brain synchrony across the entire scalp. In contrast, this synchrony diminishes with binaural spatialization. These findings suggest that maternal singing constitutes a highly salient auditory stimulus for preterm newborns, eliciting a distinct neural signature. Given that brain synchrony is a critical component of healthy brain function and development, harnessing maternal singing may offer a promising, natural intervention to support neurodevelopment--particularly in vulnerable populations such as preterm infants.
Singing to infants is a universal human practice that has beneficial effects on infants cognitive and affective development. Children born preterm have impaired brain development, and their perception of maternal speech is known to be affected by the atypical hospital auditory environment. Understanding how preterm infants perceive maternal singing is of critical importance, yet it remains largely unexplored. Using high-density EEG, we examined neural responses to the same melody presented through maternal singing, stranger singing, and instrument, and compared the responses in 12 preterm infants. Moreover, to examine their processing of spatialisation, auditory stimuli were presented under monaural and binaural conditions. Preterm newborns are able to discriminate the same melody when sung by their mother, a stranger, or played by an instrument. When presented monaurally, the mothers singing voice enhances widespread brain synchrony across the entire scalp. In contrast, this synchrony diminishes with binaural spatialization. These findings suggest that maternal singing constitutes a highly salient auditory stimulus for preterm newborns, eliciting a distinct neural signature. Given that brain synchrony is a critical component of healthy brain function and development, harnessing maternal singing may offer a promising, natural intervention to support neurodevelopment--particularly in vulnerable populations such as preterm infants.
The hippocampus has long been regarded as a neural map of physical space, with its neurons categorized as spatially or non-spatially tuned according to their response selectivity. However, growing evidence suggests that this dichotomy oversimplifies the complex roles hippocampal neurons play in integrating spatial and non-spatial information. Through computational modeling and in-vivo electrophysiology in macaques, we show that neurons classified as spatially tuned primarily encode linear combinations of immediate behaviorally relevant factors, while those labeled as non-spatially tuned rely on nonlinear mechanisms to integrate temporally distant experiences. Furthermore, our findings reveal a temporal gradient in the primate CA3 region, where spatial selectivity diminishes as neurons encode increasingly distant past events. Finally, using artificial neural networks, we demonstrate that nonlinear recurrent connections are crucial for capturing the response dynamics of non-spatially tuned neurons, particularly those encoding memory-related information. These findings challenge the traditional dichotomy of spatial versus non-spatial representations and instead suggest a continuum of linear and nonlinear computations that underpin hippocampal function. This framework provides new insights into how the hippocampus bridges perception and memory, informing on its role in episodic memory, spatial navigation, and associative learning.
Proteins are the functional effectors of virtually all biological processes, and accurately measuring their abundance and dynamics is essential for understanding development and disease. Although mRNA levels have historically been used as proxies for protein expression, growing evidence, especially from studies of the human cerebral cortex, has revealed widespread discordance between transcript and protein abundance. To directly address this limitation, we developed a rigorously optimized workflow that combines single-cell mass spectrometry with precise sample preparation to resolve, for the first time, quantitative proteomes of individual cells from the developing human brain. Our platform achieved deep proteomic coverage ([~]800 proteins per cell) even in immature prenatal human neurons (5-10 m diameter, [~]100 pg of protein per cell), capturing major brain cell types and enabling proteome-wide characterization at single-cell resolution. This approach revealed extensive transcriptome-proteome discordance across cell types, with particularly strong discrepancies in genes associated with neurodevelopmental disorders, a finding validated through orthogonal experiments. Proteins exhibited markedly higher cell-type specificity than their mRNA counterparts, underscoring the importance of proteomic-level analysis for resolving cellular identity and function. By reconstructing developmental trajectories from radial glia to excitatory neurons at the proteomic level, we identified dynamic stage-specific protein co-expression modules and pinpointed the intermediate progenitor-to-neuron transition as a molecularly vulnerable phase linked to autism. Altogether, by enabling single cell proteomics, this study establishes a foundational resource and technological advance for developmental neuroscience. It demonstrates that single-cell proteomics can capture critical developmental events and disease mechanisms that are undetectable at the transcript level. As this technology continues to improve in sensitivity and scalability, single-cell proteomics will become an indispensable tool for uncovering the molecular logic of brain development and for illuminating pathophysiological processes underlying neurodevelopmental disorders.
Humans spend time contemplating the minds of others. But this ability is not limited to external agents - we also turn the lens for reading minds inward, reflecting on our own thoughts, emotions, and sense of self. Some processes involved in reasoning about minds may rely on shared mechanisms, while others may be specific to the agent under consideration. We developed a paradigm where participants performed either a mental state inference task or a control task targeting either another person presented onscreen or their own mind. Using fMRI and multi-voxel pattern analysis, we replicate a well-established self-other axis along the medial wall of prefrontal cortex: ventral regions selectively decoded mental state inference patterns for self, but not other, whereas more dorsal regions decoded mental state inference for both self and other, compared to control conditions. Posterior cingulate cortex, on the other hand, differentiated the target of mental state inference. Using a cross-classification analysis, we also found patterns in the dorsomedial prefrontal cortex, ventromedial prefrontal cortex, and right temporoparietal junction were sensitive to mental state reasoning in general, regardless of the target agent. These findings highlight one process reflecting reasoning specific to the agent and another reflecting the reasoning process itself.
When a visual stimulus is repeated, the cortex has the opportunity to adjust its processing. Indeed, repeated stimuli induce reduced neuronal spike rates and increased neuronal gamma-band synchronization. Previous studies found the repetition-related gamma increase to occur both in human and non-human primates, for artificial and natural stimuli, to persist for minutes and to not transfer between strongly differing stimuli. Here, we further investigated the repetition-related effects using laminar recordings of multi-unit activity and local field potentials from awake macaque areas V1 and V2. We find that the effects on spike rate and gamma occur in all laminar compartments of V1 and V2. We quantify the degree of stimulus specificity with oriented gratings and find that the repetition-related gamma increase does not transfer to gratings differing by merely 10 {degrees}, the smallest difference tested. Furthermore, we find that the repetition-related effects are robust to stimulus set size, occurring both when one stimulus was repeated and when eighteen different interleaved stimuli were repeated. Finally, we show that alpha-beta activity increases and remains elevated when a stimulus is repeated, and decreases sharply when an unexpected stimulus is presented. These results suggest that repetition-related plasticity leads to changes in spike rates and rhythmic neuronal synchronization in different frequency bands that adjust the cortical processing of repeated stimuli.
Reactive astrocytes shape central nervous system (CNS) inflammation and participate in myelin damage and repair mechanisms in multiple sclerosis (MS). Through the activation of cannabinoid CB1 receptors (CB1R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promote remyelination in preclinical MS models. However, despite accumulating evidence that supports a crucial role for these receptor populations in brain physiology and pathology, the implications of astrocyte CB1R signaling in MS initiation and progression remain uncertain. Using complementary in vivo disease models, here we investigated the effects of targeted genetic deletion of astrocytes CB1R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB1R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB1R inactivation displayed unaltered oligodendrocyte populations both in EAE lesions and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that astrocyte CB1R modulate myelin repair processes. Conversely, inactivation of CB1R in astroglial cells restricted humoral and leukocyte parenchymal infiltration and reduced the expression of vascular effectors in EAE lesions. Finally, loss of blood-brain barrier (BBB) function induced by cortical microinjection of VEGF-A was less severe in GFAP-CB1R-KO mice. These results show that astrocyte CB1R signaling constitutes a significant pro-inflammatory mechanism in MS and bring to light a deleterious role for endocannabinoid-mediated modulation of astroglial cells with potential implications in the etiopathology and therapy of neuroinflammatory disorders.
Learning to detect and respond to threats is fundamental for survival and is often modeled through threat conditioning (TC) paradigms. While these paradigms reliably produce implicit memories that elicit physiological and behavioral responses to conditioned stimuli (CS), less is explored about how TC influences cognitive and emotional biases, particularly those implicated in anxiety disorders, such as threat overestimation and negative stimulus representation. In this study, we investigated the dynamic interaction between the reactivation of the implicit threat memory and these cognitive biases using a validated TC paradigm in humans. In Experiment 1, participants underwent TC on Day 1, followed by a memory reactivation session (incomplete reminder: one unreinforced CS+) and a highly demanding working memory (HWM) task, used as an amnesic manipulation, or a control condition on Day 2. On Day 3, memory retention was tested using a simplified, single-trial protocol (one CS+, one CS-, and one neutral CS), followed by tasks assessing threat valuation and representation. Results indicated that the HWM task administered post-reactivation significantly reduced skin conductance responses (SCRs) and attenuated cognitive biases, without altering expectancy of the unconditioned stimulus (US). In Experiment 2, we evaluated the effect of varying reactivation frequency (none, one, or two reminders) on implicit memory and cognitive biases. While repeated reactivations generalized the conditioned response to other stimuli, cognitive and emotional biases remained stable, suggesting a dissociation between memory generalization and evaluative processing. These findings demonstrate that implicit threat memories can be selectively modified through post-reactivation interventions, affecting both physiological and cognitive-emotional domains. Importantly, the distinct effects of memory reactivation and reconsolidation on physiological versus cognitive outcomes support the existence of temporally and functionally dissociable mechanisms. This research highlights the need to consider cognitive biases alongside physiological responses when evaluating memory-based interventions and offers novel insight into mechanisms underlying anxiety maintenance and treatment.
Chlamydia pneumoniae (Cp), an obligate intracellular bacterium, has been implicated in Alzheimers disease (AD), yet its role in retinal pathology remains unexplored. We analyzed postmortem tissues from 95 human donors and found 2.9-4.1-fold increases in Cp inclusions in AD retinas and brains, with no significant elevation in mild cognitive impairment (MCI). Proteomics revealed dysregulation of retinal and brain bacterial infection-related proteins and NLRP3 inflammasome pathways. NLRP3 expression was markedly elevated in MCI and AD retinas, and its activation was evident by increased N-terminal gasdermin D (NGSDMD) and mature interleukin-1{beta}. Retinal Cp strongly correlated with A{beta}42 and NLRP3 inflammasome components, which tightly linked to cleaved caspase-3-apoptotic and NGSDMD-pyroptotic cell death. Although retinal microgliosis was elevated in AD, Cp-associated microglia were reduced by 62%, suggesting impaired Cp phagocytosis. Higher retinal Cp burden correlated with APOE{varepsilon}4, Braak stage, and cognitive deficit. Machine learning identified retinal Cp or NLRP3 combined with A{beta}42 as strong predictors of AD diagnosis, staging, and cognitive impairment. Our findings suggest that Cp infection contributes to AD dementia but not initiating pathology, whereas early NLRP3 activation may promote disease development, warranting studies on Cps role in AD pathogenesis and early antibiotic or inflammasome-targeted therapies.
Neural fluctuations exhibit rich spectral profiles that reflects both local dynamics and structural (or anatomical) embedding. Yet, standard models of resting-state effective connectivity neglect structural embedding and assume uniformity in the timescales of regions endogenous fluctuations. We introduce a chromatic dynamic causal model (DCM) in which structural valency (or degree) modulates the spectral color of endogenous fluctuations. Specifically, we assume a linear mapping between regional structural valency and the spectral exponent of scale-free auto-spectra. Simulations show this mapping can emerge as a generic consequence of structural embedding under minimal coupling in a non-equilibrium regime. We show chromatic DCM reliably recovers ground-truth parameters across network sizes and noise conditions, outperforming standard spectral DCM. Applied to empirical data, chromatic DCM reveals that valency-exponent mappings vary across a cortical hierarchy, and that its parameters are conserved across a homologous network in humans, macaques, marmosets, and mice. These findings advance a generative account of structure-function coupling and expand the repertoire of biophysical mechanisms available for inference in effective connectivity modeling.
Predictive processing theories propose that the brain continuously generates expectations about incoming sensory information. Discrepancies between these predictions and actual inputs, sensory prediction errors, guide perceptual inference. A fundamental yet largely unresolved question is which stimulus features the brain predicts, and therefore, what kind of surprise drives neural responses. Here, we investigated this question using EEG and computational modelling based on deep neural networks (DNNs). Participants viewed object images whose identity was probabilistically predicted by preceding cues. We then quantified trial-by-trial surprise at both low-level (early DNN layers) and high-level (late DNN layers) visual feature representations. Results showed that stimulus-evoked responses around 200ms post-stimulus onset over parieto-occipital electrodes were increased by high-level, but not by low-level visual surprise. These findings demonstrate that high-level visual predictions are rapidly integrated into perceptual inference, suggesting that the brains predictive machinery is finely tuned to utilize expectations abstracted away from low-level sensory details to facilitate perception.
Neuroimaging techniques produce vast amounts of data, capturing brain activity in a high-dimensional space. However, brain dynamics are consistently shown to reside in a rather lower-dimensional space, which contains relevant information for cognition and behavior. This dimensionality reduction reflects distinct types of interactions between brain regions, such as redundancy -shared neural information distributed across regions- and synergy, where information emerges only when regions are considered collectively. Significant efforts have been devoted to developing linear and non-linear algorithms to reveal these low-dimensional dynamics, often termed "brain modes." Here, we apply various dimensionality reduction techniques to resting-state functional magnetic resonance imaging (fMRI) data from 100 healthy participants to examine how synergistic interactions in brain dynamics are preserved by these techniques. We first demonstrate that biologically informed brain parcellation modulates and preserves synergy-dominated interactions. Next, we show that synergy among low-dimensional modes enhances functional-connectivity reconstruction: nonlinear autoencoders not only achieve the lowest reconstruction error but also maximally preserve synergy, outperforming principal component analysis, diffusion maps, and Laplacian eigenmodes. Finally, we confirm previous results suggesting that global signal regression helps to identify synergistic interactions between regions. Our findings establish synergy preservation as a complementary criterion to reconstruction accuracy, highlighting autoencoders as a nonlinear tool for uncovering synergistic low-dimensional brain modes from high-dimensional neuroimaging data.
ObjectiveCranial nerve stimulation (CNS) uses electric current to modulate higher-order brain activity and organ function via nerves, including the vagus and trigeminal, with applications in migraine, epilepsy, and pediatric ADHD. The trigeminal nerve is an emerging target for non-invasive neuromodulation due to the superficial trajectory of its branches, the supraorbital (SON), infraorbital (ION), and mental nerves (MN), and the predominantly sensory composition of the SON and ION. However, the parameters and outcomes of trigeminal nerve stimulation (TNS) remain varied. ApproachThis study characterizes the anatomical course, tissue composition, and activation profiles of the SON, ION, and MN using five human donors. CT imaging was utilized to localize each nerves exit foramen and distance to midline. Microdissections quantified nerve circumference and depth relative to the skin surface. Histological analysis described the number of fascicles and fascicular tissue area. Nerve depths were incorporated into computational models to illustrate the activation function across tissue layers, comparing expected nociceptor and nerve trunk activation functions as a measure of neural engagement. Main ResultsThe SON was found to be significantly more superficial than the ION and MN and had a higher nerve-to-connective tissue ratio relative to the MN. Computational modeling demonstrated that the activation function at the depths of nociceptors was orders of magnitude greater than within the main nerve trunks, suggesting preferential recruitment of cutaneous nociceptors, dependent on nociceptor density. SignificanceThe SON presents the most accessible and anatomically favorable target for transcutaneous trigeminal nerve stimulation among the branches examined due to its superficial location. However, preferential activation of low-threshold nociceptors compared to nerve trunks may lead to treatment-limiting off-target side effects, favoring strategies that target fibers of interest within the skin. These findings offer an anatomically informed framework to guide further computational modeling and electrode design for targeted trigeminal neuromodulation.
IntroductionPatients with mild cognitive impairment (MCI) have shown disruptions in both brain structure and function, often studied separately. However, understanding the relationship between brain structure and function can provide valuable insights into this early stage of cognitive decline for better treatment strategies to avoid its progression. Network Control Theory (NCT) is a multi-modal approach that captures the alterations in the brains energetic landscape by combining the brains functional activity and the structural connectome. Our study aims to explore the differences in the brains energetic landscape between people with MCI and healthy controls (HC). MethodsFour hundred ninety-nine HC and 55 MCI patients were included. First, k-means was applied to functional MRI (fMRI) time series to identify commonly recurring brain activity states. Second, NCT was used to calculate the minimum energy required to transition between these brain activity states, otherwise known as transition energy (TE). The entropy of the fMRI time series as well as PET-derived amyloid beta (A{beta}) and tau deposition were measured for each brain region. The TE and entropy were compared between MCI and HC at the network, regional, and global levels using linear models where age, sex, and intracranial volume were added as covariates. The association of TE and entropy with A{beta} and tau deposition was investigated in MCI patients using linear models where age, sex, and intracranial volume were controlled. ResultsCommonly recurring brain activity states included those with high and low amplitude activity in visual (+/-), default mode (+/-), and dorsal attention (+/-) networks. Compared to HC, MCI patients required lower transition energy in the limbic network (adjusted p = 0.028). Decreased global entropy was observed in MCI patients compared to HC (p = 7.29e-7). There was a positive association between TE and entropy in the frontoparietal network (p = 7.03e-3). Increased global A{beta} was associated with higher global entropy in MCI patients ({rho} = 0.632, p = 0.041). ConclusionLower TE in the limbic network in MCI patients may indicate either neurodegeneration-related neural loss and atrophy or a potential functional upregulation mechanism in this early stage of cognitive impairment. Future studies that include people with AD are needed to better characterize the changes in the energetic landscape in the later stages of cognitive impairment.
Background and HypothesisTraditional fMRI analyses often ignore regions that fail to reach statistical significance, assuming they are biologically unimportant. We tested the accuracy of this assumption using causal discovery based-analysis that go beyond associations/correlations to test the causality of one regions influence over the other. We hypothesized that the network of statistically significant (active network, AN) and non-significant regions (silent network, SN) causally interact and their features will causally influence psychopathology severity and working memory performance. Study DesignWe examined AN and SN during N-BACK task on 25 FHR and 37 controls. Clusters with significantly different activations were juxtaposed to 360 Glasser atlas parcellations. The PC algorithm for causal discovery was implemented. Connectivity of regions with the highest alpha-centrality (HAC) were examined. ResultsSeventy-seven Glasser regions were in the AN and the rest were silent nodes. Two regions showed HAC for FHR and HC. Among controls, one HAC region was silent (auditory association cortex) and the other one was active (insula). Among FHR, both were silent nodes (early auditory cortex). These HAC regions in both groups had bidirectional directed edges between each other forming a reciprocal circuit whose edge-weights causally "increased" magical ideation severity. ConclusionCausal connectivity between SN and AN suggests that the statistically non-significant and significant regions influence each other. Our findings question the merit of ignoring statistically non-significant regions and exclusively including statistically significant regions in the pathophysiological models. Our study suggests that causality analysis should receive greater attention.
Mild brain trauma from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance after a CHI models. Analyzing single-cell RNA sequencing data from cortical cells from a model of CHI, we found that Pycard (Asc), the gene encoding for a common inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), is expressed particularly in microglial clusters. Sustained upregulation of inflammasome-related proteins persisted up to 21 days in a model for mild CHI, with this pattern significantly reduced in Asc-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2 expression is elevated in the hippocampus of PS19 tauopathy mice and in postmortem brains of dementia patients, particularly in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2 levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2 depletion also enhanced synaptic gene expression, synaptic density, and LTP, while attenuating microglial activation, synaptic engulfment, and pro-inflammatory cytokine levels. Importantly, CK2 depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways. Our findings highlight CK2 as a key node at the intersection of tau pathology, synaptic dysfunction, and neuroimmune signaling. Targeting CK2 may offer a novel and selective therapeutic strategy for modifying disease progression in tauopathies.
We tested whether the same principles of actuation and control that support steady-state walking are sufficient for robust, rapid gait adaptation over a wide range of step lengths and frequencies. We begin by demonstrating that periodic limit cycle gaits exist at combinations of step frequency and step length that span the full range of gaits achievable by humans. We demonstrate that open-loop local stability is not enough to rapidly transition to target gaits because some gaits in the gait space are unstable and the stable gaits have slow convergence rates. Next, we show that actuating with only one push-off and one hip spring of fixed stiffness cannot fully control the walker in the entire gait space. We solve this by adding a second hip spring with an independent stiffness with respect to the first one to actuate the second half of the swing phase. This allowed us to design local feedback controllers that provided rapid convergence to target gaits by making once-per-step adjustments to push-off and hip spring stiffnesses. To adapt to a range of target gaits that vary over time, we interpolated between local controllers. This policy performs well, accurately tracking rapidly varying combinations of target step length and step frequency with human-like response times across a wide range of human achievable gaits. To test whether this policy is biologically plausible, we use it with supervised learning to train an artificial neural network to perform nearly identical control. Author SummaryPeople can rapidly adapt their walking gaits. In this study, we used a modeling approach to study whether control of walking adaptation is identical to control of steady state walking. We first demonstrate that the model can produce human-like gaits over a wide range of step lengths and step frequencies. However, we found that unlike steady state walking, the model does not transition between gaits quickly or reliably. To address this, we introduced an additional actuation to control the swing leg and used feedback control that applies once-per-step adjustments to the actuations. This enabled the model to rapidly converge to target gaits, even when the targets changed from one step to the next. To test whether this policy is biologically plausible, we use it with supervised learning to train an artificial neural network to perform nearly identical control. This work provides insights into the mechanisms of walking adaptation and has potential implications for the design of adaptive control in robotic and wearable assistive systems.
Inferring the underlying computational processes from behavioral measurements is a fundamental approach in cognitive science and neuroscience. Although Bayesian decision theory has become a major normative framework for modeling cognition, it is unclear to what extent its modeling components (i.e., prior belief, likelihood function, and the loss function) can be recovered from behavioral data. Here, we systematically investigated the problem of inferring such Bayesian models from behavioral tasks. In contrast to a pessimistic picture often painted in previous research, our analytical results guarantee in-principle identifiability under broadly applicable conditions, without any a priori knowledge of prior or encoding. Simulations and applications on the basis of behavioral datasets validate that the predictions of this theory apply in realistic settings. Importantly, our results demonstrate that reliable recovery of the model often requires having data from multiple noise levels. This is a crucial insight that will guide future experimental design.
Along the gut-brain axis, visceral pain demonstrably evokes emotional learning and memory processes shaping behavior in clinically relevant ways. Avoidance motivated by learned fear may constitute a major obstacle to treatment success in extinction-based interventions. However, the effects of avoidance on visceral pain-related fear extinction remain poorly understood. By implementing an ecologically valid experimental protocol, we investigated how costly avoidance affects the modulation and extinction of visceral pain-related fear. Thirty-three healthy volunteers underwent conditioning with visual cues (conditioned stimuli; CS+,CS-) consistently followed by visceral pain or remaining unpaired. During avoidance, participants decided to avoid or receive pain upon confronting CS+. Avoidance decisions resulted in pain omission in some trials, while in others, participants experienced unpredictable pain. During extinction, CS were presented unpaired. CS valence, fear, and trial-by-trial decisions were analyzed. Avoidance decisions depended on prior experiences, with the highest probability of avoidance following successful pain omission. Negative CS+ valence and fear remained elevated across avoidance and extinction. Learned fear and more avoidance decisions explained 57% variance in sustained CS+ fear. Our findings indicate that avoidance, which provides short-term absence of pain even when followed by unpredictable pain, motivates its maintenance. However, it perpetuates pain-related fear and may impede extinction, with implications for persisting symptoms and therapeutic outcomes in chronic visceral pain.
Vasomotion, vascular oscillations at [~]0.1 Hz, may serve as a biomarker and therapeutic target for neurodegenerative diseases, but its origins, structure across brain vasculature, and correlation with neural activity remain unclear. This study examined the spatiotemporal characteristics of cerebral vasomotion and its relationship to neural activity in anaesthetised Hooded Lister rats using simultaneous recordings of neuronal activity and haemodynamics in motor and whisker barrel cortices. In a subset of rats, tissue oxygen was also measured. Blood pressure was pharmacologically modulated to alter vascular oscillations. We found that vasomotion was driven by the arterial tree. Two prominent activity patterns emerged: global vasomotion across the entire hemisphere and phasic vasomotion seen as a travelling wave running through the surface arteries. Moreover, vasomotion was associated with low tissue oxygen and was largely independent of spontaneous neural activity and therefore not a product of neurovascular coupling.
Understanding the principle of information flow across distributed brain networks is of paramount importance in neuroscience. Here, we introduce a novel neuroimaging framework, leveraging integrated effective connectivity (iEC) and unconstrained signal flow mapping for data-driven discovery of the human cerebral functional hierarchy. Simulation and empirical validation demonstrated the high fidelity of iEC in recovering connectome directionality and its potential relationship with histologically defined feedforward and feedback pathways. Notably, the iEC-derived hierarchy revealed a monotonically increasing level along the axis where the sensorimotor, association, and paralimbic areas are sequentially ordered - a pattern supported by the Structural Model of laminar connectivity. This hierarchy was further demonstrated to flexibly reorganize across brain states: flattening during an externally oriented condition, evidenced by a reduced slope in the hierarchy, and steepening during an internally focused condition, reflecting heightened engagement of interoceptive regions. Our study highlights the unique role of macroscale directed functional connectivity in uncovering a biologically interpretable state-dependent signal flow hierarchy.
Spinal cord injury (SCI) causes irreversible loss of motor, sensory, and autonomic functions and currently has no cure. Beyond local damage, SCI induces systemic inflammation, including cerebral inflammation that impairs neurogenesis. While cell therapies show promising effects in animal models, such as scar reduction and neuroprotection, their benefits in humans remain limited. One key difference lies in the transplantation strategy: animals receive healthy donor cells, whereas humans require autologous transplants. This led us to investigate how the lesion context affects the neuro-reparative potential of olfactory ensheathing cells (OECs) harvested from olfactory bulbs. To this end, we cultured OECs from healthy animals and from animals that had undergone SCI one week earlier. We then transplanted both types of OECs into recipient animals after SCI for therapeutic purposes. Using functional sensory-motor studies, histological and gene expression analyses, we were able to demonstrate for the first time that the lesion negatively affects the therapeutic properties of cells used to treat SCI. Indeed, transplantation of cells from previously injured animals does not modulate the fibrotic and glial scar, or the demyelinated areas at the lesion site, and therefore fails to improve functional recovery; unlike cells derived from healthy donors. Moreover, our in vitro studies show that cells derived from SCI animals secrete pro-inflammatory molecules that promote the polarization of microglia toward a pro-inflammatory phenotype. Altogether, these innovative findings provide new insights into the potential of cell transplantation in the context of autologous therapy after SCI. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/660789v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2e9b52org.highwire.dtl.DTLVardef@1d75bfaorg.highwire.dtl.DTLVardef@1d7af58org.highwire.dtl.DTLVardef@138f1b8_HPS_FORMAT_FIGEXP M_FIG C_FIG
Cognitive flexibility, the ability to switch behavior in response to changing rules in an uncertain environment, is crucial for adaptive decision making. Prior research has hypothesized a key role of prediction error and theta oscillations in medial frontal cortex in this process. However, the causal link between such processes remains to be established. To address this, we combined neural stimulation, EEG, behavioral measurement, and computational modelling. Specifically, we applied high-definition transcranial direct current stimulation (HD-tDCS) to modulate theta oscillations as measured via EEG followed by a probabilistic reversal learning task. We find that anodal stimulation reduces theta power and rule prediction error, and it increases the number of trials needed to reliably switch between rules. These findings support the role of rule prediction error signaling as a key mechanism linking neural oscillations to behavioral adaptation and highlight the importance of theta power and rule prediction error for cognitive flexibility. Significance statementCognitive flexibility--the ability to adjust behavior when rules change--is critical for adaptive behavior in uncertain environments. Although prediction error signaling and theta oscillations in medial frontal cortex have been proposed as key mechanisms, their causal relationship remains unclear. Here, we combine high-definition transcranial direct current stimulation (HD-tDCS), EEG, behavioral assessment, and computational modeling to establish a mechanistic link. We show that anodal stimulation reduces frontal theta power and rule-level prediction errors, leading to less efficient rule switching. These findings provide causal evidence that supports behavioral flexibility, advancing our understanding of the neural computations underlying adaptive decision making.
Echo state networks are well-known for their ability to learn temporal patterns through simple feedback to a large recurrent network with random connections. However, the learning process itself remains poorly understood. We develop a quantitative theory that explains learning in a regime where the network dynamics is stable and the feedback is weak. We show that the dynamics is governed by a finite number of master modes whose nonlinear interactions can be described by a normal form. This formulation provides a simple picture of learning as a Fourier decomposition of the target pattern with amplitudes determined by nonlinear interactions that, remarkably, become independent of the network randomness in the limit of large network size. We further show that the description extends to moderate feedback and recurrent networks with multiple unstable modes.
Pathogenic DNMT3A mutations cause Tatton-Brown-Rahman Syndrome (TBRS), a disorder characterized by intellectual disability and overgrowth of multiple somatic tissues including the brain. However, the functions of DNMT3A during human cortical development remain poorly understood. Here, we utilized newly developed human pluripotent stem cell models of TBRS-associated DNMT3A mutation to define DNMT3A requirements and consequences of mutation during human cortical neuron development. Profiling changes to epigenetic gene regulation across both GABAergic and glutamatergic neuron development, we identified GABAergic cortical interneurons as particularly sensitive to TBRS-associated mutation. During GABAergic neuron development, TBRS-associated DNMT3A mutations resulted in reduced DNA methylation and were associated with concomitant de-repression of gene expression, causing precocious neuronal differentiation. By contrast, the consequences of DNMT3A mutation on glutamatergic neuron development were less pronounced, due in part to compensatory repressive histone methylation, and resulted in increased expression of early neurodevelopmental genes during glutamatergic neuron differentiation. Assessing the consequences of these molecular phenotypes by patch-clamp electrophysiology, we found that DNMT3A deficient GABAergic neurons were hyperactive, while glutamatergic neuron function was largely unaffected by these DNMT3A loss of function mutations. Finally, we used both low density and high density multi electrode array techniques in conjunction with glutamatergic-GABAergic neuron co-cultures to assess how TBRS-associated GABAergic neuron hyperactivity affected the emergence and development of neuronal networks. We found that TBRS GABAergic neuron hyperactivity was sufficient to drive abnormal neuronal network development, increasing the neuronal activity consolidated into neuronal bursting and networks. Ultimately, this work elucidated new roles for DNMT3A-mediated repression in human cortical development, identifying critical requirements in regulating neuronal and synaptic gene expression during GABAergic differentiation, with these TBRS-associated molecular changes driving alterations of neuronal network function likely to contribute to TBRS etiology.
Dementia is a defining feature of Lewy body disease: its timing and onset distinguish different clinical diagnoses, and its effect on quality of life is profound. However, it remains unclear whether processes leading to cognitive and motor symptoms in Lewy body disease differ. To clarify this, we used in-vivo neuroimaging to assess spatial gradients of inter-regional differences in structural and functional connectivity in 108 people across the Lewy body disease spectrum (46 Parkinsons with normal cognition (PD-NC), 62 Lewy body dementia (LBD)) and 23 controls. We found divergent structural gradient differences with cognitive impairment: PD-NC showed increased inter-regional differentiation, whilst LBD showed overall gradient distribution similar to controls despite widespread organisational differences at the regional level. We then assessed cellular and molecular underpinnings of these organisational changes. We reveal similarities and also important differences in the drivers of cortical organisation between LBD and PD-NC, particularly in layer 4 excitatory neurons.
Decision-making stems from a sequence of information processing steps between the choice onset and the response. Despite extensive research, uncertainty remains about the actual cognitive sequence involved in the reaction time. Using the hidden multivariate pattern method we modeled the single-trial electroencephalogram of participants performing a decision task as a sequence of an unknown number of events estimated as trial-recurrent, time-varying, stable topographies. We provide evidence for three events occurring during participants decision making, respectively representing encoding, attention orientation, and decision. This interpretation is supported by the observation that a targeted manipulation of stimulus intensity yields Pierons law in the interval between encoding and attention orientation, and Fechners law in the interval between attention orientation and decision. This final, decision-related, event is represented in the brain as a positive burst in parietal areas whose timing, amplitude and build-up predict the participants decision accuracy.
Premature birth has known impacts on brain development, leading to sustained differences in cognitive function throughout the lifespan. Despite known deficits in executive functioning (EF) within individuals born premature, the extent to which neural engagement during executive functioning tasks differs between those born preterm and full-term is not fully understood. Additionally, it is unknown whether regions of differential engagement are the same in children and adults. This meta-analysis synthesizes fMRI results of activation differences between preterm and full-term subjects during executive functioning tasks in adult and child groups separately. Our results indicate that differences in neural engagement during EF tasks differ between pre-term (PT) and full term (FT) individuals in both age groups. Moreover, the regions affected contribute to well-known brain networks, including the fronto-striatal circuitry, the default mode network (DMN), and the salience network, all of which subserve broad EF capabilities. We found no differences between child and adult maps in a direct contrast, suggesting that effects of prematurity on executive functioning may persist from childhood into adulthood, although these findings should be interpreted in context of methodological limitations and potential confounding factors. This meta-analysis provides greater insight into the neural mechanisms behind EF disruption following premature birth. HighlightsO_LIDifferences in neural activation during executive function tasks exist in both children and adults with a history of premature birth. C_LIO_LIPT children show hyperactivity in fronto-striatal regions while PT adults show differential engagement of default mode network regions. C_LI
Prion diseases are fatal neurodegenerative diseases of humans and other mammals with no current treatment options. Here, we describe the characterization of a novel anti-prion compound, elacridar (GW120918), which has sub-micromolar activity in assays of prion infection, propagation and toxicity. Elacridar acts at an early step in the prion infection process, enhancing degradation of newly formed PrPSc. The lysosome is the likely site of elacridars anti-prion effects, based on transcriptomic analysis and the use of functional lysosomal probes. Elacridar alters gene expression networks controlling lysosomal sterol and lipid metabolism but, unlike other lysosomotropic drugs, it prominently upregulates genes that control lysosomal pH. Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to -synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for the treatment of protein misfolding neurodegenerative diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/661349v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@6280dorg.highwire.dtl.DTLVardef@2f8723org.highwire.dtl.DTLVardef@512492org.highwire.dtl.DTLVardef@1381569_HPS_FORMAT_FIGEXP M_FIG C_FIG
While the neuroprotective effects of vitamin D (Vit-D) have been demonstrated pre-clinically in a wide range of neurologic conditions, its potential use in the treatment of spontaneous intracerebral hemorrhage (ICH) has not been fully explored. We previously reported that Vit-D could expedite hematoma clearance in experimental ICH by inducing the conversion of M1 to M2 macrophage to enhance erythrophagocytosis1,2. Here, we provide new evidence on the dose-dependent effects of Vit-D on neuronal survival and functional recovery, lending further support for the clinical testing of Vit-D in the management of ICH.
Pain perception is modulated by expectations and learning processes, but the influence of uncertainty in this relationship is not well established. We aimed to examine the relationship between uncertainty, pain learning and perception using hierarchical Bayesian modeling. In an aversive learning task, fifty participants learned contingencies between auditory cues and painful stimulations under changing levels of uncertainty to create periods of stability and volatility. Model-free analysis of our data suggested unexpected trials resulted in reduced accuracy and greater response times. In unexpected trials, high pain perception was reduced, while low pain perception was increased, in line with documented effects of expectations on pain perception. Computational model fitting revealed participants learning was best described by a two-level hierarchical gaussian filter model, suggesting participants adapted their beliefs at multiple levels during the task. Uncertainty influenced pain perception in opposite patterns for high and low pain stimulations: high pain perception was greater under high levels of uncertainty, while there was a non-significant trend for low pain perception to be reduced. Analyses of individual differences suggested depressive symptoms were associated with a reduced learning rate throughout the task. These results shed light on processes involved in pain learning in changing environments. They also suggest a possible relationship between learning alterations and psychological traits commonly found in chronic pain, such as depressive symptoms.
Electroencephalography (EEG) is a widely applied method for decoding neural activity, offering insights into cognitive function and driving advancements in neurotechnology. However, decoding EEG data remains challenging, as classification algorithms typically require large datasets that are expensive and time-consuming to collect. Recent advances in generative artificial intelligence have enabled the creation of realistic synthetic EEG data, yet no method has consistently demonstrated that such synthetic data can lead to improvements in EEG decodability across diverse datasets. Here, we introduce EEG-GAN, an open-source generative adversarial network (GAN) designed to augment EEG data. In the most comprehensive evaluation study to date, we assessed its capacity to generate realistic EEG samples and enhance classification performance across four datasets, five classifiers, and seven sample sizes, while benchmarking it against six established augmentation techniques. We found that EEG-GAN, when trained to generate raw single-trial EEG signals, produced signals that reproduce grand-averaged waveforms and time-frequency patterns of the original data. Furthermore, training classifiers on additional synthetic data improved their ability to decode held-out empirical data. EEG-GAN achieved up to a 16% improvement in decoding accuracy, with enhancements consistent across datasets but varying among classifiers. Data augmentations were particularly effective for smaller sample sizes (30 and below), significantly improving 70% of these classification analyses and only significantly impairing 4% of analyses. Moreover, EEG-GAN significantly outperformed all benchmark techniques in 69% of the comparisons across datasets, classifiers, and sample sizes and was only significantly outperformed in 3% of comparisons. These findings establish EEG-GAN as a robust toolkit for generating realistic EEG data, which can effectively reduce the costs associated with real-world EEG data collection for neural decoding tasks.
Focal cortical dysplasia type II (FCDII), a leading cause of pediatric drug-resistant focal epilepsy, results from brain somatic variants in genes of the mTOR pathway, including germline and somatic second-hit loss-of-function variants in the mTOR repressor DEPDC5. Here, we investigated the effects of mosaic DEPDC5 two-hit variants on cortical development and neuronal activity using patient-derived human cortical organoids (hCOs). Mosaic hCOs displayed increased mTOR activity and altered neural rosette densities, which were both rescued by treatment with the mTOR inhibitor rapamycin. In addition, mosaic hCOs presented dysmorphic-like neurons and increased neuronal excitability, recapitulating FCDII pathology. Longitudinal single-cell transcriptomics at three developmental stages revealed altered neuronal differentiation, dysregulated expression of genes associated with the Notch and Wnt pathways in neural progenitors, and of synaptic- and epilepsy-associated genes in excitatory neurons. We further identified cell-autonomous alterations in metabolism and translation in mosaic two-hit hCOs. This study provides novel insights into the consequences of mosaic biallelic DEPDC5 deficiency on corticogenesis in the context of FCDII, highlighting both autonomous and non-cell autonomous effects.
It has been suggested that humans and other animals are driven by a fundamental desire to acquire information about opportunities available in their environments. Not only might such a desire explain pathological behaviors, but it may be needed to account for how everyday decisions are resolved. Here, we combine artificial neural networks (ANNs) with symbolic regression to extract an expressive yet interpretable model that specifies how human participants evaluate decision-relevant information during choice. This model accounts for behavior in our own data and in previous work, outperforming existing accounts of information sampling such as the Upper Confidence Bound heuristic. This modelling approach has broad potential for uncovering novel patterns in behavior and cognitive processes, while also specifying them in human-interpretable formats. We then used the value of information derived by our model, together with ultra-high field neuroimaging, to examine activity across a suite of subcortical neuromodulatory nuclei and two cortical regions that influence these nuclei. This established roles for midbrain dopaminergic nuclei, anterior cingulate cortex, and anterior insula in mediating the influence of value of information on behavior.
Flexible cognition depends on the ability to represent and apply context, allowing the brain to interpret sensory input and guide behavior in a context-dependent manner. Recent work has proposed Spatial Computing as a mechanism for this flexibility, suggesting that contextual signals organize information processing through spatial patterns of oscillatory activity across the cortical surface. These patterns act as "inhibitory stencils" that constrain where information (the "content" of cognition) can be expressed in spiking activity. Here, we provide a comprehensive empirical test of Spatial Computing Theory using multi-electrode recordings from the lateral prefrontal cortex in non-human primates performing a range of cognitive tasks (object working memory, sequence working memory, categorization). We found that alpha/beta oscillations encoded contextual information, reorganized their spatial patterns with context and task demands, and spatially gated the expression of content-related spiking activity. Furthermore, we found that alpha/beta oscillations reflected misattributions of task context and correlated with subjects trial-by-trial decisions. These findings validate core predictions of Spatial Computing by showing that oscillatory dynamics not only gate information in time but also shape where in the cortex cognitive content is represented. This framework offers a unifying principle for understanding how the brain flexibly coordinates cognition through structured population dynamics.
Parkinsons disease is projected to rise to pandemic proportions by 2050, which has resulted in an urgent need for disease-modifying treatments. In this regard, we previously showed that in a mouse model of parkinsonism with unilateral 6-hydroxydopamine (6-OHDA) injection into the dorsolateral striatum (DLS), low doses of the neuronal nicotinic acetylcholine receptor (nAChR) partial agonist and smoking cessation drug, cytisine exerts sex-specific neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of only female mice by reducing apoptotic endoplasmic reticulum (ER) stress. Although these data suggest that neuroprotection might occur via cytisine-mediated upregulation of {beta}2 subunit-containing ({beta}2*) nAChRs in SNc DA neurons, there is no direct evidence to support this idea. Therefore, this study asks the critical question of whether upregulation of {beta}2* nAChRs in SNc DA neurons alone is sufficient to reduce apoptotic ER stress and exert neuroprotection in a preclinical unilateral DLS mouse model of 6-OHDA-induced parkinsonism. To address this question, we generate and characterize a novel {beta}2-upregulated transgenic mouse line. These transgenic mice possess mutations in the M3-M4 intracytoplasmic loop of {beta}2 subunits that cause constitutive upregulation of {beta}2* nAChRs without nicotinic ligands. Surprisingly, when compared to wild-type littermates, only female {beta}2-upregulated transgenic mice demonstrate upregulation of {beta}2* nAChRs in SNc DA neurons as assessed by significant increases in Sec24D-containing ER exit sites (Sec24D-ERES). Using the optogenetic calcium and dopamine sensors, GCaMP6f and GRABDA respectively, we found significant increases in dihydro-beta-erythroidine (Dh{beta}E)-sensitive {beta}2* nAChR-mediated calcium influx in SNc DA neuron dendrites and Dh{beta}E-sensitive acetylcholine (ACh)-evoked dopamine release at SNc DA neuron terminals of the DLS in female transgenic mice. We then used four independent readouts to assess neuroprotection of SNc DA neurons following unilateral 6-OHDA injection into the DLS, viz., contralateral apomorphine-induced rotations, preservation of SNc DA neurons, inhibition of a major proapoptotic ER stress protein, C/EBP homologous protein (CHOP) and glial fibrillary acid protein (GFAP) expression in SNc astrocytes. In all four readouts, female {beta}2-upregulated transgenic mice showed significant neuroprotection. From a clinical perspective, this study shows that upregulation without nicotinic ligand-mediated activation of {beta}2* nAChRs in SNc DA neurons can be a translationally viable disease-modifying strategy for Parkinsons disease. In addition, we envision that the novel transgenic {beta}2-upregulated mice created in this study will provide a valuable tool for understanding the role of nAChR upregulation in major neurological disorders such as addiction, anxiety, depression and dementia.
Monoacylglycerol lipase (MAGL) inhibitors are considered as drug candidates for epilepsy. In order to determine the level of MAGL and evaluate changes in the epileptic brain, we have validated and used autoradiography and the MAGL radiotracer [3H]T-401 on resected temporal neocortex specimens obtained from patients with temporal lobe epilepsy and in brains from mice with chronic reoccurring seizures. Saturation experiments revealed a KD around 4 nM for the human temporal cortex and 7 nM for the mouse brain. In the human brain, binding of [3H]T-401 was detected mostly in the grey matter, and in the subcortical white matter in lower amounts. The levels were strongly correlated in the two cortical compartments. The level of [3H]T-401 binding in the human temporal cortex varied about a 4-fold among the patients, but was not correlated to either epilepsy duration or the age of the patients. In the epileptic mouse brain, a significant reduction was observed bilaterally in the hippocampus, as well as in other cortical regions, including the temporal cortex. Interestingly, a highly significant negative correlation was seen between MAGL and binding to the translocator protein 18 kDa (TSPO) expressed in glia. These data support the presence of MAGL in neuronal and non-neuronal cells, and indicate that MAGL levels in the brains of either patients with epilepsy or mice after intra-hippocampal kainite injection are reduced not only in the epileptic zone in the hippocampus, but more widespread in the brain.
The paravertebral sympathetic chain ganglia (SCG) are autonomic ganglia critical for regulating the "fight-or-flight" response. Symptoms of sympathetic dysfunction are prevalent in diabetes, affecting up to 90% of patients. The molecular and cellular composition of the human SCG and its alteration in diabetes remains poorly defined. To address this gap, we performed spatial transcriptomic profiling of lumbar SCGs from diabetic and non-diabetic organ donors. We identified 3 three distinct neuronal populations, two noradrenergic (NA1 and NA2) and one cholinergic (CHO), based on tyrosine hydroxylase (TH) and SLC18A3 expression, respectively. We also characterized 9 non-neuronal populations consisting of Schwann cells, immune cells, fibroblasts, adipocytes, and endothelial cells. In diabetic SCGs, we observed a significant loss of myelinating Schwann cells and a phenotypic shift of cholinergic neurons toward a noradrenergic identity. Additionally, diabetes was associated with a significant reduction in the transcripts of vasodilatory neuropeptides, such as VIP and CALCA, suggesting a mechanism for impaired vascular control. Upstream regulator analysis highlighted altered neurotrophic signaling in diabetes, with enhanced NGF/TRKA and diminished BDNF/TRKB activity, potentially driven by target-derived cues. Comparison between SCG and dorsal root ganglia (DRG) neurons revealed ganglia-specific genes, like SCN3A and NPY (SCG) versus SCN10A and GPX1 (DRG), offering specific therapeutic targets for autonomic dysfunction or pain. Our findings provide a transcriptomic characterization of human SCG, revealing molecular signatures that underlie diabetic autonomic dysfunction. This work lays a foundation for the development of therapies to restore sympathetic function and avoid unintended autonomic effects in the development of analgesics. Significance StatementAutonomic dysfunction affects up to 90% of people with diabetes, yet the human sympathetic nervous system remains poorly molecularly defined. To address this gap, we present a spatial transcriptomic profile of the human sympathetic chain ganglia (SCG), revealing how diabetes affects the human autonomic nervous system. We show that diabetes shifts the cholinergic neuronal population to a noradrenergic phenotype and reduces vasodilation neuropeptide expression, potentially explaining impaired vascular control and thermoregulation. Comparative analysis of sympathetic and sensory ganglia reveals distinct gene profiles that may inform novel therapeutic strategies. These findings offer critical insight into the molecular drivers of diabetic autonomic neuropathy and lay the groundwork for safer, more precise treatments that selectively modulate autonomic or sensory function in chronic disease.
Huntingtons disease (HD) is a monogenic autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene, yielding a gain-of-toxic-function mutant Huntingtin protein mHTT. CRISPR/Cas9 is a potentially powerful therapeutic tool for treating HD by eliminating mutant HTT (mHTT) gene. We developed a specific SaCas9 guide RNA to target human mHTT, and a self-inactivating gene editing system that abolishes SaCas9 after a short transient expression for high gene editing efficiency and maximal safety to prevent off-target effects. Both conventional and the new self-inactivating gene editing systems achieved successful elimination of mHTT gene, 60-90% mHTT protein and 90% of mHTT aggregation in BAC226Q HD mouse brains, which resulted in significant long-term rescue of neural pathology, motor deficits, weight loss and shortened lifespan. These beneficial effects were observed when gene editing was applied before, at and well after the on-set of pathological and behavioral abnormalities. These proof-of-concept data demonstrate that gene editing can be a highly effective therapeutic approach for HD and other inherited neurodegenerative diseases. One Sentence SummarySelf-inactivating CRISPR for mutant huntingtin in HD mice achieved long-term rescue of neural pathology, motor deficits, weight loss and survival.
The acquisition of temporally proximate information can impair the brains ability to consolidate earlier experiences, resulting in retroactive interference (RI). Recognition-based behavioral paradigms are well-suited for investigating RI in rodents, particularly those involving sequential learning episodes. The medial prefrontal cortex (mPFC) integrates multimodal information relevant to the regulation of memory interference and is strongly modulated by the serotonergic system. Serotonin 2A receptors (5-HT2AR), which are densely expressed in the mPFC, have been shown to influence the retrieval of competing object-recognition memories. However, their role in other phases of memory processing, particularly in modulating RI, remains unclear. Using a novel object recognition task designed to induce RI, combined with pharmacological manipulation of 5-HT2AR, we demonstrate that RI specifically impairs the object-related component of memory. Moreover, serotonin signaling through 5-HT2AR is necessary to prevent RI. Strikingly, the activation of 5-HT2AR before retrieval can rescue the expression of memories affected by RI, suggesting that RI may not erase memory traces but rather hinder access to them.
The acquisition of temporally proximate information can impair the brains ability to consolidate earlier experiences, resulting in retroactive interference (RI). Recognition-based behavioral paradigms are well-suited for investigating RI in rodents, particularly those involving sequential learning episodes. The medial prefrontal cortex (mPFC) integrates multimodal information relevant to the regulation of memory interference and is strongly modulated by the serotonergic system. Serotonin 2A receptors (5-HT2AR), which are densely expressed in the mPFC, have been shown to influence the retrieval of competing object-recognition memories. However, their role in other phases of memory processing, particularly in modulating RI, remains unclear. Using a novel object recognition task designed to induce RI, combined with pharmacological manipulation of 5-HT2AR, we demonstrate that RI specifically impairs the object-related component of memory. Moreover, serotonin signaling through 5-HT2AR is necessary to prevent RI. Strikingly, the activation of 5-HT2AR before retrieval can rescue the expression of memories affected by RI, suggesting that RI may not erase memory traces but rather hinder access to them.
Aging leads to alterations in the sensorimotor system and balance control but it is not well understood how changes in sensorimotor function affect how people respond to postural disturbances. Elucidating the relationships between balance control and sensorimotor function is crucial for developing effective rehabilitations. Here, we compared the kinematic responses to platform translations and rotations during standing in 10 young and 30 older adults and explored relationships between sensorimotor function and balance responses. We found that older adults were less able to withstand perturbations without stepping, not because their non-stepping strategies were less effective but because they chose to step at smaller deviations of the extrapolated center of mass. Older adults performed worse than young adults on measures of sensory and motor function but lower stepping thresholds were associated with susceptibility to unreliable visual information and not with reduced sensory acuity or reduced strength. Poor sensory reweighting may contribute to and combine with age-related cognitive rigidity, leading to a higher priority on safer strategies. Older adults may resort to stepping, even if a step is not necessary, rather than rely on potentially inaccurate sensory signals to inform a corrective response. Our results provide initial evidence that sensory reweighting could be a potential target for fall prevention methods. NEW & NOTEWORTHYThe relationship between age-related changes in sensorimotor function and postural control is poorly understood. Here, we did a comprehensive assessment of sensorimotor function and reactive standing balance. We found that healthy older adults chose safer strategies, i.e. they step at smaller disturbances, than young adults. Although we found many differences in sensorimotor function, only a reduced ability to suppress conflicting sensory information was related to the use of a safer strategy.
In neuroprosthetics, intracortical microstimulation (ICMS) recruits cortical networks to evoke brain responses and sensory perceptions. However, multi-electrode ICMS often generates suboptimal percepts compared to single-electrode ICMS, suggesting nonlinear neuromodulation rather than simple summation by multi-electrode ICMS. Yet, the factors and mechanisms underlying this modulation remain poorly understood. To investigate multi-electrode ICMS, we combined two-photon calcium imaging with a well-controlled dual-electrode ICMS in the mouse visual cortex to investigate how neurons integrate converging ICMS inputs at varying intensities. We found that stimulation intensity significantly shapes neuromodulation at both single-cell and population levels. Specifically, low intensities (5-7 {micro}A) have a minimal effect on neural responses. At intermediate intensities (10-15 {micro}A), we observed diverse, nonlinear bipolar modulation--both enhancement and attenuation--at the single-cell level. However, we achieved net enhancement at the population level. At higher intensities (15-20 {micro}A), although the proportion of modulated neurons increased in both enhancement and attenuation directions, the net effect at the population level was neutral (zero modulation). Furthermore, neurons strongly responsive to single-electrode ICMS were more likely to be attenuated, while weaker responding cells exhibited enhanced modulation. The strongest neuromodulatory effects occur at intermediate spatial distances in between the two electrodes. Computational modeling based on spiking neural network composed of adaptive exponential integrate-and-field neurons implicated the importance of inhibitory network dynamics and network variability as key mechanisms. Our experimental data was used to train an advanced deep learning approach, which successfully predicted the neuromodulation patterns induced by dual-electrode ICMS. Our findings reveal intensity- and spatial-dependent rules of neuromodulation by ICMS, providing necessary insights to optimize multi-electrode ICMS for neuroprosthetic applications. Significance statementUnderstanding how cortical neurons integrate concurrent inputs from multi-electrode intracortical microstimulation (ICMS) is essential for advancing neuroprosthetic technologies. We show that dual-electrode ICMS evokes distinct, predictable neuromodulatory effects that depend on (i) stimulation intensity, (ii) a neurons baseline responsiveness to single electrode input, and (iii) its proximity to the electrodes. Low and intermediate intensity dual-electrode ICMS amplifies neural activity compared to single-electrode ICMS, whereas high-intensity stimulation leads to attenuation, limiting net activation.
1.Sleep is critical for brain plasticity during early development, yet the individual maturation of sleep neurophysiology in infancy remains poorly characterized. In particular, slow wave activity (SWA) has emerged as a key marker of both cortical maturation and experience-dependent plasticity. Understanding the regional dynamics of sleep neurophysiology early in life could yield critical insights into neurodevelopmental health. We conducted a longitudinal high-density EEG study in 11 healthy infants (3-6 months) assessing non-rapid eye movement (NREM) sleep. We analyzed the maturation of SWA (0.75-4.25 Hz), theta power (4.5-7.5 Hz), and sigma power (9.75-14.75 Hz) across scalp regions and examined their association with behavioral development. From 3 to 6 months, SWA increased maximally in occipital regions, while theta power exhibited a global increase. Sigma power, initially concentrated centrally, dispersed towards frontal regions. Greater power increases over frontal regions correlated with higher motor (theta) and personal-social skill scores (sigma) at 6 months. These findings establish a framework for typical infant sleep EEG maturation, highlighting frequency-specific and regionally distinct developmental patterns. This study provides the first longitudinal evidence that early changes in sleep EEG topography reflect individual developmental trajectories, supporting its utility as a non-invasive and yet precise biomarker for early identification of atypical neurodevelopment at preverbal ages.
Altered sensory perception is a hallmark of autism and determines how autistic individuals engage with their environment. These sensory differences are shaped by top-down cognitive processes--such as categorization, attention, and priors--which themselves exhibit characteristic atypicalities in the condition. Among sensory modalities, tactile perception is particularly critical for daily functioning and social interactions. However, the dynamic interplay between tactile and cognitive processes remains poorly understood. In this study, we investigated the influence of top-down cognitive processes on tactile perception in the Fmr1-/y genetic mouse model of autism. We developed a translational, forepaw-based decision-making task designed to dissociate stimulus-driven tactile responses from those modulated by cognitive factors. This approach enabled us to assess multiple aspects of perceptual processing, including perceptual learning, stimulus categorization and discrimination, as well as the influence of prior experience and attention. Mice were initially trained to distinguish between high- and low-salience stimuli and were subsequently tested with a continuum of intermediate stimulus intensities. Our results revealed salience-dependent cognitive alterations that significantly influenced sensory performance. During the training phase, Fmr1-/y mice exhibited an increased choice consistency bias in low-salience trials, resulting in impaired perceptual learning. In the testing phase, Fmr1-/y mice demonstrated enhanced tactile discrimination under low-salience conditions, driven by a reduced influence of categorization. Moreover, under conditions of high cognitive load, Fmr1-/y mice displayed attentional deficits that were dissociable from their enhanced tactile sensitivity. Together, our findings reveal that cognitive context critically shapes sensory phenotypes in autism. They advocate for a shift beyond traditional sensory-cognitive dichotomies to better capture the dynamic interplay between perceptual and cognitive alterations in autism.
BackgroundThe use of methamphetamine has continued to rise in the US. In addition to facilitating dopamine neurotransmission, methamphetamine indirectly increases glutamate release which activates N-methyl-D-aspartate receptors (NMDARs). Ketamine is a noncompetitive NMDAR antagonist. Ketamine also has actions on -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and promotes synaptogenesis. Thus, we hypothesized that ketamine may be a potential therapeutic to reduce methamphetamine-seeking behaviors and associated negative affect in a rat model. MethodsMale and female rats underwent methamphetamine or saline intravenous self-administration for 10 sessions, followed by extinction training. Rats received ketamine or saline treatment either prior to 10 daily extinction sessions or only prior to the last extinction session. Anxiety-like behaviors were measured 24 hours after extinction, followed by cue-induced and drug-primed reinstatement two and six days later respectively. ResultsMethamphetamine withdrawal increased anxiety-like behaviors in male rats on the elevated plus maze test compared to rats that self-administered saline. Moreover, anxiety-like behaviors were significantly attenuated by daily ketamine treatment during extinction. Drug-primed but not cue-induced reinstatement, tested six days after the last extinction session, was significantly attenuated in male rats that received ten or one ketamine treatments during extinction compared with rats receiving vehicle during extinction. Ketamine was ineffective in female rats in reducing cue-induced or drug-primed reinstatement. ConclusionsKetamine may confer sex-specific benefits during methamphetamine withdrawal and relapse vulnerability, particularly by reducing anxiety-like behaviors and attenuating drug-primed reinstatement in males. These results support the potential of ketamine as a targeted adjunct therapy during early methamphetamine abstinence in males.
We introduce Generative Phenomenology: making viewable images of peoples perceptions (Perceptograms) and generating the images from neural models, as a powerful technique for understanding the neural bases of perception. Amblyopia, a disorder of spatial vision, provides a perfect case because signals from the two eyes go through partly different cortical neurons, and many amblyopes report phantom forms when viewing sinusoidal gratings through their amblyopic eye (AE) but not through the fellow eye (FE). Using a dichoptic display, we acquired high-fidelity perceptograms for 24 gratings shown to AE while sums-of-gratings plaids were shown to FE with contrast, frequency, phase, and orientation of the plaid gratings adjusted to match the two percepts exactly. Plaids provided exact matches to 92.6% of distortions. A formal equation that the signals generated in visual cortex by the test gratings seen through AE match the signals generated by their matched perceptograms seen through FE for each observer, was used to analytically derive cortical filters processing AE signals as linear transforms of standard steerable filters modeling normal V1 neurons for FE. Passing gratings through AE filters accurately generated the measured perceptograms. The filter transformations reflected complex changes in V1 receptive fields and possibly in cross-correlations. The AE filters also explained amblyopic deficits in perceiving sinusoidally modulated circular contours and were consistent with orientation perceptive fields estimated from reverse-correlation experiments. Changes in neuronal receptive fields thus have profound effects on perception, to the extent that observers can see more features than are present in the viewed stimulus. SIGNIFICANCE STATEMENTWhat we see is generated by our cortical neurons processing sensory input. With their amblyopic eye, whose signals are processed by deficiently developed cortical cells, many amblyopes see phantom forms that contain more features than the viewed stimulus, providing a perfect case for studying the neural generation of percepts (Generative Phenomenolog)y). We acquired computer aided perceptograms (viewable records of perceived images) of the phantom forms and then derived a cortical model that accurately generated the perceptograms by using linear transforms of normal V1 receptive fields. The modifications also explained amblyopic deficits at discerning departures from circularity and were validated with reverse-correlation experiments. These results show that small changes in cortical neuronal properties can cause major differences in what people perceive.
We introduce Generative Phenomenology: making viewable images of peoples perceptions (Perceptograms) and generating the images from neural models, as a powerful technique for understanding the neural bases of perception. Amblyopia, a disorder of spatial vision, provides a perfect case because signals from the two eyes go through partly different cortical neurons, and many amblyopes report phantom forms when viewing sinusoidal gratings through their amblyopic eye (AE) but not through the fellow eye (FE). Using a dichoptic display, we acquired high-fidelity perceptograms for 24 gratings shown to AE while sums-of-gratings plaids were shown to FE with contrast, frequency, phase, and orientation of the plaid gratings adjusted to match the two percepts exactly. Plaids provided exact matches to 92.6% of distortions. A formal equation that the signals generated in visual cortex by the test gratings seen through AE match the signals generated by their matched perceptograms seen through FE for each observer, was used to analytically derive cortical filters processing AE signals as linear transforms of standard steerable filters modeling normal V1 neurons for FE. Passing gratings through AE filters accurately generated the measured perceptograms. The filter transformations reflected complex changes in V1 receptive fields and possibly in cross-correlations. The AE filters also explained amblyopic deficits in perceiving sinusoidally modulated circular contours and were consistent with orientation perceptive fields estimated from reverse-correlation experiments. Changes in neuronal receptive fields thus have profound effects on perception, to the extent that observers can see more features than are present in the viewed stimulus. SIGNIFICANCE STATEMENTWhat we see is generated by our cortical neurons processing sensory input. With their amblyopic eye, whose signals are processed by deficiently developed cortical cells, many amblyopes see phantom forms that contain more features than the viewed stimulus, providing a perfect case for studying the neural generation of percepts (Generative Phenomenolog)y). We acquired computer aided perceptograms (viewable records of perceived images) of the phantom forms and then derived a cortical model that accurately generated the perceptograms by using linear transforms of normal V1 receptive fields. The modifications also explained amblyopic deficits at discerning departures from circularity and were validated with reverse-correlation experiments. These results show that small changes in cortical neuronal properties can cause major differences in what people perceive.
Peroxisomes are critical organelles that detoxify wastes while also catabolizing and anabolizing lipids. How peroxisomes coordinate protein import and support metabolic functions across complex tissues and timescales remains poorly understood in vivo. Using the Drosophila brain, we discover a striking enrichment of peroxisomes in the neuronal soma and the cortex glia that enwrap them. Unexpectedly, import of peroxisomal proteins into cortex glia, but not neurons, dramatically oscillated across time and peaked in the early morning. Rhythmic peroxisomal import in cortex glia autonomously required the circadian clock and Peroxin 5 (Pex5; peroxisomal biogenesis factor 5 homolog), with endogenous Pex5 protein peaking in the morning. Notably, removing Pex5 in cortex glia severely reduced sleep while concomitantly causing aberrant lipid metabolism characterized by ectopic lipid droplets and increases across multiple lipid families. Thus, the circadian import of peroxisomal proteins via Pex5 in cortex glia is essential for lipid homeostasis and organismal behavior. HighlightsO_LIPeroxisomal membrane and importer proteins are enriched in cortex glia (CG). C_LIO_LIThe circadian clock autonomously decreases peroxisomal import in CG. C_LIO_LIThe cytosolic importer Pex5 controls circadian peroxisomal import in CG. C_LIO_LILoss of Pex5 in CG disrupts brain lipid metabolism and sleep behavior. C_LI
Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neurodevelopmental disorders, including congenital malformations and autism spectrum disorder. In animal models and neural organoids, VPA has been shown to alter signaling pathways, such as Wnt pathway, providing insights into VPA-induced neurodevelopmental defects. Here, we exposed dorsal forebrain organoids to VPA for 30 days and examined effects at the tissue, cellular, and molecular level. VPA treatment disrupted ventricular-like regions, indicating defects in cell-cell and cell-matrix interactions. Transcriptomics analysis confirmed altered expression of extracellular matrix (ECM) genes and single cell RNA sequencing analysis identified genes involved in microenvironment sensing, such as cellular mechanosensing and Hippo-YAP/TAZ signaling pathway. Finally, proteomics analysis corroborated that VPA alters the microenvironment of the human dorsal forebrain organoids by disrupting the secretion of ECM proteins. Altogether, our study suggests that VPA-treated dorsal forebrain organoids serve as a model to investigate the role of extracellular processes in brain development and to understand how their disruptions might contribute to neurodevelopmental disorders.
Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABAA synapses on dopamine neurons (LTPGABA) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. We optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTPGABA. Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTPGABA. Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTPGABA at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTPGABA that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.
Tuberous Sclerosis Complex (TSC) is a genetic disease which manifests as a range of neurological symptoms, including benign brain tumors, epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Among the latter, according to recent reports, anxiety and mood disorders affect over 50% of patients. We have previously demonstrated anxiety-like behavioral symptoms in the zebrafish model of TSC, which were rescued by treatment with the TrkB antagonist ANA-12. Here, we aimed to investigate the mechanism of how ANA-12 regulates behavior by analyzing brain activity in the telencephalon of TSC zebrafish larvae, and we identified the affected regions as corresponding to the known mammalian circuitry involved in anxiety processing. Due to differences in development, the identification of telencephalic territories that are homologous between zebrafish and mammals remains challenging, particularly at early, dynamic stages of development. However, we were able to identify populations of neurons in the zebrafish habenula and ventral subpallium whose involvement in anxiety parallels that of mammals. Those regions were dysregulated in the TSC mutant. This dysregulation correlated with aberrant anxiety behavior and was rescued by treatment with ANA-12. Our results suggest that hyperactivation of TrkB in those regions is a major contributor to anxiety-like behavior as seen in TSC fish, and that those mechanisms could be evolutionarily conserved between zebrafish and mammals.
Approximately 14% of U.S. households are estimated to be food insecure. The neurocognitive and metabolic impacts of unpredictable food access during early-life periods of development are poorly understood. To address these gaps we devised a novel rat model of food insecurity to control the timing, type, and quantity of accessible food using programmable feeders. Male rats were divided into 3 groups: Secure-chow (SC), a control group given 100% of daily caloric needs, distributed evenly across 4 daily meals of standard chow at set mealtimes; Secure-mixed (SM), a 2nd control group identical to the SC group except that the food type predictably alternated daily between chow and a high-fat, high-sugar diet (HFHS); and Insecure-mixed (IM), the experimental group given randomly alternating daily access to either chow or HFHS at either 85% or 115% of daily caloric needs, distributed evenly across 3 daily meals with unpredictable mealtimes. These feeding schedules were implemented from postnatal days (PNs) 26-45, after which all groups received chow ad libitum. Metabolic assessments performed in adulthood revealed no group differences in caloric intake, body weight, or body composition when maintained on either chow (PN46-149) or a cafeteria diet (PN150-174). Behavioral measures (PN66-126) revealed no group differences in anxiety-like, exploratory, or impulsive behavior (zero maze, open field, differential reinforcement of low rates of responding procedures). However, the IM group exhibited hippocampus-dependent memory impairments compared to both control groups in the novel location recognition test. These findings suggest that early-life food insecurity may contribute to long-term impairments in memory function.
Lysosomal dysfunction and mitochondrial health are intricately connected, playing essential roles in cellular homeostasis. Lysosomes are acidic membrane-bound organelles responsible for degrading and recycling cellular waste, while mitochondria generate the energy required for cellular functions. Growing evidence implicates roles for lysosomal and mitochondrial dysfunction in neurodegenerative diseases, including Alzheimers and Parkinsons disease. With novel therapeutics targeting both the lysosomal and mitochondrial functions, robust assays for compound screening are becoming critical to evaluate modulation of both organelles in disease-relevant cellular models. Here, we investigated human fibroblasts derived from healthy donors, as well as patients with Alzheimers and Parkinsons disease, to assess their capacity to model key aspects of lysosomal and mitochondrial dysfunction. Lysosomal function was evaluated using various assays, including quantification of lysosomal proteins (TMEM175 and LAMP1), LysoTracker staining, measurement of lysosomal pH, and lysosomal enzymatic activity. Autophagic flux was assessed by measuring p62 levels as a marker of autophagy. Mitochondrial function was investigated by measuring mitochondrial calcium levels, membrane potential, oxidative stress, and mitochondrial content using MitoTracker. To explore the potential of using human fibroblasts for in vitro compound screening, we validated these assays in a 384-well high-throughput format using compounds such as chloroquine and ammonium chloride. Our findings demonstrate that human fibroblasts faithfully recapitulate lysosomal and mitochondrial dysfunctions characteristic of neurodegenerative diseases. Moreover, the use of robust assays positions these cells as a valuable platform for high-throughput screening to identify novel therapeutics targeting lysosomal and mitochondrial pathways.
Cerebral aneurysm (CA) rupture is the most common cause of nontraumatic subarachnoid hemorrhage. Recent data suggests that tortuosity is associated with aneurysm formation and rupture risk. We aimed to determine if tortuosity correlates with CA development and rupture in a mouse CA model and to develop a novel tortuosity scale to be used for in vivo CA studies. A highly validated, elastase-mouse CA model was used to assess cerebral vessel tortuosity with CA formation and rupture in sham and elastase groups. A 4-point ordinal scale was created to evaluate predictive capacity for vessel tortuosity level and CA formation and rupture. Nearly all sham animals (92%) had little to no vessel tortuosity on the visual scale (median, IQR: 1, [1-2]), compared to 24% in the elastase groups (2, [2-3]) (p=0.001). Sham cohorts had zero animals with highly tortuous vessels, while 3.5mU and 35mU cohorts had >35% of animals with significant visual tortuosity, p=0.003 and p<0.000, respectively. CA formation and rupture was higher in the elastase groups compared to the sham group (p=0.002). Both the visual scale and tortuosity index significantly predicted CA formation (p<0.001) and rupture (p<0.001). A novel tortuosity scale is highly predictive of CA formation and rupture in vivo. It may offer a new measurement to better understand vessel stress in the pathogenesis and progression of CAs.
Brain-computer interface (BCI) is a system that translates neural activity into commands, allowing direct communication between the brain and external devices. Despite its clinical application, BCI systems fail to robustly capture subjects intent due to a limited understanding of the neural mechanisms underlying BCI control. To address this issue, we introduce a biophysical modeling approach that leverages a linear neural mass model to investigate the associated neural mechanisms of motor imagery-based BCI experiments. We tailor this model to simulate both motor imagery task and resting state. We apply this approach to a cohort of 19 healthy subjects trained along four sessions where magnetoencephralography (MEG) and electroencephalography (EEG) signals were simultaneously recorded. The neural synaptic gain and time scale of the modeled excitatory and inhibitory neural mass populations capture changes in neural activity across conditions and sessions. Those changes appear in important areas of the sensorimotor cortex, relevant for motor imagery tasks. We observed these effects in both EEG and MEG modalities. These findings provide insights into the underlying neural mechanisms in a motor imagery task in BCI, paving the way to tailored BCI training protocols.
The central nervous system (CNS) has a limited intrinsic capacity for axonal regeneration, making functional recovery after injury extremely challenging. Numerous strategies have been explored to overcome this blockade, among others, molecular interventions or modulation of the inhibitory extracellular environment. Despite some advances, effective regeneration remains elusive, particularly in adult CNS neurons. To investigate these mechanisms in a controlled and reproducible setting, we employ organotypic slice cultures (OSCs), which retain key structural and cellular features of the intact brain while allowing for long-term in vitro experimentation. In particular, the entorhino-hippocampal (EH) co-culture model preserves the anatomical and functional connectivity of the perforant pathway, providing an excellent platform for studying axonal degeneration and regeneration. This model reproduces laminar specificity, axonal myelination, and inhibitory signaling after axotomy, closely mimicking in vivo conditions. Furthermore, EH co-cultures facilitate the application of optogenetic tools to monitor and manipulate neuronal activity. Our study explores whether enhancing activity in entorhinal cortex neurons can promote axonal regeneration after a EH lesion. Our results show that increased activity in entorhinal neurons alters the development of the EH connection and fails to enhance the regrowth of injured mature entorhinal axons. These findings suggest that both extrinsic and intrinsic factors shape the regenerative response and highlight the utility of EH OSCs as a versatile model for testing future pro-regenerative interventions.
Variants in GBA1 are common genetic risk factors for several synucleinopathies. The increased risk has been attributed to the toxic effects of misfolded glucocerebrosidase (GCase) (gain-of-function), and the accumulation of lipid substrates due to reduced enzyme activity (loss-of-function). To delineate GBA1 pathogenicity, an iPSC line was generated from a patient with both type 1 Gaucher disease (GBA1: N370S/N370S; p.N409S/p.N409S) and Parkinson disease (PD). From this line, we created a reverted wild-type (WT) line and a GBA1 knockout (KO) line to eliminate misfolded GCase and intensify lipid accumulation. N370S/N370S and KO dopaminergic neurons (DANs) exhibited decreasing GCase levels and progressive accumulation of lipid substrates compared to WT DANs. Notably, the expression of GPNMB, whose levels correlate with PD risk, was upregulated by the mild lipid accumulation in N370S/N370S DANs but disrupted in KO DANs. These findings refine the loss-of-function mechanism by associating PD risk levels of GPNMB with lipid levels specific to GBA1 risk variants.
Inhibitory control is essential for adaptive behaviour and declines with age, yet the underlying neural dynamics remain poorly understood. The {beta}-rhythm (15-29 Hz) is thought to reflect inhibitory signalling within the fronto-basal ganglia network. Recent evidence suggests that transient {beta}-bursts support inhibitory performance, often masked by conventional analyses of trial-averaged {beta}-power. To reveal the link between trial-by-trial {beta}-bursting and inhibition, we applied a recently developed analysis framework combining linear mixed-effects modelling (LMM) with threshold-free cluster enhancement (TFCE) during response inhibition and initiation in older adults. Twenty healthy older adults performed a bimanual anticipatory response inhibition task, while electroencephalography and electromyography were recorded to capture {beta}-activity ({beta}-burst rate/duration; averaged {beta}-power) and muscle bursting dynamics, respectively. Our analysis revealed distinct {beta}-bursting signatures absent in averaged {beta}-power data. Following the stop-signal, parieto-occipital {beta}-bursting presented before a temporal cascade from attentional to inhibitory processes. In addition to expected right fronto-central and bilateral sensorimotor activity, we observed left prefrontal {beta}-bursting, indexing broader inhibitory network engagement during bimanual response inhibition. Moreover, we established a functional link between right sensorimotor {beta}-bursting and muscle bursts during stopping, indicating rapid cortical suppression of initiated motor output. These results help clarify the mechanistic role of {beta}-oscillations and underscore the sensitivity of {beta}-bursting to both the timing and context of inhibitory demands in healthy older adults. Future research will help establish the potential of {beta}-bursting, combined with LMM-TFCE analysis, as a clinically relevant marker of impulse control dysfunction. Significance statementOur novel application of an advanced statistical framework revealed distinct spatiotemporal {beta}-bursting patterns during response inhibition and response withholding in healthy older adults, which were not captured by averaged {beta}-power. Identifying a further link between cortical {beta}-bursting and muscle-level suppression, the findings offer a mechanistic account of how the brain halts action in real time in older adults. This work provides a sensitive, trial-level framework for studying {beta}-bursting measures in general, as well as inhibitory control across aging and clinical populations.
Brain function relies on energy supplied by mitochondrial energy transformation, but how cellular energetics constrain neurological function and cognition remains poorly understood. Genetic defects in mitochondrial DNA cause rare mitochondrial diseases (MitoD) that offer a unique window into the energetic foundations of cognition, shedding light on the neural processes that are most energetically constrained. In this study, we assessed functional magnetic resonance imaging (fMRI) on 29 participants with MitoD and 62 matched controls during resting state and tasks probing cognitive (N-back task), affective (cold pain), and sensory (multisensory visual and auditory perception) functions. MitoD individuals exhibited significant cognitive deficits across a range of functions, including executive function and working memory, mental and physical fatigability, low exercise tolerance, and low mood. These deficits were accompanied by markedly elevated blood levels of metabolic stress markers, including GDF15 and FGF21. Surprisingly, overall BOLD fMRI activity and connectivity were largely intact across all tasks in MitoD individuals. However, those with more severe cognitive impairment and higher GDF15 levels showed reduced working memory-related activity, which in turn mediated poorer task performance. Conversely, individuals with relatively preserved cognitive function exhibited hyperactivation in working memory regions and working memory performance compared to controls, suggesting compensatory engagement of cortical systems in high-functioning MitoD individuals. These effects were weaker in the sensory domain and absent during affective (cold pain) processing, suggesting an energy hierarchy in the brain that prioritizes essential functions such as affective responses while downregulating more energy-demanding, complex cognitive processes when resources are limited.
Brain function relies on energy supplied by mitochondrial energy transformation, but how cellular energetics constrain neurological function and cognition remains poorly understood. Genetic defects in mitochondrial DNA cause rare mitochondrial diseases (MitoD) that offer a unique window into the energetic foundations of cognition, shedding light on the neural processes that are most energetically constrained. In this study, we assessed functional magnetic resonance imaging (fMRI) on 29 participants with MitoD and 62 matched controls during resting state and tasks probing cognitive (N-back task), affective (cold pain), and sensory (multisensory visual and auditory perception) functions. MitoD individuals exhibited significant cognitive deficits across a range of functions, including executive function and working memory, mental and physical fatigability, low exercise tolerance, and low mood. These deficits were accompanied by markedly elevated blood levels of metabolic stress markers, including GDF15 and FGF21. Surprisingly, overall BOLD fMRI activity and connectivity were largely intact across all tasks in MitoD individuals. However, those with more severe cognitive impairment and higher GDF15 levels showed reduced working memory-related activity, which in turn mediated poorer task performance. Conversely, individuals with relatively preserved cognitive function exhibited hyperactivation in working memory regions and working memory performance compared to controls, suggesting compensatory engagement of cortical systems in high-functioning MitoD individuals. These effects were weaker in the sensory domain and absent during affective (cold pain) processing, suggesting an energy hierarchy in the brain that prioritizes essential functions such as affective responses while downregulating more energy-demanding, complex cognitive processes when resources are limited.
Eye movements directed to high-valued objects in the environment are executed with greater vigor. Superior Colliculus (SC) - a subcortical structure that controls eye movements - contains multiple subtypes of neurons that have distinct functional roles in generating saccades. How does value-related information processed in other parts of the brain affect the responses of these different subtypes of SC neurons to facilitate faster saccades? To test this, we recorded four subtypes of neurons simultaneously while the monkey made saccades to objects they had been extensively trained to associate with large or small rewards (i.e., good or bad). In three subtypes of neurons (visual, visuomotor, and motor), the good objects elicited more spikes than bad objects. More importantly, using a bootstrapping procedure, we identified three separable phases of activity: 1) early visual response (EVIS), 2) late visual response (LVIS), and 3) pre-saccadic (PreSAC) motor response in these neuronal subtypes. In each subtype of neurons, the value of objects (good vs. bad) was positively correlated with the activity in the LVIS and PreSAC phases but not the EVIS phase. These data suggest that the value information from other brain regions modulates the visual (LVIS) and the motor (PreSAC) responses of visual, visuomotor, and motor neurons. This enhanced activation facilitates the faster initiation and execution of the saccade based on the value of each object. In addition, we found a novel class of tonically active neurons that decrease their activity in response to object onset and remain inhibited till the end of the saccade. We suggest that these tonic neurons facilitate the saccade to objects by disinhibiting the interactions between the other three SC neurons.
The state of neural dynamics prior to the presentation of an external stimulus significantly influences its subsequent processing. This neural preparatory mechanism might be of particular importance for crossmodal memory formation. The integration of stimuli across different sensory modalities is a fundamental mechanism underlying the formation of episodic memories. However, the causal role of pre-stimulus neural activity in this process remains largely unclear. In this preregistered study, we investigate the direct relationship between transient brain states induced by sensory entrainment and crossmodal memory encoding. Participants (n = 105) received rhythmic visual stimuli at theta (5 Hz) or alpha (9 Hz) frequencies to evoke specific brain states. EEG recordings confirmed successful entrainment, with sustained increases in neural activity within the stimulated frequency bands persisting until stimulus onset. Notably, induced alpha oscillatory activity enhanced recognition memory performance reflected by increased sensitivity, and suggesting that alpha oscillations prepare the brain for optimal multisensory integration. These findings highlight the functional significance of distinct oscillatory brain states in facilitating memory encoding by increasing cortical excitability before stimulus presentation. Overall, our results emphasize the importance of pre-stimulus brain states in shaping the efficiency of memory formation across sensory modalities and shed light on how dynamic neural preparations support learning. Impact StatementBy using sensory entrainment of pre-stimulus oscillations we could show thatalpha-band stimulation in particular enhanced crossmodal memory. These findings reveal a frequency-specific functional dissociation and highlight the potential of targeting preparatory brain rhythms to improve crossmodal memory formation.
The state of neural dynamics prior to the presentation of an external stimulus significantly influences its subsequent processing. This neural preparatory mechanism might be of particular importance for crossmodal memory formation. The integration of stimuli across different sensory modalities is a fundamental mechanism underlying the formation of episodic memories. However, the causal role of pre-stimulus neural activity in this process remains largely unclear. In this preregistered study, we investigate the direct relationship between transient brain states induced by sensory entrainment and crossmodal memory encoding. Participants (n = 105) received rhythmic visual stimuli at theta (5 Hz) or alpha (9 Hz) frequencies to evoke specific brain states. EEG recordings confirmed successful entrainment, with sustained increases in neural activity within the stimulated frequency bands persisting until stimulus onset. Notably, induced alpha oscillatory activity enhanced recognition memory performance reflected by increased sensitivity, and suggesting that alpha oscillations prepare the brain for optimal multisensory integration. These findings highlight the functional significance of distinct oscillatory brain states in facilitating memory encoding by increasing cortical excitability before stimulus presentation. Overall, our results emphasize the importance of pre-stimulus brain states in shaping the efficiency of memory formation across sensory modalities and shed light on how dynamic neural preparations support learning. Impact StatementBy using sensory entrainment of pre-stimulus oscillations we could show thatalpha-band stimulation in particular enhanced crossmodal memory. These findings reveal a frequency-specific functional dissociation and highlight the potential of targeting preparatory brain rhythms to improve crossmodal memory formation.
Smartphone use varies ranging from rapid, rhythmic tapping (e.g., texting) to slower, irregular scrolling (e.g., browsing), resulting in diverse temporal patterns of inter-touch intervals. The underlying brain processes may dynamically align to these behaviors. We investigated population neural signals captured by using EEG during hour long smartphone use sessions (n = 53 subjects, accumulating 136869 interactions). We grouped the brain signals according to the transition patterns between consecutive touchscreen intervals (next-interval statistics), resulting in a matrix of EEG signals. Using data-driven dimensionality reduction on this matrix, we identified low-dimensional neuro-behavioral clusters that captured brain signal features associated with specific next-interval statistics. These neuro-behavioral clusters were found for diverse cortical locations spanning occipital, parietal and frontal cortices, suggesting a cortex-wide alignment to the next-interval statistics. Notably, these clusters were observed predominantly before rather than after the touchscreen interactions and they varied across individuals, suggesting personalized strategies for planning and executing smartphone use. Our findings indicate that the brain tracks and adapts to the fine-grained temporal patterns in touchscreen behavior, likely to support efficient smartphone interactions. More broadly, this work demonstrates how naturalistic smartphone use can reveal dynamic, individualized cortical adaptations to real-world temporal structure.
Acute stress triggers the release of stress hormones such as cortisol, increasing stress reactivity and aiding post-stress recovery. Prior work in rodents revealed the modulating role of the gut microbiota in stress reactivity, but whether this is also the case in humans is unclear. Additionally, to what degree stress reactivity is tied to ones capacity to produce microbial metabolites such as short-chain fatty acids (SCFAs) is untested. To close this gap, we invited 80 healthy human adults to the laboratory who were either exposed to a well-established, standardized intervention that induced acute stress or to a non-stressful control condition (n = 40 per group). Changes in stress hormones were assessed from repeated saliva sampling. Stool samples were obtained at baseline, and the gut microbiota were characterized through 16S rRNA gene amplicon sequencing. We found that higher gut microbiota diversity was associated with lower cortisol stress reactivity and lower levels of subjectively experienced stress, but not faster post-stress recovery, across the individuals of the stress group. Moreover, lower cortisol stress reactivity was associated with a higher relative abundance of taxa that encode metabolic pathways for the production of butyrate, a key SCFA. These results are the first to highlight the role of gut microbial diversity and inferred butyrate production capacity in modulating stress reactivity in healthy adults, underscoring the microbiotas potential to buffer against the detrimental effects of acute stress.
Visceral pain-related fear, shaped by associative learning, drives maladaptive emotional reactions and may contribute to the chronicity of pain in disorders of gut-brain interaction. However, the role of contingency awareness remains unclear. In a translational model of pain-related conditioning, we investigated the brain-behavior relationships underlying contingency awareness in shaping the neural circuitry involved in visceral pain-related fear and safety learning. Data from 75 healthy individuals undergoing differential conditioning were acquired in two functional magnetic resonance imaging studies. Visceral pain as unconditioned stimulus (US) was paired with a visual cue as conditioned stimulus (CS+) while another cue (CS-) remained unpaired. Differential neural responses to predictive cues were analyzed using a full factorial model and regression analyses to evaluate the predictive value of neural activation patterns based on contingency awareness. Analyses revealed a significant interaction between CS-type and contingency awareness involving dorsolateral prefrontal cortex (dlPFC) and parahippocampus, driven by an enhanced CS+>CS- differentiation in highly aware participants. The reverse contrast revealed widespread activation in fronto-parietal and limbic networks, more pronounced in the highly aware group. Regression analyses showed that enhanced CS--related were associated with increased contingency awareness and CS- valence change, while no activation clusters predictive of behavioral responses were found for CS+. The recruitment of emotional arousal and executive control networks as a function of contingency awareness highlights its relevance in shaping pain- and, particularly, safety-predictive cue properties. These results suggest distinct processes for fear acquisition and inhibition, with significant implications for exposure-based treatments of disorders of gut-brain interaction.
Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a progressive inherited retinal degenerative disorder currently lacking effective treatments. A recurrent 3-base pair deletion in the RHO gene, resulting in the loss of isoleucine at codon 255 or 256 (RHO{Delta}I255 or RHO{Delta}I256), has been identified in patients from the United Kingdom, Germany, Belgium, China, and Korea, suggesting a broad geographic distribution. This mutation leads to rhodopsin (RHO) misfolding, its retention in the endoplasmic reticulum (ER), and aggregation with wild-type (WT) RHO, ultimately triggering ER stress and photoreceptor degeneration. These aggregates are primarily cleared via the ER-associated degradation (ERAD) pathway, with valosin-containing protein (VCP) playing a key role in their retrotranslocation and proteasomal degradation. Pharmacological or genetic inhibition of VCP has shown neuroprotective effects in other models of adRP, but the poor aqueous solubility of VCP inhibitors and challenges in retinal drug delivery hinders clinical translation. To overcome these limitations, we evaluated and compared three VCP-targeted therapeutic strategies in Rho{Delta}I255 knock-in mouse retinae: (1) small-molecule inhibitors (ML240, NMS-873) solubilized in DMSO, (2) ML240 encapsulated in monomethoxy-polyethylene glycol (mPEG)-cholane nanoparticles, and (3) small interfering RNA (siRNA) targeting VCP, delivered via magnetic nanoparticles. Neuroprotective effects were assessed in vitro in retinal explants and in vivo following intravitreal injection. Our findings provide the first evidence that VCP inhibition restores RHO trafficking to the outer segments and prevents photoreceptor cell death in the Rho{Delta}I255 model. Among the three approaches, nanocarrier-encapsulated ML240 exhibited superior efficacy, enabling sustained drug delivery and enhanced photoreceptor protection. These results establish a preclinical proof-of-concept for nanocarrier-mediated VCP inhibition as a promising therapeutic strategy for RHO-adRP and potentially other ER-stress-related retinal degenerations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/661245v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@12f9366org.highwire.dtl.DTLVardef@76437dorg.highwire.dtl.DTLVardef@48dd6corg.highwire.dtl.DTLVardef@1c11812_HPS_FORMAT_FIGEXP M_FIG C_FIG
Frontal Cortex (FC) plays a pivotal role in controlling actions and their dynamics in response to incoming sensory stimuli. We explored FC representations of the same stimuli when signifying diametrically opposite behavioral meanings depending on task context. Two groups of ferrets performed Go-NoGo auditory categorization tasks with opposite contingencies and rewards, and varied stimuli. Remarkably, despite the opposite stimulus-action associations, single-unit responses were similar across all tasks, being more sustained and stronger to (Target) sounds signaling a change in action, than to (Reference) sounds indicating maintenance of ongoing actions, especially during task engagement. Three major dynamic response profiles were extracted from the overall responses, and their combination defined separate neuronal clusters that exhibited different roles in relation to task events. Decoding based on the temporal structure of the population responses revealed distinct decoders that were aligned to different task events. Furthermore, the {beta}-band power, extracted from the FC local field potentials, was similarly and strongly modulated during Target stimuli in all tasks despite opposite behavioral actions. Based on these findings, we propose a model of pathway-specific functional projections from the tripartite FC neuronal clusters to the basal ganglia that is consistent with previous evidence for the conjoint roles of the FC and striatum in adaptive motor control.
Sensory operators are classically modelled using small circuits involving canonical computations, such as energy extraction and gain control. Notwithstanding their utility, circuit models do not provide a unified framework encompassing the variety of effects observed experimentally. We develop a novel, alternative framework that recasts sensory operators in the language of intrinsic geometry. We start from a plausible representation of perceptual processes that is akin to measuring distances over a sensory manifold. We show that this representation is sufficiently expressive to capture a wide range of empirical effects associated with elementary sensory computations. The resulting geometrical framework offers a new perspective on state-of-the-art empirical descriptors of sensory behavior, such as first-order and second-order perceptual kernels. For example, it relates these descriptors to notions of flatness and curvature in perceptual space.
Efforts to restore vision via neural implants have outpaced the ability to predict what users will perceive, leaving patients and clinicians without reliable tools for surgical planning or device selection. To bridge this critical gap, we introduce a computational virtual patient (CVP) pipeline that integrates anatomically grounded phosphene simulation with task-optimized deep neural networks (DNNs) to forecast patient perceptual capabilities across diverse prosthetic designs and tasks. We evaluate performance across six visual tasks, six electrode configurations, and two artificial vision models, positioning our CVP approach as a scalable pre-implantation method. Several chosen tasks align with the Functional Low-Vision Observer Rated Assessment (FLORA), revealing correspondence between model-predicted difficulty and real-world patient outcomes. Further, DNNs exhibited strong correspondence with psychophysical data collected from normally sighted subjects viewing phosphene simulations, capturing both overall task difficulty and performance variation across implant configurations. While performance was generally aligned, DNNs sometimes diverged from humans in which specific stimuli were misclassified, reflecting differences in underlying decision strategies between artificial agents and human observers. The findings position CVP as a scientific tool for probing perception under prosthetic vision, an engine to inform device development, and a clinically relevant framework for pre-surgical forecasting.
The healthy human eyes optical components are misaligned. Although important in studying vision quality, it has been overlooked in research on binocular and oculomotor vision. This study presents the construction of ocular torsion in the binocular system that incorporates the fovea displaced from the posterior pole and the lens tilted away from the eyes optical axis. When the eyes binocular posture changes, each eyes torsional position transformations, computed in the framework of Rodrigues vector, are visualized in GeoGebra simulations. Listings law, important in oculomotor control by constraining a single eye redundant torsional degree of freedom, is ab initio formulated for bifoveal fixations in the binocular system with misaligned optical components for the fixed upright head. It leads to the configuration space of binocularly constrained eyes rotations, including the noncommutativity rule. This formulation modifies the Listing plane of the straight-ahead eyes primary position by replacing it with the binocular eyes posture corresponding to the empirical horopters abathic distance fixation, a unique bifoveal fixation for which the longitudinal horopter is a straight frontal line. Notably, it corresponds to the eye muscles natural tonus resting position, which serves as a zero-reference level for convergence effort. Supported by ophthalmology studies, it revises the elusive neurophysiological significance of the Listing plane. Furthermore, the binocular constraints couple 3D changes in the eyes orientation and, hence, torsional positions during simulations with GeoGebras dynamic geometry. The binocular Listings law developed here can support this coupling, which is important in oculomotor control. The results obtained in this study should be a part of the answers to the questions posted in the literature on the relevance of Listings law to clinical practices. Author summaryOur eye optical components are misaligned: the fovea is displaced from the eyes posterior pole, and the lens is tilted away from the optical axis. Listings law, important in oculomotor control, has not only overlooked the misaligned eyes optics but was also formulated for a single eye, with a later ad hoc extension added for binocular vision. The purpose of Listings law is to constrain the eyes redundant torsional degrees of freedom, thereby supporting neural processing in the development of our spatial understanding by controlling the noncommutativity of the eyes rotations. This goal cannot be fully met because Listings law is monocular, but we acquire an understanding of the scene through bifoveal fixations on objects. In this work, I construct ocular torsion that accounts for the eyes misaligned optics and incorporate it into Listings law. It directly leads to its first ab initio consistent binocular formulation, which is visualized in a computer simulation. Supported by ophthalmological studies, it revises the still elusive neurophysiological significance of the Listing plane, the basic ingredient of Listings law. It also resolves the persistent lack of a generally accepted explanation for Listings law. The results of this study are likely to be important in the ongoing discussion in the literature regarding the relevance of Listings law to clinical practices.
Rhythmic ability has been studied for more than a century in laboratory settings testing timed finger taps. While robust results emerged, it remains unclear whether these findings reflect behavioral limitations in realistic scenarios. This study tested the synchronization-continuation task in a museum with 455 visitors of a wide variety of ages (5-74yrs), musical experiences (0-40yrs) and educational and cultural backgrounds. Adopting a dynamic systems perspective, three metronome pacing periods were anchored around each individuals preferred tempo, and 20% faster and 20% slower. Key laboratory findings were replicated and extended: timing error and variability decreased during childhood and increased in older adults and were lower, even with moderate musical experience. Consistent with an oscillator perspective, timing at non-preferred tempi drifted toward their preferred rate. Overall, these findings demonstrate that timing limitations may reflect attractor properties of a neural oscillator and its signature is still present even in noisy, naturalistic settings.
Interoceptive attention--the ability to selectively focus on internal bodily signals--has been linked to distinct neural responses, yet the contribution of oscillatory dynamics to this process remains underexplored. This study investigates the neural mechanisms underlying interoceptive attention by examining beta-band power suppression during heartbeat and auditory discrimination tasks. Fifty-one healthy participants engaged in interoceptive (heartbeat detection) and exteroceptive (auditory discrimination) tasks while their brain activity was measured using magnetoencephalography (MEG). The results revealed significant beta suppression time-locked to the R-peak in the somatosensory cortex, anterior cingulate cortex, mid-cingulate cortex, and dorsolateral prefrontal cortex from 310 to 530 ms post-R-peak. Beta suppression was more pronounced during interoceptive attention, correlating positively with interoceptive accuracy. The findings support the notion that beta suppression in fronto-cingulo- somatosensory network may serve as a neural marker of interoceptive processing, contributing to predictive coding models of interoception. This study highlights the potential for using beta suppression as an objective measure of interoceptive accuracy and suggests that neural oscillations play a critical role in the brains regulation of heartbeat-related information. Furthermore, the study proposes that interoceptive attention involves a top-down mechanism that dynamically adjusts the brains response to cardiac afferent signals, enhancing the precision of interoceptive processing. These findings have implications for understanding how the brain integrates interoceptive signals and may provide insights into clinical applications targeting interoceptive dysfunctions.
Alzheimers disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimers disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1{Delta}E9/WT, PSEN1M146V/WT, or APPswe/WT. Our CO model reveals time-progressive accumulation of amyloid beta (A{beta}) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of A{beta} and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.
Study ObjectivesTo investigate associations between social jetlag and developing brain circuits and structures in adolescents. MethodsN = 3507 youth (median (IQR) age = 12.0 (1.1) years; 50.9% females) from the Adolescent Brain Cognitive Development (ABCD) cohort were studied. Social jetlag (adjusted for sleep debt (SJLSC) versus non-adjusted (SJL)), topological properties and intrinsic dynamics of resting-state networks, and morphometric characteristics were analyzed. ResultsOver 35% of participants had SJLSC [≥]2.0 h. Boys, Hispanic and Black non-Hispanic youth, and/or those at later pubertal stages had longer SJLSC ({beta}=0.06 to 0.68, CI=[0.02, 0.83], p[≤]0.02), which was also associated with higher BMI ({beta}=0.13, CI=[0.08, 0.18], p<0.01). SJLSC and SJL were associated with weaker thalamic projections ({beta}=- 0.22, CI=[-0.39, -0.05], p=0.03), potentially reflecting a disrupted sleep-wake cycle. Longer SJLSC was also associated with less topologically resilient and weakly connected salience network ({beta}=-0.04, CI=[-0.08, -0.01], p=0.04), and lower thickness and/or volume of cortical and subcortical structures overlapping with this and other networks supporting emotional and reward processing and regulation, and social function ({beta}=- 0.08 to -0.05, CI=[-0.12, -0.01], p<0.05). SJLSC and SJL were associated with alterations in spontaneous brain activity and coordination that indicate disrupted neural maturation and plasticity. SJL was associated with lower information transfer between regions supporting sensorimotor integration, social function and emotion regulation ({beta}=-0.07 to-0.05, CI=[-0.12, -0.01], p<0.04). ConclusionsMisaligned sleep may have detrimental effects on adolescent brain circuit organization and dynamics, and structural characteristics of regions that play critical roles in cognitive function and regulation of fundamental biological processes.
Adolescence is a critical period that requires balancing exploration of uncertain and novel environments while maintaining safety. This task requires sophisticated neural integration of threat and safety cues to guide behavior. Yet little work has been conducted on threat and safety processing outside of conditioning paradigms, which, while valuable, lack the complexity to identify how the adolescent brain supports distinguishing threat from safety when both are present and as task contingencies change. In the current study, we take an approach that expands on elements of differential conditioning as well as conditioned inhibition. We recorded brain responses to external threat and self-oriented protection cues to examine how the adolescent brain supports threat-safety discrimination using 7-Tesla functional magnetic resonance imaging (fMRI). Our findings reveal an adolescent transition in the neural mechanisms supporting accurate threat-safety discrimination, with younger adolescents (12-14 years) relying predominantly on the hippocampus and older adolescents (15-17 years) utilizing a more integrated circuit involving the hippocampus and anterior ventromedial prefrontal cortex (vmPFC) connectivity. Our results clarify how competition between threat and safety cues is resolved within the visual cortex, demonstrating enhanced perceptual sensitivity to protection that is independent of threat. By examining the dynamic encoding of safety to different stimuli, the current study advances our understanding of adolescent neurodevelopment and provides valuable insights into threat-safety discrimination beyond conventional conditioning models. HighlightsO_LIProtection is more strongly weighted than threat in adolescent safety estimation. C_LIO_LIHippocampus aids accurate safety detection in younger adolescents. C_LIO_LIHippocampal-vmPFC connectivity aids accurate safety detection in older adolescents. C_LIO_LIProtection enhances visual processing, reflecting perceptual prioritization. C_LI
Normative modeling provides a principled framework for quantifying individual deviations from typical brain development and is increasingly used to study heterogeneity in neuropsychiatric conditions. While widely applied to structural phenotypes, functional normative models remain underdeveloped. Here, we introduce MEGaNorm, the first normative modeling framework for charting lifespan trajectories of resting-state magnetoencephalography (MEG) brain oscillations. Using a large, multi-site dataset comprising 1,846 individuals aged 6-88 and spanning three MEG systems, we model relative oscillatory power in canonical frequency bands using hierarchical Bayesian regression, accounting for age, sex, and site effects. To support interpretation at multiple scales, we introduce Neuro-Oscillo Charts, visual tools that summarize normative trajectories at the population level and quantify individual-level deviations, enabling personalized assessment of functional brain dynamics. Applying this framework to a Parkinsons disease cohort (n = 160), we show that normative deviation scores reveal disease-related abnormalities and uncover a continuum of patients in theta-beta deviation space. This work provides the first lifespan-encompassing normative reference for MEG oscillations, enabling population-level characterization and individualized benchmarking. All models and tools are openly available and designed for federated, continual adaptation as new data become available, offering a scalable resource for precision neuropsychiatry.
Traditional models of brain connectivity have primarily focused on pairwise interactions, over-looking the rich dynamics that emerge from simultaneous interactions among multiple brain regions. Although a plethora of higher-order interaction (HOI) metrics have been proposed, a systematic evaluation of their comparative properties and utility is missing. Here, we present the first large-scale analysis of information-theoretic and topological HOI metrics, applied to both resting-state and task fMRI data from 100 unrelated subjects of the Human Connectome Project. We identify a clear taxonomy of HOI metrics -- redundant, synergistic, and topological--, with the latter acting as bridges along the redundancy-synergy continuum. Despite methodological differences, all HOI metrics align with the brains overarching unimodal-to-transmodal functional hierarchy. However, certain metrics show specific associations with the neurotransmitter receptor architecture. HOI metrics outperform traditional pairwise models in brain fingerprinting and perform comparably in task decoding, underscoring their value for characterizing individual functional profiles. Finally, multivariate analysis reveals that -- among all HOI metrics -- topological descriptors are key to linking brain function with behavioral variability, positioning them as valuable tools for linking neural architecture and cognitive function. Overall, our findings establish HOIs as a powerful framework for capturing the brains multidimensional dynamics, providing a conceptual map to guide their application across cognitive and clinical neuroscience.
This research challenges the traditional localizationist view that brain tumors affect only regions directly associated with the lesion, by examining whether they also induce macrostructural alterations in the contralesional hemisphere. We applied Voxel-Based Morphometry, linear regression, and Principal Component Analysis (PCA) to a cohort of 107 adults, including patients with gliomas in the language-dominant left hemisphere and healthy participants. Unlike previous studies, a subset of the clinical population was followed longitudinally for up to four months after oncological treatment, allowing us to describe the temporal progression of structural grey matter changes. Interestingly, a principal component model based on anomaly detection enabled robust differentiation between patients and controls. Patients exhibited significantly greater grey matter volume in the contralesional hemisphere compared to healthy participants, and these structural differences evolved over time, improving the models AUC-ROC metrics. Although exploratory, a correlation analysis revealed that these structural changes were negatively associated with postsurgical cognitive performance. Together with the PCA findings, these results suggest that brain tumors induce extensive and dynamic adaptive mechanisms in the contralateral, unaffected hemisphere, likely reflecting altered patterns of structural covariance rather than simple regional volume increases. Understanding whether these changes could represent potential predictors of postoperative cognitive recovery is crucial for developing comprehensive clinical strategies. Key PointsO_LILeft-hemisphere tumors induce contralesional grey matter increases pre- and post-sugery C_LIO_LIPCA detects altered structural covariance and distinguishes patients from healthy participants C_LIO_LIContralesional grey matter volume changes correlate with postoperative cognitive performance C_LI Importance of the StudyThis study challenges the traditional view that brain tumors cause only localized effects by demonstrating widespread macrostructural alterations in the contralesional hemisphere. We reveal increased grey matter volume and altered patterns of structural covariance outside the tumor region. Longitudinal follow-up after surgery shows these changes are dynamic and evolve over time. Further, we identify moderate associations between contralesional grey matter alterations and cognitive performance, suggesting a link between large-scale neuroplastic responses and functional outcomes. These findings offer new insights into tumor-related neuroplasticity and position structural covariance as a promising marker for tracking brain-wide adaptation in this population. The study has translational relevance for developing predictive tools to monitor recovery and guide personalized rehabilitation.
Rett Syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in the X-linked MECP2 gene, results in profound life-long neurological dysfunction. RTT patients live an apparently normal initial life until 12-18 months of age following which, a progressive accumulation of a wide range of phenotypic manifestations sets in. While MeCP2 is known to regulate chromatin, its impact on global histone composition and dynamics remains poorly understood. Here, we combine mass spectrometry imaging (MSI) and laser capture microdissection (LCM) coupled to LC-MS/MS to systematically profile histone proteoforms in three key brain regions: the dentate gyrus (DG) and cornu ammonis (CA) of the hippocampus, and the cerebellum (Cb). Our analysis reveals striking neuron-specific differences in histone composition between Mecp2-deficient and wildtype (WT) mice. Interestingly, the expression of a pathogenic Mecp2 missense mutant (Y120D) results in subtler changes in histone composition that are distinct from the null mutations. This study provides the first spatially resolved epigenetic atlas of histone proteoforms in RTT and suggests that Mecp2 loss perturbs chromatin homeostasis in a neuron- and mutation-dependent manner. Our findings underscore the critical need for cell-type-resolved analyses to unravel the mechanistic underpinnings of RTT and emphasize the importance of personalised therapeutic strategies that consider both the affected cell-type and particular Mecp2 mutation.
Huntingtons disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Two major molecular drivers--somatic expansion of inherited CAG repeats and toxic mutant HTT (mHTT) variants--lead to neuronal dysfunction. Despite multiple trials, HTT-lowering strategies have not shown meaningful clinical benefit. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MSH3 (a key regulator of somatic expansion), HTT, or both. In Q111 HD mice (>110 CAGs), which exhibit robust expansion, mHTT inclusions, and transcriptional dysregulation by 12 months, long-term MSH3 silencing blocked expansion, reduced inclusions, and reversed gene expression changes. HTT silencing alone had limited effect, but combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based co-silencing of MSH3 and HTT as a disease-modifying strategy for HD.
Retinal degenerative diseases are a major cause of blindness in humans that often result in permanent and progressive loss of vision. Unlike humans, zebrafish possess the remarkable ability to regenerate lost retinal neurons through Muller glia (MG) reprogramming and asymmetric cell division to produce multipotent retinal progenitor cells (RPCs). While most studies on the molecular mechanisms underlying this regeneration process have focused on intracellular mechanisms, the role of the microenvironment surrounding retinal cells, the extracellular matrix (ECM), has been understudied. Laminins are heterotrimeric glycoproteins, are principal components of the ECM basement membrane, and play important roles in vertebrate retinal development. Here, we examine the role of {beta}1b chain-containing laminins in the regenerative response of the zebrafish retina. We found that the zebrafish lamb1b gene is differentially expressed during MG reprogramming and MG and NPC proliferation during retinal regeneration. Further, we found that {beta}1b-containing laminins play important roles in regulating MG and NPC proliferation and neuroprotection of photoreceptors in light-damaged zebrafish retinas. Finally, Lam{beta}1b plays an important role in regulating the expression of integrin receptors and other laminin genes during the regeneration response. Taken together, Lam{beta}1b, and likely other ECM components, play a critical role in the MG-dependent neuronal regeneration response in the zebrafish retina.
Sensory perception often relies on the brains integration of multiple noisy inputs (cues), a process known as cue combination. Cue combination within the sense of touch has been understudied. Here, we investigated whether humans optimally combine haptic cutaneous and hand configuration cues when discerning the size (e.g., diameter) of a disk held edge-on between the thumb and index fingers. When these two fingers span the diameter of a disk to contact its perimeter, a hand configuration cue (relating to the perceived distance between the fingers) provides information about the disks size. Less obviously, cutaneous cues to disk size may be provided simultaneously from the indentation of the skin caused by the curvature of the disk (smaller disks cause greater indentation). It is unknown whether humans make use of all these cues when perceiving the size of the held object, and if so, whether they integrate the cues optimally. We considered three hypotheses for how humans might use these cues: they might rely solely on the least noisy cue (Winner-Take-All Model, WTA), combine cues based on a simple arithmetic average (Average-Measurement Model, AVG), or combine cues via an optimal weighted average (Optimally-Weighted Model, OPT). In three experiments involving 34 participants, we measured the reliabilities of these cues and compared participant performance to the predictions of the three models. Each experiment tested participants using a two-interval forced-choice (2IFC) paradigm with 3D printed disk stimuli. On each trial, under occluded vision, participants felt two disks sequentially and responded which felt larger. Participants were tested with each fingers cutaneous cue alone, the configuration cue alone, and all three cues together. In two experiments, the disks presented were circular. In a third experiment, unknown to participants, some of the presented disks were oval-like cue-conflict stimuli. The improvement of accuracy observed in multi-cue conditions over single-cue conditions, and the Point of Subjective Equality (PSE) shifts observed in cue-conflict conditions, were consistent with optimal cue combination. We conclude that humans are capable of combining haptic cutaneous and configuration cues optimally to judge the sizes of held objects.
The brains resting-state activity can serve as an indicator of cognitive flexibility and predict the likelihood of an upcoming Aha experience. This suggests that spontaneous neural dynamics reflect a persons readiness for creative insight and underscore the potential of resting-state measures as biomarkers for anticipating creative breakthroughs. However, solutions accompanied by an Aha experience are not always truly creative, so it may be more valuable to identify biomarkers specifically linked to novelty and usefulness--two key dimensions of creative performance. To achieve this, we recruit 49 participants to complete the Alternative Uses Test, in which unconventional uses for everyday items are generated. We evaluate the responses for both novelty and feasibility using automated GPT-based methods and analyze resting-state EEG prior to the test. We find that creative performance is better predicted by interactions between different brain areas than by the activation of individual regions. Specifically, the degree centrality of theta-band functional connectivity in the right parietal and occipital areas correlates with novelty, while connectivity in the right middle and inferior frontal areas is associated with more feasible answers. These findings highlight distinct resting-state brain networks underlying the "creative potential" for novelty and feasibility, which could be leveraged to monitor and enhance brain flexibility. Significance statementOur study introduces the Creativity Potential Network (CPN), a resting-state brain network that can predict the novelty and feasibility of the upcoming solution in creative problem-solving. We show that the CPN is represented by communication between brain areas, and that the networks for novelty and feasibility are spatially distinct. This work provides a potential method to assess the potential to be creative without relying on behavioral measures and could be combined with neurofeedback to monitor and enhance brain flexibility.
In glaucoma, the optic nerve head (ONH) is exposed to increased biomechanical strain, impacting the resident astrocytes that maintain neural homeostasis. After injury, astrocytes exhibit morphologic and metabolic shifts; however, the specific impact of glaucoma-related biomechanical strains on astrocyte behavior remains poorly understood. To address this, we utilized our previously established 3D cell-encapsulated ECM hydrogel to elucidate ONH astrocyte transcriptomic and cellular responses to varying biomechanical strain levels over time. Murine ONH astrocyte-encapsulated hydrogels were subjected to 0, 3, or 10% cyclic strain for 4h and 24h. Using confocal reflectance microscopy, we observed that hydrogel porosity was adequate for nutrient supplementation, while bulk hydrogel stiffness and cell viability remained unchanged after biomechanical strain. Mechanotranscriptional responses were robustly altered within 4h in a hydrogel region-, strain-, and time-dependent manner. RNA sequencing revealed changes in gene expression related to cell morphology, division, senescence, hypoxia, metabolism, and ECM regulation. Morphometric analyses of strained ONH astrocytes showed reduced F-actin area coverage, increased GFAP, HIF-1, fibronectin, and collagen fibril reorganization. Our findings demonstrate that ONH astrocyte transcriptional responses are highly dependent on duration/magnitude of biomechanical strain and surrounding ECM density, corresponding with altered cell morphology, hypoxia, and ECM modification. This ONH astrocyte-encapsulated hydrogel provides a valuable platform for nuanced future manipulation of porosity, ECM composition, and cellularity to study the impact of biomechanical strain on ONH pathophysiology.
Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) as one of the key imaging biomarkers. Our understanding of its pathophysiology remains limited due to the lack of appropriate animal models. We report a novel mouse CMB model created by disrupting collagen IV, a core component of the vascular basement membrane (BM), specifically within brain microvessels. Targeted deletion of Col4a1 was achieved in adult mice using brain endothelial-specific AAV vectors with CRISPR/Cas9. MRI revealed numerous CMBs with distributions similar to those of human CMBs. CMB burden increased progressively over six months following Col4a1 deletion in a dose-dependent manner, accompanied by cognitive decline and motor incoordination. Histological examination revealed hemosiderin deposits corresponding to MRI-detected CMBs without evidence of macroscopic hemorrhage or white matter lesions, while ultrastructural analysis demonstrated significant BM thinning in Col4a1-depleted microvessels. Analysis of human MRI and genomic data identified significant associations between CMB susceptibility and genetic variants in TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2, underscoring the clinical relevance of our model. These findings establish a direct causal relationship between microvessel COL4A1 and CMB, suggesting that dysregulated collagen IV homeostasis in BM underlies CMB development.
Cocaine addiction is marked by high relapse rates, often triggered by drug-associated cues. These cues can be conditioned stimuli (CSs), which occur after drug intake and are paired with drug effects, and discriminative stimuli (DSs), which signal drug availability, regardless of ongoing drug-seeking behaviour. While projections from the infralimbic cortex (IL) to the nucleus accumbens (NAc) shell are known to regulate CS-induced cocaine relapse, their role in DS-triggered relapse is not known. To investigate this, we examined how activating IL[->]NAc shell projections influences relapse driven by DSs and CSs during abstinence from intermittent cocaine use. Female Sprague-Dawley rats received viral-mediated gene expression of excitatory designer receptors exclusively activated by designer drugs in the IL. Rats then self-administered cocaine during 12 intermittent-access sessions (5-min cocaine ON/25-min cocaine OFF, 4h/day). A discrete light (DS+) signalled drug-available periods, while a different light (DS-) signalled drug non-availability. During each DS+ period, cocaine infusions were paired with a compound light-tone (CS+). Four weeks later, rats were tested for cue-induced cocaine seeking following response-independent presentation of DS+, CS+ or both. Immediately prior to testing, rats received intra-NAc shell clozapine N-oxide or aCSF to activate IL terminals. DS+ alone and DS+/CS+ combined triggered greater cocaine seeking than did the CS+. Activation of IL[->]NAc shell projections suppressed relapse behaviour in DS+ and DS+/CS+ conditions. These findings highlight the distinct and powerful influence of DSs on relapse and identify the IL[->]NAc shell circuit as a promising target for relapse prevention.
Amyloid-{beta} (A{beta}) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE {varepsilon}4, a key genetic risk factor for Alzheimers disease (AD). Although the presence of A{beta}, tau, and APOE {varepsilon}4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9{+/-}5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. A{beta} was measured using CSF A{beta}42/A{beta}40 or Florbetaben-PET imaging and tau was measured using CSF pTau181. Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE {varepsilon}4 was independently associated with greater A{beta} and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE {varepsilon}4. Among APOE {varepsilon}4 non-carriers, A{beta} burden was linked to a pattern of hippocampal hyperactivity. Among APOE {varepsilon}4 carriers, CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE {varepsilon}4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD. Significance StatementHippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimers disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by APOE {varepsilon}4 in cognitively unimpaired older adults. Amyloid-{beta}-related hyperactivity was observed in the hippocampus among APOE {varepsilon}4 non-carriers, while CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE {varepsilon}4 carriers. Our findings highlight synergistic effects of APOE and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.
The reproduction of a perceived stimulus, such as a distance or a duration, is often influenced by two biases. Central tendency indicates that reproductions are biased toward the mean of the stimulus distribution. Serial dependence reflects that the reproduction of the current stimulus is influenced by the previous stimulus. Although these biases are well-documented, their origins remain to be determined. Studies on duration reproduction suggest that autocorrelation within a stimulus sequence may play a role. In this study, we explored whether the level of autocorrelation in a stimulus sequence affects central tendency and serial dependence in vestibular path integration. Participants (n = 24) performed a vestibular distance reproduction task in total darkness by actively replicating a passively moved stimulus distance with a linear motion platform. We compared two conditions: a high-autocorrelation condition, where stimulus distances followed a random walk, and a no-autocorrelation condition, where the same distances were presented in a randomly shuffled order. We quantified both biases using two approaches: separate simple linear regressions and a joint multiple linear regression model that accounts for the autocorrelation in the stimulus sequence. Simple linear regressions revealed that central tendency was weaker and serial dependence reversed in the high-autocorrelation condition compared to the no-autocorrelation condition. However, these differences were no longer observed in the multiple linear regression analysis, indicating that these biases were independent of the specific stimulus sequence protocol. We conclude that these perceptual biases in vestibular path integration persist regardless of stimulus autocorrelation, suggesting that they reflect robust strategies of the brain to process vestibular information in self-motion perception. Author summaryHow are we able to successfully navigate our surroundings? An essential part of navigation is distance estimation based on self-motion signals. We previously found that distance reproductions based on vestibular self-motion signals were affected by stimulus history. Reproductions showed a central tendency toward the mean of the stimulus distribution and an attractive serial dependence toward the immediately preceding stimulus distance. The stimulus distances were presented in a low-autocorrelation, randomized order. Here we ask whether reproductions show the same central tendency and serial dependence when consecutive stimulus distances are similar (i.e., in a high-autocorrelation, random-walk order). Participants performed a distance reproduction task in the dark: a linear motion platform first passively moved the participant over a stimulus distance, after which they actively reproduced this distance by steering the platform back to the estimated start position. We found that the reproductions showed similar central tendency and attractive serial dependence in both a no- and high-autocorrelation condition, but only if the analysis accounted for the covariation of the two effects in the high-autocorrelation condition. In conclusion, our findings indicate that central tendency and serial dependence of vestibular distance reproductions are not a result of the stimulus sequence protocol, but have neurocognitive origins.
Ultrahigh-density electrocorticography (ECoG) provides unprecedented spatial resolution for recording cortical electrical activity. This study uses simulated scalp projections from an ECoG recording to challenge the assumption that channel-level electroencephalography (EEG) reflects only local field potentials near the recording electrode. Using a 1024-electrode ECoG array placed on the primary motor cortex during finger movements, we applied Adaptive Mixture Independent Component Analysis (AMICA) to decompose activity into maximally independent grid activity components and projected these to 207 simulated EEG scalp electrode channels using a high-definition MR image-based electrical forward-problem head model. Our findings demonstrate how cortical surface-recorded potentials propagate to scalp electrodes both far from and near to the generating location. This work has significant implications for interpreting both EEG and ECoG data in clinical and research applications. Clinical RelevanceThis study provides insights for interpreting scalp EEG data, demonstrating that scalp channel activity represents a complex mixture of distributed cortical source activities rather than primarily activity generated nearest to the scalp electrodes. These findings may hopefully spur improvement in EEG-based diagnostics for neurological disorders.
Amphetamine and nicotine are two widely used and abused drugs that are taken for legitimate pharmaceutical purposes but are also highly abused through illicit recreational use. Both of these drugs have been widely shown to decrease food intake in both humans and pre-clinical models, and although amphetamine and nicotine clearly affect food intake under normal baseline ( homeostatic) conditions, there has been limited examination of the ability of these drugs to affect reward-related ( hedonic) aspects of feeding. Furthermore, there are sex differences in the behavioral responses to both drugs, but it is unclear if these sex differences also translate to their effects on feeding. This study examined whether nicotine and amphetamine regulate sucrose intake in a food self-administration paradigm in a sex-dependent manner across both fixed and progressive schedules of reinforcement. Amphetamine reduced operant responding for sucrose pellets and decreased acute intake of sucrose during ad libitum free-feeding access in a dose-dependent manner, whereas nicotine reduced sucrose self-administration and free intake only at higher doses that also impaired locomotor activity in open field tests. The effects of both amphetamine and nicotine did not differ by sex for either drug. Overall, these results suggest that the mechanisms mediating the addictive qualities of these drugs and their appetite suppressing effects may be distinct and therefore could be a potential target for future obesity therapeutics.
BackgroundThe discovery and development of therapeutics for Parkinsons disease (PD) requires preclinical models and an understanding of the disease mechanisms reflected in each model is crucial to success. ObjectiveTo illuminate disease mechanisms and translational value of two commonly utilized rat models of synucleinopathy - AAV-delivered human mutant hA53T alpha synuclein (-Syn) and -Syn preformed fibril (PFF) injection - using a top-down, unbiased, large-scale approach. MethodsTandem mass tag mass spectrometry (TMT-MS), RNA sequencing, and bioinformatic analyses were used to assess proteins, genes, and pathways disrupted in rat striatum and substantia nigra. Comparative analyses were performed with PD drug candidate targets and an existing human PD and dementia with Lewy body (DLB) proteomics dataset. ResultsUnbiased proteomics identified 388 proteins significantly altered by hA53T--Syn and 1550 by PFF--Syn compared to sham controls. Pathway and correlation analyses of these revealed common and distinct pathophysiological processes altered in each model: dopaminergic signaling/metabolism, mitochondria and energy metabolism, and motor processes were disrupted in AAV-hA53T--Syn, while immune response, intracellular/secretory vesicles, synaptic vesicles, and autophagy were more impacted by PFF--Syn. Synapses, neural growth and remodeling, and protein localization were prominently represented in both models. Analyses revealed potential biomarkers of disease processes and proteins and pathways also altered in patients, elucidating drug targets/ disease mechanisms the models best reflect. ConclusionsAlignment of unbiased multi-omics analyses of AAV-hA53T and PFF--Syn models of synucleinopathy with PD and DLB patient data and PD drug development pipeline candidates identifies optimal models for testing novel therapeutics based on biological mechanisms.
The growing channel count of silicon probes has substantially increased the number of neurons recorded in electrophysiology (ephys) experiments, rendering traditional manual spike sorting impractical. Instead, modern ephys recordings are processed with automated methods that use waveform template matching to isolate putative single neurons. While scalable, automated methods are subject to assumptions that often fail to account for biophysical changes in action potential waveforms, leading to systematic errors. Consequently, manual curation of these errors, which is both time-consuming and lacks reproducibility, remains necessary. To improve efficiency and reproducibility in the spike-sorting pipeline, we introduce here the Spike-sorting Lapse Amelioration System (SLAy), an algorithm that automatically merges oversplit spike clusters. SLAy employs two novel metrics: (1) a waveform similarity metric that uses a neural network to obtain spatially informed, time-shift invariant low-dimensional waveform representations, and (2) a cross-correlogram significance metric based on the earth-movers distance between the observed and null cross-correlograms. We demonstrate that SLAy achieves[~] 85% agreement with human curators across a diverse set of animal models, brain regions, and probe geometries. To illustrate the impact of spike sorting errors on downstream analyses, we develop a new burst-detection algorithm and show that SLAy fixes spike sorting errors that preclude the accurate detection of bursts in neural data. SLAy leverages GPU parallelization and multithreading for computational efficiency, and is compatible with Phy and NeuroData Without Borders, making it a practical and flexible solution for large-scale ephys data analysis.
Spatial long-read technologies are becoming more common but lack nanometer- and therefore often single-cell resolution. This leaves the question unanswered whether spatially variable isoforms represent spatial variability within one cell type or differences in cell-type abundance between different regions. Here, we develop Spl-ISO-Seq2 with 220nm spot size and 500nm resolution, and the accompanying software packages Spl-IsoQuant-2 and Spl-IsoFind and apply it to the adult mouse brain. We compare spatial variability within a fixed cell type by examining (a) differential isoform abundance between known brain regions and (b) spatial isoform patterns that do not align with predefined regions. The former reveals larger numbers of spatial isoform differences, e.g. Rps24 in oligodendrocytes. For the previously appreciated gene with spatially-variable isoforms Snap25, we can now show that this variability exists in excitatory neurons. However, the latter approach reveals patterns that the former cannot conceptually model, e.g., Tnnc1 in excitatory neurons. Taken together, our experimental and analytical methods enrich spatial transcriptomics with a so-far elusive isoform view of spatial variation for individual cell types.
Deep brain stimulation of the temporal cortex can enhance learning and memory in the face of cognitive impairment. Despite the potential of such therapies, the neural and genetic mechanisms underlying the effect of stimulation on human brain circuits are not understood. To explicate direct mechanisms of neural modulation elicited by brain stimulation, we developed an ex vivo approach utilizing microelectrode array stimulation and recording of resected temporal cortex from neurosurgical patients. We find that stimulation preferentially increases firing rates in pyramidal cells compared to interneurons and also strengthens cell assemblies. Using single cell multiomics, we link the observed physiological changes to cell type-specific gene expression patterns. We detail gene regulatory networks that indicate preferential involvement of specific excitatory neuron subtypes and the response of non-neurons. We conclude that the overall impact of stimulation on the human temporal cortex is activation of specific excitatory neurons and enhanced cell assembly activity, and that these changes are supported by gene networks involving immediate early, synaptic, and ion channel genes. Our findings establish a foundation to identify targetable cell type-specific genetic signatures that may be harnessed for therapeutic benefit in future neuromodulation strategies.
Single-cell transcriptomics has uncovered the enormous heterogeneity of cell types that compose each region of the mammalian brain, but describing how such diverse types connect to form functional circuits has remained challenging. Current methods for measuring the probability and strength of cell-type specific connectivity motifs principally rely on low-throughput whole-cell recording approaches. The recent development of optical tools for perturbing and observing neural circuit activity, now notably including genetically encoded voltage indicators, presents an exciting opportunity to employ optical methods to greatly increase the throughput with which circuit connectivity can be mapped physiologically. At the same time, advances in spatial transcriptomics now enable the identification of cell types in situ based on their unique gene expression signatures. Here, we demonstrate how long-range synaptic connectivity can be assayed optically with high sensitivity, high throughput, and cell-type specificity. We apply this approach in the motor cortex to examine cell-type-specific synaptic innervation patterns of long-range thalamic and contralateral input onto more than 1000 motor cortical neurons. We find that even cell types occupying the same cortical lamina receive vastly different levels of synaptic input, a finding which was previously not possible to uncover using lower-throughput approaches that can only describe the connectivity of broad cell types.
Variation in over 100 genes are now associated with increased risk for autism and related neurodevelopmental condition, but how this variation results in distinct and overlapping behavioral changes is still not well understood. Recent efforts have focused on screening many autism genes at once for functional and phenotypic convergence, and identified subsets that are crucial for many early steps of neurodevelopment. Few studies have screened later steps of neurodevelopment, circuit function, circuit plasticity, or behaviors. We screened twenty conserved autism-associated genes for impact on experience-dependent neuron remodeling in C. elegans. Loss of unc-44/ANK2, set-4/KMT5B, daf-18/PTEN, gap-2/SYNGAP1, and chd-1/CHD8 increased, while CACNA2D3/unc-36 decreased, neurite outgrowth of the GABAergic DVB neuron in adults. Although daf-18/PTEN, set-4/KMD5B, and unc-44/ANK2 had convergent phenotypes, they arise from distinct temporal trajectories with differential impact on DVB pre-synaptic morphology. Screening for the DVB regulated spicule protraction behavior identified multiple autism genes involved, but only unc-44/ANK2 and CACNA2D3/unc-36 were shared between screens. Application of a metric geometry computational framework (CAJAL) to the DVB morphology dataset identified 5 additional genes that impact DVB morphology, including unc-2/CACNA1A and unc-10/RIMS1, which also significantly impacted behavior. This work defines new regulators and molecular mechanisms of experience-dependent neuron remodeling and circuit plasticity, and further links these processes with conserved autism genes. It also demonstrates the utility of using intact, behavior generating circuits in C. elegans, to screen for novel roles for conserved autism genes.
Variation in over 100 genes are now associated with increased risk for autism and related neurodevelopmental condition, but how this variation results in distinct and overlapping behavioral changes is still not well understood. Recent efforts have focused on screening many autism genes at once for functional and phenotypic convergence, and identified subsets that are crucial for many early steps of neurodevelopment. Few studies have screened later steps of neurodevelopment, circuit function, circuit plasticity, or behaviors. We screened twenty conserved autism-associated genes for impact on experience-dependent neuron remodeling in C. elegans. Loss of unc-44/ANK2, set-4/KMT5B, daf-18/PTEN, gap-2/SYNGAP1, and chd-1/CHD8 increased, while CACNA2D3/unc-36 decreased, neurite outgrowth of the GABAergic DVB neuron in adults. Although daf-18/PTEN, set-4/KMD5B, and unc-44/ANK2 had convergent phenotypes, they arise from distinct temporal trajectories with differential impact on DVB pre-synaptic morphology. Screening for the DVB regulated spicule protraction behavior identified multiple autism genes involved, but only unc-44/ANK2 and CACNA2D3/unc-36 were shared between screens. Application of a metric geometry computational framework (CAJAL) to the DVB morphology dataset identified 5 additional genes that impact DVB morphology, including unc-2/CACNA1A and unc-10/RIMS1, which also significantly impacted behavior. This work defines new regulators and molecular mechanisms of experience-dependent neuron remodeling and circuit plasticity, and further links these processes with conserved autism genes. It also demonstrates the utility of using intact, behavior generating circuits in C. elegans, to screen for novel roles for conserved autism genes.
Energy expenditure (EE) is essential for metabolic homeostasis, yet its central regulation remains poorly understood. Here, we identify arcuate Kiss1 neurons as key regulators of EE in male mice. Ablation of these neurons induced obesity, while their chemogenetic activation increased brown adipose tissue (BAT) thermogenesis without affecting food intake. This action is mediated by glutamatergic projections from Kiss1ARC neurons to CART/Lepr-expressing neurons in the dorsomedial hypothalamus, which activate the raphe pallidus-BAT pathway. CRISPR-mediated deletion of the vesicular glutamate transporter 2 (Vglut2) from Kiss1ARC neurons replicated the obesogenic effect. Furthermore, deletion of the melanocortin 4 receptor (MC4R) from Kiss1 neurons resulted in obesity, reduced energy expenditure and impaired thermogenesis. Optogenetic stimulation of pro-opiomelanocortin (POMC) fibers evoked inward currents in Kiss1 neurons, that were attenuated by MC4R antagonism. Our findings reveal a previously unrecognized neural circuit that mediates melanocortin action on energy expenditure, offering new insights into central mechanisms of metabolic control.
An axiomatic view in contemporary neuroscience is that EEG components such as event-related brain potentials (ERPs) and oscillations are directly interpretable as manifestations of biological processes that support sensory, motor, and cognitive constructs of interest. This premise justifies and propels research programs in laboratories worldwide, but with a substantial social and economic cost, warranted by the potential for basic-science discovery and the resulting bench-to-bedside transfer for health and disease. But a different premise would be more fruitful. This article proposes that EEG components in psychophysiological experiments relate to cognition indirectly through their more direct relationship with oculomotor action. The common experimental design that includes a baseline ocular fixation period preceding stimulus presentation provides an excellent template with which to develop the present proposal. Electrophysiological and eye-tracking evidence (3 published and 3 new data sets: 6 experiments, Ntotal = 204, in the context of face and affective picture viewing, reading, listening, rest, and microsleep) demonstrates how and why common conclusions, and reliance on them in clinical practice/treatment efficacy and drug development studies, are at best premature. Results indicate that the oculomotor system plays a mediating role between such EEG phenomena and cognition. Present evidence supports a complementary view of how EEG can shape the development of a broader thought horizon in psychophysiological theory and practice.
It has been suggested that hierarchical synchronization of theta and gamma oscillations coordinates neural activity during sequence memory. Yet, the role of gamma oscillations and their interaction with theta and single-unit activity (SUA) has not been directly examined in humans. We analysed simultaneous micro wire recordings of single-unit activity (N = 1417) and local field potentials (N = 917 channels) from the medial temporal lobe (MTL) of epilepsy patients performing a visual multi-item sequence memory task. During encoding, both spiking activity and gamma power contained item-specific information and were temporally coupled. During memory maintenance, stimulus-specific gamma was characterized by recurring bursts during which spiking was tightly synchronized and both, gamma and spiking, were preferentially aligned to similar theta phases predictive of sequential stimulus position. These findings demonstrate that theta-gamma-spike interactions support a phase-based multiplexed code for sequential memories in the human MTL.
Neuroimaging research has identified focal differences in the cerebral cortex of individuals with autism spectrum disorder (ASD), particularly in the cortical folds (sulci) within higher-level association cortices. The present study investigated the sulcal patterning and morphology of the anterior cingulate cortex (ACC) in individuals with ASD compared to neurotypical (NT) individuals for the first time. We used neuroimaging data from 50 NT and 50 ASD participants. All participants were under 20 years old and male. The two groups were age-matched. Using established criteria and cortical reconstructions generated from each participants T1-weighted magnetic resonance imaging scans with FreeSurfer, we identified the defining sulcal feature of ACC, the variably present paracingulate sulcus (PCGS): its presence in the left and right hemispheres, and asymmetry in PCGS presence between hemispheres. Finally, multiple quantitative morphological features (length, depth, and cortical thickness mean and standard deviation) were extracted from the PCGS using FreeSurfer tools. Analyses revealed that NT participants were more likely to have asymmetrical PCGS patterns than ASD participants (controlling for age and scanner site). However, none of the quantitative morphological features differed between groups. These findings suggest the presence of a variation in the prenatal neurodevelopment of ACC in young males with ASD; however, further research is necessary to uncover the role of this observed difference in the pathogenesis of ASD. The present study also adds to the growing literature implicating variations in PCGS patterning as a trait marker across multiple disorders. Lay SummaryThis study found that young males with autism spectrum disorder (ASD) show less hemispheric asymmetry in the presence of a notoriously variable brain structure (paracingulate sulcus (PCGS)) compared to neurotypical individuals. Considering that this feature of the PCGS develops before birth, the reduced asymmetry may indicate focal differences in brain development in ASD. These findings further enhance our understanding of the neurodevelopmental characteristics of ASD and highlight growing findings indicating that the PCGS may be a useful transdiagnostic marker for various psychiatric conditions.
Evidence accumulation models have been successfully applied to decision-making in sensory and cognitive domains; however, it remains unclear how this process is regulated when perceptual ambiguity arises from social-affective content. Here, we integrate computational modeling with multimodal neuroscience to characterize how perceptual ambiguity in emotion judgment shapes decision dynamics. Participants viewed perceptually ambiguous stimuli - morphed images of two categories, such as happy and fearful facial expression - and made binary categorization decisions. Using drift diffusion modeling (DDM), we first demonstrate that drift rate, a key index of evidence accumulation, decreases as perceptual ambiguity increases. Scalp electroencephalography (EEG) data reveal that the magnitude of the late positive potential (LPP) tracks the speed of evidence accumulation in both emotional and non-emotional stimulus categories, but only when the ambiguous dimension is relevant to the categorization decision. Similar to LPP magnitude, single-unit recordings from the dorsomedial prefrontal cortex (dmPFC) and amygdala show that neuronal firing rates in both regions also encode drift rate during the emotion categorization task. Moreover, fMRI-based functional connectivity reveals that the strength of connectivity between the amygdala and dmPFC correlates with individual differences in drift rate. To establish the causal role of the dmPFC, we applied anodal transcranial direct current stimulation (tDCS) targeting the dmPFC in patients with schizophrenia and found that stimulation enhanced evidence accumulation speed in emotion categorization under perceptual ambiguity. These findings identify a distributed corticolimbic circuit that dynamically modulates evidence accumulation during social-affective decision-making under perceptual ambiguity. Our results bridge social-affective and perceptual neuroscience, offering a translational framework for understanding emotion recognition and decision-making impairments.
BACKGROUNDNerve growth factor (NGF), a key mediator of pain and inflammation, is increased in joints with osteoarthritis (OA). Neutralizing NGF with monoclonal antibodies has shown analgesic effects in painful knee OA, but clinical development was stopped due to side effects in the joints. Knowledge about the biological effects of long-term exposure of joint tissues to NGF is limited. Therefore, we aimed to explore the effects of repeated intra-articular (IA) injections of NGF into the knee joints of healthy mice on pain and sensitization, as well as joint innervation and structure. METHODSWe conducted five experiments in male C57BL/6 mice. In Experiment 1, NGF (50ng or 500ng) or vehicle was injected IA into the knee of naive wildtype (WT) mice, twice a week for 4 weeks. We assessed knee swelling, knee hyperalgesia and histopathology. In Experiment 2, mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks and microCT of the knee was performed. In Experiment 3, NaV1.8-tdTomato reporter mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks, and joint innervation was assessed. In Experiment 4, WT mice received 500ng NGF or vehicle twice a week for 4 weeks and were used for single cell RNA sequencing (scRNAseq) of the synovium. In Experiment 5, L3-L5 DRGs of mice that received 3 IA injections of 500ng NGF or vehicle twice a week were used for bulk RNA sequencing. RESULTSRepeated bi-weekly IA injections of NGF caused knee hyperalgesia in naive mice. NGF caused dose-dependent knee swelling, synovial pathology, increased bone mineral density and trabecular bone thickness in the medial subchondral bone, growth of pre-osteophytes in the medial compartment, but no cartilage degeneration. NGF injection caused sprouting of NaV1.8+ neurons in the medial but not the lateral synovium. ScRNAseq of the synovium revealed upregulated genes related to neuronal sprouting, synovial fibrosis and ossification, confirming histopathological findings. Bulk RNA seq of DRG showed upregulated pathways related to axonal growth. CONCLUSIONSIn healthy mouse knees, NGF induced mechanical sensitization, synovitis, neoinnervation in the medial synovium, subchondral bone changes and pre-osteophyte growth in the medial compartment, thus capturing many pathological changes observed in OA, except cartilage damage.
Left ventral occipitotemporal cortex (vOT) is crucial in reading, yet its functional role remains debated. Competing theories paint it as either a prelexical feedforward hub or a bidirectional interface between sensory and higher-order linguistic systems. To address the debate, we investigated the temporal and spectral dynamics of information flow involving left vOT during visual word and pseudoword reading using magnetoencephalography (MEG). The pseudowords varied in the degree to which they orthographically resembled real words. By combining two directed connectivity metrics, i.e., phase slope index (PSI) and Granger causality (GC), we converged on a hybrid model of left vOT function that reconciles the competing perspectives. Feedforward connectivity from low-level visual areas to vOT emerged at around 100 ms post stimulus similarly across all conditions, spanning a wide frequency range. Subsequently, feedforward orthographic information flowed from left vOT to higherorder areas, especially left superior temporal cortex (ST), at the low gamma band. This flow strength was modulated by word-likeness, being stronger for real words and word-like pseudowords than complete pseudowords. Conversely, feedback flow from left ST to vOT was observed in the low beta band for pseudowords, and occurred later for word-like than complete pseudowords. This indicates that greater processing demands modulate the direction of information flow, necessitating top-down linguistic constraints to facilitate reading. Our findings clarify the functional role of left vOT and explain when and why its connectivity may show as feedforward or bidirectional depending on time and task.
Contextual fear conditioning is an experimental framework widely used to investigate how aversive experiences affect the valence an animal associates with an environment. While the initial formation of associative context-fear memories is well studied - dependent on plasticity in hippocampus and amygdala - the neural mechanisms underlying their subsequent consolidation remain less understood. Recent evidence suggests that the recall of contextual fear memories shifts from hippocampal-amygdalar to amygdalo-cortical networks as they age. This transition is thought to rely on sleep. In particular, neural replay during hippocampal sharp-wave ripple events seems crucial, though open questions regarding the involved neural interactions remain. Here, we propose a biologically informed neural network model of context-fear learning. It expands the scope of previous models through the addition of a sleep phase. Hippocampal representations of context, formed during wakefulness, are replayed in conjunction with cortical and amygdalar activity patterns to establish long-term encodings of learned fear associations. Additionally, valence-coding synapses within the amygdala undergo overnight adjustments consistent with the synaptic homeostasis hypothesis of sleep. The model reproduces experimentally observed phenomena, including context-dependent fear renewal and time-dependent increases in fear generalisation. Few neural network models have addressed fear memory consolidation and to our knowledge, ours is the first to incorporate a neural mechanism enabling it. Our framework yields testable predictions about how disruptions in synaptic homeostasis may lead to pathological fear sensitization and generalisation, thus potentially bridging computational models of fear learning and mechanisms underlying anxiety symptoms in disorders such as PTSD. Author SummaryHow do we learn to fear certain environments? Why do some fear memories fade while others persist or even grow stronger over time? Scientists have long used laboratory experiments to study how animals associate danger with a particular context. These studies have helped identify brain regions involved in fear learning, including the amygdala, hippocampus, and cortex, and have inspired many computational models of how fear is acquired in the brain. However, most models focus only on what happens when fear is first learned, overlooking how these memories evolve in the days that follow and the role of sleep in this process. In this work, we present a neural network model that captures how fear memories are strengthened or reshaped during sleep. It builds on earlier models by incorporating memory replay and synaptic homeostasis, two brain processes believed to support emotional memory consolidation. Our model identifies neural processes that help make fear memories persistent, suggests that sleep is necessary to maintain adaptive behaviour after threatening experiences, and proposes that sleep disruptions mediate the harmful impact of stress on emotional regulation. By extending amygdala-based models of fear learning to include post-learning dynamics, our work offers new insight into how emotional memories are stabilised.
Brain-wide neural circuits are formed by the diverse axonal branching patterns of many individual neurons. Here we introduce POINTseq (projections of interest by sequencing), a high-throughput and user-friendly barcoded connectomics method that uses cell type specific barcoding and sequencing to rapidly map single-cell projections of a cell type of interest for thousands of neurons per animal. POINTseq leverages pseudotyping of Sindbis virus and a specific alphavirus-cellular receptor pair to make Sindbis infections cell type specific. It thus integrates MAPseq-style high-throughput barcoded projection mapping with the established viral-genetic neural circuit analysis toolbox. We validated POINTseq by mapping genetically and projection-defined cell populations in the mouse motor cortex. We then applied POINTseq to midbrain dopaminergic neurons and reconstructed the brain-wide single-cell projections of 3,813 dopaminergic neurons in ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). We define over 30 connectomic cell types, vastly exceeding the known diversity of dopaminergic cell types, and identify stereotyped projection motifs that may mediate parallel dopamine signaling. This data constitutes the anatomical substrate on which the diverse functions of dopamine in the brain are built. HIGHLIGHTSO_LIWe develop POINTseq, which uses pseudotyped Sindbis virus and cell type-specific expression of a viral receptor for cell type-specific barcoding. C_LIO_LIPOINTseq enables massively multiplexed single-cell projection mapping of cell types of interest. C_LIO_LIWe map the brain-wide projections of 3,813 individual VTA and SNc dopaminergic neurons. C_LIO_LIVTA and SNc dopaminergic neurons form over 30 connectomic cell types. C_LIO_LIProjections organize into stereotyped motifs that may mediate parallel dopamine signalling. C_LI
In computational neuroscience, simulation platforms generally do not have adequate tools to model the brain, body and environment simultaneously. We demonstrate a method for simulating neuromechanical models using a novel combination of widely used software platforms: NEURON and MuJoCo. Different neural models are used to control a realistic musculoskeletal model in both open-loop and closed-loop configurations. Three models are presented: (1) an open-loop model using simple spiking neurons from the NEURON model library; (2) an open-loop model using realistic, spiking motoneurons; and (3) a closed-loop central pattern generator with feedback from the physics engine.
A growing number of magnetic resonance imaging (MRI) studies are examining brain changes across pregnancy and early motherhood, gaining fundamental insight into the neural adaptations of motherhood, with critical clinical and policy implications for supporting mother, child, and family unit. As the field takes off, now is the time to take stock of the current literature and neuroscience practices, to ensure that the field is based on studies that are robust, representative, and transparent. Here, we conducted a scoping review to understand the racial and ethnic diversity of participants reported in MRI studies of the maternal brain, guided by the Joanna Briggs Institute methodology. Our findings highlight three key issues in the 185 identified studies of the maternal brain using MRI: (1) the widespread underreporting of participant racial and ethnic data, with only 38.38% of studies reporting race and/or ethnicity demographics; (2) the overrepresentation of white participants, with 46.83% of the samples that report race and/or ethnicity identifying as white/Caucasian; and (3) the disproportionate geographical locations of studies, with 68.65% of studies from North America or Europe and Central Asia. These findings raise concerns about the generalizability of existing research beyond WEIRD (western, educated, industrialized, rich and democratic) populations, and underscore the urgent need for concerted structural change in neuroscience research practices. While identifying a lack of diversity is only the first step, this scoping review serves as a call to action for greater representation in future research, for our own research group as well as others.
Biophysical models of diffusion tailored to characterize gray matter (GM) microstructure are gaining traction in the neuroimaging community. NEXI, SMEX, SANDI, and SANDIX represent recent efforts to incorporate different microstructural features,such as soma contributions and inter-compartment exchange, into the diffusion MRI (dMRI) signal. In this work, we present a comparative evaluation of these four gray matter models on a single, publicly available in vivo human dataset, the Connectome Diffusion Microstructure Dataset (CDMD), acquired with two diffusion times. Using the open-source Gray Matter Swiss Knife toolbox, we estimate cortical microstructure metrics in 26 healthy subjects and evaluate goodness of fit, anatomical patterns and consistency with previous studies. CDMD data yielded GM parameter estimates consistent with values reported in previous studies. This retrospective cross-model analysis establishes the feasibility of estimating exchange models from only two diffusion times and highlights trade-offs in biological specificity, model complexity, and fitting robustness, critical considerations when choosing a model for future clinical and research applications.
In younger adults, newly formed procedural memories are weakened by the subsequent formation of episodic memories (E[->]P interference) and vice versa (P[->]E interference; "cross-memory interference"). Older adults experience significant decline in episodic memory but maintain relatively intact procedural memory. This asymmetric decline in memory may also cause an asymmetric change in cross-memory interference compared to younger adults. For example, older adults may experience a significant increase in one type of cross-memory interference while leaving the other unchanged. Additionally, decline in episodic memory may cause E[->]P interference to either increase or decrease depending on how the episodic and procedural memory systems interact. However, no study to our knowledge has compared cross-memory interference between younger and older adults. We investigated cross-memory interference in younger and older adults by measuring E[->]P (Exp. 1) and P[->]E (Exp. 2) interference in 40 younger (18-40 years old) and 40 older ([≥] 55 years old) adults. Compared to younger adults, the results show that older adults experience significantly stronger E[->]P interference while P[->]E interference was statistically indistinguishable between groups. These results confirm that older adults experience an asymmetric increase in cross-memory interference and suggest that the increase in E[->]P interference is related to the asymmetric decline in episodic memory relative to procedural memory.
Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations. Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have [~]50% of cells expressing either a mutant or wild-type copy of MECP2 (mosaic) and males have 100% of cells expressing a mutant MECP2 (non-mosaic). Typical RTT females have a short window of normal early development until [~]6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males. How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female (Mecp2+/-) and male (Mecp2-/y) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice. We identified a core disease signature consisting of 12 genes consistently dysregulated only in MeCP2-cells across RTT models. Moreover, we uncovered non-cell-autonomous effects exclusively in female MeCP2+ excitatory neurons, but not inhibitory neurons, suggesting excitatory circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed that a previously underappreciated MeCP2-interneuron subtype had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and non-mosaic environment that appear early in RTT pathogenesis.
Monte Carlo diffusion simulations in numerical substrates are valuable for exploring the sensitivity and specificity of the diffusion MRI (dMRI) signal to realistic cell microstructure features. A crucial component of such simulations is the use of numerical phantoms that accurately represent the target tissue, which is in this case, cerebral white matter (WM). This study introduces CATERPillar (Computational Axonal Threading Engine for Realistic Proliferation), a novel method that simulates the mechanic of axonal growth using overlapping spheres as elementary units. CATERPillar facilitates parallel axon development while preventing collisions, offering user control over key structural parameters such as cellular density, tortuosity, beading and myelination. Its uniqueness lies in its ability to generate not only realistic axonal structures but also realistic glial cells, enhancing the biological fidelity of simulations. We showed that our grown substrates feature distributions of key morphological parameters that agree with those from histological studies. The structural realism of the astrocytic components was quantitatively validated using Sholl analysis. Furthermore, the time-dependent diffusion in the extra- and intra-axonal compartments accurately reflected expected characteristics of short-range disorder, as predicted by theoretical models. CATERPillar is open source and can be used to (a) develop new acquisition schemes that sensitise the MRI signal to unique tissue microstructure features, (b) test the accuracy of a broad range of analytical models, and (c) build a set of substrates to train machine learning models on. 1 HighlightsO_LICATERPillar generates realistic axons and glial cells that may co-exist within numerical substrates. C_LIO_LISynthetic axons had similar morphologies to those segmented from human electron microscopy in previous works. C_LIO_LIThe morphological features of synthetic astrocytes closely matched those observed in rodent histology. C_LIO_LIThe functional form of diffusion time-dependence in the intra- and extra-axonal spaces agreed with experimentally observed disorder power laws in voxels composed of synthetic axons. C_LI
The mechanical stiffness of brain parenchyma varies across physiological states and pathophysiological conditions, such as during normal and abnormal development, in degenerative diseases and disorders, like Alzheimers disease and traumatic brain injury (TBI), neuronal activation, and sleep via the glymphatic brain waste clearance mechanism. Despite its biological and clinical importance, relatively few techniques exist to measure and map mechanical properties of brain tissue non-invasively and in vivo. MR elastography (MRE) is an established method that has been widely used to estimate tissue stiffness in the liver by applying mechanical waves using an external tamper and measuring their resulting deformations. However, applying MRE in the brain is more challenging due to the skull and cerebrospinal fluid (CSF), which impede mechanical wave propagation, and tissue mechanical anisotropy, which requires a 4th-order tensor description. In this study, we propose using the intrinsic deformation of brain tissue caused by periodic cardiac pulsation to measure the 4th-order stiffness tensor throughout the brain while simultaneously estimating the 2nd-order diffusion tensor in each voxel throughout the cardiac cycle, which we use as a priori information in the reconstruction of the stiffness tensor. While the DTI-derived mean diffusivity (MD) appears uniform throughout brain parenchyma, stiffness maps obtained at about 1 Hz (i.e., at the fundamental cardiac frequency) show contrast within gray matter, and within white matter pathways such as along the corpus callosum, internal capsule, corona radiata, etc. Generally, stiffness differences at internal tissue boundaries are expected to lead to local stress concentration, which may predispose tissues to damage in TBI. Therefore, our novel tamperless MRE method has the potential to not only identify such interfaces, but assess changes in tissue stiffness there that might occur following injury.
Machine learning algorithms are affording new opportunities for building bio-inspired and data-driven models characterizing neural activity. Critical to understanding decision making and behavior is quantifying the relationship between the activity of neuronal population codes and individual neurons. We leverage a SHallow REcurrent Decoding (SHRED) architecture for mapping the dynamics of population codes to individual neurons and other proxy measures of neural activity and behavior. SHRED is a robust and flexible sensing strategy which allows for decoding the diversity of neural measurements with only a few sensor measurements. Thus estimates of whole brain activity, behavior and individual neurons can be constructed with only a few neural time-series recordings. This opens up the potential for using non-invasive, or minimally invasive, measurements for estimating difficult to achieve, or invasive, large scale brain and neural recordings. SHRED is constructed from a temporal sequence model, which encodes the temporal dynamics of limited sensor data in multiple scenarios, and a shallow decoder, which reconstructs the corresponding high-dimensional neuronal and/or behavioral states. We demonstrate the capabilities of the method on a number of model organisms including C. elegans, mouse, zebrafish, and human biolocomotion.
Meditation encompasses diverse practices that train attention inward, in contrast to externally oriented task states. However, the neurodynamic features distinguishing meditative states from non-meditative states across traditions remain unclear. We analyzed high-density EEG data (N=170; 121 advanced meditators, 49 controls) across four traditions: Vipassana, Brahma Kumaris Raja Yoga, Heartfulness, and Isha Yoga. EEG features spanned oscillatory, aperiodic, nonlinear, and timescale components. Using random forest classifiers, we distinguished meditative from non-meditative states with robust classification performance (91%). Nonlinear features contributed the most, suggesting a core neurodynamic profile. Classification performance was higher in advanced meditators (92%) than in controls (85%), with distinct feature importance: nonlinear and aperiodic features dominated in meditators, and oscillatory and timescale features in controls. Each tradition showed distinct neurodynamic profiles, indicating technique-specific constellations. Our findings revealed shared yet distinct neurodynamic signatures across meditation techniques, suggesting that multiple neurodynamic pathways lead to meditative states.
Introduction: Canine Cognitive Dysfunction (CCD) is an increasingly prevalent naturally occurring neurodegenerative condition in senescent dogs that share neuropathological and clinical features with human Alzheimers disease (AD). Metabolic profiling allows for identification of new candidates for AD biomarkers, diagnostics, and therapeutics. Despite its translational potential, plasma metabolomic profiling of dogs with CDD has not been previously characterized. Methods: This case control study analyzed plasma samples from ten client owned geriatric dogs, including five with severe CCD and five age matched, clinically healthy controls. Untargeted plasma metabolomics was performed using ultra-performance liquid chromatography mass spectrometry (UPLC-MS). Multivariate and univariate statistical analyses identified significant metabolic differences between the groups. Metabolites were considered significant based on a variable importance in projection (VIP) score > 1.5, fold change (FC) > 2.0, and adjusted p-value < 0.05. Results: Fifteen metabolites across seven chemical classes were significantly altered in CCD dogs compared to controls, including glycerophospholipids, steroid derivatives, indoles, and mitochondrial-related compounds. Notably, elevated lysophosphatidic acid (LPA 20:2/0:0) and reduced ubiquinone-2 levels suggest dysregulation in neuroinflammatory and oxidative stress pathways. Cholesterol exhibited the highest FC and VIP scores, further reinforcing its role in AD pathogenesis. Hierarchical clustering and pathway enrichment analyses supported distinct metabolic signatures in CCD that mirror those observed in human AD. Discussion: This is the first untargeted plasma metabolomic profiling of dogs with CCD, revealing systemic metabolic disturbances that align with AD pathophysiology. Data was collected from senescent community-dwelling companion dogs, which enhances the studys ecological and translational relevance. It supports the utility of CCD as an AD model and highlight candidate plasma biomarkers that warrant further investigation. Future longitudinal studies integrating metabolomics with neuroimaging, histopathology, and behavioral assessments are required to validate these findings and contribute to AD biomarker discovery and therapeutic development
Humans rapidly update the control of an ongoing movement following changes in contextual parameters. This involves adjusting the controller to exploit redundancy in the movement goal, such as when reaching for a narrow or wide target, and adapting to dynamic changes such as velocity-dependent force fields (FFs). Although flexible control and motor adaptation are computationally distinct, the fact that both unfold within the same movement suggests they may share common neural resources for task-specific adjustments. To test this hypothesis, we conducted a series of experiments combining changes in the target structure and a force field presented separately or in combination. Seventy-six human participants (both sexes) took part in this study, with each experiment involving different participants. They were asked to reach for a target that could change from a narrow square to a wide rectangle between or during trials. Step loads were used to assess whether participants exploited target redundancy. In a separate experiment, we added a force field in addition to target changes and step loads. Our results revealed a reduced ability to exploit target redundancy when sudden target changes occurred concurrently with FF adaptation. Furthermore, the magnitude of adaptation was reduced when step loads were added to the FF. Crucially, this interference emerged specifically when all perturbations impacted motor execution simultaneously. These results indicate that flexible control and motor adaptation interact in a non-trivial manner, suggesting possible overlap between their underlying neural mechanisms, and a clear identification of the timescale at which they are engaged - namely, during movement. Significant statementHumans rapidly adapt to changes in task demands, such as target structure changes or exposure to force fields (FFs). These two types of adjustments occur within a single movement, suggesting potential interactions between them. Our experiments revealed that the combination of FF exposure with online target shape changes selectively reduced participants ability to exploit target redundancy, while the combination of FF and step loads led to a reduced extent of motor adaptation. These findings confirm that motor adaptation occurs not only between trials but also during movement. The selective nature of the observed interference highlights an interplay between flexible control and motor adaptation, underscoring the importance of understanding the timing of these processes to better characterise their underlying neural circuits.
NLRP3 plays an essential role in secondary neuroinflammatory damage following traumatic brain injury (TBI). However, the specific mechanisms mediating NLRP3s effects in TBI remain poorly understood, and it is unknown whether its pharmacological inhibition with oral compounds during initial phases confers long-term protection. In this study, we investigated the role of the NLRP3 inflammasome pathway in TBI-induced neuroinflammation and long-term neurobehavioral impairment, as well as the impact of its pharmacological inhibition. Following controlled cortical impact (CCI), most NLRP3 inflammasome-related proteins and key inflammatory markers were elevated during the first week post-injury. Genetic Nlrp3 deletion and treatment with oral NLRP3-specific inhibitors preserved microglial homeostatic architecture, reduced ASC aggregation, and enhanced neurological and cognitive recovery after CCI. Repeated intravital imaging confirmed that NLRP3 inhibition prevents microglial activation post-TBI. These findings suggest NLRP3 inflammasome targeting represents a viable translational strategy for clinical trials and may mitigate long-term neurocognitive decline following TBI.
Memory-related transcriptional events in brain remain poorly understood. Visual imprinting is a form of learning in which young animals develop preferences through early exposure to specific stimuli. In chicks, visual imprinting memory is stored in the intermediate medial mesopallium (IMM) of the forebrain. To investigate learning-associated molecular changes, we performed single-nucleus RNA sequencing of the left IMM in strongly imprinted chicks and untrained controls. This analysis identified over 30 cell clusters with distinct transcriptional differences putatively linked to memory formation, nearly half of them in long non-coding RNAs (lncRNAs). Expression levels of two lncRNAs and four protein-coding genes FOXP2, RORA, LUC7L, and ROBO1 correlate with memory strength, reflecting either innate learning potential or imprinting experience. Notably, the brain- and avian-specific lncRNA ENSGALG00010007489 is enriched in the nuclei of specific glutamatergic clusters. These findings offer the first single-cell resolution map of transcriptional changes underlying memory formation in the avian brain.
While early life sets the stage for later learning, comparatively less is known about newborns cognition than that of older infants. A striking example is the lack of consensus regarding the extent to which newborns spontaneously mimic gestures, and whether such behavior drives bonding and learning. Despite the theoretical importance of these questions, practical challenges limit researchers ability to engage newborns in behavioral research. Webcam-based, asynchronous online studies have expanded developmental sciences capacity to reach older infants. However, such scalable and replicable methods have yet to be deployed with younger infants. Taking a commonly-used neonatal mimicry paradigm as a test case, we assessed the feasibility of leveraging an open-source online platform (Children Helping Science) for asynchronous research with 0-6-week-olds and their caregivers. Caregivers modeled face movements to their 4-45 days-old infants (N = 29, N = 17 included) while webcams filmed their infants responses; 13 dyads participated more than once (72 included test videos). There was preliminary, moderate evidence against group-level neonatal mimicry of caregivers tongue protrusions (Bayes Factor [~] [1/3]), and inconclusive evidence for or against mimicry of caregivers mouth openings ([1/3] < BF < 3). Simulations identified a target sample size for more conclusive evidence. Finally, we asked whether caregivers perceived their newborns behavior as imitative. Caregivers perceptions of mimicry reflected infants behaviors but did not align with an often-used metric of mimicry ("imitators"). These results demonstrate the feasibility of asynchronous online behavioral studies with newborns and provide a foundation for future research on neonatal mimicry of caregivers.x1
While simulating compartmental dynamics in response to various input patterns is the prevalent technique for understanding dendritic computation, a great deal can be learned from classical analytical methods that provide solutions for the dendritic voltage. For example, such solutions are needed to simplify spatially extended neuron models, to understand frequency-dependent response properties, to elucidate the interaction between synaptic inputs, and hence to reveal the effective compartmentalization of dendrites into functional subunits. Nevertheless, these methods have not been implemented in modern software tools. This works describes the NEural Analysis Toolkit (NEAT), a Python toolbox that implements classical algorithms to compute response properties of spatially extended neuron models, and that leverages these algorithms to simplify them. Packaged with this are a range of useful utilities to plot morphologies and spatial quantities defined on the morphology, to distribute locations on the morphology, and to select parts of the morphology to e.g. apply morphological ablations or alter the membrane properties. The resulting models can be exported to NEURON and NEST, two commonly used simulators, the former focused on detailed single neuron model simulations, and the latter geared towards distributed network simulations. As a consequence, this toolbox provides a missing link between single neuron computation and large-scale network analysis, substantially facilitating the study of the role of dendritic computation in shaping emergent network dynamics. NEAT is available through pip under the name nest-neat, or from its source code (https://github.com/nest/NEAT), which is provided under the GNU General Public License. Furthermore, support for NEAT is provided on its GitHub page and through the NEST user mailing list (users@nest-simulator.org).
Extant research has implicated functional connectivity of the subgenual anterior cingulate cortex (sgACC) in major depressive disorders or depressive traits in neurotypical populations. However, prior studies have not distinguished the inputs and outputs of the sgACC, and the diagnostic accuracy of these connectivity metrics remains elusive. Here, we analyzed data of 890 subjects (459 women, age 22 to 35) from the Human Connectome Project using Granger causality analyses (GCA) with the sgACC as the seed and 268 regions of interest from the Shen atlas as targets. Individual connectivities were assessed with an F test and group results were evaluated with a binomial test, both at a corrected threshold. We identified brain regions with significant input to and output from the sgACC. Clustering analyses of Granger causality input, but not Granger causality output or resting state connectivity features revealed distinct subject clusters, effectively distinguishing individuals with severe and mild depressive symptoms and those with comorbidities. Specifically, weaker projections from the fronto-parietal and orbitofrontal cortices, anterior insula, temporal cortices, and cerebellum to the sgACC characterized five clusters with low to high scores of depression as well as comorbid internalizing and externalizing problems. Machine learning using a logistic classifier with the significant GCA-in features and 5-fold cross-validation achieved 87% accuracy in distinguishing subject clusters, including those with high vs. low depression. These new findings specify the functional inputs and outputs of the sgACC and highlight an outsized role of sgACC inputs in distinguishing individuals with depressive and comorbid problems.
Cognitive control is believed to arise from interactions among multiple brain networks depending on task demands. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Because the claustrum possesses widespread connections with cortex and can synchronize distant cortical regions, we tested whether the claustrum activates task-dependent network states using fMRI during working memory (n = 420) and autobiographical memory (n = 35), tasks which elicit opposing responses from key cognitive control networks. In both tasks, the claustrum exhibited increased activity and excitatory influence on task-associated cognitive control network nodes, with corroborating underlying structural connectivity. The claustrum also displayed stronger excitatory effective connectivity during task performance and greater structural connectivity with task-related network nodes than regions prominently implicated in directing network states - the anterior insula and pulvinar. These findings establish a role for the claustrum in initiating network states for cognitive control.
For maximizing survival, animals must accurately memorize the structure of their environment. This is achieved by stabilizing and enriching hippocampal place cells near salient features, while the representation of neutral locations incrementally drifts with time. However, the circuit mechanisms by which top-down and bottom-up inputs selectively embed saliency into the hippocampal spatial map remain poorly understood. Here we identified a specific top-down input from the anterior cingulate cortex (ACC) to the dysgranular zone of the retrosplenial cortex (RSCd) that becomes active exclusively at reward locations. Activity of these ACC neurons is both necessary and sufficient for shaping the hippocampal saliency map. Unlike dopaminergic neurons in the ventral tegmental area, which respond to reward irrespective of the context, this class of ACC neurons encodes reward-context associations. Their optogenetic activation induces a reduction in locomotor speed, a behavioral correlate of saliency detection, while their inhibition disrupts the formation of the hippocampal place map. This work not only provides the first mechanistic insight into how context-dependent saliency is integrated in a top-down fashion into the hippocampal map to guide adaptive behavior but also challenges the classical view of memory consolidation theory where memory unidirectionally moves in bottom-up fashion from the hippocampus to the neocortex.
Sensory inputs are progressively transformed into internal representations of the environment along the cortical hierarchy. How does the behavioral relevance of these inputs affect this encoding? Using two-photon calcium imaging in mice navigating virtual-reality environments, we found that visual cortex maintained high sensory discrimination regardless of behavioural engagement, whereas the hippocampal dentate gyrus required active navigation for effective discrimination. These findings suggest that sensory cortices act as general-purpose sensory discriminators, while the hippocampus filters information based on task relevance.
The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptomically-defined identity programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naive neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.
Auditory cortex connectivity extends beyond the processing of acoustic stimuli, playing a crucial role in cognitive and emotional regulation through its interactions with higher-order brain regions. Although the neural mechanisms underlying acoustic information processing along the auditory pathway are well-documented, the connections supporting auditory-related cognitive and emotional processing, particularly in comparative studies between mice and human adults, are not yet fully clarified. In this study, we aim to investigate connections between the auditory cortex and brain regions involved in cognitive and emotional processing using retrograde fluoro-gold (FG) tracer in mice and 3-tesla high-resolution diffusion tensor tractography (DTI) in human adults. The FG injections into the primary (AI)/ secondary (AII) auditory cortices showed afferent connections with cortical (olfactory bulb, piriform, orbitofrontal, cingulate, motor, primary somatosensory, insular, visual, parietal, entorhinal and perirhinal cortices), subcortical (amygdala, hippocampus, globus pallidus, claustrum, bed nucleus of stria terminalis, diagonal band of the Broca and medial septal nucleus) and brainstem (raphe nuclei, pedunculopontine nucleus and locus coeruleus) structures. The DTI data obtained from human adults mostly corresponded with the experimental findings. Auditory cortical processing integrates auditory signals with other sensory, limbic and motor inputs. The connections collectively may suggest its role in cognitive and emotional functions. The auditory cortex is likely a critical hub within the neural circuitry underlying multisensory integration, decision-making, prediction, learning and memory functions. Understanding the connectivity of the auditory cortex can deepen our insight into its contribution to cognitive/emotional functions, offering new perspectives on the underlying mechanism linking hearing deficits with cognitive/emotional disorders.
The two main cell types in the striatum, dopamine receptor 1 and adenosine receptor 2a spiny projection neurons (D1-SPNs and A2A-SPNs), have distinct roles in regulating motor- and reward-related behaviors. Cre-selective CRISPR-dCas9 systems allow for cell-type specific, epigenomic-based manipulation of gene expression with gene-specific single guide RNAs (sgRNAs) and have potential to elucidate molecular mechanisms underlying striatal subtype mediated behaviors. Conditional transgenic Rosa26:LSL-dCas9-p300 mice were recently generated to allow for robust expression of dCas9-p300 expression with Cre-driven cell-type specificity. This system utilizes p300, a histone acetyltransferase which regulates gene expression by unwinding chromatin and making that region of the genome more accessible for transcription. Rosa26-LSL-dCas9-p300 mice were paired with Drd1-Cre and Ador2a-Cre mice to generate Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 mouse lines and underwent behavioral phenotyping when sgRNAs were not present. Both Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 have cell-type specific expression of spCas9 mRNA. Baseline behavioral assessments revealed that, under a sgRNA absent nontargeted state, Drd1-Cre:dCas9-p300 mice display repetitive spinning behavior, hyperlocomotion and enhanced acquisition of reward learning in comparison to all genotypic littermates. In contrast, Ador2a-Cre:dCas9-p300 do not exhibit any changes in behavior in comparison to their littermates. Electrophysiological recordings of dorsal striatum D1-SPNs revealed that Drd1-Cre:dCas9-p300 mice have increased input resistance and increased spontaneous excitatory postsynaptic current amplitude, together suggesting greater excitatory drive of D1-SPNs. Overall, these data demonstrate the necessity to validate CRISPR-dCas9 lines for research investigations. Additionally, the Drd1-Cre:dCas9-p300 line has the potential to be used to study underlying mechanisms of stereotypy and reward-learning.
Synaptic dysfunction resulting from pathogenic variants in genes encoding synaptic proteins is a major contributor to brain and behavioural disorders, collectively termed synaptopathies. To facilitate research into the genetic basis and clinical manifestations of synaptopathy we have created SynaptopathyDB, an online resource that integrates data from 64 mammalian synapse proteomic studies and multiple genetic and phenotypic resources. We identified a consensus set of 3,437 mammalian synapse proteins from presynaptic and postsynaptic compartments, which have wide application in genetic and omic studies. Mutations in 954 genes encoding 28% of the consensus synapse proteome were associated with 1,266 OMIM diseases of the central and peripheral nervous system. We present findings that underscore the pervasive role of synaptic gene variants in the phenotypes of neurological, psychiatric, developmental, and systemic disorders highlighting the significant burden they impose on individuals and healthcare systems. SynaptopathyDB is a versatile platform and discovery tool for understanding the role of synapse proteins and genetic variants in human disease phenotypes.
Understanding how emotional and general vocabulary develop across the lifespan offers key insights into cognitive and socioemotional processes. While emotional vocabulary is foundational for emotion regulation and social interaction, general vocabulary underpins broader cognitive functions such as reasoning and reading comprehension. In this study, we modeled the growth trajectories of emotional and general vocabulary using Gompertz functions in a large cross-sectional sample (N = 820; age range = 12 - 84 years). To control for item difficulty, we selected a subset of vocabulary items with similar and low difficulty in adulthood. Both vocabulary types showed non-linear growth patterns, with emotional vocabulary exhibiting earlier and faster development, reaching near-asymptotic levels by early adulthood. General vocabulary showed a more gradual increase and later inflection point. A joint nonlinear mixed-effects model confirmed significant differences in developmental timing, with emotional vocabulary peaking approximately four years earlier than general vocabulary. These findings support theoretical models emphasizing the early emergence and adaptive relevance of emotional concepts and highlight adolescence as a sensitive period for emotional vocabulary acquisition. The Gompertz model proved effective in capturing asymmetric vocabulary growth, providing interpretable parameters aligned with developmental theory. Implications for education and emotional development interventions are discussed.
A ventral tectal longitudinal column (TLCv) has been described in rats and is hypothesized to provide multisensory modulation of acoustic processing in the superior olivary complex (Saldana et al., 2007, J Neurosci 27, 13108-16). The TLCv is a column of cells in the dorsomedial tectum extending rostro-caudally through the inferior and superior colliculi. It receives ascending auditory input and projects to the superior olivary complex. Further insight into TLCv function has been hampered by limited information on its connections. Here, we provide evidence that a TLCv is recognizable in mice and that it has more extensive connections than previously believed. Deposit of retrograde tracer into the superior olivary complex labels cells bilaterally in the TLCv, comparable to results seen in rats. Viral labeling of neuronal projections demonstrate input to the TLCv from the superior olivary complex and from the inferior colliculus. Thus, the TLCv in mice has inputs and outputs similar to those described in rats. Additional experiments with retrograde tracers revealed more extensive outputs from the TLCv. Neurons in the TLCv are labeled after deposit of retrograde tracers into the cochlear nucleus or into the inferior colliculus. The projections from the TLCv to these targets, like those to the superior olivary complex, are bilateral. These projections are much broader than those described previously. The results suggest that the TLCv could exert modulation over a wide expanse of the auditory brainstem, from the cochlear nucleus through the inferior colliculus.
Peripheral nociceptive sensory neurons integrate various noxious inputs, resulting in local depolarization that triggers the firing of action potentials and thus the sensation of pain. We recently reported that nociceptor depolarization itself initiates signaling by the calcium channel CaV1.2 causing acute hyperalgesia in vivo. However, whether this mechanism initiates excitation-transcription (E-T) coupling and thereby leads to long-lasting modulation of nociceptor activity remains poorly understood. Using high content imaging of dorsal root ganglion (DRG) neurons, we here found that depolarization of nociceptors induces phosphorylation of the transcription factor (TF) cAMP-response element binding protein (CREB), which was affected by inhibition of protein kinase A (PKA) and calcineurin, but not Ca2+/calmodulin-dependent protein kinases. Genetic deletion or pharmacological inhibition of CaV1.2 confirmed its role in calcium-dependent kinase signaling and CREB phosphorylation after depolarization. In line with this, pharmacological modulation of CaV1 channels affected the expression of a subset of depolarization-regulated immediate early genes known to orchestrate a broader transcriptional response. Indeed, RNA-Seq analysis of DRG neurons from mice with a tissue-specific deletion of CaV1.2 in nociceptive sensory neurons (SNS-Cacna1c-/- mice) revealed downregulation of multiple calcium and potassium channel subunits as well as proteins involved in synaptic vesicle release and cell adhesion. Furthermore, repetitive firing of action potentials and release of the neuropeptide CGRP was impaired in CaV1.2-deficient sensory neurons. SNS-Cacna1c-/- mice showed increased sensitivity to noxious heat and exacerbated inflammatory but not neuropathic pain. In conclusion, our data suggest a CaV1.2-dependent E-T coupling mechanism in nociceptors that counteracts nociception in vivo.
Internal bodily signals, notably the heartbeat, influence our perception of the external world - but the nature of this influence remains unclear. One line of evidence (Competition) indicates that interoceptive and exteroceptive inputs compete for neural resources. Another line (Self-related Facilitation) shows a link between interoceptive and self-related processing, that might also include computing the self-relevance of exteroceptive inputs. We tested these seemingly opposing views within a single experimental task. Measuring heartbeat-evoked potentials (HEPs, a measure of cardiac interoception) with EEG, we manipulated the self-relevance of an audio-tactile stimulus by placing the audio source either inside or outside the peripersonal space immediately around the body. This design ensured that Competition and Self-related Facilitation accounts yielded contrasting predictions. On the one hand, pre-stimulus HEP amplitudes over somatosensory cortex were linked to slower reaction times, and affected audio-tactile stimulus-evoked responses in the same area, indicating competition for shared neural resources. On the other hand, pre-stimulus HEPs over integrative sensorimotor and default-mode network regions facilitated subsequent self-relevance encoding, both in reaction times and audio-tactile stimulus evoked responses. Importantly, Competition and Facilitation effects were spatially and statistically independent from each other. We thereby reconcile the two views by showing the co-existence of two independent mechanisms: one that allocates neural resources to either internal bodily signals or the external world, and another by which interoception and exteroception are combined to determine the self-relevance of external signals. Our results highlight the multi-dimensionality of HEPs as neurophysiological markers, and thus of internal states more generally.
Theory of Mind (ToM) refers to the capacity to infer others' latent mental states, such as intentions, beliefs, and strategies, and use these inferences to predict behavior. A defining characteristic of ToM is its recursive nature: individuals reason not only about what others are thinking, but also about what others think about them. Most computational models of ToM adopt a hierarchical structure in which Level-0 (L0) agents are assumed to follow simple, fixed heuristics (e.g., Win-Stay-Lose-Shift, WSLS) without mentalizing. However, this assumption overlooks the diversity of non-mentalizing strategies exhibited in human behavior, such as imitation or tit-for-tat, which do not conform to WSLS yet require no recursive reasoning. To address this limitation, we introduce a novel ToM framework (BELIEFS) that flexibly infers latent L0 strategies from behavior rather than relying on predefined heuristics. We evaluated the model in four classic dyadic games: Matching Pennies, Prisoner's Dilemma, Bach or Stravinsky, and Stag Hunt, manipulating model's learning rates and the volatility of L0 strategy switching. Predictive accuracy was assessed using cumulative negative log-likelihood (NLL) of opponent's next choice and compared against both a ToM model that assumes only WSLS at L0 and chance-level performance. Our model outperformed both baselines, particularly under low-volatility conditions and at intermediate learning rate. Moreover, to evaluate strategy inference, we computed trial-wise confusion matrices and Cohen's k; between inferred and true L0 strategies, reaching significantly above-chance classification. We further tested the model's ability to distinguish between action sequences generated by the opponent's true Theory of Mind (ToM) level (L0 vs. L1) and those generated using an incorrect ToM level. The model assigned lower negative log-likelihoods (NLLs) to sequences from the true level, suggesting an indirect method for identifying the opponent's actual ToM level. Finally, we assessed whether the model effectively tracks behaviorally distinguishable action probabilities across ToM levels. Using Fisher-transformed correlations between model-generated action probabilities at L0, L1, and L2, we found significant dissimilarities, especially in competitive games. In summary, our model introduces a flexible, probabilistic approach to Theory of Mind that captures both surface-level strategy use and recursive reasoning depth. By jointly tracking dynamic beliefs over L0 strategies and ToM levels, the model adapts to behavioral shifts and outperforms static heuristics. These advances provide a powerful framework for modeling human behavior in interactive contexts, with implications for both human-human and human-machine interaction research.
The triceps surae, composed of the soleus (SOL) and medial (MG) and lateral (LG) gastrocnemii, are anatomically-derived synergists which act as a functional unit to plantarflex the ankle. However, anatomical differences suggest that each muscle is capable of generating distinct torques at the ankle, raising the possibility that each can be independently controlled to suit the needs of a given task. This possibility was explored by investigating the activation patterns of the triceps surae during two balance tasks that use different neuromechanical control strategies to maintain equilibrium. High-density surface EMG was recorded from the triceps surae of 14 healthy young adults during multiple trials of dual- and single-legged standing. Newly developed analyses examined how each muscle tuned its activity with center of pressure (COP) movement throughout 2-D space. During dual-legged standing, only the SOL and MG were active and both tuned their activity uniformly with anteroposterior COP movement. By contrast, during single-legged standing, each muscle showed robust activation and significantly different directional tuning, with the LG most active before medial COP movement, while SOL and MG were most active before lateral COP movement. Further analyses demonstrated the LG could be activated entirely independent of the SOL and MG, and vice versa, with independent activation of each muscle causing different angular deflections of the COP during single-, but not dual-legged standing. These observations reveal a sophisticated level of neural control, whereby the nervous system exploits subtle differences between highly similar muscles to tune balance corrective adjustments in a task-dependent manner.
Neuropeptides are a highly conserved and diverse class of intercellular signaling molecules that regulate a broad range of neural and hormonal processes across animal phyla. The American lobster, Homarus americanus, has long served as a powerful invertebrate model for the discovery and functional investigation of neuropeptides. Among common post-translational modifications (PTMs) found in neuropeptides, glycosylation remains underexplored due to the inherently low in vivo abundance and intrinsically complex structural heterogeneity. In this study, we employed hydrophilic interaction liquid chromatography (HILIC) enrichment coupled with oxonium-ion triggered EThcD fragmentation strategy to simultaneously profile novel endogenous and glycosylated neuropeptides across eight distinct neural tissues and neuroendocrine organs of Homarus americanus. This integrative mass spectrometry-based approach led to the identification of 154 endogenous neuropeptides derived from 25 families, approximately one-third of which are newly reported, and uncovered 28 O-linked glycosylated neuropeptides in this species for the first time. These peptides exhibit strong tissue-specific expression, distinct proteolytic cleavage patterns, and confidently localized glycosylation sites. Our results highlight the utility of integrated sampling enrichment and hybrid fragmentation strategies for deep neuropeptidomic profiling and provide a valuable resource for future studies on the functional roles of newly identified neuropeptides and glycosylation in crustacean neuromodulation and peptidergic signaling.
Septic encephalopathy (SE) is a devastating complication of sepsis, marked by neuroinflammation and metabolic dysfunction, with the cerebellum being among the most affected brain regions. Progress in the field has been hindered by: (1) the incomplete characterization of cerebellar metabolic disruption in SE, (2) the limited understanding of the therapeutic mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) treatments in SE, and (3) the absence of reliable biomarkers for detecting SE. To address these gaps, we employed a murine sepsis model and performed metabolomic analyses of cerebellar tissue and plasma with and without MSC-sEV treatment. Sepsis induced profound cerebellar metabolic dysfunction, suppression of oxidative energy metabolism, and redox imbalance. MSC-sEVs mitigated these effects through their cargo, restoring cellular energetics and rebalancing antioxidant pathways. Cross-compartment analyses identified six plasma metabolites with strong diagnostic potential. These findings define key cerebellar metabolic mechanisms of SE and MSC-sEV treatment and propose plasma biomarkers for SE diagnostics.
Our fMRI study investigates dependencies between brain areas during resting and working memory states using directed spillover indices estimated from vector autoregressive models that recognize dynamics in the network. A dorsolateral prefrontal centered system (DLPFC) demonstrates spillover memory capacity at rest, labeled resting memory, which facilitates self-referential thinking. Resting memory contains roughly 9 times more neurocognitive dependencies (spillover) as the difference in spillover between working and resting brains, suggesting that resting brains are highly active. The transitioning from resting memory to working memory is initiated by a right inferior fontal (IFG) centered system which connects to the DLPFC centered system when relevant information is detected in the outside world and also inhibits self-referential feedback in parietal cortices. Spillover between the IFG and DLPFC centered systems facilitate a smooth transition in attention from events that take place outside the brain to (sustained) representations of external events within the brain.
The global spread and increasing populations of disease vector mosquitoes expose hundreds of millions of people to mosquito-borne illnesses each year. Female Aedes aegypti mosquitoes, global vectors of dengue, require protein from host blood to support egg development and undergo repeated cycles of blood-feeding and egg-laying. After biting, females temporarily alter their behavioral state and suppress host-seeking while using blood-derived nutrients to develop eggs. Host-seeking suppression ends once eggs are laid. While this period has generally been thought of as one of behavioral inactivity, we reveal that it instead reflects behavioral reprogramming, during which females transition from post-blood-meal inactivity into active searching for egg-laying sites. Females with mature eggs show a distinct behavioral state characterized by increased locomotor activity and a shift in circadian behavioral timing, leading to nocturnal humidity-seeking and egg-laying in an otherwise diurnal species. We show that the circadian clock gene cycle is critical for regulating this transition; its absence disrupts the timing of oviposition behaviors, leading to poor site selection and reduced predicted offspring survival. These findings suggest that during egg development, circadian clock-dependent behavioral reprogramming triggers nocturnal hyperactivity and oviposition site search, an essential process for mosquito reproduction and population viability.
Astrocytes adapt to injury and disease by entering a reactive state defined by transcriptomic, morphological, and functional changes. Using a combination of human cortical organoids (hCOs) and primary fetal brain tissue, we investigated the plasticity of human astrocyte reactivity. We observed robust inflammatory transcriptomic and chromatin signatures following cytokine exposure, which varied with duration. To assess reversibility, we withdrew cytokines after acute or chronic exposure. In both cases, astrocytes returned to a quiescent genomic state within days. Chronic exposure induced MHC class II gene ex-pression, normally restricted to professional antigen-presenting cells. We validated MHCII protein in primary tissue and hCOs and used co-immunoprecipitation and mass spectrometry to identify candidate antigens. Finally, we showed that exogenous peptides from fetal neurons could be presented by astrocytic MHCII.
Our brains dynamically adapt to a multisensory world by orchestrating diverse inputs across sensory streams. This process engages multiple brain regions, but it remains unclear how audiovisual stimuli are represented and evolve over time, especially in naturalistic scenarios. Here, we employed movie-watching to explore this question. We recorded intracranial electrocorticography (iEEG) to measure brain activity in 19 participants watching a short multilingual movie. Using unsupervised clustering and supervised encoding models, we identified a robust modality-specific gradient in the frontal cortex, wherein the ventral division primarily processes auditory information and the dorsal division processes visual inputs. Further, we found that this cortical organization dynamically changed, adapting to different movie contexts. This result potentially reflects flexible audiovisual-resource assignment to construct a coherent percept of the movie. Leveraging behavioral ratings, we found that the frontal cortex is the primary site in this modality assignment process. Together, our findings shed new light on the functional architecture of the frontal cortex underlying flexible multisensory representation and integration in natural contexts.
Contingent learning, the process by which specific courses of action become associated with subsequent outcomes, is dependent on the amygdala and ventrolateral prefrontal cortex (vlPFC). The amygdala and vlPFC are bidirectionally connected but it is unclear what the contribution of individual feedforward and feedback pathways is to contingent learning. Here we tested the role of amygdala projections to vlPFC in mediating two key components of contingent learning: signaling the outcome (reward/no reward) that follows a choice and maintaining representation of the choice that was made prior to outcome delivery. To test for these two aspects of contingent learning, we trained macaques to perform a probabilistic reward learning task where for separate stimulus pairs reward was either delivered immediately or after a trace interval. Inhibiting vlPFC-projecting amygdala neurons impacted contingent learning irrespective of whether there was a trace interval or not, and this effect was primarily driven by maladaptive learning on unrewarded trials. Notably, deficits in contingent learning caused by manipulating activity in the amygdala-vlPFC pathway were distinct from impairments in motivation and the ability to update the value of specific rewards in a reinforcer devaluation task. Thus, vlPFC-projecting amygdala neurons appear to play a specific role in contingent learning through signaling the outcomes of a choice, but not in maintaining a memory of the prior choice.
During typical development, non social visual object recognition emerges in the first year of life, engaging both low level cues (e.g., color, orientation) and higher level mechanisms involving inference and prior knowledge. Little is known about how these processes function in minimally verbal children with autism (mvASD). We studied 22 children with mvASD using touchscreen based oddball and contour detection tasks, targeting low level (e.g., shape, orientation) and mid level (e.g., Kanizsa figures, 3D shapes) visual stimuli, measuring both pointing and eye gaze responses. All children detected the oddball in the easiest condition with faint distractors, and approximately half succeeded across all low level tasks. Notably, some high performers showed reduced accuracy under mid level conditions with greater stimulus complexity. Strikingly, and not originally anticipated, several low performers who failed to point correctly nonetheless fixated on the correct target. In the Kanizsa oddball task, several mvASD participants, unlike typically developing (TD) peers, consistently pointed to local inducers rather than to the center of the illusory triangle. While the overall deterioration in performance with increased visual complexity suggests that mvASD visual perception may rely on low level representations with attenuated inference based processing, the dissociation between gaze and pointing, along with atypical local pointing behavior, indicates that performance depends not only on what is perceived, but also on how they use the visual signal to drive their behavior. They may, see the point, but not point to what they see.
Alzheimer's Disease (AD) disrupts neural circuits vital for memory and cognition. We used two-photon microscopy to investigate these disruptions in behaving mice, focusing on the link between amyloid plaques - a hallmark of AD - and aberrant neural activity. Using the 5xFAD mouse model, we observed significant changes in hippocampal neurons, including elevated baseline activity and reduced locomotion-driven firing, leading to a diminished neuronal dynamic range. These abnormalities were more pronounced near amyloid plaques. We also found degraded spatial coding, reduced synchrony, and increased variability in neuronal responses. Furthermore, place fields emerged more slowly in both familiar and novel environments, indicative of recall and learning impairments respectively. By showing a specific link between plaque vicinity and neural coding deficits including reduced dynamic range in mice performing spatial tasks, our study offers new insights into the circuit basis of progressive cognitive degradation in AD.
In both vertebrates and invertebrates, the developing brain becomes electrically active before it is ready to process sensory input. During neural circuit maturation, developmental activity is thought to refine synaptic connections by driving neuronal co-activation in rhythmic patterns. Here we describe cellular interactions that shape brainwide developmental activity and their molecular basis. In Drosophila, patterned stimulus independent neural activity (PSINA) engages the entire brain in highly stereotyped, globally coordinated cycles of activity. A molecularly-defined population of ~2,000 neurons (Transient Receptor Potential Gamma, Trp{gamma}+ neurons) act as an activity template for PSINA. We show that this activity template is patterned by four neurons expressing the neuropeptide SIFamide (SIFa). Signaling through the SIFa Receptor, SIFa modulates the activity of both SIFa and Trp{gamma}+ neurons to establish the brainwide activity cycles of PSINA. In turn, Trp{gamma}+ neurons sustain SIFa neuron activity through a recurrent interaction. Neuropeptides modulate neuronal activity through synapse-free, or wireless, signaling; a fitting mode of communication for a process tasked with refining on-going synapse formation. By placing neuropeptide signaling at the core of developmental activity, this work highlights the rich neurophysiological potential of the chemical connectome in shaping the developing brain.
Context. The cerebral substrates of fatigue in patients with Multiple Sclerosis (pwMS) are not elucidated yet. This study aims at exploring the disease-specific functional brain substrates of fatigue in pwMS with a recent disease history. Methods. Sixteen pwMS (disease history < 5 years) and 17 matched Healthy Controls (HC) performed a N-Back task with three difficulty levels during fMRI acquisitions following high vs. low fatigue induction. Measures of subjective trait and state fatigue were also recorded. Behavioral performance at n-back task and evolution of subjective fatigue states were analyzed by means of Bayesian repeated measures analyses of variance. Functional MRI data were analyzed to determine between-group differences (1) in task-related brain activity, independently of trait fatigue score; (2) in the association between trait fatigue and brain activity. Results. A similar trajectory was observed in the two groups for subjective and task-related measures following fatigue induction. No between-group difference was observed in brain activity unrelated to fatigue score. However, negative associations between trait fatigue score and brain activity were observed in pwMS, while the associations are positive in HC. Specifically, interactions between group and task difficulty were observed in regions belonging to the Striato-Thalamo-Cortical (STC) network and the fronto-parietal cortex. Conclusion. Group-specific patterns of brain activity related to fatigue were identified in pwMS and HC in the STC circuitry, despite similar behavioral performance and subjective fatigue level. This confirms the implication of the STC loops in fatigue pathophysiology, occurring from the early stages of the disease.
Adolescent opioid use in the United States commands attention: millions of twelve- to nineteen-year-olds are exposed to opioids each year by prescription and misuse. Recent findings show that opioids bind not only to canonical opioid receptors but also interact with receptors on immune cells within both the central and peripheral nervous systems. The potential for early life opioid exposure to induce long-term changes in the neuroimmune system is not fully understood, particularly given the adolescent brains high susceptibility to neuroplastic changes. The goal of this study was to investigate the hypothesis that adolescent opioid use potentiates physiological and behavioral responses to pathogen-induced sickness later in life. To achieve this, we treated adolescent mice (PND 35-42) with bi-daily escalating doses of morphine to model dependence and then administered a low dose of lipopolysaccharide (LPS, 0.1 mg/kg) in adulthood (PND 60-76) to induce an immune response. In contrast to our hypotheses, we found that adolescent morphine exposure had no additive effect on low-dose LPS-induced sickness measures when assessed in adulthood. These data suggest that adolescent opioid exposure may have minimal effects on future immune challenges, although further research is needed to confirm this.
Visual information from the retina is sent to diverse targets throughout the brain by different retinal ganglion cells (RGCs). Much of our knowledge about the different RGC types and how they are routed to these brain targets is based on mice, largely due to the extensive library of genetically modified mouse lines. To alleviate the need for using genetically modified animal models for studying retinal projections, we developed a high-throughput approach called projection targeting with phototagging that combines retrograde viral labeling, optogenetic identification, functional characterization using multi-electrode arrays, and morphological analysis. This method enables the simultaneous investigation of projections, physiology, and structure-function relationships across dozens to hundreds of cells in a single experiment. We validated this method in rats by targeting RGCs projecting to the superior colliculus, revealing multiple functionally defined cell types that align with prior studies in mice. By integrating established techniques into a scalable workflow, this framework enables comparative investigations of visual circuits across species, expanding beyond genetically tractable models.
Aggregation of TAR DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases with FTLD-TDP, as well as FTLD-MND and MND-TDP cases subclassified neuropathologically into PLS, ALS, and PMA. All FTLD-TDP type C cases had ANXA11 proteinopathy. However, ANXA11 proteinopathy was present in over 40% of FTLD-MND and in 38 out of 40 FTLD-PLS cases (95%), of which 80% had TDP type B or an unclassifiable TDP-43 proteinopathy and 15% had TDP type C. Genetic analyses excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated novel forms of ANXA11 proteinopathy strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship of ANXA11 in TDP-43 proteinopathies, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises the molecular pathology of cases with abundant inclusions that are co-immunoreactive for both proteins and we subclassify three types of TAP based on distinct clinical and neuropathologic features.
Our visual capabilities depend on neural response properties in visual areas of our brains. Neurons exhibit a wide variety of selective response properties, but the reasons for this diversity are unknown. Here, we related the distribution of neuronal tuning properties to the information capacity of the population. Our results from theory, simulations, and analysis of recordings from macaque primary visual cortex (V1) reveal that diversity of amplitude and bandwidth drive complementary changes to the representational geometry of a population. Amplitude diversity pushes the centers of the representations further apart, whereas bandwidth heterogeneity decorrelates the center locations. These geometric changes separate out representations for distinct stimuli, creating more efficient encoding. We study how both types of diversity affect the population code for two different perceptual tasks: discrimination and identification. While both types of diversity improve encoding for both tasks, their distinct impacts on geometry make each more beneficial for one of the two tasks. Amplitude diversity impacts coding efficiency more for discrimination than it does for identification, while bandwidth diversity has a stronger impact on identification. These complementary effects indicate the importance of both types of diversity for perception. Finally, because tuning diversity exists across species and brain areas, our results suggest a fundamental neural coding strategy that may be applicable to a wide range of behavior.
The basal ganglia, particularly the striatum, are critical for orchestrating skilled behavioral sequences, yet the precise mechanisms underlying this process remain unclear. Using high-resolution kinematic tracking and neural recordings in mice performing a water-reaching task, we found spatially distributed modules of striatal projection neurons whose activity corresponded to the generation of each element in the sequence (aiming, reaching, and drinking). They are activated sequentially and exhibit reciprocal inhibition, ensuring a strict serial order. Optogenetic activation of the direct pathway of the orofacial module promoted licking while suppressing reaching. Reaching could in turn suppress stimulation-evoked licking, revealing bidirectional inhibitory interactions. Our findings demonstrate that the modular organization in the striatum, coupled with reciprocal inhibition, sculpts the temporal progression of actions, providing a mechanistic framework for understanding how the basal ganglia coordinate complex behaviors.
Parameterizing electroencephalography (EEG) signals in the spectral domain reveals physiologically relevant components of neural stochastic processes, yet the linearity or nonlinearity of these components remains debated and could not solved by the current Spectral Parameter Analysis (SPA). We address this using BiSCA (BiSpectral EEG Component Analysis), a likelihood-based model unifies EEG spectrum and bispectrum analysis to identify inter-frequency harmonic relationships and distinguish signal components. Simulations demonstrate BiSCA's ability to separate nonlinearity from non-Gaussianity (e.g., linear non-Gaussian systems exhibit diffuse bicoherence, while nonlinear Gaussian systems show localized peaks). Analyzing 1,771 intracranial EEG (iEEG) channels and a large scalp EEG dataset, we uncover a clear organizational principle: the brain's aperiodic ({xi}) activity is predominantly linear, whereas its resonant ({rho}) oscillations, including Alpha () rhythms and other peaks, are the primary source of cortical quadratic nonlinearity. This finding challenges the long-held notion of widespread linearity in large-scale brain signals, as our analysis reveals that over two-thirds of EEG and iEEG channels exhibit significant nonlinear characteristics. Spatially, we uncover a striking dissociation between signal power and nonlinearity: while the occipital Alpha () rhythm dominates in power, the parietal Mu () rhythm generates the strongest nonlinear signature. These findings highlight that nonlinearity is present across the brain, arising from resonant activity.
While glutamatergic synaptic plasticity is believed to be a fundamental mechanism mediating learning, the behavioral significance of plasticity at cortical GABAergic synapses remains less well understood. Furthermore, despite recent discoveries of long-range projections from neocortical GABAergic neurons, details about how they function are also sparse. Here we combine behavioral optogenetics with patch-clamp electrophysiology to link plasticity at long-range GABAergic synapses with higher-order cognitive functions. Specifically, learning extradimensional rule shifts potentiates callosal GABAergic synapses from prefrontal parvalbumin-expressing (PV) neurons onto corticothalamic neurons. Disrupting this potentiation by inhibiting callosal PV terminals during rule shifts induces perseveration, whereas reinstating this potentiation with subsequent gamma-frequency callosal PV terminal stimulation restores flexible behavior. This shows how a novel plasticity locus can regulate brain circuits underlying normal cognition and pathological states.
Accurate motor behavior relies on our ability to refine movements based on errors. While sensory prediction errors (SPEs), mismatches between expected and actual sensory feedback, predominantly drive such adaptation, task performance errors (TPEs), or failures in achieving movement goals, also appear to contribute. However, whether and how TPEs interact with SPEs to shape net learning, remains controversial. This controversy stems from difficulties in experimentally decorrelating these errors, ambiguity related to possible interpretations of task instructions, and inconsistencies between theory and computational models. To try and resolve this issue, we employed variants of an ''error-clamp'' adaptation paradigm across four reaching experiments (N = 144). Addressing the ambiguity of whether or not the TPE is indeed ignored in standard error-clamp designs as assumed in theoretical (but not computational) models, Experiment 1 explicitly manipulated TPE magnitude by shifting the endpoint feedback location while holding SPE constant. We found that learning was uninfluenced by TPE size. Experiment 2 assumed that the TPE is in fact disregarded under clamp instructions. To then study SPE-TPE interactions, we induced TPEs of varying magnitudes by shifting the target location (''target jump'') while always clamping feedback to the original target location. Here, instructions to reach the new target also induced an SPE. Crucially, learning driven by this SPE was again unaffected by TPE magnitude, a result validated by two additional experiments. Our findings consistently demonstrate that SPE-mediated learning remains impervious to variations in task performance feedback, and point to a distinction in learning mechanisms triggered by these two error signals.
The human brain is sensitive to temporal regularities across bodily and environmental signals. Here, we investigated the pupil and neural correlates of regularity encoding established across cardiac and auditory stimuli. Auditory sequences were presented in synchrony with the heartbeat (synchronous), at a fixed pace, or without temporal regularity while recording pupillometry, electroencephalography, and electrocardiography in healthy participants. Sounds evoked typical pupil dilation in all conditions. However, only in the synchronous condition, pupil dilation progressively decreased over the course of the sequence, possibly reflecting adaptation to the repeated cardio-auditory alignment. A concurrent increase in global EEG activity suggested enhanced cortical processing in response to the synchronous sequence. Pupil constriction was driven by participants with higher heart rate, indicating that pupil adaptation mostly occurs in response to fast auditory sequences. Cardio-audio regularity encoding manifests as a pupil adaptation and an amplification of global EEG activity, likely reflecting improved temporal prediction precision.
The locus coeruleus-norepinephrine (LC-NE) system has been implicated in perceptual decision-making, but its causal contribution and underlying mechanisms in humans remain unclear. Here, we used transcutaneous vagus nerve stimulation (tVNS) to modulate LC-NE activity during a random dot motion task, with stimulation delivered at three distinct time points across groups, each targeting different stages of LC-NE engagement during the task. tVNS reliably increased pupil-linked LC-NE activity across all groups. Notably, early stimulation, at a time when LC-NE activity was still at baseline, elicited a more sustained pupil dilation that extended into the decision phase, resulting in comparable pupil responses during decision-making across groups. For behavior, tVNS selectively improved decision accuracy in contexts characterized by initially low performance, without affecting response times. Drift diffusion modeling revealed that this improvement was specifically associated with increased drift rate, consistent with more efficient evidence accumulation with tVNS. These effects were consistent across groups but most pronounced when tVNS was applied at the early time point. Our results provide causal evidence that tVNS enhances decision-making in a state-dependent manner, likely by stabilizing attentional engagement and facilitating evidence accumulation when endogenous control is suboptimal.
Epilepsy is a brain disorder, characterized by recurrent seizures due to abnormal neuronal activity originating from a population of cortical neurons. It is known that seizures are often associated with abnormal glial cell function at the seizure focus. Recent studies have shown that each glial type such as astrocytes display significant degree of heterogeneity in their development, molecular signatures, and function depending on the brain region in which they are located. It is unknown if such heterogeneity differentially influence/cause seizures. Previous studies in Drosophila have shown that aberrant cortex glial function led to light inducible seizures in Ceramide phosphoethanolamine synthase (cpes) and temperature inducible seizures in zyd mutants. Here, we have optimized Gal4/Split-Gal4/Gal80/LexA drivers to specifically express a gene of interest throughout development in cortex glial subpopulations in different parts of the brain including optic lobe (OL), central brain (CB) and ventral nerve cord (VNC). Using these tools, we performed brain region specific cortex glial rescue experiments in cpes and zyd mutants. We found that OL and CB, but not VNC specific cortex glial expression of UAS CPES, were able to significantly suppress light inducible seizures in cpes mutants. In contrast, VNC but not OL or CB specific cortex glial expression of UAS Zyd suppressed temperature sensitive seizures. Further, in a third model, expression and activation of transient receptor potential (dTrpA1) just in the VNC specific cortex glia was sufficient to induce temperature sensitive seizures in wild type flies. Our findings suggest that regionally specialized cortex glial subtypes differentially regulate seizure susceptibility in seizure models.
The brain excels at extracting meaning from noisy and degraded input, yet the computational principles that underlie this robustness remain unclear. We propose a theory of spatiotemporal abstraction (STA), in which neural networks integrate inputs across space and time to produce multi-scale, concept-level representations that remain stable despite loss of detail. We demonstrate this principle using spectrograms of spoken sentences and their degraded analogs from cochlear implants, showing that as integration kernels widen, distorted input converges toward the original representation. This mechanism may explain how cochlear implant users comprehend speech despite severely scrambled afferent signals. STA provides a unified framework for understanding abstraction as an emergent property of cortical architecture, with implications for memory, neuroprosthesis design, and robust artificial systems.
Adult stem cells inhabit specialized niches where local and systemic cues regulate their behavior. In the mouse ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) dynamically transition between quiescence and activation and reside amidst unique deposits of extracellular matrix (ECM) known as fractones. We show that NSCs that enter quiescence in response to BMP4 secrete a complex ECM that, on its own, is capable of inducing NSC quiescence. This specific ECM triggers the nuclear translocation of Yes-associated protein (YAP), to induce further ECM remodeling and adhesion. Together, the BMP-ECM-YAP pathway creates a two-step mechanism where a soluble and transient quiescence-inducing signal leads to the formation of a physical niche to maintain the quiescent state. In the intact niche, YAP and its paralog TAZ (Transcriptional coactivator with PDZ-binding motif) essentially sustain quiescence by preserving fractones and the characteristic structural organization. Moreover, our findings reveal a previously unrecognized role for YAP/TAZ in quiescence.
Respiration dynamically modulates sensory perception by orchestrating transient states of the brain and the body. Using simultaneous recordings of high-density magneto-encephalography (MEG), respiration, and pupillometry, we show that human perceptual sensitivity to near-threshold visual stimuli was enhanced during inspiration, coinciding with respiration-modulated increases in arousal neuromodulation and cortical excitability. Participants adapted their breathing patterns to align with predictable stimulus onset, and this adaptive respiratory control correlated with improved performance. We further reveal that respiration-modulated changes in alpha and beta oscillations reflect distinct shifts in sensory and motor excitability, respectively. Crucially, respiration-resolved multivariate Granger causality analyses demonstrate that the breathing rhythm systematically shapes directed information flow within a widespread interoceptive network. This respiration-brain coupling was flexibly adjusted based on stimulus predictability, highlighting a novel mechanism for active sensing which integrates internal bodily rhythms with external sensory demands to optimize perception.
Functional improvement following traumatic spinal cord injury (SCI) remains limited, therefore, it is necessary to develop therapeutic interventions such as cell transplantation to replace lost cells and promote connectivity. While transplantation typically focuses on neurons, it is important to include other neural cells, such as immature astrocytes, to provide a permissive environment, promote neuroprotection and regeneration, and ultimately restore connectivity. In this study, we leveraged cellular engineering using human induced pluripotent stem cells (hiPSCs) to generate astrocyte progenitor cells (hAPCs). We tested two hiPSC lines (WTC11 and KOLF2.1J) to characterize the fate of the hAPCs in vitro and following transplantation at the cervical level of the intact spinal cord for up to 3 weeks. Our results demonstrated efficient and consistent differentiation of the hiPSCs into hAPCs, their survival and integration with the adult spinal cord, with no signs of tumors, deleterious outcomes, and unexpected locations. The ability to survive and the absence of adverse effects indicate that hAPC transplantation could be a safe element of therapy in treating spinal cord injuries.
Adverse childhood experiences significantly increase the risk of developing alcohol use disorder (AUD) in adulthood. We used a model of combined limited bedding/nesting and maternal separation (LBN+MS) in C57BL/6J background mice to investigate how early life stress (ELS) modulates behavioral sensitivity to alcohol, long-term alcohol drinking patterns, and the effects of alcohol on social behaviors. Our findings reveal that ELS increased sensitivity to the stimulatory locomotor effects of alcohol (1.75 g/kg) selectively in females and reduced sensitivity to the sedative effects of alcohol (4.0 g/kg) particularly in males. This pattern of enhanced stimulation and diminished sedation is consistent with phenotypes observed in human subjects at high risk for developing AUD. ELS also significantly enhanced escalation of voluntary alcohol intake and preference over eight weeks of two-bottle choice intermittent access drinking particularly in males. Additionally, social behavior assessments revealed that ELS impaired sociability selectively in females with a history of alcohol drinking, highlighting the detrimental interactive effects of ELS and alcohol exposure on adaptive behaviors. These results underscore the complex interplay between ELS, alcohol responses, and sex differences, suggesting that ELS creates a high-risk phenotype for AUD through altered alcohol behavioral sensitivity. Our study highlights the importance of future studies that seek to identify the neurobiological mechanisms underlying these interactions, which may pave the way for targeted interventions in populations affected by childhood adversity and excessive alcohol consumption.
Adaptive circuit plasticity plays crucial roles in the brain during development, learning, sensory experience, and after injury. During chronic whisker trimming, a well-studied paradigm for inducing experience dependent plasticity, whisker representations in the somatosensory barrel cortex (S1BF) undergo remapping, with expansion of maps for spared whiskers and contraction of maps for trimmed whiskers. At the cellular level, excitatory pyramidal cells in Layer 2/3 shift their whisker tuning, increasing selectivity to spared whiskers and away from deprived whiskers. While these changes are well documented, the circuit mechanisms regulating experience-dependent plasticity remain incompletely characterized. Parvalbumin (PV) interneurons play important roles in regulating the spatial and temporal dynamics of sensory evoked activity in Pyr cells and have been implicated in the regulation of experience dependent plasticity in other cortical regions. However, there is little evidence as to how the sensory evoked activity of PV cells change in S1BF during whisker trimming or how those changes might affect cortical remapping. To address these questions, we used longitudinal in vivo two-photon (2P) calcium imaging of PV cells in S1BF before, during, and after inducing experience-dependent plasticity by whisker trimming. At baseline, we found that PV cells have spatially distributed responses to whisker deflections, responding best to the principal whisker of a given barrel and less frequently to surround whiskers in a distance-dependent manner. After whisker trimming, there is a substantial recruitment of PV cells responsive to the spared whisker in deprived, but not spared, barrels. Upon whisker regrowth, this recruitment is reversed, but changes in individual PV cell whisker selectivity can persist for weeks. To probe the potential casual effects of increased PV activity during whisker trimming, we used chemogenetics to acutely manipulate the activity of PV cells and found that modulating PV cell activity strongly affects sensory evoked responses in local Pyr and PV cells, as well as Somatostatin (SST) interneurons. In particular, increased PV cell activity strongly suppressed activity in all three cell types. Together, our results reveal dynamic changes in the spatial distribution and tuning of PV cells during experience dependent plasticity and suggest that increased PV cell activity could constrain the extent of potential cortical remapping in the adult S1BF.
The psychostimulant methylphenidate may exert its effects on cognition and associated brain signals via action on the dopamine or noradrenaline transporter (DAT/NET). A recently developed and increasingly popular dual-regression approach (REACT; Dipasquale et al. (2019)) attempts to hone in on the molecular mechanisms underlying (drug-induced) changes in fMRI signal by enriching the analysis with information about the spatial distribution of molecular targets of interest. This method has great potential, but hitherto lacked validation of its molecular specificity and functional relevance. Here we leverage a unique pharmaco-fMRI dataset with established dopamine-dependent methylphenidate effects on neural reward prediction error (RPE) signaling, the canonical functional signature of dopamine. Using REACT we found that methylphenidate significantly modulated both DAT and NET-related functional connectivity networks, but only the effect on the DAT network varied with interindividual differences in striatal dopamine synthesis capacity, as measured with [18F]FDOPA PET. Furthermore, methylphenidate affected DAT-related connectivity in the prefrontal cortex in the same location where it affected neural RPE signaling. Together, these findings firmly establish the validity of REACT as a tool for isolating the role of dopamine from that of noradrenaline in methylphenidate's effects on brain function.
Infarct-induced neurodegeneration increases dementia risk for at least a decade in humans. It can be modeled in wildtype mice, where a cortical stroke results in chronic lymphocytic infiltration into the infarct and delayed cognitive decline. Vascular cell adhesion molecule 1 (VCAM1) on endothelial cells is increased by stroke and facilitates immune cell diapedesis by binding very late antigen 4 (VLA4) on immune cells. We report here that after stroke, chronic but not acute treatment with a VCAM1 blocking antibody reduces B and T lymphocyte infiltration and prevents chronic cognitive dysfunction in wildtype male and female mice. Preservation of cognitive function also occurred after chronic anti-VLA4 treatment despite anti-VLA4s lack of effect on lymphocyte infiltration. High-depth single-cell RNA sequencing of the chronic infarct and peri-infarct cortex revealed an infarct-induced decrease in expression of blood vessel growth and maturation genes in endothelial cells that was reversed by both anti-VLA4 and anti-VCAM1. Plasma proteomics also support a vasculoprotective mechanism of anti-VCAM1. Finally, immunostaining demonstrated that both antibodies improve pericyte coverage of the vasculature and prevent extravascular fibrinogen leakage. Together, our findings indicate that vascular structure and function remain abnormal long after stroke and that the VLA4/VCAM1 axis is a promising treatment target for infarct-induced neurodegeneration as blockade of either molecule restores cerebrovasculature and prevents cognitive decline.
Maternal infection during pregnancy is a well-established risk factor for neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain poorly understood. Lipocalin-2 (Lcn2), an innate immune protein that is highly upregulated during infection, also affects neuronal and glial function. This study investigates the role of Lcn2 in shaping brain development, particularly after maternal immune activation (MIA). To mimic maternal infection, pregnant mice received intraperitoneal injections of either lipopolysaccharide (LPS) or saline on embryonic days 16 to 18 to model infection during the second trimester of pregnancy in humans. We first showed that Lcn2 mRNA is expressed in the fetal brain and that MIA significantly upregulates Lcn2 mRNA and protein in the hippocampus and neocortex of both sexes. To assess functional relevance, we employed Lcn2 heterozygous females to generate wild-type and Lcn2 KO offspring from the MIA and control groups. Both female and male offspring underwent a battery of behavioral assays. Lcn2 deletion and MIA independently induced deficits in social behavior and increased repetitive behavior phenotypes relevant to NDDs in adult animals. However, their combination did not exacerbate these effects, suggesting an occlusion effect. Interestingly, no deficits were observed in the learning and memory task. To investigate potential shared molecular mechanisms, we performed RNA sequencing of the fetal forebrain 4 hours after the final LPS injection. This analysis revealed an overlapping group of differentially expressed genes in the Lcn2 KO and MIA groups, indicating convergence on similar transcriptional pathways that may underlie the observed behavioral phenotypes. These results suggest that while Lcn2 may not mediate the pathological effects of prenatal immune challenge, it plays a critical role in normal brain development.
This study used variations of a sensory preconditioning protocol in male and female rats to test a theory that the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) represent focal and peripheral states of attention, respectively. It specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required activation of NMDAR in the BLA and not the PRh (Experiments 2A and 2B) regardless of whether the stimulus-shock pairings were contiguous or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required activation of NMDAR in the BLA and not the PRh (Experiments 1A, 1B, 3A and 3B). However, when a pre-exposed stimulus was indirectly paired with shock - because it was associatively activated at the time of shock or separated from the shock by another stimulus - its conditioning required activation of NMDAR in the PRh and not the BLA (Experiments 1A, 1B, 3A and 3B). These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.
The vomeronasal system (VNS) plays a central role in mammalian chemical communication, mediating critical social and reproductive behaviors. In the wapiti (Cervus canadensis), a cervid species with complex social structures and pronounced chemical signaling during the rut, the VNS had not been previously characterized. This study provides the first comprehensive anatomical and neurochemical analysis of the VNS in wapiti using histological, lectin-histochemical, and immunohistochemical techniques. The vomeronasal organ (VNO) exhibited clear rostrocaudal differentiation, with distinct sensory and respiratory epithelia, a complex glandular distribution, and region-specific expression of neural markers. Lectin binding patterns confirmed functional compartmentalization along the epithelium, and immunoreactivity for markers such as OMP, PGP9.5, CR, and G-protein subunits (Gi2, G{gamma}8, and G0) revealed detailed molecular organization. Notably, G0-positive neurons in the epithelium did not project to the accessory olfactory bulb (AOB), suggesting alternative targets, possibly within transitional zones. The AOB showed all canonical layers, including well-defined glomeruli and expression of markers such as calbindin, CR, GFAP, and LEA lectin. Novel findings include the presence of large white matter tracts and region-specific lectin distribution. Confocal double immunofluorescence and autofluorescence imaging were also employed, allowing high-resolution visualization of neuroepithelial architecture and glomerular domains. Altogether, our results demonstrate that the vomeronasal system in wapiti is highly developed and functionally specialized. These findings contribute to a better understanding of chemosensory communication in wild ungulates and provide a comparative framework for future studies in cervid behavior, reproduction, and conservation.
Sleep regulation depends on the complex interplay between homeostatic and circadian processes synchronized by the light/dark cycle. Sleep is also directly regulated by light via projections from the retina to the preoptic area (POA). Although the light-responsive POA neurons project to several wake-promoting neurons, including histaminergic neurons in the tuberomammillary nucleus (TMn), there is no functional evidence for their involvement in light-induced sleep. To bridge this gap, we used histidine decarboxylase (HDC, the histamine-synthetizing enzyme) knockout mice (HDC-/-, n=7) and hM4Di-HDC-cre mice (HDC+/+, n=8) subjected to an ultradian light/dark protocol (LD 1h:1h over 24h), and another group of hM4Di-HDC-cre mice (n=8) exposed to a 1-h light pulse. We found that light pulses during the biological night enhanced slow wave sleep and increased cortical EEG power in the delta range (0.5-3Hz), and that these effects were significantly attenuated both in HDC-/- (83 vs 23 min/6h, p=0.005) under LD 1h:1h condition and in hM4Di-HDC-cre mice after acute chemogenetic silencing of histamine neurons by the DREADD ligand deschloroclozapine (15 vs 6 min/h, p=0.0016) under a 1-h light pulse. In addition, the sleep-inducing effect of light was circadian dependent, with the strongest effect at the beginning and end of the night but no effect at all during the biological day in HDC+/+ mice. The response dynamics to light were slowed down when lacking histamine neurotransmission. Our study provides functional evidence that the acute sleep-inducing effects of light on sleep require histamine neurotransmission in mice.
The ability of the brain to briefly retain information, in processes ranging from sensory perception to complex cognition, is believed to be supported by persistent neural firing. Historically, such firing has been attributed to recurrent synaptic networks, in which neural activity reverberates. Here, we present in vivo evidence challenging this view, demonstrating that individual neurons can sustain persistent firing in behaving mice. Disruption of this capability in hippocampal neurons via silencing of TRPC4 channels significantly and selectively reduces persistent firing in vivo, impairs the maintenance of spatial representations, and compromises spatial working memory performance. These findings redefine neurons as active contributors to information retention beyond their conventional role as passive input-output units, potentially reshaping our general understanding of brain computation.
Odorants stimulate olfactory sensory neurons (OSNs) to create a bilateral sensory map defined by a set of glomeruli present in the left and right olfactory bulbs. Using Xenopus tropicalis tadpoles we challenged the notion that glomerular activation is exclusively determined ipsilaterally. Glomerular responses evoked by unilateral stimulation were potentiated following transection of the contralateral olfactory nerve. The gain of function was observed as early as 2 hours after injury and faded away with a time constant of 4 days. Potentiation was mediated by the presence of larger and faster calcium transients driving glutamate release from OSN axon terminals. The cause was the reduction of the tonic presynaptic inhibition exerted by dopamine D2 receptors. Inflammatory mediators generated by injury were not involved. These findings reveal the presence of a bilateral modulation of glomerular output driven by dopamine that compensates for imbalances in the number of operative OSNs present in the two olfactory epithelia. Considering that the constant turnover of OSNs is an evolutionary conserved feature of the olfactory system and determines the innervation of glomeruli, the compensatory mechanism here described may represent a general property of the vertebrate olfactory system to establish an odor map.
Emotional processing is a crucial adaptive function. Research suggests that sleep, particularly rapid eye movement (REM) sleep, may have a role in processing the emotional load of past events. Notably, dream experiences may offer insight into this nighttime process. Some studies have reported increased emotionality in dreams as the night progresses, possibly reflecting ongoing emotional processing in the sleeping brain. However, findings on how dream affect evolves throughout the night remain mixed. In this study, we investigated how emotional intensity in conscious experiences during sleep changes across the night and sleep stages. Participants (Nsubjects = 20) were subjected to a multiple awakening paradigm, where they were awakened 4-5 times throughout the night and asked to recall their dreams (Ndreams = 61). Additionally, they rated the emotional intensity of their experiences using a structured cued questionnaire. Emotional intensity in dreams increased significantly throughout the night, with late-night dreams being more emotional than dreams collected during earlier sleep. Contrary to our expectation, this increase was not driven by dream reports obtained from REM sleep awakenings. Moreover, late-night dream reports were also significantly longer than those from early sleep, yet the length of the dream reports did not correlate with their emotional intensity. This suggests that the emotionality of dreams is not directly linked to the ability to recall the dream or its narrative complexity. Instead, it could be driven by emotional processes occurring independently throughout the night, or by other factors that regulate our access to dream experiences and their emotional content.
Cannabis use during pregnancy is increasing, often to alleviate stress and anxiety, yet the long-term effect of prenatal cannabis exposure alone or in combination with psychosocial stress on offspring neurodevelopment or maternal behaviors remains unclear. Here, we developed a translational rodent model combining prenatal {Delta}-tetrahydrocannabinol (THC) exposure with chronic psychosocial stress using the maternal witness defeat stress (MWDS) paradigm. Pregnant C57BL/6 mice were exposed to MWDS from gestational day (GD) 3-12 and received daily subcutaneous THC (2 mg/kg) or vehicle until birth. All exposure groups showed impaired maternal behavior, with negative postnatal outcomes and caregiving, with additive effects observed in the combined exposure group. In adolescence, male and female offspring exhibited exposure-specific behavioral alterations. Prenatal stress and combined exposures led to increased anxiety-like behavior and reduced motivated behavior in both sexes, while THC alone primarily impacted female self-care and social behavior. Transcriptomic profiling of the prefrontal cortex (PFC) and nucleus accumbens (NAc) of adolescent offspring revealed sex- and region-specific gene expression changes across all exposure groups. Prenatal THC-, stress-, and combined exposures each altered distinct molecular pathways related to mitochondrial function, synaptic organization, and glial signaling. Comparative analysis with a perinatal fentanyl model revealed shared transcriptional substrates involved in synaptic signaling and circadian regulation. These findings indicate that THC and stress independently and additively impair maternal behaviors with lasting neurodevelopment signatures in offspring.
The different aspects of a face, like sex or identity, can be decoded from the cortical patterns related to its processing. Many studies have investigated this phenomenon with similar outcomes. These studies usually utilize a low number of facial identities and high repetition numbers, which affects the recognizability and familiarity of a face, thus altering the processing. We propose that this commonly employed paradigm influences cortical patterns associated with features seemingly unrelated to identity, such as the sex of a face. In the first experiment, we recreated the findings of previous studies using a few identities and a high presentation number for decoding facial sex. In the second experiment, the identity-presentation ratio was switched. This change resulted in a narrower time window where facial sex related cortical patterns were detected. Decoding accuracy was also diminished, yielding lower values and suggesting a reduced signal-to-noise ratio in the cortex. After expanding the sample size with balanced gender representation, we identified shared cortical patterns related to face-sex processing both within the population and across gender-based subpopulations. These results provide further evidence that familiarity impacts face processing and suggest that previous findings on sex information decoding were likely influenced by the experimental paradigms employed.
One of the major characteristics of sleep is homeostatic sleep rebound following sleep loss. While the molecular mechanisms of baseline sleep regulation have been intensively studied, a specific molecular understanding of sleep rebound remains elusive. Here, we show that a constitutively active form of the Munc13-family presynaptic release factor Unc13A, which lacks the inhibitory Ca2+/calmodulin interaction domain (Unc13AWRWR), dominantly suppressed sleep rebound upon acute sleep deprivation, leading to a nearly complete elimination of recovery sleep (''reboundless''). In contrast, baseline sleep remained largely normal. Through a genetic modifier screen, we found that this dominant ''reboundless'' phenotype of Unc13AWRWR was rescued by a partial loss of Snap, a cofactor of NSF required for disassembly and recycling of post-fusion cis-SNARE complex. Given that Unc13A promotes fusion-competent trans-SNARE complex formation, these findings suggest that sleep rebound may depend on a delicate balance between SNARE complex assembly and recycling. Additionally, we found that expression of a human disease-associated active Unc13A (Unc13APL) variant attenuated baseline and rebound sleep. Since both Unc13AWRWR and Unc13APL were shown to promote presynaptic release probability (Pr), we speculate that Unc13A suppresses recovery sleep likely by increasing Pr and subsequently enhancing synaptic transmission, probably through elevated trans-SNARE formation and efficient cis-SNARE recycling. Taken together, our data demonstrate a fundamental role of Unc13A and SNARE dynamics in sleep homeostasis.
During sleep, ensemble activity patterns encoding recent experiences are reactivated in the hippocampus and cortex. This reactivation is coordinated by hippocampal sharp-wave ripples (SWRs) and is believed to support the early stages of memory consolidation. However, only a minority of sleep SWRs are associated with memory reactivation in the hippocampus and its downstream areas. Whether that subset of SWRs have specific physiological characteristics and directly contribute to memory performance is not known. We identified a specific subset of large SWRs linked to memory reactivation in both the hippocampus and prefrontal cortex (PFC) of mice, and found that their occurrence selectively increased during sleep following new learning. Closed-loop optogenetic SWR boosting during sleep was sufficient to enhance ensemble memory reactivation in hippocampus and PFC. This manipulation also improved subsequent memory retrieval and hippocampal-PFC coordination, causally linking both phenomena to SWR-associated ensemble reactivation during sleep.
Cough is a hallmark sign of tuberculosis and key driver of transmission. While traditionally attributed to host-driven inflammation, we previously demonstrated that Mycobacterium tuberculosis lipid extract (Mtb extract) and its component sulfolipid-1 (SL-1) directly activate nociceptive neurons to induce cough in guinea pigs. However, the cellular mechanisms by which Mtb extract and SL-1 modulate nociceptive sensory neurons remain incompletely understood. Here, we show that Mtb extract enhances action potential (AP) generation in mouse nodose nociceptors via an SL-1-dependent mechanism. Using calcium imaging, we found that Mtb extract and SL-1 increased intracellular calcium; signals in TRPV1-positive; neurons from both mouse nodose and human dorsal root ganglia (hDRG). These calcium; signals were attenuated by the Galpha;q/11 pathway inhibitor YM254890, even in the absence of extracellular calcium;, suggesting involvement of intracellular calcium; stores. Together, these findings indicate that SL-1 engages Galphaq/11 coupled pathways to sensitize nociceptors via intracellular calcium release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention.
Transcranial magnetic stimulation (TMS) has transformed non-invasive brain therapies but faces challenges due to variability in outcomes, likely stemming from inter-individual differences in brain function. This study aimed to address this challenge by integrating personalized functional networks (PFNs) derived from functional magnetic resonance imaging (fMRI) with a neural network-based decoder to optimize stimulation in real time during a working memory (WM) task. After identification of individualized stimulation targets, participants completed a TMS/fMRI session, performing a WM task while receiving rTMS at randomized frequencies. Decoder outputs and behavioral data during this session guided selection of optimal and suboptimal stimulation frequencies. Participants then underwent six stimulation sessions (three optimal, three suboptimal) in a randomized crossover design, performing WM and control tasks. The optimal stimulation improved WM performance by the final session, with no improvement observed in the control task. Additionally, the decoder output predicted behavioral performance on the WM task, both during the TMS/fMRI and neuromodulation sessions. These findings show that neural network-guided closed-loop neuromodulation can improve TMS effectiveness, marking a step forward in personalized brain stimulation.
Ethanol rapidly produces widespread neuronal apoptosis during early development, but this susceptibility declines as the brain matures. In previous research, we found Myt1l (a proneuronal transcription factor) mutations can cause precocious differentiation, neuronal immaturity, and transcriptomic alterations, including many in apoptotic regulators. Therefore, we used a recently developed Myt1l haploinsufficient mouse model to examine this gene\'s effects on ethanol-induced apoptosis across different developmental stages. We discovered that haploinsufficiency can moderately influence vulnerability to ethanol in a complex, age- and cell type-specific manner: apoptosis was reduced on P7, increased P21, but unaffected on P60. Remarkably, we also discovered the previously unrecognized ability of a single binge of ethanol to rapidly increase apoptosis within six hours in early adolescent and adult wild-type mice occurring in microglia and the newborn granule neurons in the hippocampus. This suggests apoptosis is an underappreciated contributor to ethanol\'s neuropathology at older ages and, translated to human use, occurs far more frequently than previously recognized.
Many newly encoded memories are labile when acquired but then consolidate to more stable states. Reconsolidation theory posits that reactivating a consolidated memory again destabilizes it, increasing its vulnerability to interference from competing memories. In a series of 3-day experiments, we investigated the fate of a motor memory when it is reactivated and challenged with a competing one. We pursued a modular design in which humans adapted to a visuomotor rotation A (day 1), then an opposite rotation B (day 2), followed by a retest on A (day 3). We first found that reactivating A before learning B (A-AB-A) caused no greater impairment in A retention than non-reactivation (A-B-A). That is, while interference occurred, it appeared to be uninfluenced by reactivation, contradicting reconsolidation predictions. We then tested an alternate idea, that reactivation might serve to protect the original memory from interference. In subsequent experiments, we introduced no rotation (N) trials either prior to A relearning (A-AB-NA and A-B-NA groups), or immediately after B learning (A-ABN-A and A-BN-A groups). Here, we observed that reactivation served a protective function, but only when B was washed out immediately, preventing its consolidation (A-ABN-A group). Collectively, our results show that reactivation does not necessarily increase the susceptibility of a motor memory to interference but may rather shield it from degradation by competing learning. Our findings align with theories positing memory transitions between active and inactive states, and hold implications for strategies focused on improving memory retention in rehabilitation, sports and skills training.
A fundamental feature of the visual system is its ability to detect image contrast. The contrast processing starts in the first synapse of the retina where parallel pathways are established to compute contrast to bright (ON pathway) and dark (OFF pathway) objects, separately transferred to morphologically identified ON and OFF cells throughout the visual system. Here, we found that response polarity in ON and OFF neurons is not fixed but rather switches dynamically to the opposite sign. The switch was not observed in rod-knockout mice, indicating that rods generate the polarity switch. We determined that neither horizontal cells nor rod-signaling pathways were responsible for the switch. Instead, we discovered that EAAT5 glutamate transporters located at photoreceptor terminals were required to produce the polarity switch. Our findings provide a new perspective on the adaptive properties of neural networks and their ability to encode contrast across the visual dynamic range.
Central post-stroke pain (CPSP) is a highly distressing condition that develops in 50% of people who suffer a thalamic stroke, and is typically unresponsive to current clinical treatments. Hypoxic damage to the ventral posterolateral (VPL) and ventral posteromedial (VPM) sensory thalamic nuclei, in particular, precipitates CPSP. One barrier to developing treatments for CPSP is the lack of preclinical models of thalamic ischemic stroke. In this study, we present a novel mouse model of CPSP induced through targeted photothrombotic ischemia. After eliciting hypoxia in the sensory thalamus of male mice, we assessed pain behaviors over a four-week period. Stroke-affected mice exhibited a persistent spontaneous facial grimace from day four to week four post-stroke, indicative of pain. Hind-paw mechanical hypersensitivity indicative of altered nociception, characteristic of VPL and VPM hemorrhagic CPSP models, was not detected in our model. Immunofluorescence analysis revealed increased activated microglia (Iba1) and reactive astrocytes (GFAP). Iba1 fluorescence intensity in the VPL thalamus, but not the VPM thalamus, correlated with the severity of facial grimace at four weeks post-stroke. Clustering based on behavioral phenotypes identified a subpopulation of mice in which grimace pain spontaneously resolved, by four weeks post-stroke, relative to sham controls, suggesting that this model can be used to understand how stroke recovery may influence pain chronification. This model provides a valuable tool to investigate the cellular and circuit mechanisms underlying CPSP after an ischemic thalamic stroke.
Most insects, including agricultural pests and disease vectors, rely on olfaction for key innate behaviors. Consequently, there is growing interest in studying insect olfaction to gain insights into odor-driven behavior and to support efforts in vector control. Calcium imaging using GCaMP fluorescence is widely used to identify olfactory receptor neurons (ORNs) responsive to ethologically relevant odors. However, accurate interpretation of GCaMP signals in the antenna requires understanding both response uniformity within an ORN population and how calcium signals relate to spike activity. To address this, we optimized a dual-modality recording method combining single-sensillum electrophysiology and widefield imaging for Drosophila ORNs. Calcium imaging showed that homotypic ab2A neurons exhibit similar odor sensitivity, consistent with spike recordings, indicating that a single ORN\'s response can reliably represent its homotypic counterparts. Furthermore, concurrent dual recordings revealed that peak calcium responses are linearly correlated with spike activity, regardless of imaging site (soma or dendrites), GCaMP variant, odorant, or fly age. These findings validate the use of somatic calcium signals as a reliable proxy for spike activity in fly ORNs and provide a foundation for future large-scale surveys of spike vs. calcium response relationships across diverse ORN types.
Background: Synthetic Cannabinoids Receptor Agonists (SCRAs) are the largest group of new psychoactive substances monitored worldwide. 5F-MDMB-PICA is a recent SCRA classified as a potent full agonist at CB1/CB2 receptors able to activate the mesolimbic dopamine (DA) transmission in adolescent but not in adult mice. Here, we have studied its reinforcing effects in adolescent mice and characterized the neurochemical and behavioral effects induced in the same animals in adulthood. Methods: We utilized an intravenous self-administration (IVSA) protocol in adolescent (PND 40-56) CD-1 male mice. In adulthood (PND 66-78), we conducted several behavioral and neurobiological assessments including: Sucrose Preference Test (SPT); Resident Intruder Test (RIT); Olfactory Reactivity Test (ORT); brain microdialysis to quantify DA levels in the medial Prefrontal Cortex (mPFC); and fiber photometry analysis using the GCaMP calcium sensor to monitor excitatory neural dynamics in the mPFC after exposure to an aversive odorant. Results: We found that 5F-MDMB-PICA, administered through IVSA in adolescent mice, produced an inverted U-shaped dose-response curve. The dose of 2.5 g/kg/25ul elicited behavior consistent with drug seeking. Adult mice exposed to 5F-MDMB-PICA during adolescence exhibited significant behavioral and neurochemical changes in adulthood compared to control mice. These behaviors included increased aggression, reduced social interaction, an anhedonic state, and an abolishment of mPFC DA response to an aversive odorant, as measured by in vivo brain microdialysis. Moreover, fiber photometry analysis of excitatory neuronal activity in the mPFC showed diminished calcium activity in response to the same aversive odorant in 5F-MDMB-PICA-exposed mice compared to controls. Conclusions: Notably, this study is the first to demonstrate that adolescent mice can acquire and sustain IVSA of 5F-MDMB-PICA. Furthermore, it highlights the long-term behavioral and neurochemical changes associated with adolescent exposure to 5F-MDMB-PICA, underscoring the potential detrimental effects of its use during this critical developmental period.
Our ability to transfer motor skills across tools and contexts is what makes modern technology usable. The success of motor augmentation devices, such as supernumerary robotic limbs, hinges on users\' capacity for generalised motor performance. We trained participants over seven days to use an extra robotic thumb (Third Thumb, Dani Clode Design), worn on the right hand and controlled via the toes. We tested whether motor learning was confined to the specific tasks and body parts involved in controlling and interacting with the Third Thumb, or whether it could generalise beyond them. Participants showed broad skill generalisation across tasks, body postures, and even when either the Third Thumb or the controller was reassigned to a different body part, suggesting the development of abstract, body-independent motor representations. Training also reduced cognitive demands and increased the sense of agency over the device. However, participants still preferred using their biological hand over the Third Thumb when given the option, suggesting that factors beyond motor skill generalisation, cognitive effort, and embodiment must be addressed to support the real-world adoption of such technologies.
Animals rely on both sensory perception and memory when navigating relative to learned allocentric locations. Incoming sensory stimuli, which arrive from an egocentric perspective, must be integrated into an allocentric reference frame to allow neural computations that direct an animal toward a learned goal. This egocentric-allocentric spatial transformation has been proposed to involve projections from the rodent postrhinal cortex (POR), which receives strong visual input, to the medial entorhinal cortex (MEC), which contains allocentric spatial cell types such as grid and border cells. A major step toward understanding this transformation is to identify how POR and MEC spatial representations differ during place navigation, which is currently unknown. To answer this question, we recorded single neurons from POR and MEC as rats engaged in a navigation task that required them to repeatedly visit a learned uncued allocentric location in an open field arena to receive a randomly scattered food reward. While neurons in both regions displayed strong tuning to the spatial structure of the environment, neither showed bias toward the goal location despite strongly biased behavior. Critically, when local visual landmarks were manipulated to place the visual scene in conflict with the learned location, POR neurons adjusted their tuning preferences to follow the visual landmarks, while MEC neurons remained in register with the true global reference frame. These findings reveal a strong dissociation between POR and MEC spatial reference frames during place navigation and raise questions regarding the mechanisms underlying integration of POR egocentric signals into the MEC allocentric spatial map.
Background: Optic flow is vital for locomotor control and is often perturbed to study the impact of optic flow on balance control. However, it remains unclear whether gait speed influences responses to such perturbations. This study aims to examine the effects of gait speed on gait parameters following immediate and prolonged exposure to mediolateral optic flow perturbations. Methods: Twenty-one young adults (23.43 +/- 4.19 years) walked on an instrumented treadmill, including 3 phases: baseline (3 min), perturbation with mediolateral optic flow (8 min), and post-perturbation (3 min). Trials were conducted at 0.6, 1.2, and 1.8 m/s. Ground reaction forces and 3D motion data were collected to calculate mediolateral margin of stability (MoS), mean step length (SL), step width (SW) and their variabilities. Three repeated-measures ANOVAs (Speed by Phase) were used to compare: baseline vs. early perturbation, early vs. late perturbation, and baseline vs. post-perturbation. Results: The responses to immediate and prolonged exposure to optic flow perturbation were speed dependent. Walking at slow speeds induced greater immediate responses in mediolateral gait parameters (SW and mediolateral MoS, both p < 0.001) compared to walking at faster speeds. During the perturbation phase, the adaptations were larger at faster vs. slower speeds for gait parameters in the direction of movement (SL, p = 0.007). Conclusion: Immediate responses and adaptations to mediolateral optic flow perturbations are speed-dependent and larger at slower gait speeds. The responses to prolonged perturbation are interpreted as step-to-step adaptations that may inform future interventions and studies on gait speed selection.
The steroid hormone 5-androstene-3{beta},17{beta}-diol (ADIOL) was discovered in humans nearly a century ago, yet its physiological roles remain poorly defined. Here, we show that fasting and caloric restriction, two forms of dietary restriction, induce transcriptional upregulation of genes encoding CYP11A1, CYP17A1, and 17{beta}-hydroxysteroid dehydrogenase family enzymes, promoting ADIOL biosynthesis. ADIOL, in turn, acts on the nervous system to reduce levels of kynurenic acid, a neuroactive metabolite linked to cognitive decline and neurodegeneration. This effect requires NHR-91, the C. elegans homolog of estrogen receptor {beta}, specifically in the RIM neuron, a key site of kynurenic acid production. Consistent with the known benefits of fasting and caloric restriction on healthspan, enhancing ADIOL signaling improves multiple healthspan indicators during aging. Conversely, animals deficient in ADIOL signaling exhibit reduced healthspan under normal conditions and in genetic models of caloric restriction, underscoring the functional significance of this pathway. Furthermore, ADIOL suppresses cellular stresses induced by the Alzheimer\'s-associated APOE4 variant, highlighting its potential as a neuroprotective agent. Notably, ADIOL does not significantly impact lifespan, indicating that its healthspan benefits are not simply a byproduct of lifespan extension. Together, these findings establish a physiological role for ADIOL in mediating the neuroprotective and pro-healthspan effects of fasting and caloric restriction and suggest that boosting ADIOL signaling may help narrow the gap between lifespan and healthspan. This positions ADIOL as a promising mimetic of dietary restriction effects on healthspan that could be used as a therapeutic strategy for age-related neurodegenerative conditions.
Progress at the intersection of artificial intelligence and pediatric neuroimaging necessitates large, heterogeneous datasets to generate robust and generalizable models. Retrospective analysis of clinical brain magnetic resonance imaging (MRI) scans offers a promising avenue to augment prospective research datasets, leveraging the extensive repositories of scans routinely acquired by hospital systems in the course of clinical care. Here, we present a systematic protocol for identifying scans with limited imaging pathology through machine-assisted manual review of radiology reports. The protocol employs a standardized grading scheme developed with expert neuroradiologists and implemented by non-clinician graders. Categorizing scans based on the presence or absence of significant pathology and image quality concerns, facilitates the repurposing of clinical brain MRI data for brain research. Such an approach has the potential to harness vast clinical imaging archives exemplified by over 250,000 brain MRIs at the Childrens Hospital of Philadelphia to address demographic biases in research participation, to increase sample size, and to improve replicability in neurodevelopmental imaging research. Ultimately, this protocol aims to enable scalable, reliable identification of clinical control brain MRIs, supporting large-scale, generalizable neuroimaging studies of typical brain development and neurogenetic conditions.
A role for the trafficking receptor SORLA in reducing A{beta} levels has been well-established, however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo. Here, we show that transgenic SORLA upregulation (SORLA TG) can reverse pathological effects in aged PS19 (P301S tau) mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, LTP impairment and glial hyperactivation. Proteomic analysis indicates reversion of PS19 profiles in PS19/SORLA TG hippocampus, including pathological changes in synapse-related proteins as well as key drivers of synaptic dysfunction such as Apoe and C1q. snRNA-seq analysis reveals suppression of PS19- signatures with SORLA upregulation, including proinflammatory induction of Plxnb1/Plxnb2 in glia. Tau seeding and aggregation, neuroinflammation, as well as PlxnB1/B2 induction are exacerbated in PS19 hippocampus with SORLA deletion. These results implicate a global role for SORLA in neuroprotection from tau toxicity in PS19 mouse brain.
TAR DNA-binding protein 43 kDa (TDP-43) is an essential splicing repressor whose loss of function underlies the pathophysiology of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Nuclear clearance of TDP-43 disrupts its function and leads to the inclusion of aberrant cryptic exons. These cryptic exons frequently introduce premature termination codons resulting in the degradation of affected transcripts through nonsense-mediated mRNA decay (NMD). Conventional RNA sequencing approaches thus may fail to detect cryptic exons that are efficiently degraded by NMD, precluding identification of potential therapeutic targets. We generated a comprehensive set of neuronal targets of TDP-43 in human iPSC-derived i3Neurons (i3N) by combining TDP-43 knockdown with inhibition of multiple factors essential for NMD, revealing novel cryptic targets. We then restored expression of selected NMD targets in TDP-43 deficient i3Ns and determined which genes improved neuronal viability. Our findings highlight the role of NMD in masking cryptic splicing events and identify novel potential therapeutic targets for TDP-43-related neurodegenerative disorders.
There are many sources of heterogeneity in the CA1 network, including plasticity, connectivity and cell properties, yet the extent and functional consequences of this diversity remains poorly understood. We used patterned optogenetic stimulation of CA3 pyramidal neurons and whole-cell patch clamp recordings from CA1 pyramidal neurons in acute mouse hippocampal slices, to characterize the contributions of different forms of heterogeneity to information flow. We found pronounced heterogeneity in synaptic responses and short-term plasticity (STP), influenced by the neurotransmitter identity, input pattern, and size of the activated presynaptic ensemble. Inhibitory synapses exhibited greater diversity in both response variability and depression profiles than excitatory synapses. We incorporated these readings in a molecule-to-network multiscale model of the CA3->CA1 circuit. The reference model shows strong decorrelation of autocorrelated input, but removal of STP makes the decorrelation frequency dependent. Removal of stochasticity and heterogeneity in connections makes the output periodic. Thus heterogeneity, short-term plasticity, and stochasticity each have distinct effects on cellular information transmission.
Memory-based inference allows individuals to integrate information acquired across separate episodes to support novel decisions and reasoning. Although prior knowledge, such as schemas, is known to influence learning and memory, its impact on the neural mechanisms underlying inference remains unclear. In this study, we investigated how schema congruency affects the encoding and retrieval of overlapping events and how these processes contribute to memory-based inference. Thirty-nine participants encoded AB associations, consisting of picture-word pairs presented on either schema-congruent or schema-incongruent backgrounds. These were followed by BC associations involving the same word paired with a new picture on a neutral background. At test, participants were asked to infer the indirect AC association. While overall inference accuracy did not differ as a function of schema congruency, behavioral and neural data revealed distinct mechanisms. Inference for schema-incongruent events depended on accurate retrieval of both AB and BC associations, whereas schema-congruent inferences did not. To investigate the neural processes involved, we trained hierarchical multivariate pattern classifiers on EEG data to detect schema and context reinstatement during task performance. For schema-congruent events, successful inference was predicted by schema reinstatement during BC encoding, consistent with integrating overlapping information into a unified memory trace. In contrast, successful inference for schema-incongruent events was predicted by context reinstatement during AC retrieval, reflecting a reliance on flexible recombination of separate memory representations. These findings demonstrate that schema congruency modulates the neural basis of memory-based inference. Congruent events are integrated during encoding, whereas incongruent events rely on retrieval-based inference. Keywords: memory integration, schema, congruency, context, MVPA, EEG
Visual, vestibular, proprioceptive and cutaneous sensory information is important for posture control during quiet stance. When the reliability of one source of sensory information used to detect self-motion for posture control is reduced, there may be a reweighting of inputs within and/or across the remaining sensory systems determining self-motion for postural control. Muscle vibration, which creates an illusion of muscle stretch and a compensatory movement to shorten the vibrated muscle, may be used to determine the weighting of muscle spindle Ia proprioception for posture control. The objective of this study was to determine the effect of vision occlusion on triceps surae muscle Ia proprioceptive weighting for postural control during quiet stance, utilizing 80 Hz muscle vibration and a quantitative measure of the bodys anterior to posterior ground center of pressure response to triceps surae muscle vibration in freely standing subjects. Subjects (N = 41; mean(standard deviation), 19.6(2.0) years) were examined as they stood with eyes open or eyes closed. Ground center of pressure was measured during quiet standing with, and without, bilateral vibration of the triceps surae muscles. The mean backward center of pressure shift induced by triceps surae vibration was significantly greater during the eyes closed condition compared to eyes open (eyes closed: -4.93(1.62) centimeters; eyes open: -3.21(1.33) centimeters; p = 6.85E-10; Cohens d = 1.29). Thirty-seven subjects increased, and two subjects decreased, their vibration induced center of pressure backward shift in the eyes closed condition compared to eyes open, although the magnitude of the change varied. Results support the idea that for most subjects, during an eyes closed stance there is an increased triceps surae muscle Ia proprioceptive weighting for postural control, due to the need for posture control to depend more on non-visual feedback.
Insect proprioception, vibration and sound detection rely on the scolopidium--a mechanosensory unit enclosing the sensory cilium of chordotonal organ neurons. The cilium contains mechanosensitive ion channels, and is enclosed by a scolopale cell with its tip embedded in a cap. Despite knowledge of the scolopidium\'s structure in multiple insects, the mechanism by which mechanical force elicits the transduction current remains speculative. We examined scolopidia in the auditory Muller\'s organ of the desert locust and present a comprehensive three-dimensional ultrastructure of a scolopidium using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). Next, we characterised sound-evoked motions of Muller\'s organ and the scolopidium using Optical Coherence Tomography (OCT) and high-speed light microscopy. We further measured transduction currents via patch clamp electrophysiology during mechanical stimulation of individual scolopidia. By combining ultrastructure, sound-evoked motions, and transduction current recordings, our finding suggests that the scolopidium is activated best by stretch along the ciliary axis.
Purpose To identify the origin of out-of-voxel (OOV) signals based on the coherence transfer pathway (CTP) formalism using signal phase conferred by the acquisition phase cycling scheme. Knowing the CTP driving OOV artifacts enables optimization of crusher gradients to improve their suppression without additional data acquisition. Theory and Methods A phase cycle systematically changes the phase of RF pulses across the transients of an experiment, encoding phase shifts into the data that can be used to suppress unwanted CTPs. We present a new approach, phase cycle inversion (PCI), which removes the receiver phase originally applied to the stored transients, replacing it with new receiver phases, matching the phase evolutions associated with each unwanted CTP, to identify the OOV signals. We demonstrated the efficacy of PCI using the MEGA-edited PRESS sequence in simulations, phantom and in vivo experiments. Based on these findings, the crusher gradient scheme was optimized. Results The simulation results demonstrated that PCI can fully separate signals originating from different CTPs using a complete phase cycling scheme. PCI effectively identified the CTP responsible for OOV signals in phantom experiments and in vivo, though with reduced specificity in vivo due to phase instabilities. Re-optimization of the gradient scheme based on the identified OOV-associated CTP to suppress these signals, resulted in cleaner spectra in six volunteers. Conclusion PCI can be broadly applied across pulse sequences and voxel locations, making it a flexible and generalizable approach for diagnosing the CTP origin of OOV signals.
Alpha-synuclein (asyn) fibril accumulation is the defining feature of Parkinson disease and is a target for disease-modifying treatments. One therapeutic strategy to reduce fibril accumulation is inhibition of asyn fibril growth. We developed a sensitive fluorescence-based fibril growth assay to screen for small molecule inhibitors. After validating the inhibition assay using a previously identified inhibitor, epigallocatechin-3-gallate, we identified compound 1 as a lead for inhibition of fibril growth. We analysed structure-activity relationships with analogs of 1 to optimize inhibition potency. Our results identified two dimethoxyphenyl piperazine analogs with more potent inhibition of in-vitro assembled fibrils. These analogs also inhibited the growth of asyn fibrils amplified from Lewy Body Disease brain tissue, further validating the inhibitor screening assay. Molecular docking studies indicate that these compounds can bind to the fibril ends, suggesting a potential capping mechanism through which these compounds inhibit the sequential association of monomeric asyn required for fibril growth.
The vomeronasal system (VNS) is critical for detecting pheromonal cues that modulate sociosexual behaviors. Despite its central role in chemical communication, our understanding of its anatomical and functional variability across mammals remains incomplete. This study provides the first detailed characterization of the VNS in the Iberian mole (Talpa occidentalis), a fossorial species endemic to the Iberian Peninsula. We performed a morphofunctional and neurochemical analysis of the vomeronasal organ (VNO) and the accessory olfactory bulb (AOB) using histology, immunohistochemistry, and lectin histochemistry. The VNO in T. occidentalis exhibited an unusual circular lumen lined by a uniform sensory epithelium, lacking the dual epithelial organization seen in most species. The vomeronasal cartilage was limited in extent and did not form the typical J-shaped structure. Importantly, no evidence of a vomeronasal pump was found, suggesting alternative mechanisms for semiochemical entry, likely facilitated by the anatomical position of the organ and continuous receptor distribution. Immunohistochemical analysis revealed strong expression of Gai2 and Gg8 in sensory neurons, with weaker Ga0 expression, suggesting predominance of V1R-type signal transduction. The AOB, though small, exhibited clear lamination and specific marker localization (Gai2, OMP, CR, MAP2), indicating robust functional organization. Lectin binding revealed specific glycosylation patterns in the glomerular layer, with STL and LEA marking synaptic regions. These findings uncover unprecedented anatomical and molecular features in the VNS of T. occidentalis, positioning this species as a valuable model for studying vomeronasal diversity and evolution among Laurasiatherian mammals.
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AbstractThe Tweety homologues (TTYHs) constitute a family of eukaryotic membrane proteins that, on the basis of structural features, were recently proposed to contribute to lipid transfer between soluble carriers and cellular membranes1. However, in the absence of supporting data, this function was hypothetical. Here through pull-down of endogenous proteins, we identify APOE as the interaction partner of human TTYH2. Subcellular fractionation and immunocytochemistry assays showed that both proteins colocalize in endosomal compartments. Characterization of the specific interaction between APOE and TTYH2 through binding assays and structural studies enabled us to identify an epitope in an extended domain of TTYH2 that faces the endosomal lumen. Structures of complexes with APOE-containing lipoprotein particles revealed a binding mode that places lipids in a suitable position to facilitate their diffusion into the membrane. Moreover, in vitro studies revealed that lipid transfer is accelerated by TTYH2. Collectively, our findings indicate that TTYH2 has a role in the unloading of APOE-containing lipoproteins after they are endocytosed. These results define a new protein class that facilitates the extraction of lipids from and their insertion into cellular membranes. Although ubiquitous, this process could be of particular relevance in the brain, where APOE is involved in the transfer of lipids between astrocytes and neurons.
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AbstractThe brain represents sensory variables in the coordinated activity of neural populations, in which tuning curves of single neurons define the geometry of the population code1,2. Whether the same coding principle holds for dynamic cognitive variables remains unknown because internal cognitive processes unfold with a unique time course on single trials observed only in the irregular spiking of heterogeneous neural populations3–8. Here we show the existence of such a population code for the dynamics of choice formation in the primate premotor cortex. We developed an approach to simultaneously infer population dynamics and tuning functions of single neurons to the population state. Applied to spike data recorded during decision-making, our model revealed that populations of neurons encoded the same dynamic variable predicting choices, and heterogeneous firing rates resulted from the diverse tuning of single neurons to this decision variable. The inferred dynamics indicated an attractor mechanism for decision computation. Our results reveal a unifying geometric principle for neural encoding of sensory and dynamic cognitive variables.
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AbstractLanthanides have shown magnetic memory at both the atomic1,2and molecular3,4level. The magnetic remanence temperatures of lanthanide single-molecule magnets can surpassd-transition metal examples5,6, and since 2017, energy barriers to magnetic reversal (Ueff) from 1,237(28) cm–1to 1,631(25) cm–1and open magnetic hysteresis loops between 40 K and 80 K have typically been achieved with axial dysprosium(III) bis(cyclopentadienyl) complexes7–17. It has been predicted that linear dysprosium(III) compounds could deliver greatermJ(the projection of the total angular momentum,J, on a quantization axis labelledz) state splitting and therefore higherUeffand hysteresis temperatures18–21, but as lanthanide bonding is predominantly ionic22,23, so far dysprosium bis(amide) complexes have shown highly bent geometries that promote fast magnetic reversal24,25. Here we report a dysprosium bis(amide)–alkene complex, [Dy{N(SiiPr3)[Si(iPr)2C(CH3)=CHCH3]}{N(SiiPr3)(SiiPr2Et)}][Al{OC(CF3)3}4] (1-Dy), that showsUeff= 1,843(11) cm–1and slow closing of soft magnetic hysteresis loops up to 100 K. Calculations show that theUeffvalue for1-Dyarises from the charge-dense amide ligands, with a pendant alkene taking a structural role to enforce a large N–Dy–N angle while imposing only a weak equatorial interaction. This leads to molecular spin dynamics up to 100 times slower than the current best single-molecule magnets above 90 K.
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AbstractMaterials emitting circularly polarized light (CPL) are highly sought after for applications ranging from efficient displays to quantum information technologies1–7. However, established methods for time-resolved CPL (TRCPL) characterization have notable limitations8–17, generally requiring a compromise between sensitivity, accessible timescales and spectral information. This has limited the acquisition of in-depth photophysical insight necessary for materials development. Here we demonstrate a high-sensitivity (noise level of the order of 10−4), broadband (about 400–900 nm), transient (nanosecond resolution, millisecond range) full-Stokes (CPL and linear polarizations) spectroscopy setup. The achieved combination of high-sensitivity, broad wavelength response and flexible time ranges represents a substantial advancement over previous TRCPL approaches. As a result, TRCPL measurements are shown to be applicable to hitherto inaccessible material systems and photophysical processes, including systems with low (10−3) dissymmetry factors and luminescence pathways spanning nanosecond to millisecond time ranges. Finally, full-Stokes measurements allow tracking the temporal evolution of linear polarization components, of interest by themselves, but especially relevant in the context of controlling for associated CPL artefacts18,19in the time domain.
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AbstractA key virtue of spin qubits is their sub-micron footprint, enabling a single silicon chip to host the millions of qubits required to execute useful quantum algorithms with error correction1–3. However, with each physical qubit needing multiple control lines, a fundamental barrier to scale is the extreme density of connections that bridge quantum devices to their external control and readout hardware4–6. A promising solution is to co-locate the control system proximal to the qubit platform at milli-kelvin temperatures, wired up by miniaturized interconnects7–10. Even so, heat and crosstalk from closely integrated control have the potential to degrade qubit performance, particularly for two-qubit entangling gates based on exchange coupling that are sensitive to electrical noise11,12. Here we benchmark silicon metal-oxide-semiconductor (MOS)-style electron spin qubits controlled by heterogeneously integrated cryo-complementary metal-oxide-semiconductor (cryo-CMOS) circuits with a power density sufficiently low to enable scale-up. Demonstrating that cryo-CMOS can efficiently perform universal logic operations for spin qubits, we go on to show that milli-kelvin control has little impact on the performance of single- and two-qubit gates. Given the complexity of our sub-kelvin CMOS platform, with about 100,000 transistors, these results open the prospect of scalable control based on the tight packaging of spin qubits with a ‘chiplet-style’ control architecture.
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AbstractMirroring the complex structures and diverse functions of natural organisms is a long-standing challenge in robotics1–4. Modern fabrication techniques have greatly expanded the feasible hardware5–8, but using these systems requires control software to translate the desired motions into actuator commands. Conventional robots can easily be modelled as rigid links connected by joints, but it remains an open challenge to model and control biologically inspired robots that are often soft or made of several materials, lack sensing capabilities and may change their material properties with use9–12. Here, we introduce a method that uses deep neural networks to map a video stream of a robot to its visuomotor Jacobian field (the sensitivity of all 3D points to the robot’s actuators). Our method enables the control of robots from only a single camera, makes no assumptions about the robots’ materials, actuation or sensing, and is trained without expert intervention by observing the execution of random commands. We demonstrate our method on a diverse set of robot manipulators that vary in actuation, materials, fabrication and cost. Our approach achieves accurate closed-loop control and recovers the causal dynamic structure of each robot. Because it enables robot control using a generic camera as the only sensor, we anticipate that our work will broaden the design space of robotic systems and serve as a starting point for lowering the barrier to robotic automation.
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AbstractMitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis1–3. Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown4–8. Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin–CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin–CDK acts as a ‘signal relayer’. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm.
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AbstractGastrointestinal (GI) motility disorders represent a major medical challenge, with few effective therapies available. These disorders often result from dysfunction of inhibitory nitric oxide (NO)-producing motor neurons in the enteric nervous system, which are essential for regulating gut motility. Loss or dysfunction of NO neurons is linked to severe conditions, including achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation1,2. Here we introduce a platform based on human pluripotent stem cells (hPSCs) for therapeutic development targeting GI motility disorders. Using an unbiased screen, we identified drug candidates that modulate NO neuron activity and enhance motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define developmental programs driving the specification of NO neurons and found that inhibition of platelet-derived growth factor receptors (PDGFRs) promotes their differentiation from precursors of the enteric nervous system. Transplantation of these neurons into NO-neuron-deficient mice led to robust engraftment and improved GI motility, offering a promising cell-based therapy for neurodegenerative GI disorders. These studies provide a new framework for understanding and treating enteric neuropathies.
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AbstractEmergence of universal collective behaviour from interactions within a sufficiently large group of elementary constituents is a fundamental scientific concept1. In physics, correlations in fluctuating microscopic observables can provide key information about collective states of matter, such as deconfined quark–gluon plasma in heavy-ion collisions2or expanding quantum degenerate gases3,4. Mesoscopic colliders, through shot-noise measurements, have provided smoking-gun evidence on the nature of exotic electronic excitations such as fractional charges5,6, levitons7and anyon statistics8. Yet, bridging the gap between two-particle collisions and the emergence of collectivity9as the number of interacting particles increases10remains a challenging task at the microscopic level. Here we demonstrate all-body correlations in the partitioning of electron droplets containing up toN= 5 electrons, driven by a moving potential well through a Y-junction in a semiconductor device. Analysing the partitioning data using high-order multivariate cumulants and finite-size scaling towards the thermodynamic limit reveals distinctive fingerprints of a strongly correlated Coulomb liquid. These fingerprints agree well with a universal limit at which the partitioning of a droplet is predicted by a single collective variable. Our electron-droplet scattering experiments illustrate how coordinated behaviour emerges through interactions of only a few elementary constituents. Studying similar signatures in other physical platforms such as cold-atom simulators4,11or collections of anyonic excitations8,12may help identify emergence of exotic phases and, more broadly, advance understanding of matter engineering.
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AbstractAll contemporary Eurasians trace most of their ancestry to a small population that dispersed out of Africa about 50,000 years ago (ka)1–9. By contrast, fossil evidence attests to earlier migrations out of Africa10–15. These lines of evidence can only be reconciled if early dispersals made little to no genetic contribution to the later, major wave. A key question therefore concerns what factors facilitated the successful later dispersal that led to long-term settlement beyond Africa. Here we show that a notable expansion in human niche breadth within Africa precedes this later dispersal. We assembled a pan-African database of chronometrically dated archaeological sites and used species distribution models (SDMs) to quantify changes in the bioclimatic niche over the past 120,000 years. We found that the human niche began to expand substantially from 70 ka and that this expansion was driven by humans increasing their use of diverse habitat types, from forests to arid deserts. Thus, humans dispersing out of Africa after 50 ka were equipped with a distinctive ecological flexibility among hominins as they encountered climatically challenging habitats, providing a key mechanism for their adaptive success.
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AbstractEach spring, billions of Bogong moths escape hot conditions across southeast Australia by migrating up to 1,000 km to a place that they have never previously visited—a limited number of cool caves in the Australian Alps, historically used for aestivating over summer1,2. At the beginning of autumn, the same individuals make a return migration to their breeding grounds to reproduce and die. Here we show that Bogong moths use the starry night sky as a compass to distinguish between specific geographical directions, thereby navigating in their inherited migratory direction towards their distant goal. By tethering spring and autumn migratory moths in a flight simulator3–5, we found that, under naturalistic moonless night skies and in a nulled geomagnetic field (disabling the moth’s known magnetic sense4), moths flew in their seasonally appropriate migratory directions. Visual interneurons in different regions of the moth’s brain responded specifically to rotations of the night sky and were tuned to a common sky orientation, firing maximally when the moth was headed southwards. Our results suggest that Bogong moths use stellar cues and the Earth’s magnetic field to create a robust compass system for long-distance nocturnal navigation towards a specific destination.
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AbstractSexual reproduction relies on meiotic chromosome pairing to form bivalents, a process that is complicated in polyploids owing to the presence of multiple subgenomes1. Uneven ploidy mostly results in sterility due to unbalanced chromosome pairing and segregation during meiosis. However, pentaploid dogroses (Rosasect.Caninae; 2n= 5x= 35) achieve stable sexual reproduction through a unique mechanism: 14 chromosomes form bivalents and are transmitted biparentally, while the remaining 21 chromosomes are maternally inherited as univalents2,3. Despite being studied for over a century, the role of centromeres in this process has remained unclear. Here we analyse haplotype-resolved chromosome-level genome assemblies for three pentaploid dogroses. Subgenome phasing revealed a bivalent-forming subgenome with two highly homozygous chromosome sets and three divergent subgenomes lacking homologous partners, therefore explaining their meiotic behaviour. Comparative analyses of chromosome synteny, phylogenetic relationships and centromere composition indicate that the subgenomes originated from two divergent clades of the genusRosa. Pollen genome analysis shows that subgenomes from different evolutionary origins form bivalents, supporting multiple origins of dogroses and highlighting variation in subgenome contributions. We reveal that bivalent-forming centromeres are enriched withATHILAretrotransposons, contrasting with larger tandem-repeat-based centromeres mainly found in univalents. This centromere structural bimodality possibly contributes to univalent drive during female meiosis. Our findings provide insights into the unique reproductive strategies of dogroses, advancing our understanding of genome evolution, centromere diversity and meiotic mechanisms in organisms with asymmetrical inheritance systems.
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AbstractRepresentation learning in neural networks may be implemented with supervised or unsupervised algorithms, distinguished by the availability of instruction. In the sensory cortex, perceptual learning drives neural plasticity1–13, but it is not known whether this is due to supervised or unsupervised learning. Here we recorded populations of up to 90,000 neurons simultaneously from the primary visual cortex (V1) and higher visual areas (HVAs) while mice learned multiple tasks, as well as during unrewarded exposure to the same stimuli. Similar to previous studies, we found that neural changes in task mice were correlated with their behavioural learning. However, the neural changes were mostly replicated in mice with unrewarded exposure, suggesting that the changes were in fact due to unsupervised learning. The neural plasticity was highest in the medial HVAs and obeyed visual, rather than spatial, learning rules. In task mice only, we found a ramping reward-prediction signal in anterior HVAs, potentially involved in supervised learning. Our neural results predict that unsupervised learning may accelerate subsequent task learning, a prediction that we validated with behavioural experiments.
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AbstractBrain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems1–3. Here we establish long-term, live light-sheet microscopy on unguided brain organoids generated from fluorescently labelled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviours and subcellular features over weeks of organoid development4. We provide a novel dual-channel, multi-mosaic and multi-protein labelling strategy combined with a computational demultiplexing approach to enable simultaneous quantification of distinct subcellular features during organoid development. We track actin, tubulin, plasma membrane, nucleus and nuclear envelope dynamics, and quantify cell morphometric and alignment changes during tissue-state transitions including neuroepithelial induction, maturation, lumenization and brain regionalization. On the basis of imaging and single-cell transcriptome modalities, we find that lumenal expansion and cell morphotype composition within the developing neuroepithelium are associated with modulation of gene expression programs involving extracellular matrix pathway regulators and mechanosensing. We show that an extrinsically provided matrix enhances lumen expansion as well as telencephalon formation, and unguided organoids grown in the absence of an extrinsic matrix have altered morphologies with increased neural crest and caudalized tissue identity. Matrix-induced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signalling pathways, including spatially restricted induction of the WNT ligand secretion mediator (WLS) that marks the earliest emergence of non-telencephalic brain regions. Together, our work provides an inroad into studying human brain morphodynamics and supports a view that matrix-linked mechanosensing dynamics have a central role during brain regionalization.
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AbstractModern colour image sensors face challenges in further improving sensitivity and image quality because of inherent limitations in light utilization efficiency1. A major factor contributing to these limitations is the use of passive optical filters, which absorb and dissipate a substantial amount of light, thereby reducing the efficiency of light capture2. On the contrary, active optical filtering in Foveon-type vertically stacked architectures still struggles to deliver optimal performance owing to their lack of colour selectivity, making them inefficient for precise colour imaging3. Here we introduce an innovative architecture for colour sensor arrays that uses multilayer monolithically stacked lead halide perovskite thin-film photodetectors. Perovskite bandgap tunability4is utilized to selectively absorb the visible light spectrum’s red, green and blue regions, eliminating the need for colour filters. External quantum efficiencies of 50%, 47% and 53% are demonstrated for the red, green and blue channels, respectively, as well as a colour accuracy of 3.8% in ΔELaboutperforming the state-of-the-art colour-filter array and Foveon-type photosensors. The image sensor design improves light utilization in colour sensors and paves the way for the next generation of highly sensitive, artefact-free images with enhanced colour fidelity.
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AbstractTrace elements and isotopes (TEIs) are important to marine life and are essential tools for studying ocean processes1. Two different frameworks have arisen regarding marine TEI cycling: reversible scavenging favours water-column control on TEI distributions2–5, and seafloor boundary exchange emphasizes sedimentary imprints on water-column biogeochemistry6,7. These two views lead to disparate interpretations of TEI behaviours8–10. Here we use rare earth elements and neodymium isotopes as exemplar tracers of particle scavenging11and boundary exchange6,7,12. We integrate these data with models of particle cycling and sediment diagenesis to propose a general framework for marine TEI cycling. We show that, for elements with greater affinity for manganese oxide than biogenic particles, scavenging is a net sink throughout the water column, contrary to a common assumption for reversible scavenging3,13. In this case, a benthic flux supports increasing elemental concentrations with water depth. This sedimentary source consists of two components: one recycled from elements scavenged by water-column particles, and another newly introduced to the water column through marine silicate weathering inside sediment8,14,15. Abyssal oxic diagenesis drives this benthic source, and exerts a strong influence on water-column biogeochemistry through seafloor geometry and bottom-intensified turbulent mixing16,17. Our findings affirm the role of authigenic minerals, often overshadowed by biogenic particles, in water-column cycling18, and suggest that the abyssal seafloor, often regarded as inactive, is a focus of biogeochemical transformation19,20.
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Highlights from theSciencefamily of journals
Nanostructured reflecting plates in squid cells enable a rapid switch between colored and near-transparent states
In Thailand, the wordBaiKhao(ใบข้าว)—meaning “rice leaf”—embodies a quiet agricultural revolution. For generations, farmers gauged crops’ nitrogen fertilizer needs by visually assessing leaf greenness, a method vulnerable to variations in lighting conditions and human error. Today, the “BaiKhaoNK” mobile app transforms smartphones into optical sensors. Using built-in cameras, it quantifies chlorophyll levels through spectral analysis and recommends precise fertilizer doses. This innovation epitomizes agriphotonics, a field dedicated to harnessing light-based tools to monitor, analyze, and diagnose crops and their environments.
A scholar confronts how powerful groups use food as a means of control
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The evolution of soft-bodied squids, which provide a major part of the biomass in modern oceans globally, is poorly understood owing to their patchy fossil record. We provide a comprehensive evolutionary history of squids through “digital fossil-mining” techniques, revealing a new lagerstätte. The more than 250 fossil beaks of 40 species show that squids originated and rapidly radiated by 100 million years ago. Our data suggest that the radical shift from heavily shelled, slowly moving cephalopods to soft-bodied forms did not result from the end-Cretaceous mass extinction (66 million years ago). Early squids had already formed large populations, and their biomass exceeded that of ammonites and fishes. They pioneered the modern-type marine ecosystem as intelligent, fast swimmers.
Editors’ selections from the current scientific literature
Our experience of the world is a continuous stream of events that must be segmented and organized at multiple timescales. The neural mechanisms underlying this process remain unknown. In this work, we simultaneously recorded hundreds to thousands of neurons in the lateral entorhinal cortex of freely behaving rats. Neural population activity drifted continuously along a one-dimensional manifold during all behaviors and behavioral states, including sleep, which points to an intrinsic origin of the drift. In awake animals, boundaries between events were associated with discrete shifts in population dynamics, which segmented the neural activity into temporal units. During tasks with recurring temporal structure, activity traveled additionally in directions orthogonal to the drift, encoding event information across multiple timescales. The results identify a hierarchical coding scheme for organizing events in time.
Combining 131 paleogenomes with bioarchaeological and archaeological data, we studied social organization and gendered practices in Çatalhöyük East Mound (7100 to 5950 BCE), a major Neolithic settlement in Central Anatolia. In early Çatalhöyük, burials in the same building were frequently close genetic relatives, suggesting that houses were used by biological family members. In later periods, however, individuals buried in the same building were often genetically unrelated, despite sharing similar diets. We found no indication of sex-biased mobility into Çatalhöyük. Meanwhile, in all periods, within-building genetic connections were predominantly maternal rather than paternal. Burials of female subadults also received a higher frequency of gifts than male subadults. Our results reveal how kinship practices changed while specific practices prioritizing female lines persisted for 1000 years at Neolithic Çatalhöyük.
The manipulation of light by means of materials with varying refractive index distributions is widespread among natural systems and modern technologies. However, understanding how animals leverage refractive index differences for dynamic color changes and then translating such insight into tunable optical devices remains challenging. We experimentally and computationally demonstrated that iridescent cells (iridophores) containing Bragg reflectors with sinusoidal-wave (rugate) refractive index profiles enable squid dorsal mantle tissues to reversibly transition between nearly transparent and vibrantly colored states. We then drew inspiration from these findings for the design and development of iridophore-inspired multispectral composite materials with tunable visible and infrared functionalities. Our study provides insight into squid dynamic structural coloration mechanisms and furnishes a technology for camouflage, heat management, display, and sensing applications.
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FOXA1 is altered in 10 to 40% of prostate cancers, yet its oncogenic mechanisms remain uncharacterized in vivo. We developed knock-in mouse models representing distinct classes of FOXA1 mutations. Histopathological and multi-omic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction withp53inactivation, drive androgen-dependent adenocarcinomas through co-activation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. In contrast, Class 2 mutations induce intra-luminal plasticity by reprogramming differentiated luminal cells into a progenitor-like state through activation of KLF5 and AP-1 neo-enhancer circuitries, which enables enhanced survival and proliferation even under castrate androgen levels. Our findings establish FOXA1 as a multifaceted oncogene, with distinct mutational classes divergently evolving to drive prostate tumorigenesis or therapy-resistant progression.
Using Global Navigation Satellite System data, we investigated the interplate slip before, during, and after the 2024 Hyuga-nada earthquake in Japan. Before the earthquake, a moment magnitude (Mw) 6.0 slow-slip event (SSE) was observed from late 2023 in a downdip extension of the mainshock. The coseismic slip was adjacent to the 1996 Hyuga-nada earthquake source. The afterslip resolved near the hypocenter area and in the downdip extension of the mainshock, reachingMw6.7 on 16 September 2024. Leading up to the earthquake, the recurrence interval for SSEs in the preslip area shortened from an average of 2 years, estimated from observations over the past 30 years, to 1 year, consistent with simulations in which the weakening of the Nankai megathrust was attributed to the cause.
Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching onAldh1a2or RA supplementation reactivated regeneration. Evolutionary inactivation of multipleAldh1a2-linkedregulatory elements accounted for the deficientAldh1a2expression upon injury in mice and rats. Furthermore, the activation ofAldh1a2by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration.
In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively prepared by de novo synthesis; the existing approach to swap carbon with sulfur is inefficient and involves stoichiometric mercury reagents. In this study, we report a two-step carbonyl-to-sulfur (CO-to-S) atom swap approach, enabled by a rationally designedN′-alkyl-hydrazonamide (NAHA) reagent that promotes forming pre-aromatic intermediates twice sequentially by different mechanisms, thereby achieving homolytic cleavage of both α-C−C bonds of the ketone substrates. A Ts−S−Ts (Ts,p-toluenesulfonyl) reagent mediates this process through successive intermolecular and intramolecular alkyl radical trapping by the central sulfur. This method shows a broad substrate scope and excellent chemoselectivity, providing a streamlined route to sulfur-containing scaffolds from readily available ketones.
A field scientist candidly reflects on navigating personal and institutional challenges
Stable zeolites with extra-large pores and nano dimensions that are capable of processing large molecules are in high demand but have been difficult to produce. Their complex structures and nanoscale crystal sizes present challenges for analysis using conventional x-ray diffraction techniques, leading to inefficiencies in material development. We report NJU120-1 and NJU120-2, two robust and fully connected aluminosilicate nano zeolites featuring interconnected channel systems with extra-large 22-ring pores. NJU120-1 is a nanosheet with only about 8-nanometer thickness, corresponding to 1.5 unit cells, and NJU120-2 is a nanorod with 50 by 250 nanometer dimensions. Their synthesis optimization was greatly accelerated through rapid structure determination with MicroED, revealing their multidimensional pore structures. Their very large largest-free-sphere diameters of approximately 1.2 nanometers coupled with nano morphologies enabled catalytic cracking of large molecules.
West Anatolia has been a crucial yet elusive element in the Neolithic expansion from the Fertile Crescent to Europe. In this work, we describe the changing genetic and cultural landscapes of early Holocene West Anatolia using 30 new paleogenomes. We show that Neolithization in West Anatolia was a multifaceted process, characterized by the assimilation of Neolithic practices by local foragers, the influx of eastern populations, and their admixture, with their descendants subsequently establishing Neolithic Southeast Europe. We then coanalyzed genetic and cultural similarities across early Holocene Anatolian and Aegean Neolithic villages using 58 material culture elements. Cultural distances among villages correlate with their spatial distances but not with their genetic distances after controlling for geography. This suggests that cultural change was often decoupled from genetically visible mobility.
The United States reneged on its foreign aid commitments. Nepal’s malnourished children and their families are paying the price
Federal judge decries NIH’s rationale for killing blacklisted grants as capricious and arbitrary
As the Trump administration systematically defunds the American research ecosystem, while disingenuously promising a return to so-called “gold standard science,” hope can be drawn from the new bipartisan initiative from Senators Martin Heinrich (Democrat, New Mexico) and Michael Rounds (Republican, South Dakota). Their American Science Acceleration Project (ASAP) seeks to make science in the United States “ten times faster by 2030” through five pillars: data, computing, artificial intelligence (AI), collaboration, and process improvement. But simply accelerating will exacerbate historical weaknesses in our innovation system and reproduce the damaging Silicon Valley ethos of “move fast and break things.” Faster is not necessarily better when it comes to innovation and discovery. Supercharging a research ecosystem that already struggles with accessibility and public trust risks more than it achieves.
This Review synthesizes progress and outlines a new framework for understanding how land surface hazards interact and propagate as sediment cascades across Earth’s surface, influenced by interactions among the atmosphere, biosphere, hydrosphere, and solid Earth. Recent research highlights a gap in understanding these interactions on human timescales, given rapid climatic change and urban expansion into hazard-prone zones. We review how surface processes such as coseismic landslides and post-fire debris flows form a complex sequence of events that exacerbate hazard susceptibility. Moreover, innovations in modeling, remote sensing, and critical zone science can offer new opportunities for quantifying cascading hazards. Looking forward, societal resilience can increase by transforming our understanding of cascading hazards through advances in integrating data into comprehensive models that link across Earth systems.
Matriarchs and foragers emerge as important players in early farming villages
Realignment of major program units aims to improve efficiency and make up for loss of federal contracts
Adjacent slow slip events affect megathrust earthquakes
Organic self-assembled molecules (SAMs), widely used in perovskite solar cells (PSCs), should exhibit enhanced performance to support the ongoing advancement of perovskite photovoltaics. We designed diradical SAMs through a coplanar-conjugation of donor-acceptor strategy to facilitate hole transport across the SAMs. The diradical SAMs exhibited high photothermal and electrochemical stability, as well as improved assembly uniformity and large-area solution processability attributed to molecular steric hindrance design. An advanced scanning electrochemical cell microscopy-thin-layer cyclic voltammetry technique was used to accurately determine the carrier transfer rate, stability, and assembly properties of SAMs. Ultimately, the efficiencies of PSCs exceeded 26.3%, mini-modules (10.05 cm2) reached 23.6%, and perovskite-silicon tandem devices (1 cm2) surpassed 34.2%. PSCs maintained > 97% after 2000 hours tracking at 45°C.
Study shows the organelles traveling through “bridges” into nearby cancer cells
Rapid evolution through small shifts in allele frequencies at thousands of loci is a long-standing neo-Darwinian prediction but is hard to characterize in the wild. European ash tree (Fraxinus excelsior) populations have recently come under strong selection by the invasive fungal pathogenHymenoscyphus fraxineus. Using genomic prediction models based on field trial phenotypes and 7985 loci, we show a shift in genomically estimated breeding values in an ancient woodland, between adult trees established before the epidemic started and juvenile trees established since. Using simulations, we estimate that natural selection has eliminated 31% of the juvenile population. Thus, we document a highly polygenic heritable microevolutionary adaptive change over a single generation in the wild.
Many questions remain regarding Earth’s earliest crust owing to the rarity of Hadean (>4.03 billion-year-old) rocks and minerals. The Nuvvuagittuq Greenstone Belt (NGB) in Canada may be the only known remnant of Hadean crust, although its age is debated, ranging from ≥3.75 to 4.3 billion years old. Mafic intrusions within this belt were specifically sampled and analyzed to investigate the timing of their magmatic differentiation. Correlations between samarium/neodymium (Sm/Nd) and143Nd/144Nd and142Nd/144Nd ratios correspond to ages of 4157 ± 174 and4196−81+53million years for the long-lived147Sm-143Nd and the short-lived146Sm-142Nd systems, respectively. The age agreement between both extant and extinct radiogenic systems, in rocks related through igneous fractionation, is compelling evidence for preservation of Hadean rocks in the NGB, opening a rare window into Earth’s earliest times.
Urea is a key molecule in the search for the origin of life and a basic chemical produced in large quantities by industry. Its formation from ammonia and carbon dioxide requires either high pressures and temperatures or, under milder conditions, catalysts or additional reagents. In this study, we observed the spontaneous formation of urea under ambient conditions from ammonia and carbon dioxide in the surface layer of aqueous droplets. Single, optically trapped droplets were probed by using Raman bands as markers. We found the surface layer to act like a microscopic flow reactor, with chemical gradients providing access to unconventional reaction pathways. This observation revealed a general mechanistic scheme for distinctive droplet chemistry. Interfacial chemistry is a possible nonenergetic route for urea formation under prebiotic conditions.
“GlycoCaging” uses gut bacteria to activate drugs for inflammatory bowel disease
During apoptosis, cytosolic BAX monomers are translocated to the mitochondria to permeabilize the outer membrane. Here, we identified a dimer of BAX dimers as the basic repeating unit of its various oligomeric forms: arcs, lines, and rings. Cryo–electron microscopy structure of the BAX repeating unit at 3.2-angstrom resolution revealed the interactions within and between dimers. End-to-end stacking of the repeating units through the protruding α9 pairs yielded lines, arcs, polygons, and rings. We structurally characterized the tetragon, pentagon, hexagon, and heptagon, which comprise 16, 20, 24, and 28 BAX protomers, respectively. Missense mutations at the BAX inter-protomer interface damage pore formation and cripple its proapoptotic function. The assembly principle of the various BAX oligomers reported here provides the structural basis of membrane permeabilization by BAX.
Seafloor monitoring is revealing how “slow slip” earthquakes can lead to big ones
Patterns of strain accumulation and release offshore in subduction zones are directly linked to the potential for shallow coseismic slip and tsunamigenesis, but these patterns remain elusive. In this work, we analyze formation pore pressure records from three offshore borehole observatories at the Nankai subduction zone, Honshu, Japan, to capture detailed slip-time histories of two slow slip events (SSEs) along the outermost reaches of the plate boundary. Slip initiates ~30 kilometers landward of the trench; migrates seaward at 1 to 2 kilometers per day to within a few kilometers of, and possibly breaching, the trench; and coincides with the onset and migration of tremor and/or very-low-frequency earthquakes. The SSE source region lies in a zone of high pore fluid pressure and low stress, which provides clear observational evidence linking these factors to shallow slow earthquakes.
Science can help to target climate finance at better-quality adaptation
The gut microbiota of mammals possess distinctive metabolic pathways with untapped therapeutic potential. Using molecular insights into dietary fiber metabolism by the human gut microbiota, we designed a targeted drug delivery system, called GlycoCaging, that is based on bespoke glycoconjugates of a complex plant oligosaccharide. GlycoCaging of exemplar anti-inflammatory drugs enabled release of active molecules triggered by specific glycosidases of autochthonous gut bacteria. GlycoCaging ensured that drug efficacy was potentiated, and off-target effects were eliminated in murine models of inflammatory bowel disease. Biochemical and metagenomic analyses of gut microbiota of individual humans confirmed the broad applicability of this strategy.
Through two grassroots efforts, approximately 200 op-eds showcasing federally funded science have been published across the country
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Taste is crucial in shaping animal perception. Sourness, one of the primary tastes, is aversive in mammals, whereas many birds frequently consume acidic fruits, suggesting a potential tolerance. Our study uncovers a mechanism enabling avian sour tolerance that involves changes to the sour receptor [otopetrin 1 (OTOP1)]. We demonstrate that sour tolerance is a conserved trait in birds, with avian OTOP1 exhibiting acid-induced inhibition and OTOP1 modulation affecting sour perception and tolerance. Ancestral reconstruction reveals that the increase in acid tolerance may have evolved at the same point in the songbird phylogeny as the regain of sweet sensing in this clade. This shift might have enabled songbirds to feed on a wider range of fruits, affecting the evolution and diversification of the songbird radiation.
FDA’s anticipated approval of lenacapavir comes at a time of global health cuts
Prolonged wakefulness leads to persistent, deep recovery sleep (RS). However, the neuronal circuits that mediate this process remain elusive. From a circuit screen in mice, we identified a group of thalamic nucleus reuniens (RE) neurons activated during sleep deprivation (SD) and required for sleep homeostasis. Optogenetic activation of RE neurons leads to an unusual phenotype: presleep behaviors (grooming and nest organizing) followed by prolonged, intense sleep that resembles RS. Inhibiting RE activity during SD impairs subsequent RS, which suggests that these neurons signal sleep need. RE neurons act upstream of sleep-promoting zona incerta cells, and SD triggers plasticity of this circuit to strengthen their connectivity. These findings reveal a circuit mechanism by which sleep need transforms the functional coupling of a sleep circuit to promote persistent, deep sleep.
Lawmakers reject some cuts, question others
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Editors’ selections from the current scientific literature
Canceled and curtailed grants from federal agencies have hit research projects, collections, and training
Neurons in the thalamus drive restorative sleep
Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.
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Highlights from theSciencefamily of journals
Shifts in phytoplankton populations could affect marine ecology and fisheries around the world
The constraints that govern the evolution of gene expression patterns across development remain unclear. Single-cell RNA sequencing can detail these constraints by systematically profiling homologous cells. The conserved invariant embryonic lineage ofCaenorhabditis elegansandC. briggsaemakes them ideal for comparing cell type gene expression across evolution. Measuring the spatiotemporal divergence of gene expression across embryogenesis, we find a high level of similarity in gene expression programs between species despite tens of millions of years of evolutionary divergence. Nonetheless, thousands of genes show divergence in their cell type specific expression patterns, with enrichment for functions in environmental response and behavior. Neuronal cell types show higher divergence than others such as the intestine and germline. This work identifies likely constraints on the evolution of developmental gene expression.
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Mystery signals used to locate gases in the spaces between galaxies
The brain’s response to injury includes the activation of intrinsic microglia and the influx of leukocytes, collectively constituting neuroinflammation, the “flame” of the brain. Although details differ and matter, neuroinflammation exacerbating neurodegeneration has similarities across multiple sclerosis and other neurological disorders, such as stroke and neurodegenerative diseases. Thus, lessons from successful disease-modifying therapies in multiple sclerosis may provide insights into strategies for modulating neuroinflammation and reducing neural injury in other neurological conditions. In this Review, we discuss these lessons and potential strategies for counteracting neuroinflammation, including taming the microglia-orchestrated brain immune responses that contribute to progressing neuropathology.
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Photoredox catalysis driven by visible light has improved chemical synthesis by enabling milder reaction conditions and unlocking distinct reaction mechanisms. Despite the transformative impact, visible-light photoredox catalysis remains constrained by the thermodynamic limits of photon energy and inefficiencies arising from unproductive back electron transfer, both of which become particularly pronounced in thermodynamically demanding reactions. In this work, we introduce an organic photoredox catalyst system that overcomes these obstacles to drive chemical transformations that require super-reducing capabilities. This advancement is accomplished by coupling the energy of two photons into a single chemical reduction, whereas inefficiencies from back electron transfer are mitigated through a distinct proton-coupled electron transfer mechanism embedded in the catalyst design. The super-reducing capabilities of this organic catalyst system are demonstrated through efficient application in a broad scope of challenging arene reductions.
The brain’s ability to prioritize sensory information is crucial for adaptive behavior, yet its mechanisms remain unclear. We investigated basal forebrain cholinergic neurons modulating olfactory bulb (OB) circuits in mice. The activity of cholinergic feedback axons in OB correlated with orofacial movements, with little responses to passively experienced odors. When mice engaged in an olfactory task, OB cholinergic axons rapidly shifted their response patterns from movement correlated to odor aligned. This response shift was absent in cholinergic axons projecting to the dorsal cortex during olfactory task engagement, and in OB, during an auditory task. Inactivation of OB-projecting cholinergic neurons impaired olfactory task performance and reduced odor responses in OB granule cells. Thus, the cholinergic system dynamically modulates sensory processing in a modality-specific and context-dependent manner.
The nature and spectrum of elementary excitations are defining features of a many-body system. Here, we use a Rydberg quantum simulator to demonstrate a form of spectroscopy, called quench spectroscopy, that probes these low-energy excitations. We illustrate the method on a two-dimensional simulation of the spin-1/2 dipolar XY model. Through microscopic measurements of the spatial spin correlation dynamics following a quench, we extract the dispersion relation of the elementary excitations for both ferro- and anti-ferromagnetic couplings. The ferromagnet exhibits elementary excitations behaving as linear spin waves, whereas in the anti-ferromagnet, spin waves appear to decay, suggesting the presence of strong nonlinearities. Our demonstration highlights the importance of power-law interactions on the excitation spectrum of a many-body system.
Lipid nanoparticles are designed to generate therapeutic T cells inside living animal models
The Sun’s corona is its tenuous outer atmosphere of hot plasma, which is difficult to observe. Most models of the corona extrapolate its magnetic field from that measured on the photosphere (the Sun’s optical surface) over a full 27-day solar rotational period, providing a time-stationary approximation. We present a model of the corona that evolves continuously in time, by assimilating photospheric magnetic field observations as they become available. This approach reproduces dynamical features that do not appear in time-stationary models. We used the model to predict coronal structure during the total solar eclipse of 8 April 2024 near the maximum of the solar activity cycle. There is better agreement between the model predictions and eclipse observations in coronal regions located above recently assimilated photospheric data.
As the world nears 1.5°C of global warming, near-term emissions reductions and adequate adaptation become ever more important to ensure a safe and livable planet for present and future generations
Collapsing international support for population data collection is compromising government planning all around the world
RFK Jr.’s purge of key advisory committee represents a major loss of expertise, as measured by scientific papers
The Vera C. Rubin Observatory is set to transform astronomy. Its wide and fast survey will discover billions of dynamic objects while building up a deep map of the universe
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Prokaryotic defense-associated reverse transcriptases (DRTs) were recently identified with antiviral functions; however, their functional mechanisms remain largely unexplored. Here we show that DRT9 forms a hexameric complex with its upstream noncoding RNA (ncRNA) to mediate antiphage defense by inducing cell growth arrest through abortive infection. Upon phage infection, the phage-encoded ribonucleotide reductase NrdAB complex increases intracellular deoxyadenosine triphosphate levels, activating DRT9 to synthesize long, polyadenylate [poly(A)]–rich single-stranded complementary DNA (cDNA), which likely sequesters the essential phage single-stranded DNA binding (SSB) protein and disrupts phage propagation. We further determined the cryo–electron microscopy structure of the DRT9-ncRNA hexamer complex, providing mechanistic insights into its cDNA synthesis. These findings highlight the diversity of RT-based antiviral defense mechanisms, expand our understanding of RT biological functions, and provide a structural basis for developing DRT9-based biotechnological tools.
Although the global greening associated with climate change is well documented on land, similar trends in the ocean have not been thoroughly identified. Using satellite observations of ocean chlorophylla(Chl) concentration, we show that the surface ocean experienced a poleward greening from 2003 to 2022. Contemporaneously, the subtropical regions of the Northern Hemisphere experienced a decrease in Chl. As such, the latitudinal disparity in Chl, as documented by an inequality index, has been increasing over the past two decades, particularly in the Northern Hemisphere. Rising water temperatures may primarily influence the Chl trends. The increasing Chl inequality—marked by “greener green and bluer blue” waters—has the potential to cascade to higher trophic levels, with implications for the fisheries and economies of coastal nations.
How birds retuned sour perception to eat fruits
Molecules are typically synthesized through stepwise processes involving chemical reactions between simple molecular precursors. Here, we report an advance in the synthesis of new organic molecules based on the approach of clip-off chemistry, in which molecules are excised from ordered, extended organic structures. We synthesized macrocycles by selectively cleaving them out of covalent organic frameworks. The synthesized macrocycles include eight macrocyclic polyamides with 114-, 138-, and 162-atom rings, and one 114-atom ring macrocyclic polyimide. This excision approach expands the scope of chemical organic synthesis to previously inaccessible macromolecules.
Already rocked by decades of political interference, corporate influence, mismanagement, and partisan efforts to undermine its authority, the expert bureaucracy, the “lifeblood” of the US administrative state, is now gasping for air. On 23 May, President Trump issued an executive order (EO)—Restoring Gold Standard Science—promising to fix these issues. Instead, the EO is poised to make them far worse: It officially empowers political appointees to override conclusions and interpretations of government scientists, threaten their professional autonomy, and undermine the scientific capacity of research and regulatory agencies.
Macroscale evaluations of chemical monitoring data require the integration of chemical, spatial, and temporal dimensions. Here, we linked 64 million US surface water monitoring records (1900 chemicals, date range 1958 to 2019, 310,000 sites) and 37 million analytical limits and in vivo and in silico toxicity thresholds. We found that the exposure data required for retrospective risk assessment were available for less than 1% of chemicals with potential environmental concern (n≈ 297,000). In contrast to the situation with persistent and often inorganic contaminants in the 1970s, current monitoring schemes lack control of a much larger number of organic chemicals and their degradates. Insufficient chemical and spatial coverage of monitoring, along with analytical limits being far too high to track some of the most toxic chemicals, biases risk perceptions for important chemicals.
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Translation termination is essential in all living organisms because it ensures that proteins have lengths strictly defined by their genes. This universal process is mediated by peptide release factors (RFs) that recognize stop codons and catalyze the hydrolysis of peptidyl transfer RNA (peptidyl-tRNA) on the ribosome, presumably by activating a water molecule. We report structures of the bacterial ribosome in complex with peptidyl-tRNA and RFs in the prepeptide release state. No hydrolytic water molecule was seen in the peptidyl transferase center. Instead, RFs induced rearrangements of the peptidyl-tRNA adenine 76 (A76) ribose pucker that orient the 2′-OH for the nucleophilic attack onto the neighboring carbonyl group. These findings suggest a catalytic mechanism of RF-mediated peptide release and provide a structural basis for the universal conservation of the catalytic domain in peptide RFs.
With DNA focused almost entirely on replication, newly discovered organism blurs the line between cells and viruses
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Plastic pollution threatens marine and freshwater ecosystems and the services they provide. Although plastic bag bans and taxes are increasingly implemented worldwide, their effectiveness in reducing plastic litter remains unknown. Leveraging the patchwork of bag policies across different geographic scales in the United States and citizen science data on 45,067 shoreline cleanups, we assess the impact of these policies on plastic bag litter. We find that plastic bag policies lead to a 25 to 47% decrease in plastic bags as a share of total items collected at cleanups relative to areas without policies, with taxes possibly further reducing shoreline litter. At a time when many jurisdictions are considering bag policies, while others are preemptively prohibiting them, our study provides evidence that they mitigate shoreline plastic pollution.
Denisovans are a hominin group primarily known through genomes or proteins, but the precise morphological features of Denisovans remain elusive due to the fragmentary nature of discovered fossils. Here we report ninety-five endogenous proteins retrieved from a nearly complete cranium from Harbin, China, dating to at least 146,000 years ago and previous assigned to a new species,Homo longi. This individual has three Denisovan derived amino acid variants and clusters with Denisova 3, suggesting the Harbin individual belongs to a Denisovan population. This study fills the gap between morphological and molecular evidence, enhancing our understanding of Denisovans’ spatiotemporal dispersal and evolutionary history.
A tiny sliver of NIH, the institute has provided evidence base for bedside care
Editors’ selections from the current scientific literature
Ivy League universities have dominated recent news headlines, having become popular targets for critics of higher education. But the threats they face—cuts to federal research funding, assaults on academic freedom, and bans on admitting international students—extend far beyond their campuses. Research universities across the country—large and small, public and private—are grappling with these same pressures. These institutions are behind the breakthroughs that shape daily lives. Undermining them doesn’t just jeopardize higher education, it threatens national and global strength. This means that economic, technological, and intellectual collapse is inevitable if US research institutions fall to federal and state disinvestment.
Technology could be a boon for science, but raises ethical concerns
Tailoring carrier density in atomically thin two-dimensional (2D) semiconductors is challenging because of the inherently limited physical space for incorporating charge dopants. Here, we report that interlayer charge-transfer doping in type III van der Waals heterostructures can be greatly modulated by an external gate to realize a hyperdoping effect. Systematic gated-Hall measurements revealed that the modulated carrier density is about five times that of the gate capacitive charge, achieving an ultrahigh 2D hole density of 1.49 × 1014per square centimeter, far exceeding the maximum possible electrostatic doping limit imposed by typical dielectric breakdown. The highly efficient hole-doping enables high-performance p-type 2D transistors with an ultralow contact resistance of ~0.041 kilohm micrometers and a record-high ON-state current density of ~2.30 milliamperes per micrometer.
Quantitatively mapping enzyme sequence-catalysis landscapes remains a critical challenge in understanding enzyme function, evolution, and design. In this study, we leveraged emerging microfluidic technology to measure catalytic constants—kcatandKM—for hundreds of diverse orthologs and mutants of adenylate kinase (ADK). We dissected this sequence-catalysis landscape’s topology, navigability, and mechanistic underpinnings, revealing catalytically heterogeneous neighborhoods organized by domain architecture. These results challenge long-standing hypotheses in enzyme adaptation, demonstrating that thermophilic enzymes are not universally slower than their mesophilic counterparts. Semisupervised models that combine our data with the rich sequence representations from large protein language models predict orthologous ADK-sequence catalytic parameters better than existing approaches. Our work demonstrates a promising strategy for dissecting sequence-catalysis landscapes across enzymatic evolution, opening previously unexplored avenues for enzyme engineering and functional prediction.
Biological nitrogen fixation is a key driver of global primary production and climate. Decades of effort have repeatedly updated nitrogen fixation estimates for terrestrial and open ocean systems, yet other aquatic systems in between have largely been ignored. Here we present an evaluation of nitrogen fixation for inland and coastal waters. We demonstrate that water column and sediment nitrogen fixation is ubiquitous across these diverse aquatic habitats, with rates ranging six orders of magnitude. We conservatively estimate that, despite accounting for less than 10% of the global surface area, inland and coastal aquatic systems fix 40 (30 to 54) teragrams of nitrogen per year, equivalent to 15% of the nitrogen fixed on land and in the open ocean. Inland systems contribute more than half of this biological nitrogen fixation.
Type III CRISPR-Cas systems defend against viral infection in prokaryotes by using an RNA-guided complex that recognizes foreign transcripts and synthesizes cyclic oligoadenylate (cOA) messengers to activate CRISPR-associated Rossmann-fold (CARF) immune effectors. In this study, we investigated a protein containing a CARF domain–fused Toll/interleukin-1 receptor (TIR) domain, Cat1. We found that Cat1 provides immunity by cleaving and depleting oxidized nicotinamide adenine dinucleotide (NAD+) molecules from the infected host, inducing a growth arrest that prevents viral propagation. Cat1 forms dimers that stack upon each other to generate long filaments that are maintained by bound cOA ligands, with stacked TIR domains forming the NAD+cleavage catalytic sites. Furthermore, Cat1 filaments assemble into distinct trigonal and pentagonal networks that enhance NAD+degradation. Cat1 presents an unprecedented chemistry and higher-order protein assembly for the CRISPR-Cas response.
Predicting plant responses to rising temperatures, including acute heat waves and hot droughts of varying intensity and duration, is central to addressing the climate and biodiversity crises. However, plant responses to heat are scale-dependent, complicating cross-scale prediction. We highlight recent progress revealing how and why plant responses to heat change across scales, including scales of biological organization and space versus time. We give examples of scaling up from molecular- and leaf-scale data and processes, which are modified by homeostatic and buffering mechanisms at whole plant and ecosystem scales. We show that scaling down—predicting plant responses to warming from broad-scale spatial patterns—can also be misleading, even in direction. Addressing such scale dependencies is essential to improving the prediction of plant responses to heat.
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Highlights from theSciencefamily of journals
Continuous geodetic measurements near volcanic systems can image magma transport dynamics, yet resolving dike intrusions with high spatiotemporal resolution remains challenging. We introduce fiber-optic geodesy, leveraging low-frequency distributed acoustic sensing (LFDAS) recordings along a telecommunication fiber-optic cable, to track dike intrusions near Grindavík, Iceland, on a minute timescale. LFDAS revealed distinct strain responses from nine intrusive events, six resulting in fissure eruptions. Geodetic inversion of LFDAS strain reveals detailed magmatic intrusions, with inferred dike volume rate peaking systematically 15 to 22 min before the onset of each eruption. Our results demonstrate DAS’s potential for a dense strainmeter array, enabling high-resolution, nearly real-time imaging of subsurface quasistatic deformations. In active volcanic regions, LFDAS recordings can offer critical insights into magmatic evolution, eruption forecasting, and hazard assessment.
Chromosomal inversions can contribute to adaptive speciation by linking coadapted alleles. By querying 1375 genomes of the species-rich Malawi cichlid fish radiation, we discovered five large inversions segregating in the benthic subradiation that each suppress recombination over more than half a chromosome. Two inversions were transferred from deepwater pelagicDiplotaxodonthrough admixture, whereas the others established early in the deep benthic clade. Introgression of haplotypes from lineages inside and outside the Malawi radiation coincided with bursts of species diversification. Inversions show evidence for transient sex linkage, and a notable excess of protein changing substitutions points toward selection on neurosensory, physiological, and reproductive genes. These results indicate that repeated interplay between depth adaptation and sex-specific selection on large inversions has been central to the evolution of this iconic system.
In natural habitats, nutrient availability limits bacterial growth. We discovered that bacteria can overcome this limitation by acquiring nutrients by lysing neighboring cells through contact-dependent antagonism. Using single-cell live imaging and isotopic markers, we found that during starvation, the type VI secretion system (T6SS) lysed neighboring cells and thus provided nutrients from lysing cells for growth. Genomic adaptations in antagonists, characterized by a reduced metabolic gene repertoire, and the previously unexplored distribution of the T6SS across bacterial taxa in natural environments suggest that bacterial antagonism may contribute to nutrient transfer within microbial communities in many ecosystems.
Reactive oxygen species function as key signals in plant adaptation to environmental stresses like drought. Roots respond to transient water unavailability by temporarily ceasing branching through the acclimative response xerobranching. In this study, we report how a xerobranching stimulus triggers rapid changes of ROS levels in root nuclei, triggering redox-dependent multimerization of the auxin repressor protein IAA3. Mutations in specific cysteine residues of IAA3 disrupt redox-mediated multimerization and interaction with co-repressor TPL, thereby attenuating IAA3 mediated target gene repression. Other AUX/IAA proteins also vary in their redox mediated multimerization, revealing a regulatory mechanism that connects dynamic changes in cellular redox status to auxin signaling. Our study reveals how ROS, auxin and water availability intersect and shape root adaptive responses, thereby maintaining phenotypic plasticity in plants.
Bottom sediments are important for nitrogen production in inland and coastal waters
Plants are highly sensitive to temperature, and climate change is predicted to have negative impacts on agricultural productivity. Warming temperatures, coupled with a growing population, present a substantial challenge for food security and motivate research to understand how plants sense and respond to changes in temperature. Here, we synthesize our current understanding of temperature sensing and response in plants. We outline how temperature cues are integrated into preexisting signaling cascades using inherently temperature-sensitive proteins or processes. This dispersed nature of thermo-sensitive proteins and processes makes distinct signaling cascades sensitive to temperature. This model integrates current knowledge and distinguishes thermosensing from other conventional sensing and signaling mechanisms in plants.
Recent case law can shape how innovation unfolds
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The region’s grasslands—vital ecosystems and carbon sinks—have been farmed and ranched beyond recognition
Wild plant species harbor a vast but largely unknown diversity of temperature stress solutions
In the world’s hottest forests, scientists are probing how plants cope with rising temperatures
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Rising temperatures change the structure and function of plant microbial communities
A no-fault compensation scheme may help balance innovation and patient protection
Bacteria leverage a secretion system to kill and scavenge nutrients from nearby competitors
Driven largely by open access, the trend puts society programming at risk
Our ability to produce human-scale biomanufactured organs is limited by inadequate vascularization and perfusion. For arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion poses a major hurdle. We introduce a model-driven design platform that demonstrates rapid synthetic vascular model generation alongside multifidelity computational fluid dynamics simulations and three-dimensional bioprinting. Key algorithmic advances accelerate vascular generation 230-fold and enable application to arbitrarily complex shapes. We demonstrate that organ-scale vascular network models can be generated and used to computationally vascularize >200 engineered and anatomic models. Synthetic vascular perfusion improves cell viability in fabricated living-tissue constructs. This platform enables the rapid, scalable vascular model generation and fluid physics analysis for biomanufactured tissues that are necessary for future scale-up and production.
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Jaundice is a common presentation ofPlasmodiumfalciparummalaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response toPlasmodiumspp. infection. We found that asymptomaticP. falciparuminfection in humans was associated with a higher ratio of unconjugated over conjugated bilirubin and parasite burden compared with symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, through genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was protective against malaria in mice. Unconjugated bilirubin inhibitedP. falciparumproliferation in red blood cells by a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin crystallization and compromised the parasite’s food vacuole. Hence, jaundice appears to represent a metabolic response toPlasmodiumspp. infection that limits malaria severity.
Retrons are antiphage defense systems that produce multicopy single-stranded DNA (msDNA) and hold promises for genome engineering. However, the mechanisms of defense remain unclear. The Retron-Septu system uniquely integrates retron and Septu antiphage defenses. Cryo-electron microscopy structures reveal asymmetric nucleoprotein complexes comprising a reverse transcriptase (RT), msDNA (a hybrid of msdDNA and msrRNA), and two PtuAB copies. msdDNA and msrRNA are essential for assembling this complex, with msrRNA adopting a conserved lariat-like structure that regulates reverse transcription. Notably, the assembled Retron-Septu complex is inactive, with msdDNA occupying the PtuA DNA-binding site. Activation occurs upon disassembly, releasing PtuAB, which degrades single-stranded DNA to restrict phage replication. This “arrest-and-release” mechanism underscores the dynamic regulatory roles of msDNA, advancing our understanding of antiphage defense strategies.
Defining viral proteomes is crucial to understanding viral life cycles and immune recognition but the landscape of translated regions remains unknown for most viruses. We have developed massively parallel ribosome profiling (MPRP) to determine open reading frames (ORFs) across tens of thousands of designed oligonucleotides. MPRP identified 4208 unannotated ORFs in 679 human-associated viral genomes. We found viral peptides originating from detected noncanonical ORFs presented on class-I human leukocyte antigen in infected cells and hundreds of upstream ORFs that likely modulate translation initiation of viral proteins. The discovery of viral ORFs across a wide range of viral families—including highly pathogenic viruses—expands the repertoire of vaccine targets and reveals potential cis-regulatory sequences.
Climate forcings by greenhouse gases and aerosols cause an imbalance at the top of the atmosphere between the net incoming solar radiation and outgoing longwave radiation from Earth. This Earth energy imbalance has strengthened over the period 2001 to 2023 with satellite data. Here, we show that low climate sensitivity models fail to reproduce the trend in Earth energy imbalance, particularly in the individual longwave and shortwave contributions to the imbalance trend. The inability to produce a strong positive shortwave and strong negative longwave Earth energy imbalance trend is found to be a robust feature in the low climate sensitivity models, especially for models with a climate sensitivity below 2.5 kelvin. The negative longwave contribution to Earth energy imbalance is driven by surface temperature increases and is therefore most pronounced in high climate sensitivity models, whereas the shortwave contribution is generally positive and amplified by greater surface warming.
BBO-10203 is an orally available drug that covalently and specifically binds to the RAS-binding domain of phosphoinositide 3-kinase α (PI3Kα), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3Kα activation in tumors with oncogenic mutations inKRASorPIK3CA, and in tumors with human epidermal growth factor receptor 2 (HER2) amplification or overexpression. In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2 and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and Serine/Threonine Kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, as insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake.
Reform movement should have seen call for “gold standard science” coming, critics say
A computational algorithm can render a complex artificial vascular structure in minutes
“You’re killing a newborn baby,” says one astrophysicist
Crystalline solids are governed by universal structure-property relationships derived from their crystal symmetry, leading to paradigmatic rules on what properties they can and cannot exhibit. A long-held structure-property relationship is that centrosymmetric crystals cannot differentially absorb circularly polarized light. In this study, we demonstrate the design, synthesis, and characterization of the centrosymmetric material Li2Co3(SeO3)4, which violates this relationship not by defying symmetry-imposed selection rules but by invoking a photophysical process not previously characterized for crystalline solids. This process originates from an interference between linear dichroism and linear birefringence, referred to as LD-LB, and involves strong chiroptical signals that invert upon sample flipping. In addition to enabling a chiroptical response under centrosymmetry, this process opens up photonic engineering opportunities based on crystalline solids.
A new film celebrates the subterranean
(Bi)carbonate salt formation has been widely recognized as a primary factor in poor operational stability of the electrochemical carbon dioxide reduction reaction (CO2RR). We demonstrate that flowing CO2gas into an acid bubbler—which carries trace amounts of acid vapor into a gas diffusion electrode for silver-catalyzed CO2RR to carbon monoxide (CO)—can prevent salt accumulation. In a 100-square-centimeter, scaled-up CO2RR membrane electrode assembly electrolyzer with single serpentine flow channels, the acid humidification method achieved the 4500 hours of stability milestone at 100 mA cm−2without compromising the CO faradaic efficiency, whereas a conventional water-humidified CO2feed only operated stably for ~80 hours. The acid-humidified CO2approach was extended to bismuth, copper, and zinc catalysts.
Scientists say India-Pakistan treaty needs to be rethought for a changing world
G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ–mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival.
For decades, empirical evidence has pointed to the unsustainable trajectory of global food systems, linking industrialized production tosoil degradation,water stress, andnutrition deficitsacross vulnerable populations and underscoring the urgent need for science-based policy interventions. But despite robust, peer‐reviewed evidence outlining both the magnitude of food‐system threats and an extensive array of potential science-backed interventions, structural obstacles such as institutional inertia, competing policy agendas, and chronic resource constraints have consistently prevented the uptake of scientific recommendations into effective policy frameworks.
Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we found that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions developed from a few highly mutated clones that dominate most of the bronchial tree. Multisite sequencing in human patients confirmed the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung.
A buildup of unconjugated bilirubin may be a protective response to malaria
Continued greenhouse gas emissions will accelerate global warming and intensity of heat waves, which already harm crop productivity. From the stability of key enzymes to canopy processes, photosynthesis is affected by temperature. All crops suffer declines in photosynthetic rate when temperatures cross critical thresholds, with irreversible losses typically occurring above 40° to 45°C. Protective measures within plants can be induced by growth at elevated temperatures but not from the sudden temperature elevation of heat waves. Strategies to improve the heat resilience of photosynthesis include modifying surface energy balance, optimizing canopy architecture, improving enzymatic heat tolerance, and (re)engineering key metabolic pathways for greater efficiency or to remove bottlenecks. This Review summarizes present knowledge on the major mechanisms that underlie high-temperature inhibition of photosynthesis and explores opportunities for breeding and biotechnological interventions to overcome them.
The phrase “Sputnik moment” is often used to describe a moment when a country—usually the United States—needs to respond to some technological leap made by another nation. The wake-up call is meant to provoke more investment in research, development, and education. Today, the United States faces another Sputnik moment, but this time, the threat isn’t coming from abroad—it’s coming from within.
Editors’ selections from the current scientific literature
The renowned American management consultant and author Peter Drucker is often credited as saying that “the best way to predict the future is to create it”—a view that applies to science as much as to the business world. It implies that gaining insights and ideas that lead to new discoveries and technologies allows victory in the marketplace, ahead of the competition. As the Trump administration continues to drastically defund and dismantle basic science in America, the United States is presenting other countries with opportunities to take the lead in seeing farther ahead, anticipate where scientific and technological prowess is going, and create the future, while the United States stands on the sidelines. This is a matter not only of scientific prestige but also of economic vitality. The country will no longer be at the forefront of commercializing breakthroughs and leveraging them for maximum economic and societal benefit. Moreover, this will trigger a massive transition for the global scientific community and alter the framework that shapes how the world’s economies connect and grow.
Innovative techniques yielded corn, beans, and squash for 600 years before European contact
A biologist pushes back against attacks on curiosity-driven research
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Trump request favors one giant telescope and kills a gravitational wave detector
Integrating radiative and evaporative cooling shows promise for enhancing passive cooling, but durable self-curing integrated cooling paints remain underdeveloped. We designed a modified cementitious structure with advanced thermal-optical and mass transfer properties, boosting cooling power while ensuring durability, mechanical strength, and broad adhesion. The paint achieves 88 to 92% solar reflectance (depending on wetting), 95% atmospheric window emittance, ~30% water retention, and self-replenishing properties, maintaining stable optical performance even when wet. Field tests in tropical Singapore demonstrated superior cooling performance compared with commercial white paints. Pilot-scale demonstrations highlighted consistent electricity savings under varying weather conditions, supported by theoretical modeling. By leveraging sustainable water evaporation and thermal radiation, this paint offers a practical and long-term solution for mitigating the urban heat island effect.
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“Knowledge is power”—or at least it was whenSir Francis Bacon coined this phrasein the 16th century. In today’s world, we frequently encounter a different variant of this philosophy, perhaps best described as “power dismisses knowledge.” We need look no further than the recent US measles outbreak to see how this modern framework wreaks havoc when applied to public health.
Present vision restoration technologies have substantial constraints that limit their application in the clinical setting. In this work, we fabricated a subretinal nanoprosthesis using tellurium nanowire networks (TeNWNs) that converts light of both the visible and near-infrared–II spectra into electrical signals. The broad-spectrum coverage is made possible by a combination of narrow bandgaps, strong absorption, and engineered asymmetries. Implanted into blind mice, the TeNWNs restored pupillary reflexes and enabled visually cued learning under visible and near-infrared 1550-nanometer light. In nonhuman primates, TeNWNs elicited robust retina-derived neural responses, confirming biocompatibility and feasibility. By restoring lost photosensitivity and extending vision to near-infrared, this nanoprosthesis offers a promising approach for restoring vision.
Projecting the local impacts of global warming is a stubborn challenge. But cities need answers fast
Halt to foreign “subawards” disrupts studies and compromises ethical obligations to trial volunteers
Long-running experiment concludes muon is no more magnetic than theory predicts
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A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
The quantum metric tensor is a central geometric quantity in modern physics that is defined as the distance between nearby quantum states. Despite numerous studies highlighting its relevance to fundamental physical phenomena in solids, measuring the complete quantum metric tensors in real solid-state materials is challenging. In this work, we report a direct measurement of the full quantum metric tensors of Bloch electrons in solids using black phosphorus as a representative material. We extracted the momentum space distribution of the pseudospin texture of the valence band from the polarization dependence of angle-resolved photoemission spectroscopy measurement. Our approach is poised to advance our understanding of quantum geometric responses in a wide class of crystalline systems.
Dopamine (DA) plays a crucial role in a variety of brain functions through intricate interactions with other neuromodulators and intracellular signaling pathways. However, studying these complex networks has been hindered by the challenge of detecting multiple neurochemicals in vivo simultaneously. To overcome this limitation, we developed a single-protein chemigenetic DA sensor, HaloDA1.0, which combines a cpHaloTag–chemical dye approach with the G protein–coupled receptor activation–based (GRAB) strategy, providing high sensitivity for DA, subsecond response kinetics, and a far-red to near-infrared spectral range. When used together with existing green and red fluorescent neuromodulator sensors, calcium indicators, cyclic adenosine 5′-monophosphate sensors, and optogenetic tools, HaloDA1.0 showed high versatility for multiplex imaging in cultured neurons, brain slices, and behaving animals, facilitating in-depth studies of dynamic neurochemical networks.
Chromatin remodelers utilize the energy of adenosine triphosphate (ATP) hydrolysis to slide nucleosomes, regulating chromatin structure and gene activity in cells. In this work, we report structures of imitation switch (ISWI) bound to the nucleosome during active ATP hydrolysis and remodeling, revealing conformational transitions of the remodeling motor across the adenosine triphosphatase (ATPase) cycle. The DNA strands were distorted accordingly, showing one full base-pair bulge and a loss of histone contact at the site of motor binding in the adenosine diphosphate* (ADP*) and apo* (unbound) states. We also identified several important elements for regulation of the remodeling activity. Notably, an enzyme conformation exiting the remodeling cycle reveals a linker DNA–sensing brake mechanism. Together, our findings elucidate a multistate model of ISWI action, providing a comprehensive mechanism of DNA translocation and regulation underpinning chromatin remodeling.
Variants in a ciliary receptor are associated with obesity
The recent Kunming-Montreal Global Biodiversity Framework (GBF) sets ambitious goals but no clear pathway for how zero loss of important biodiversity areas and halting human-induced extinction of threatened species will be achieved. We assembled a multi-taxa tracking dataset (11 million geopositions from 15,845 tracked individuals across 121 species) to provide a global assessment of space use of highly mobile marine megafauna, showing that 63% of the area that they cover is used 80% of the time as important migratory corridors or residence areas. The GBF 30% threshold (Target 3) will be insufficient for marine megafauna’s effective conservation, leaving important areas exposed to major anthropogenic threats. Coupling area protection with mitigation strategies (e.g., fishing regulation, wildlife-traffic separation) will be essential to reach international goals and conserve biodiversity.
Many functional molecules and materials have been produced with organic chemistry or with in vitro enzymatic approaches. Individual organisms, such as insects, have the potential to serve as natural reaction platforms in which high densities of multiple enzymes can perform new and complex reactions. We report an “in-insect” unnatural product synthesis that takes advantage of their xenobiotic metabolism. We selectively transform belt- and ring-shaped molecular nanocarbons into otherwise difficult-to-prepare derivatives in which oxygen atoms are inserted into aromatic rings. Cytochrome P450 variants are most likely the enzymes responsible for this reaction. Molecular dynamics simulations and quantum chemical calculations indicated a possible mode of substrate incorporation into the enzyme and an unconventional mechanism of direct oxygen insertion into carbon–carbon bonds.
The complex morphological evolution of lithium metal at the solid-state electrolyte interface limits performance of solid-state batteries, leading to inhomogeneous reactions and contact loss. Inspired by biological morphogenesis, we developed an interfacial self-regulation concept in which a deformable secondary phase dynamically aggregates at the interface in response to local electro-chemo-mechanical stimuli, enhancing contact. The stripping of a lithium electrode that contains 5 to 20 mole % electrochemically inactive sodium domains causes spontaneous sodium accumulation across the interface, with the sodium deforming to attain intimate electrical contact without blocking lithium transport. This process, characterized with operando x-ray tomography and electron microscopy, mitigates voiding and improves cycling at low stack pressures. The counterintuitive strategy of adding electrochemically inactive alkali metal to improve performance demonstrates the utility of interfacial self-regulation for solid-state batteries.
Anaerobic metabolisms are thought to dominate nitrogen cycling in anoxic marine zones (AMZs). However, thriving populations of aerobic nitrite-oxidizing bacteria (NOB) in AMZs challenge this assumption and remain unexplained. Using theory and modeling, we show how periodic oxygen intrusions sustain aerobic NOB in AMZs alongside more competitive aerobic heterotrophs. Ecological theory, supported by numerical simulations and genomics, frames NOB as opportunists exploiting a fleeting supply of oxygen. Consistent with in situ observations, simulated NOB contribute substantially to total oxygen consumption at AMZ boundaries, which implies that NOB may provide a major stabilizing feedback to AMZs. Fine-scale ocean currents increase the metabolic diversity in AMZs, which could stabilize AMZ volume under climate change.
Venerable advisory organization hit by Trump’s contract cancellations
Carbon and nitrogen are central elements in global biogeochemical cycles. To effectively manage carbon and nitrogen in China, we developed a comprehensive model for quantifying their fluxes, investigating their interplay across 16 human and natural subsystems. Between 1980 and 2020, nitrogen losses in China increased 2.3-fold and carbon emissions surged 6.5-fold. Integrated carbon and nitrogen management holds the potential for a 74% reduction in nitrogen losses to air and water and a 91% decrease in carbon emissions to the atmosphere by 2060. Compared with separate control of carbon or nitrogen, integrated management delivers an additional reduction of 1.8 million tons of nitrogen and 26.5 million tons of carbon by 2060, bringing out a 37% decrease in unit abatement cost and a net societal benefit of 1384 billion USD.
Across 11 southern African reserves protecting the world’s largest rhino population, we documented the poaching of 1985 rhinos (2017–2023, ~6.5% of the population annually) despite approximately USD 74 million spent on antipoaching. Most investment focused on reactive law enforcement—rangers, tracking dogs, access controls, and detection cameras—which helped achieve >700 poacher arrests. Yet we found no statistical evidence that these interventions reduced poaching (horn demand, wealth inequality, embedded criminal syndicates, and corruption likely combine to drive even high-risk poaching). By contrast, reducing poacher reward through dehorning (2284 rhinos across eight reserves) achieved large (~78%) and abrupt reductions in poaching using 1.2% of the budget. Some poaching of dehorned rhinos continued because poachers targeted horn stumps and regrowth, signaling the need for regular dehorning alongside judicious use of law enforcement.
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The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations inMC4RandADCY3as well as ciliary dysfunction lead to obesity, but how melanocortin signaling works in cilia remains unclear. Using mouse random germline mutagenesis, we identified two missense mutations inG protein–coupled receptor 45 (Gpr45)that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gαsto increase ciliary cyclic adenosine monophosphate (cAMP) via ADCY3. GPR45 colocalized with MC4R in PVH cilia and promoted ciliary MC4R activation. Loss of GPR45 in the PVH or MC4R+neurons caused obesity. These findings establish GPR45 as a key regulator of the ciliary melanocortin system, bridging MC4R and ADCY3.
The field ignores moral plurality at its peril
Area-based conservation is not sufficient to protect the ocean’s most highly mobile species
Sodium in the lithium anode promotes fast discharge in a solid-state battery
Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographically distinct human cohorts as well as in nonhuman primates and mice when measured longitudinally (repeatedly in the same population) or cross-sectionally (sampling distinct populations at various ages). Moreover, considerable variability was observed in associations between taurine and age-related changes in health outcomes pertaining to gross motor function and energy homeostasis. Our results suggest that changes in circulating taurine are not a universal feature of aging and that its pleiotropic effects may be dependent on the temporal and physiological context of each individual.
Tellurium nanowire networks could open up new avenues for artificial vision
Critical mineral supply and demand require global coordination to reduce market volatility and conflict risk
Proposal comes as White House pulls its nominee to lead NASA
We describe archaeological evidence of intensive ancestral Native American agriculture in the now heavily forested Upper Peninsula of Michigan. Recent LIDAR (light detection and ranging) and excavation data have uncovered densely clustered ancient agricultural raised garden bed ridges covering an expanse far greater than previously realized. These raised agricultural fields are deeply enmeshed in the broader cultural landscape, as ceremonial and other features were also found. Our results demonstrate a rich anthropogenic landscape created by small-scale ancestral Menominee communities, located near the northern limits of maize agriculture. The excellent preservation of this site is exceptional in eastern North America and suggests that the precolonial landscape was more anthropogenically influenced than currently recognized.
Although model organisms have provided insight into the earliest stages of cardiac and hepatic vascularization, we know very little about this process in humans because of ethical restrictions and the technical difficulty of obtaining embryos during very early development. In this study, we demonstrate that micropatterned human pluripotent stem cell–derived gastruloids enable in vitro modeling of the earliest stages of vascularization. We identify a combination of vascular-inducing factors that give rise to cardiac vascularized organoids with a spatially organized and branched vascular network. To show the broader utility of our vascularization strategy, we use the same vascular-inducing factors to produce hepatic vascularized organoids. Our results suggest that a conserved developmental program generates the vasculature within different types of organs.
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AbstractA critical challenge in mass spectrometry proteomics is accurately assessing error control, especially given that software tools employ distinct methods for reporting errors. Many tools are closed-source and poorly documented, leading to inconsistent validation strategies. Here we identify three prevalent methods for validating false discovery rate (FDR) control: one invalid, one providing only a lower bound, and one valid but under-powered. The result is that the proteomics community has limited insight into actual FDR control effectiveness, especially for data-independent acquisition (DIA) analyses. We propose a theoretical framework for entrapment experiments, allowing us to rigorously characterize different approaches. Moreover, we introduce a more powerful evaluation method and apply it alongside existing techniques to assess existing tools. We first validate our analysis in the better-understood data-dependent acquisition setup, and then, we analyze DIA data, where we find that no DIA search tool consistently controls the FDR, with particularly poor performance on single-cell datasets.
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AbstractThe networked architecture of the brain promotes synchrony among neuronal populations. These communication patterns can be mapped using functional imaging, yielding functional connectivity (FC) networks. While most studies use Pearson’s correlations by default, numerous pairwise interaction statistics exist in the scientific literature. How does the organization of the FC matrix vary with the choice of pairwise statistic? Here we use a library of 239 pairwise statistics to benchmark canonical features of FC networks, including hub mapping, weight–distance trade-offs, structure–function coupling, correspondence with other neurophysiological networks, individual fingerprinting and brain–behavior prediction. We find substantial quantitative and qualitative variation across FC methods. Measures such as covariance, precision and distance display multiple desirable properties, including correspondence with structural connectivity and the capacity to differentiate individuals and predict individual differences in behavior. Our report highlights how FC mapping can be optimized by tailoring pairwise statistics to specific neurophysiological mechanisms and research questions.
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AbstractBrain connectivity can be estimated in many ways, depending on modality and processing strategy. Here, we present the Krakencoder, a joint connectome mapping tool that simultaneously bidirectionally translates between structural and functional connectivity, and between different atlases and processing choices via a common latent representation. These mappings demonstrate exceptional accuracy and individual-level identifiability; the mapping between structural and functional connectivity has identifiability 42–54% higher than existing models. The Krakencoder combines all connectome flavors via a shared low-dimensional latent space. This fusion representation better reflects familial relatedness, preserves age- and sex-relevant information, and enhances cognition-relevant information. The Krakencoder can be applied, without retraining, to new out-of-distribution data while still preserving inter-individual differences in the connectome predictions and familial relationships in the latent representations. The Krakencoder is a notable leap forward in capturing the relationship between multimodal brain connectomes in an individualized, behaviorally and demographically relevant way.
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AbstractHigh-density silicon probes have transformed neuroscience by enabling large-scale neural recordings at single-cell resolution. However, existing technologies have provided limited functionality in nonhuman primates (NHPs) such as macaques. In the present report, we describe the design, fabrication and performance of Neuropixels 1.0 NHP, a high-channel electrode array designed to enable large-scale acute recording throughout large animal brains. The probe features 4,416 recording sites distributed along a 45-mm shank. Experimenters can programmably select 384 recording channels, enabling simultaneous multi-area recording from thousands of neurons with single or multiple probes. This technology substantially increases scalability and recording access relative to existing technologies and enables new classes of experiments that involve electrophysiological mapping of brain areas at single-neuron and single-spike resolution, measurement of spike–spike correlations between cells and simultaneous brain-wide recordings at scale.
AbstractInterictal epileptiform discharges (IEDs) are expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes, as most therapeutic approaches target seizures. We show, in a kindling model of progressive focal epilepsy, that IEDs produce pathological oscillatory coupling associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expand the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human participants with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing the spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation.
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AbstractTo reinforce rewarding behaviors, events leading up to and following rewards must be remembered. Hippocampal place cell activity spans spatial and non-spatial episodes, but whether hippocampal activity encodes entire sequences of events relative to reward is unknown. Here, to test this possibility, we performed two-photon imaging of hippocampal CA1 as mice navigated virtual environments with changing hidden reward locations. We found that when the reward moved, a subpopulation of neurons updated their firing fields to the same relative position with respect to reward, constructing behavioral timescale sequences spanning the entire task. Over learning, this reward-relative representation became more robust as additional neurons were recruited, and changes in reward-relative firing often preceded behavioral adaptations following reward relocation. Concurrently, the spatial environment code was maintained through a parallel, dynamic subpopulation rather than through dedicated cell classes. These findings reveal how hippocampal ensembles flexibly encode multiple aspects of experience while amplifying behaviorally relevant information.
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AbstractCortical function, including sensory processing, is surprisingly resilient to neuron loss during aging and neurodegeneration. In this Article, we used the mouse auditory cortex to investigate how homeostatic mechanisms protect the representational map of sounds after neuron loss. We combined two-photon calcium imaging with targeted microablation of 30–40 sound-responsive neurons in layer 2/3. Microablation led to a temporary disturbance of the representational map, but it recovered in the following days. Recovery was primarily driven by neurons that were initially unresponsive to sounds but gained responsiveness and strengthened the network’s correlation structure. By contrast, selective microablation of inhibitory neurons caused prolonged disturbance, characterized by destabilized sound responses. Our results link individual neuron tuning and plasticity to the stability of the population-level representational map, highlighting homeostatic mechanisms that safeguard sensory processing in the neocortex.
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AbstractFrom visual perception to language, sensory stimuli change their meaning depending on previous experience. Recurrent neural dynamics can interpret stimuli based on externally cued context, but it is unknown whether they can compute and employ internal hypotheses to resolve ambiguities. Here we show that mouse retrosplenial cortex (RSC) can form several hypotheses over time and perform spatial reasoning through recurrent dynamics. In our task, mice navigated using ambiguous landmarks that are identified through their mutual spatial relationship, requiring sequential refinement of hypotheses. Neurons in RSC and in artificial neural networks encoded mixtures of hypotheses, location and sensory information, and were constrained by robust low-dimensional dynamics. RSC encoded hypotheses as locations in activity space with divergent trajectories for identical sensory inputs, enabling their correct interpretation. Our results indicate that interactions between internal hypotheses and external sensory data in recurrent circuits can provide a substrate for complex sequential cognitive reasoning.
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AbstractAging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins—like the dementia- and ALS-associated protein TDP-43—mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.
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AbstractLipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)–PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.
AbstractIn plants, the maintenance of DNA methylation is controlled by several self-reinforcing loops involving histone methylation and non-coding RNAs. However, how methylation is initially patterned at specific genomic loci is largely unknown. Here we describe fourArabidopsisREM transcription factors, VDD, VAL, REM12 and REM13, that recognize specific sequence regions and, together with the protein GENETICS DETERMINES EPIGENETICS1 (GDE1), recruit RNA polymerase IV transcription complexes. This targeted recruitment leads to the production of 24-nucleotide small interfering RNAs that guide DNA methylation to specific genomic sites in plant female reproductive tissues. In the absence ofGDE1, polymerase IV transcription complexes are directed to loci bound by an alternative transcription factor, REM8, highlighting the role of REM transcription factors and GDE1 proteins as positional cues for epigenetic modulation. These findings establish a direct connection between sequence-specific transcription factors and the spatial regulation of siRNA production and DNA methylation, offering new insights into the genetic control of epigenetic patterning.
AbstractLysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example,vha-6), which are essential for intestinal lumen acidification inCaenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.
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AbstractMitotic spindles are dynamically intertwined with the cytoplasm they assemble in. How the physicochemical properties of the cytoplasm affect spindle architecture and size remains largely unknown. Using quantitative biochemistry in combination with adaptive feedback microscopy, we investigated mitotic cell and spindle morphology during neural differentiation of embryonic stem cells. While tubulin biochemistry and microtubule dynamics remained unchanged, spindles changed their scaling behaviour; in differentiating cells, spindles were considerably smaller than those in equally sized undifferentiated stem cells. Integrating quantitative phase imaging, biophysical perturbations and theory, we found that as cells differentiated, their cytoplasm became more dilute. The concomitant decrease in free tubulin activated CPAP (centrosomal P4.1-associated protein) to enhance the centrosomal nucleation capacity. As a consequence, in differentiating cells, microtubule mass shifted towards spindle poles at the expense of the spindle bulk, explaining the differentiation-associated switch in spindle architecture. This study shows that cell state-specific cytoplasmic density tunes mitotic spindle architecture. Thus, we reveal physical properties of the cytoplasm as a major determinant in organelle size control.
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AbstractHepatitis B virus (HBV) infection is associated with hepatitis and hepatocellular carcinoma (HCC). Considering that most HBV-infected individuals remain asymptomatic, the mechanism linking HBV to hepatitis and HCC remains uncertain. Herein, we demonstrate that HBV alone does not cause liver inflammation or cancer. Instead, HBV alters the chronic inflammation induced by chemical carcinogens to promote liver carcinogenesis. Long-term HBV genome expression in mouse liver increases liver inflammation and cancer propensity caused by a carcinogen, diethylnitrosamine (DEN). HBV plus DEN-activated interleukin-33 (IL-33)/regulatory T cell axis is required for liver carcinogenesis. Pitavastatin, an IL-33 inhibitor, suppresses HBV plus DEN-induced liver cancer. IL-33 is markedly elevated in HBV+hepatitis patients, and pitavastatin use significantly correlates with reduced risk of hepatitis and its associated HCC in patients. Collectively, our findings reveal that environmental carcinogens are the link between HBV and HCC risk, creating a window of opportunity for cancer prevention in HBV carriers.
AbstractT-ALL relapses are characterized by chemotherapy resistance, cellular diversity and dismal outcome. To gain a deeper understanding of the mechanisms underlying relapses, we conduct single-cell RNA sequencing on 13 matched pediatric T-ALL patient-derived samples at diagnosis and relapse, along with samples derived from 5 non-relapsing patients collected at diagnosis. This comprehensive longitudinal single-cell study in T-ALL reveals significant transcriptomic diversity. Notably, 11 out of 18 samples exhibit a subpopulation of T-ALL cells with stem-like features characterized by a common set of active regulons, expression patterns and splice isoforms. This subpopulation, accounting for a small proportion of leukemia cells at diagnosis, expands substantially at relapse, indicating resistance to therapy. Strikingly, increased stemness at diagnosis is associated with higher risk of treatment induction failure. Chemotherapy resistance is validated through in-vitro and in-vivo drug testing. Thus, we report the discovery of treatment-resistant stem-like cells in T-ALL, underscoring the potential for devising future therapeutic strategies targeting stemness-related pathways.
AbstractMelanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combiningBrafactivation with heterozygous loss ofPten. Here we show that similar tumors can arise in albino mice bearing only aBrafmutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only aBrafmutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify a cell type resembling “neural crest-like” cells in human and mouse melanomas. These exist in normal mouse skin, expand uponBrafactivation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that may provide a diagnostically and therapeutically important source of cellular heterogeneity.
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AbstractSpinal cord injury (SCI) can cause permanent loss of sensory, motor, and autonomic functions, with limited therapeutic options available. Low-frequency electric fields with changing polarity have shown promise in promoting axon regeneration and improving outcomes. However, the metal electrodes used previously were prone to corrosion, and their epidural placement limited the penetration of the electric field into the spinal cord. Here, we demonstrate that a thin-film implant with supercapacitive electrodes placed under the dura mater can safely and effectively deliver electric field treatment in rats with thoracic SCI. Subdural stimulation enhanced hind limb function and touch sensitivity compared to controls, without inducing a neuroinflammatory response in the spinal cord. While axon density around the lesion site remained unchanged after 12 weeks, in vivo monitoring and electrochemical testing of electrodes indicated that treatment was administered throughout the study. These results highlight the promise of electric field treatment as a viable therapeutic strategy for achieving long-term functional recovery in SCI.
AbstractHepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we develop a high content RNA-FISH-based imaging assay that allows for the investigation of the entry pathways of both naked and quasi-enveloped HEV particles. Surprisingly, we find that integrin α3, previously implicated in nHEV cell entry, is not expressed in the cell types that are most permissive for HEV infection. Instead, we identify integrin β1 (ITGB1) pairing with different α-integrins as the key player mediating nHEV cell entry. Our results indicate that the interaction of nHEV with ITGB1 facilitates entry through Rab11-positive recycling endosomes. In contrast, eHEV particles do not interact with ITGB1 and enter cells using a classical endocytic route via Rab5a-positive early endosomes. The entry of both types of HEV particles requires endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm.
AbstractFrameshifts can be caused by specific combinations of tRNA and mRNA. The wildtype AGC-decodingE. colitRNASer3GCUhas been shown to induce −1 ribosomal frameshifting on GCA alanine codons, and proposed to read a two-base codon instead of a canonical triplet. However, it has remained unclear whether this type of non-cognate decoding can be accommodated by the ribosome. Here, we perform single-particle cryo-EM reconstructions onE. coli70S ribosomes with the frameshift-inducing tRNASer3bound to the non-cognate GCA codon or the cognate AGC codon in the ribosomal A site. The structures demonstrate that doublet decoding is made possible when A1493, the conserved monitoring base in 16S rRNA, mimics a first codon base, forming a Hoogsteen base pair with U36 from the anticodon and stacking with the mRNA. This interaction pushes the first two bases of the A-site codon in position for base pairing with C35 and G34 of the anticodon.
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AbstractHIV-1 infection establishes a reservoir of long-lived cells with integrated proviral DNA that can persist despite antiretroviral therapy (ART). Certain reservoir cells can be reactivated to reinitiate infection. The mechanisms governing proviral latency and transcriptional regulation of the provirus are complex. Here, we identify a role for histone H3 citrullination, a post-translational modification catalyzed by protein-arginine deiminase type-4 (PADI4), in HIV-1 transcription and latency. PADI4 inhibition by the small molecule inhibitor GSK484 reduces HIV-1 transcription after T cell activation in ex vivo cultures of CD4+T cells from people living with HIV-1 in a cross-sectional study. The effect is more pronounced in individuals with active viremia compared to individuals under effective ART. Cell models of HIV-1 latency show that citrullination of histone H3 occurs at the HIV-1 promoter upon T cell stimulation, which facilitates proviral transcription. HIV-1 integrates into genomic regions marked by H3 citrullination and these proviruses are less prone to latency compared to those in non-citrullinated chromatin. Inhibiting PADI4 leads to compaction of the HIV-1 promoter chromatin and an increase of heterochromatin protein 1α (HP1α)-covered heterochromatin, in a mechanism partly dependent on the HUSH complex. Our data reveal a novel mechanism to explain HIV-1 latency and transcriptional regulation.
AbstractObesity-driven pathological expansion of white adipose tissue (WAT) is a key driver of endothelial dysfunction. However, early vascular alterations associated with over-nutrition also serve to exacerbate WAT dysfunction. Here, we conduct a single-cell transcriptomic analysis of WAT endothelium to delineate endothelial heterogeneity and elucidate vascular alterations and its consequence in a male murine model of obesity. We demarcate depot-specific differences in subcutaneous (sWAT) and visceral WAT (vWAT) endothelium through in sillico analysis and further corroboration of our findings. Moreover, we identify a sWAT-specific fenestrated endothelial cell (EC) subtype, which declines in obese conditions. Utilizing systemic anti-VEGFA blockade and geneticVegfamanipulation, we demonstrate that VEGFA is necessary for maintaining fenestration in sWAT. Additionally, we detect this fenestrated EC subtype in male human WAT, which undergoes reduction in individuals with obesity. Collectively, this atlas serves as a valuable tool for future studies to decipher the functional significance of different WAT EC subtypes.
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AbstractRecent studies emphasize that incorporating lithium metal electrodes can increase the energy density of next generation batteries. However, the production of lithium metal with high purity requires multi-stage purification steps due to its high reactivity. Furthermore, subsequent handling under inert conditions is required to prevent degradation. To circumvent handling of lithium metal and further improve energy density, researchers are exploring reservoir-free cells often referred to as “anode-free” cells. Reservoir-free cells are assembled without using lithium metal. Instead, lithium is electrodeposited at the interface between a current collector and a solid electrolyte from positive electrode materials during the first charge. Despite the potential of reservoir-free cells, there is limited understanding of the purity of electrodeposited lithium metal and how impurities might affect the electrochemical kinetics. This study examines first the purity of electrodeposited lithium at the steel|Li6PS5Cl interface. Then, it shows how impurities in lithium electrodes affect stripping capacity when using commercial lithium metal foils with both Li6PS5Cl and Li6.25Al0.25La3Zr2O12as solid electrolytes. By using time-of-flight secondary mass spectrometry and X-ray photoelectron spectrometry, we reveal that a lithium layer with high purity is electrodeposited at the negative electrode in reservoir-free cells and that common impurities in lithium metal (reservoir-type) electrodes like e.g. sodium negatively influence the accessible lithium capacity during discharge.
AbstractRapid learning in complex and changing environments is a hallmark of intelligent behavior. Humans achieve this in part through abstract concepts applicable to multiple, related situations. It is unclear, however, whether the computational mechanisms underlying rapid learning are unique to humans or also exist in other species. We combined behavioral, computational and electrophysiological analyses of a multidimensional rule-learning paradigm in male rats and in humans. We report that both species infer task rules by sequentially testing different hypotheses, rather than learning the correct action for all possible cue combinations. Neural substrates of hypothetical rules were detected in prefrontal network activity of both species. This species-conserved mechanism reduces task dimensionality and explains key experimental observations: sudden behavioral transitions and facilitated learning after prior experience. Our findings help to narrow the explanatory gap between human macroscopic and rodent microcircuit levels and provide a foundation for the translational investigation of impaired cognitive flexibility.
AbstractLymphostatin is a key virulence factor of enteropathogenic and enterohaemorrhagicEscherichia coli, playing roles in bacterial colonisation of the gut and in the inhibition of lymphocyte proliferation and proinflammatory responses. The protein’s glycosyltransferase and cysteine protease motifs are required for activity against lymphocytes, but high-resolution structural information has proven elusive. Here, we describe the structure of lymphostatin from enteropathogenicE. coli O127:H6, determined by electron cryo-microscopy at different pH values. We observe three conformations of a highly complex molecule with two glycosyltransferase domains, one PaToxP-like protease domain, an ADP-ribosyltransferase domain, a vertex domain and a delivery domain. Long linkers hold these domains together and occlude the catalytic sites of the N-terminal glycosyltransferase and protease domains. Lymphostatin binds to bovine T-lymphocytes and HEK-293T cells, forming clusters at the plasma membrane that are internalized. With six distinct domains, lymphostatin can be regarded as a multitool of pathogenicEscherichia coli, enabling complex interactions with host cells.
AbstractDespite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P.1 vaccines and WA-1 or P.1 infection are immunized with a bivalent WA-1/Omicron BA.5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA.5-specific responses. Reinfection with heterologous Omicron XBB.1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-naïve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69+CD103+lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.
AbstractTo select appropriate behaviour, individuals must rely on encoding of relevant features within their environment in the context of current and past experiences. This function has been linked to goal-associated activity patterns of hippocampal principal cells. Using single-unit recordings from optogenetically identified somatostatin-expressing interneurons (SOMIs) in the dentate gyrus of head-fixed mice trained in a spatial goal-oriented reward-learning task in virtual realities, we show that SOMI activity temporally precedes reward-locations in expert mice characterized by goal-anticipatory behaviour. Predictive goal-encoding by SOMIs is lost after translocation of learned goals to novel previously unrewarded sites leading to rapid reductions in anticipatory behaviour and fast reconfiguration of SOMI activity to times after reward onset in association with reward consumption at novel goal-sites. Chemogenetic silencing of SOMIs caused a loss of memory that trained goal-sites were no longer available. Thus, our data reveal the ability of SOMIs to flexibly encode goal-locations depending on current and past experiences to bias behavioral outcomes.
AbstractPrions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPCcreates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPCand infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPCinitially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.
AbstractIκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ’s function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppressesCxcl9,Cxcl10, andCcl5expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8+T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.
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AbstractThe flow-induced activation of mechanophores embedded in linear polymers by ultrasound (US) suffers from slow mechanochemical conversions at the commonly used frequency of 20 kHz and in many cases remains ineffective with higher MHz frequencies. Here, we present polymeric microbubbles (PMBs) as a platform that accelerates the mechanochemical activation of several mechanophores under both 20 kHz and MHz irradiation. MHz irradiation generated by biocompatible high-intensity focused US (HIFU). Through their pressure-sensitive gas core, PMBs act as acousto-mechanical transducers for the transformation of sound energy into stretching and compression forces as well as fracturing the polymer shell by the volume oscillation of PMB. We investigate three different mechanophores among which one flex-activation derivative was unexpectedly activated by US. Through a combination of experiments and computation, we find that PMBs likely exert compressive force onto the copolymerized mechanophores rather than the typical elongational forces solvated chain fragments experience in flow. We thereby underscore the mechanochemical properties of the PMB platform and its versatility for accelerated mechanochemical transformations with a perspective on biomedical applications.
AbstractDevelopmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation—TTLL glutamylases vs. CCP deglutamylases—accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.
AbstractEmbryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ+pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.
AbstractMycetoma is a chronic granulomatous infection of the subcutaneous tissue, most often caused by the fungal pathogenMadurella mycetomatis. Characteristic of the infection is the formation of grains. However, knowledge of the function and formation of the grain is limited. Here, we use aGalleria mellonellalarvae infection model and transcriptomic profiling to identify processes associated withM. mycetomatisgrain formation. Larvae were infected withM. mycetomatisand, after 4, 24, 72 and 168 h post-inoculation, RNA was extracted from larval content and sequenced. We found that 3498G. mellonellaand 136M. mycetomatisgenes were differentially expressed during infection. In particular, genes encoding proteins related to iron transport were highly expressed by bothG. mellonella(transferrin and ferritin) andM. mycetomatis(SidA, SidD and SidI). LC-MS/MS analysis ofM. mycetomatiscultured under iron-limiting conditions revealed the presence of SidA and SidD orthologs, and concurrent RP-HPLC and LC-MS identified a singly charged, putative siderophore in culture supernatant. Furthermore, we show thatM. mycetomatiscan obtain iron from holoferritin. Thus, our results highlight the importance of iron acquisition pathways during grain formation, suggesting potential avenues for development of new diagnostic and therapeutic strategies for mycetoma.
AbstractS-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
AbstractCognitive processing relies on the brain’s ability to balance flexibility for encoding new information with stability for maintaining it. We examined these dynamics in three magnetoencephalography (MEG) datasets of visuospatial working memory (vsWM) tasks. Across all tasks, we identified four distinct networks in the theta and alpha bands, which were used to define functional states. Optimal transitioning rate between states was associated with better cognitive performance. Further, two of the states were linked to flexibility and stability, respectively: an encoding state dominated by a posterior theta and a maintenance state dominated by a dorsal alpha. We simulated the states in an in-silico model with biologically realistic cortical connectivity. The model, featuring spiking and oscillatory cortical layers interacting via phase-amplitude coupling, demonstrated how frequency and spatial region could modulate information flow. Our findings suggest a cognitive control mechanism, where selective transitions between large-scale networks optimize information flow, enabling both stable and flexible visual representations.
AbstractDeep tissue imaging with high contrast close to or even below the optical resolution limit is still challenging due to optical aberrations and scattering introduced by dense biological samples. This results in high complexity and cost of microscopes that can facilitate such challenges. Here, we demonstrate a cost-effective and simple to implement method to turn most two-photon laser-scanning microscopes into a super-resolution microscope for deep tissue imaging. We realize this by adding inexpensive optical devices, namely a cylindrical lens, a field rotator, and a sCMOS camera to these systems. By combining two-photon excitation with patterned line-scanning and subsequent image reconstruction, we achieve imaging of sub-cellular structures inPinus radiata, mouse heart muscle and zebrafish. In addition, the penetration depth of super-resolved imaging in highly scattering tissue is considerably extended by using the camera’s lightsheet shutter mode. The flexibility of our method allows the examination of a variety of thick samples with a variety of fluorescent markers and microscope objective lenses. Thus, with a cost-efficient modification of a multi-photon microscope, an up to twofold resolution enhancement is demonstrated down to at least 70μm deep in tissue.
AbstractDecision-makers often process new evidence selectively, depending on their current beliefs about the world. We asked whether such confirmation biases result from biases in the encoding of sensory evidence in the brain, or alternatively in the utilization of encoded evidence for behavior. Human participants estimated the source of a sequence of visual-spatial evidence samples while we measured cortical population activity with magnetoencephalography. Halfway through the sequence, participants were prompted to judge the more likely source category. We find that processing of subsequent evidence depends on its consistency with the previously chosen category. Evidence encoded in parietal cortex contributes more to the estimation report when that evidence is consistent with the previous choice compared to when it contradicts that choice. Our results indicate that information contradicting pre-existing beliefs has little impact on subsequent behavior, despite being precisely encoded in the brain. This provides room for deliberative control to counteract confirmation biases.
AbstractDysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase inDrosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan by catalase upregulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.
AbstractSpontaneous parametric down-conversion (PDC) of photons is a gateway into the quantum realm – thoroughly studied in nonlinear optics and ubiquitously used to generate non-classical states of light. Extending PDC from the visible regime towards shorter wavelengths further enables microscopic resolution of electronic structure and quantum-enhanced X-ray detection, but remained challenging due to the process’ inherently low conversion rate. Here, we resolve the full signal cone of non-degenerate down-conversion at X-ray wavelengths and identify imprints of a polariton in the extreme ultraviolet (EUV) regime. We confirm our finding of the EUV-polariton with theoretical simulations and establish that our approach directly images the characteristic anti-crossing of polaritonic dispersion branches. This insight could open a pathway to explore strong-coupling phenomena of EUV-light-matter interaction.
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AbstractLittle is known about the genetic connection system and community organization of Late Neolithic and Early Copper Age populations of the Carpathian Basin. Here, we present a comprehensive genetic investigation of these populations, leveraging whole genome data from 125 individuals. Using population genetics, kinship analyses and the study of networks of identity-by-descent haplotype segment sharing, we elucidate the social and genetic dynamics of these communities between 4800−3900 calibrated years BCE. Despite changes in settlement patterns, burial practices, and material culture, we document a high degree of genetic continuity. While one set of individuals from a large community cemetery is genetically diverse, another site is more homogenous and closed, with numerous consanguineous relationships and evidence of patrilineality and patrilocality. In this work, we document important differences in kinship systems in contemporaneous Early Copper Age communities using similar material culture and living only about 100 km apart.
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AbstractThe development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primateMicrocebus murinus(the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque (Macaca fascicularis) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.
AbstractTissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report that apical size reduction via macropinocytosis serves as a malleable and less destructive form of tissue remodeling that can alleviate the need for cell loss. We find that macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane. This drives a reduction in apical surface which alleviates crowding. We report that this mechanism regulates the long-term organization of the developing epithelium and controls the timing of proliferation-induced cell extrusion. Additionally, we observe a wave of macropinocytosis in response to acute external compression. In both scenarios, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to both developmental and external compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.
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AbstractBrain waste is cleared via a cerebrospinal fluid (CSF) pathway, the glymphatic system, whose dysfunction may underlie many brain conditions. Previous studies show coherent vascular oscillation, measured by blood oxygenation level-dependent (BOLD) fMRI, couples with CSF inflow to drive fluid flux. Yet, how this coupling is regulated, whether it mediates waste clearance, and why it is impaired remain unclear. Here we demonstrate that cholinergic neurons modulate BOLD-CSF coupling and glymphatic function. We find BOLD-CSF coupling correlates cortical cholinergic activity in aged humans. Lesioning basal forebrain cholinergic neurons in female mice impairs glymphatic efflux and associated changes in BOLD-CSF coupling, arterial pulsation and glymphatic influx. An acetylcholinesterase inhibitor alters these dynamics, primarily through peripheral mechanisms. Our results suggest cholinergic loss impairs glymphatic function by a neurovascular mechanism, potentially contributing to pathological waste accumulation. This may provide a basis for developing diagnostics and treatments for glymphatic dysfunction.
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AbstractPhytochromes are biliprotein photoreceptors widespread amongst microorganisms and ubiquitous in plants where they control developmental processes as diverse as germination, stem elongation and floral induction through the photoconversion of inactive Pr to the Pfr signalling state. Here we report crystal structures of the chromophore-binding module of soybean phytochrome A, including ~2.2 Å XFEL structures of Pr and Pfr at ambient temperature and high resolution cryogenic structures of Pr. In the Pfr structure, the chromophore is exposed to the medium, the D-ring remaining α-facial following the likely clockwise photoflip. The chromophore shifts within its pocket, while its propionate side chains, their partners as well as three neighbouring tyrosines shift radically. Helices near the chromophore show substantial shifts that might represent components of the light signal. These changes reflect those in bacteriophytochromes despite their quite different signalling mechanisms, implying that fundamental aspects of phytochrome photoactivation have been repurposed for photoregulation in the eukaryotic plant.
AbstractIron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
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AbstractWeak transitions between quantum states are of fundamental importance for a broad range of phenomena from analytical biochemistry to precision physics, but generally challenge experimental detection. Due to their small cross sections scaling with the absolute square of their transition matrix elements, spectroscopic measurements often fail in particular in the presence of competing background processes. Here we introduce a general concept to break this scaling law and enhance the transition probability by exploiting a stronger laser-coupled pathway to the same excited state. We demonstrate the concept experimentally by attosecond transient absorption spectroscopy in helium atoms. The quasi-forbidden transitions from the ground state 1s2to the weakly coupled doubly excited 2p3dandsp2,4−states are boosted by an order of magnitude. Enhancing single-photon-suppressed transitions can find widespread applicability, from spectral diagnostics of complex molecules in life and chemical sciences to precision spectroscopy of weak transitions in metastable atomic nuclei in the search for new physics.
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AbstractMany countries worldwide are transitioning from fossil fuel-dependent economies to carbon neutrality, driven by the 2030 agenda for sustainable development and the Paris Agreement. However, without considering the regional distribution of essential services like water and energy, this transition could inadvertently maintain or increase inequities, threatening sustainable development. Here, we argue that spatial equity of benefits should be considered in planning low-carbon energy transitions, especially in developing countries with multisector interdependencies and high service disparities between regions. We propose an analytical framework that can help analysts and policymakers plan for regionally equitable climate-compatible futures. The multisector design framework combines integrated river basin-power system simulation with artificial intelligence design tools. The utility of the framework is demonstrated for Ghana by identifying the most efficient infrastructure intervention portfolios and their implied trade-offs between spatial equity in water and energy service provision, carbon emissions, food production, and river ecosystem performance. Case-study results show that an equitable low-carbon energy transition will require increased investments in renewable energy and transmission alongside more informed infrastructure system planning. With low renewable investments, equity can be improved, but at the cost of higher emissions and electricity supply curtailments.
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AbstractAlthough aluminum-containing cements have gained attention as environmentally friendly construction materials, the nanocrystalline structure and mechanical behavior of their primary hydration product, calcium aluminate silicate hydrate (C-A-S-H), remain poorly understood due to its complex chemical composition and structural disorder. Here, we present a high-throughput atomistic modeling framework to systematically investigate the structural and mechanical properties of C-A-S-H across a broad range of Ca/Si (1.3–1.9) and Al/Si (0–0.15) ratios. The compositional, structural, and mechanical features of C-A-S-H are accurately captured by molecular dynamics simulations of 1600 distinct C-A-S-H structures constructed using our in-house automatic structure generation program, CASHgen. Our findings highlight the influence of Ca/Si and Al/Si ratios on key C-A-S-H characteristics, including the mean chain length (MCL), interlayer spacing, coordination number and elastic moduli. Specifically, C-A-S-H exhibits optimal mechanical performance at a Ca/Si ratio of approximately 1.5, while further increases in Ca/Si introduce disorder and reduce stiffness. In contrast, increasing the Al/Si ratio promotes chain polymerization, leading to longer MCLs and improved mechanical performance. These results provide atomic-scale insights into the structure-property relationships in C-A-S-H and offer design guidelines for high-performance, low-carbon cementitious materials.
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AbstractAfter acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.
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AbstractOver the past 50 years, Arctic sea ice has declined in all seasons, with particularly pronounced winter reductions in the Barents Sea. While temperature changes in the Atlantic Water inflow and atmospheric-driven melt have been identified as key drivers of this decline, the role of the return-flow of Atlantic Water in the northern Barents Sea Opening, linked to its recirculation back into the Nordic Seas, has remained largely unrecognized. Using a global ocean and sea ice model, we find that the volume transport of the Atlantic Water return-flow is strongly correlated with the sea ice area in the Barents Sea. In addition, we find that, over the past 40 years, the return-flow has steadily weakened without a corresponding change in inflow. Here, we show that reduced Atlantic Water removal by a weakened return-flow contributes to both interannual variability and the sustained loss of Barents Sea sea ice.
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AbstractBio-instructive materials that intrinsically inhibit biofilm formation have significant anti-biofouling potential in industrial and healthcare settings. Since bacterial surface attachment is sensitive to surface topography, we experimentally surveyed 2176 combinatorially generated shapes embossed into polymers using an unbiased screen. This identified microtopographies that, in vitro, reduce colonization by pathogens associated with medical device-related infections by up to 15-fold compared to a flat polymer surface. Machine learning provided design rules, based on generalisable descriptors, for predicting biofilm-resistant microtopographies. On tracking single bacterial cells we observed that the motile behaviour ofPseudomonas aeruginosais markedly different on anti-attachment microtopographies compared with pro-attachment or flat surfaces. Inactivation of Rhl-dependent quorum sensing inP. aeruginosathrough deletion ofrhlIorrhlRrestored biofilm formation on the anti-attachment topographies due to the loss of rhamnolipid biosurfactant production. Exogenous provision ofN-butanoyl-homoserine lactone to therhlImutant inhibited biofilm formation, as did genetic complementation of therhlI,rhlRorrhlAmutants. These data are consistent with confinement-induced anti-adhesive rhamnolipid biosurfactant ‘autolubrication’. In a murine foreign body infection model, anti-attachment topographies are refractory toP. aeruginosacolonization. Our findings highlight the potential of simple topographical patterning of implanted medical devices for preventing biofilm associated infections.
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AbstractCombinatorial control by transcription factors (TFs) is central to eukaryotic gene regulation, yet its mechanism, evolution, and regulatory impact are not well understood. Here we use natural variation in the yeast phosphate starvation (PHO) response to examine the genetic basis and species variation in TF interdependence. InSaccharomyces cerevisiae, the main TF Pho4 relies on the co-TF Pho2 to regulate ~28 genes, whereas in the related pathogenCandida glabrata, Pho4 has reduced Pho2 dependence and regulates ~70 genes. We foundC. glabrataPho4 (CgPho4) binds the same motif with 3–4 fold higher affinity. Machine learning and yeast one-hybrid assay identify two intrinsically disordered regions (IDRs) in CgPho4 that boost its activation domain’s activity. In ScPho4, an IDR next to the DNA binding domain both allows for enhanced activity with Pho2 and inhibits activity without Pho2. This study reveals how IDR divergence drives TF interdependence evolution by influencing activation potential and autoinhibition.
AbstractEquitable coverage and reliable operation of electric vehicle charging stations (EVCSs) are crucial for a just transition to a carbon-free future. Yet, a comprehensive national analysis of public EVCSs across different communities is lacking in the United States. Here, we utilize real-world reviews (n= 470,142) from a user-generated content platform to analyze public EVCSs at the census tract level. We find that disadvantaged communities (DACs) have 64% fewer public EVCSs per capita than non-DACs. This disparity rises to 73% when considering renters in multi-dwelling units. Additionally, EVCS users in DACs and urban areas experience significantly more reliability issues compared to those in non-DACs and rural areas, primarily related to hardware and technical failures. Given the limited access to home charging in DACs and their underserved public infrastructure, these findings highlight critical equity concerns and call for targeted investment in EVCS infrastructure and reliability improvements, particularly in DACs.
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AbstractCellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthesis, induces a long-term yet reversible proliferative arrest in human cells. Severely compromised biogenesis of rRNAs along with acute transcriptional reprogramming precede a gradual decline of the critical cellular functions. Unexpectedly, many arresting cells show increased levels of histone mRNAs, which accumulate locally in the cytoplasm, and S-phase DNA amount. The ensuing proliferative arrest is entered from multiple stages of the cell cycle and can last for several weeks with uncompromised cell viability. Strikingly, restoring expression of RNase MRP leads to a complete reversal of the arrested state with resumed cell proliferation at the speed of control cells. We suggest that targeting rRNA biogenesis may provide a general strategy for rapid induction of a reversible proliferative arrest, with implications for understanding and manipulating cellular quiescence.
AbstractThe eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity ofUSP37knockout cells to topoisomerase inhibitors. InXenopusegg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37’s response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.
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AbstractDue to low availability of CO2in aquatic environment, microalgae have evolved a CO2concentrating mechanism (CCM). It has long been thought that operation of CCM would suppress photorespiration by increasing the CO2concentration at the Rubisco active site, but experimental evidence is scarce. To better explore the function of photorespiration in algae, we first characterized aChlamydomonas reinhardtiimutant defected in low-CO2inducible 20 (LCI20) and show that LCI20 is a chloroplast-envelope glutamate/malate transporter playing a role in photorespiration. By monitoring growth and glycolate excretion in mutants deficient in either CCM or photorespiration, we conclude that: (i.) CCM induction does not depend on photorespiration, (ii.) glycolate excretion together with glycolate dehydrogenase down-regulation prevents the toxic accumulation of non-metabolized photorespiratory metabolites, and (iii.) photorespiration is active at low CO2when the CCM is operational. This work provides a foundation for a better understanding of the carbon cycle in the ocean where significant glycolate concentrations have been found.
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AbstractAnti-NMDA receptor (NMDAR) encephalitis is a devastating disease with severe psychiatric and neurological symptoms believed to be caused by pathogenic autoantibodies that bind to the N-terminal domain (NTD) of the NMDAR GluN1 subunit (GluN1-NTD) crosslinking adjacent NMDARs and driving their internalization. Here we describe ART5803, a humanized monovalent antibody, as a potential therapy for anti-NMDAR encephalitis. ART5803 binds with a high affinity (KD= 0.69 nM) to GluN1-NTD without affecting NMDAR activity or inducing internalization. ART5803 blocks NMDAR internalization induced by patients’ pathogenic autoantibodies, and restores NMDAR function. A marmoset animal model was developed using sustained intracerebroventricular (ICV) administration of a human pathogenic autoantibody to evoke behavioral and motor abnormalities. ART5803 ICV infusion or peripheral injections rapidly reversed these abnormalities. These data, together with the pharmacokinetic profile in cynomolgus monkeys, indicate a therapeutic potential for intravenous (IV)-administered ART5803 as a fast-acting and efficacious option for anti-NMDAR encephalitis.
AbstractAneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
AbstractIncidence of type 1 diabetes is increasing globally, which is hypothesized to be due to environmental influences. We leverage Swedish nationwide registers linked to all children (n= 2,928,704) born in 1982–2010 to investigate if the heritability of childhood-onset type 1 diabetes has changed over time and how alterations in environmental factors have contributed to the rising type 1 diabetes incidence. The heritability is estimated at 0.83 (95% confidence interval: 0.79, 0.86) and stable over the observation period (0.80 [0.71, 0.86] in 1982, 0.83 [0.79, 0.86] in 2000, and 0·83 [0.79, 0.86] in 2010, respectively). Environmental factors including maternal smoking during pregnancy and childhood adiposity explain <10% of the increasing type 1 diabetes incidence. In this work, the heritability of childhood-onset type 1 diabetes has remained high and stable over the last 30 years. Our findings indicate that the available environmental factors are not the major contributors to the rise in type 1 diabetes in Sweden.
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AbstractHistologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression ofMUC16(CA125),MUC4, andKRT24. This cell state is enriched in metastases, predicted to be highly resistant to chemotherapy, and linked with poor survival. We also find enriched expression ofTM4SF1, a transmembrane protein, in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in aTM4SF1expression-dependent manner, highlighting its potential as a therapeutic target.
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AbstractPost-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and functionally important regulatory regions. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and intervention.
AbstractMicrotubules and nuclear transmembrane SUN1/2 proteins promote the mobility of DNA Double Strand Breaks (DSBs) induced by ionizing radiation and the misrepair of one-ended DSBs induced in BRCA1-deficient cells by Poly(ADP-ribose) polymerase inhibitors (PARPi). However, whether microtubules promote aberrant DSBs repair by altering the nuclear structure and whether the nuclear structure itself plays a role in these processes is still unclear. Here we show that microtubule-dependent DSBs mobility in BRCA1-deficient cells after PARPi treatment is associated with nuclear envelope (NE) invaginations. Furthermore, increasing NE invaginations byLmnadeletion or inhibition of sphingolipid synthesis increases DSBs mobility, chromosomal aberrations, and PARPi cytotoxicity in BRCA1-deficient cells. These findings reveal a functional connection between the NE and DSB repair and suggest that drugs increasing NE deformability will enhance PARPi therapy efficacy in BRCA1-deficient cancers.
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AbstractSpatial multi-slice multi-omics (SMSMO) integration has transformed our understanding of cellular niches, particularly in tumors. However, challenges like data scale and diversity, disease heterogeneity, and limited sample population size, impede the derivation of clinical insights. Here, we propose stClinic, a dynamic graph model that integrates SMSMO and phenotype data to uncover clinically relevant niches. stClinic aggregates information from evolving neighboring nodes with similar-profiles across slices, aided by a Mixture-of-Gaussians prior on latent features. Furthermore, stClinic directly links niches to clinical manifestations by characterizing each slice with attention-based geometric statistical measures, relative to the population. In cancer studies, stClinic uses survival time to assess niche malignancy, identifying aggressive niches enriched with tumor-associated macrophages, alongside favorable prognostic niches abundant in B and plasma cells. Additionally, stClinic identifies a niche abundant inSPP1+MTRNR2L12+ myeloid cells and cancer-associated fibroblasts driving colorectal cancer cell adaptation and invasion in healthy liver tissue. These findings are supported by independent functional and clinical data. Notably, stClinic excels in label annotation through zero-shot learning and facilitates multi-omics integration by relying on other tools for latent feature initialization.
AbstractA major challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma types and the corresponding lack of suitable model systems. Here we describe the development of a genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by muscle electroporation (EPO) in wildtype mice. This EPO-GEMM (EPO-based genetically engineered mouse model) platform allows the generation of ten genetically distinct sarcomas on an isogenic background, including the first model ofETV6::NTRK3-driven sarcoma. Comprehensive histological and molecular profiling reveals that this mouse sarcoma cohort recapitulates a spectrum of molecularly diverse sarcomas with gene fusions acting as major determinants of sarcoma biology. Integrative cross-species analyses show faithful recapitulation of human sarcoma subtypes, including expression of relevant immunotherapy targets. Comparison of syngeneic allografting methods enables reliable preservation and scalability of sarcoma-EPO-GEMMs for preclinical treatment trials, such as NTRK inhibitor therapy in an immunocompetent background.
AbstractHigh ambient temperatures are associated with reduced sleep duration and quality, but effects on obstructive sleep apnea (OSA) severity are unknown. Here we quantify the effect of 24 h ambient temperature on nightly OSA severity in 116,620 users of a Food and Drug Administration-cleared nearable over 3.5 years. Wellbeing and productivity OSA burden for different levels of global warming were estimated. Globally, higher temperatures (99thvs. 25th; 27.3 vs. 6.4 °C) were associated with a 45% higher probability of having OSA on a given night (mean [95% confidence interval]; 1.45 [1.44, 1.47]). Warming-related increase in OSA prevalence in 2023 was estimated to be associated with a loss of 788,198 (489,226, 1,087,170) healthy life years (in 29 countries), and a workplace productivity loss of 30 (21 to 40) billion United States dollars. Scenarios with projected temperatures ≥1.8 °C above pre-industrial levels would incur a further 1.2 to 3-fold increase in OSA burden by 2100.
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AbstractCultural systems play an important role in shaping the interactions between humans and the environment, and are in turn shaped by these interactions. However, at present, cultural systems are poorly integrated into the models used by climate scientists to study the interaction of natural and anthropogenic processes (i.e. Earth systems models) due to pragmatic and conceptual barriers. In this Perspective, we demonstrate how the archaeology of climate change, an interdisciplinary field that uses the archaeological record to explore human-environment interactions, is uniquely placed to overcome these barriers. We use concepts drawn from climate science and evolutionary anthropology to show how complex systems modeling that focuses on the spatial structure of the environment and its impact on demographic variables, social networks and cultural evolution, can bridge the gap between large-scale climate processes and local-scale social processes. The result is a blueprint for the design of integrative models that produce testable hypotheses about the impact of climate change on human systems.
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AbstractOne of the key achievements of equilibrium polymer physics is the prediction of scaling laws governing the viscoelastic properties of entangled polymer systems, validated in both natural polymers, such as DNA, and synthetic polymers, including polyethylene, which form materials like plastics. Recently, focus has shifted to active polymers systems composed of motile units driven far from equilibrium, such as California blackworms, self-propelled biopolymers, and soft robotic grippers. Despite their growing importance, we do not yet understand their viscoelastic properties and universal scaling laws. Here, we use Brownian dynamics simulations to investigate the viscoelastic properties of highly-entangled, flexible self-propelled polymers. Our results demonstrate that activity enhances the elasticity by orders of magnitude due to the emergence of grip forces at entanglement points, leading to its scaling with polymer length ∼L. Furthermore, activity fluidizes the suspension, with the long-time viscosity scaling as ∼L2, compared to ∼L3in passive systems. These insights open new avenues for designing activity-responsive polymeric materials.
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AbstractExcitation energy transfer between photosynthetic light-harvesting complexes is vital for highly efficient primary photosynthesis. Controlling this process is the key for advancing the emerging artificial photosynthetic systems. Here, we experimentally demonstrate the enhanced excitation energy transfer between photosynthetic light-harvesting 2 complexes (LH2) mediated through the Fabry-Pérot optical microcavity. Using intensity-dependent pump-probe spectroscopy, we analyse the exciton-exciton annihilation (EEA) due to inter-LH2 energy transfer. Comparing EEA in LH2 within cavity samples and the bare LH2 films, we observe enhanced EEA in cavities indicating improved excitation energy transfer via coupling to a common cavity mode. Surprisingly, the effect remains even in the weak coupling regime. The enhancement is attributed to the additional connectivity between LH2s introduced by the resonant optical microcavity. Our results suggest that optical microcavities can be a strategic tool for modifying excitation energy transfer between molecular complexes, offering a promising approach towards efficient artificial light harvesting.
AbstractImporting renewable energy to Europe may offer many potential benefits, including reduced energy costs, lower pressure on infrastructure development, and less land use within Europe. However, open questions remain: on the achievable cost reductions, how much should be imported, whether the energy vector should be electricity, hydrogen, or derivatives like ammonia or steel, and their impact on Europe’s infrastructure needs. This study integrates a global energy supply chain model with a European energy system model to explore net-zero emission scenarios with varying import volumes, costs, and vectors. We find system cost reductions of 1-10%, within import cost variations of ± 20%, with diminishing returns for larger import volumes and a preference for methanol, steel and hydrogen imports. Keeping some domestic power-to-X production is beneficial for integrating variable renewables, leveraging local carbon sources and power-to-X waste heat. Our findings highlight the need for coordinating import strategies with infrastructure policy and reveal maneuvering space for incorporating non-cost decision factors.
AbstractPrognosis for thoracic aortic aneurysms is significantly worse for women than men, with a higher mortality rate observed among female patients. The increasing use of magnetic resonance breast imaging (MRI) offers a unique opportunity for simultaneous detection of both breast cancer and thoracic aortic aneurysms. We retrospectively validate a fully-automated artificial neural network (ANN) pipeline on 5057 breast MRI examinations from public (Duke University Hospital/EA1141 trial) and in-house (Erlangen University Hospital) data. The ANN, benchmarked against 3D-ground-truth segmentations, clinical reports, and a multireader panel, demonstrates high technical robustness (dice/clDice 0.88-0.91/0.97-0.99) across different vendors and field strengths. The ANN improves aneurysm detection rates by 3.5-fold compared with routine clinical readings, highlighting its potential to improve early diagnosis and patient outcomes. Notably, a higher odds ratio (OR = 2.29, CI: [0.55,9.61]) for thoracic aortic aneurysms is observed in women with breast cancer or breast cancer history, suggesting potential further benefits from integrated simultaneous assessment for cancer and aortic aneurysms.
AbstractSexual dysmorphism in the number and distribution of meiotic crossovers is seen across species but is poorly understood. Here, we disrupt multiple anti-crossover pathways in hermaphrodite Arabidopsis and analyze thousands of female and male progeny genomes. The greatest crossover increase is seen inzyp1 recq4mutants, with a 12-fold rise in females and 4.5-fold in males. Additional manipulation of crossover regulators does not further increase crossovers but shifts the balance between crossover pathways, suggesting competition for a shared, limited precursor pool. While wild-type crossover patterns differ between sexes, mutant crossover landscapes converge on a unique distinct profile, which we term Crossover Potential (COP). COPcan be accurately predicted using only sequence and chromatin features. We propose that COPreflects the density of eligible recombination precursors, which is determined by genomic features and is thus identical across sexes, with sexual dimorphism resulting solely from differential regulation of their maturation into crossovers.
AbstractConventional laboratory mice housed under specific pathogen-free (SPF) conditions are the standard model in biomedical research. However, in recent years, many rodent-based studies have been deemed irreproducible, raising questions about the suitability of mice as model organisms. Emerging evidence indicates that variability in SPF microbiota plays a significant role in data inconsistencies across laboratories. Although efforts have been made to standardize microbiota, existing microbial consortia lack the complexity and resilience necessary to replicate interactions in free-living mammals. We present a robust, feasible and standardizable approach for transplanting natural gut microbiota from wildlings into laboratory mice. Following engraftment, these TXwildlings adopt a structural and functional wildling-like microbiota and host physiology toward a more mature immune system, with characteristics similar to those of adult humans. We anticipate that adopting wild mouse-derived microbiota as standard for laboratory mouse models will improve the reproducibility and generalizability of basic and preclinical biomedical research.
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AbstractSalivary gland cancers are rare, diverse malignancies characterized by poor response to immunotherapy. The tumor immune environment in these cancers remains poorly understood. To address this, we perform an integrative analysis of the tumor immune microenvironment in a large cohort of advanced salivary gland cancer samples. Most tumors exhibit low immune activity with limited immune cell infiltration. Inflammation is linked to higher tumor mutational burden in non-adenoid cystic carcinoma histologies. Subtype specific expression of immune checkpoints is identified with prominent expression ofVTCN1in luminal-like cells within adenoid cystic carcinoma. Macrophages with immunosuppressive properties dominate the immune microenvironment across subtypes. Responses to immunotherapy are limited and associated with a higher ratio of T-cells relative to macrophages in individual cases, warranting further investigation. Here, we show an immunosuppressive environment in salivary gland cancers and identify subtype-specific immune vulnerabilities that could inform tailored therapeutic strategies.
AbstractWhile small carbocyclic rings have long been recognized as pivotal building blocks in chemistry, their all-boron counterparts have remained largely unexplored. In this work, we present a detailed account of the functionalization reactivity of our cyclic tetraborane B4(NCy2)4(Cy = cyclohexyl) encompassing both ring-expansion and ring-opening reactions. Specifically, diphenyl dichalcogenides effect ring expansion to five-membered B4E rings (E = S, Se, Te), while halogenating agents induce ring opening to generate linear tetraboranes with halide end groups. These transformations reveal reactivity patterns reminiscent of strained organic ring systems, thus highlighting the cyclic tetraborane’s potential as a versatile precursor for synthesizing intricate boron-rich architectures.
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AbstractNet-zero commitments have become the focal point for countries to communicate long-term climate targets. However, to this point it is not clear to what extent conventional emissions reductions and carbon dioxide removal (CDR) will contribute to net-zero. An integrated market for emissions and removals with a uniform carbon price delivers the economically efficient contribution of CDR to net-zero. Yet it might not fully internalise sustainability risks of CDR and hence could lead to its overuse. In this study, we explore the implications of separating targets for emissions and for removals delivered by novel CDR in global net-zero emissions pathways with the Integrated Assessment Model REMIND. We find that overall efficiency losses induced by such separation are moderate. Furthermore, limiting the CDR target comes with increasing emission prices but also significant benefits: lower cumulative emissions, a lower financial burden for public finance of CDR and limited reliance on geologic CO2storage but fails to lower the biomass demand. Proposed targets should also ensure sufficient CDR deployment to achieve net-negative emissions in the second half of the 21st century.
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AbstractMechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly understood due to its rarity. A subset of SNSCC is associated with human papillomavirus (HPV), but it is unclear whether HPV drives tumorigenesis or acts as a neutral bystander. Here, we show that HPV-associated SNSCC shares mutational patterns found in HPV-associated cervical and head and neck squamous cell carcinoma, including lack ofTP53mutations, hotspot mutations inPI3KandFGFR3, enrichment of APOBEC mutagenesis, viral integration at known hotspots, and frequent epigenetic regulator alterations. We identify HPV-associated SNSCC-specific recurrent mutations inKMT2C,UBXN11,AP3S1,MT-ND4, andMT-ND5, withKMT2DandFGFR3mutations correlating with reduced overall survival. We establish an HPV-associated SNSCC cell line, showing that combinatorial small-molecule inhibition of YAP/TAZ and PI3K synergistically suppresses clonogenicity. Combining YAP/TAZ blockade with vertical PI3K inhibition may benefit HPV-associated SNSCC, whereas targeting MYC and horizontal inhibition of RAS/PI3K may suit HPV-independent SNSCC.
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AbstractReforestation is a prominent climate change mitigation strategy, but available global maps of reforestation potential are widely criticized and highly variable, which limits their ability to provide robust estimates of both the locations and total area of opportunity. Here we develop global maps that address common critiques, build on a review of 89 reforestation maps created at multiple scales, and present eight reforestation scenarios with varying objectives, including providing ecosystem services, minimizing social conflicts, and delivering government policies. Across scenarios, we find up to 195 Mha (million hectares) are available (2225 TgCO2e (teragrams of carbon dioxide equivalent) per year total net mitigation potential), which is 71–92% smaller than previous estimates because of conservative modeling choices, incorporation of safeguards, and use of recent, high-resolution datasets. This area drops as low as 6 Mha (53 TgCO2e per year total net mitigation potential) if only statutorily protected areas are targeted. Few locations simultaneously achieve multiple objectives, suggesting that a mix of lands and restoration motivations will be needed to capitalize on the many potential benefits of reforestation.
AbstractIntrospection on memory states guides decision-making, but little is known about how it emerges in childhood. Toddlers’ behavioral responses to difficult memory decisions (e.g., information seeking) suggest early capacity to track uncertain situations, but it is unclear whether these behaviors relate to later emerging capacity to introspect on memory accuracy (i.e., metamemory monitoring). In a pre-registered longitudinal study, 176 25- to 34-month-olds encode images, then are asked to select the familiar image from arrays that also include a new image (Time 1). One year later (Time 2), 157 participants complete a similar memory task and report decision confidence. Higher gaze transitions between responses, indicative of evaluation processes, faster response latencies, and greater memory at Time 1 predict Time 2 metamemory monitoring (i.e., greater confidence for accurate than inaccurate decisions). At Time 2, gaze transitions are associated with lower overall confidence. Overall, this research reveals potential building blocks of emerging metamemory monitoring.
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AbstractBeyond conventional electrical modulation, flexoelectricity enables mechanical control of ferroelectric polarizations, offering a pathway for tactile-responsive ferroelectric systems. However, mechanical polarization switching typically requires substantial static threshold forces to overcome the significant energy barrier, resulting in material fatigue and slow response that compromises reliability and hinders practical applications. In this work, we address these challenges by introducing an imprint field through asymmetric electrostatic boundary design with distinct work functions. This built-in electric field stabilizes the energy landscape, effectively lowering the polarization switching barrier. Subsequently, nonvolatile polarization switching with a low threshold force of 12 nN·nm−1is achieved in CuInP2S6without material damage. Surpassing the limitations of slow static force controls, our work marks the first experimental demonstration of fast mechanical control of polarization switching with 4 millisecond-long low force pulses. To further highlight the potential of this rapid, low-force mechanical control, we propose a van der Waals heterostructured mechanically gated transistor with asymmetric electrostatic boundary, which exhibits gate force pulses-controlled multi-level, nonvolatile conductance states. Our findings establish a paradigm for next-generation ferroelectric electronics that integrate responsiveness to mechanical stimuli.
AbstractPost-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging.
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AbstractThe liver’s regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.
AbstractVisible-light-absorbing semiconductor nanocrystals have shown great promise as photocatalysts for promoting photoredox chemistry. However, their utilization in organic synthesis remains considerably limited compared to small molecule photosensitizers. Recently, the generation of hot electrons from quantum-confined systems has emerged as a powerful means of photoreduction, yet the efficiencies remain limited under mild conditions. In this study, we present an efficient hot-electron generation system facilitated by the spin-exchange Auger process in Mn2+-doped CdS/ZnS quantum dots. These hot electrons can be effectively utilized in a wide range of organic reactions, such as the Birch reduction and reductive cleavage of C-Cl, C-Br, C-I, C-O, C-C, and N-S bonds. Notably, these reactions accommodate substrate reduction potentials as low as −3.4 V versus the saturated calomel electrode. Through two-photon excitation, we achieve the generation of a “super” photoreductant using visible-light irradiation power that is only 1% of that previously reported for molecular and quantum dot systems. By modulating the intensity of light output, the spin-exchange Auger process enables the on/off generation of hot electrons, allowing for programmable assembly-point cross-coupling cascades. Our findings demonstrate the potential of quantum-confined semiconductors in facilitating challenging organic transformations that were unattainable with molecular photocatalysts.
AbstractHigh-resolution nanopore analysis technology relies on the design of novel transmembrane protein platforms. Traditional barrel-shaped protein channels are preferred for constructing nanopore sensors, which may miss protein candidates in non-barrel structures. Here, we demonstrate the globular ferritin displays excellent membrane-insertion capacity and stable transmembrane ionic current owing to its hydrophobic four-fold channels and hydrophilic three-fold channels. The ionic current rectification and voltage-gating characteristics are discovered in single-ferritin ionic current measurement. Notably, the ferritin is used as a nanopore sensor, by which we achieve the high resolution discrimination of L-cysteine, L-homocysteine, and cysteine-containing dipeptides with the assistance of equivalent Cu2+. The mechanistic studies by multiple controlled experiments and quantum mechanics/all-atom/coarse-grained multiscale MD simulations reveal that analytes are synergistically captured by His114, Cys126, and Glu130 within C3 channel, causing the current blockage signals. The promising ferritin nanopore sensor provides a guide to discovering new protein nanopores without shape restrictions.
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AbstractChemoselective dual functionalization of proteins has emerged as an invaluable tool to introduce two distinct payloads to proteins, thus greatly expanding their structural and functional repertoire for more advanced biomedical applications. Here, we introduceN-alkylpyridinium reagents as soft electrophiles for chemoselective dual modification of cysteine residues in peptides or proteins via a 1,6-addition reaction. TheN-alkylpyridinium derivatives can be synthesized in two reaction steps revealing good water solubility, high labelling efficiency and chemoselectivity towards cysteine over lysine/N-terminal amine residues, even when used in large excess. This reaction can be combined with strain-promoted azide-alkyne click (SPAAC) and inverse-electron-demand Diels−Alder (iEDDA) reactions to achieve dual functionalization of proteins in a sequential simple one-pot reaction. As a proof-of-concept, the Rho-inhibiting enzymeClostridium botulinumC3 is functionalized with a cancer cell-targeting peptide and a fluorescent dye for the inhibition of specific Rho-mediated intracellular pathways. The high stability, ease of synthesis, fast reaction kinetics, high water-solubility and chemoselectivity makeN-alkylpyridinium reagents unique for dual modification of peptides and proteins to increase their functional diversities for medical applications.
AbstractIn the era of big data, developing next-generation self-powered continuous energy harvesting systems is of great importance. Taking advantage of fallen leaves’ specific structural advantage gifted by nature, we propose a facile approach to convert fallen leaves into energy harvesters from ubiquitous moisture, based on surface treatments and asymmetric coating of hygroscopic iron hydrogels. Upon moisture absorption, a water gradient is established between areas with/without hydrogel coating, and maintained due to gel-like behaviors and leaf veins for water retention and diffusion restriction, thus forming electrical double layers over the leaf surface and showing capacitance-like behavior for energy charging and discharging. Besides, the specific leaf cell structures with small grooves enabled uniform carbon coatings instead of aggregations, and high electrical conductivity, resulting in 49 μA/cm2and 497 μW/cm3electrical output, achieving competitive performance with the state-of-art and potential for lower environmental impact compared to other types of energy harvesters.
AbstractWe develop a framework for understanding indirect assortative mating and provide updated definitions of key terms. We then develop family models that use partners of twins and siblings to freely estimate the degree of genetic and social homogamy, and account for it when investigating sources of parent-offspring similarity. We applied the models to educational attainment using 1,545,444 individuals in 212,070 extended families in the Norwegian population and Norwegian Twin Registry. Partner similarity in education was better explained by indirect assortment than direct assortment on observed educational attainment, with social homogamy being particularly important. The implied genotypic partner correlation (r= 0.34) was comparable to earlier studies, and higher than expected under direct assortment. About 38% of the parent-offspring correlation (r= 0.34) was attributable to various forms of environmental transmission. Alternative models that assumed direct assortment estimated environmental transmission to be lower, but these did not fit the data well.
AbstractMutations in theTANGO2gene cause an autosomal recessive disorder characterised by developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias along with severe metabolic crises. AlthoughTANGO2mutations result in a well characterised disease pathology, the function of TANGO2 is still unknown. To investigate the function of TANGO2, we knocked out theTANGO2gene in human cells and mice. We identify that loss of TANGO2 impairs intermediate filament structure, resulting in fragmented mitochondrial networks and formation of cup-like mitochondria. In male mice, loss of TANGO2 caused heart defects, reduced muscle function and glucose intolerance by remodelling of intermediate filaments, which altered the mitochondrial and cytoplasmic proteomes, N-glycosylation and nucleocytoplasmic O-GlcNAcylation. We identify that TANGO2 binds the small heat shock protein crystallin alpha B (CRYAB) to prevent the aggregation of the intermediate filament desmin and in the absence of TANGO2, mice develop desminopathy, which is consistent with features found in patients carrying mutations in either desmin or CRYAB.
AbstractThe self-powered photoelectrochemical components themselves featured advancements in operating independently without external supply. Ultimately, due to lack of assistance from the external bias, the photoelectrochemical response is commonly restricted by the deficient photo-quantum efficiency for the absence of carrier multiplication. This work demonstrates a self-powered photoelectrochemical photodetector based on CuOx/AlGaN nanowires with staggered band structure and enhanced built-in potential for efficient exciton extraction. The generated multiple excitons within reach-through CuOxlayer could be speedily separated before Auger recombination. This yields a 131.5% external quantum efficiency and 270.6 mA W−1responsivity at 255 nm. The work confirms the role of multiple exciton generation in photoelectrochemical systems, offering a solution on paving path of advance for self-powered optoelectronics and weak-light UV imaging applications.
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AbstractOptically generated microwaves exhibit unprecedented low noise, benefiting applications such as communications, radar, instrumentation, and metrology. To date, the purest microwave signals are produced using optical frequency division with femtosecond mode-locked lasers. However, their typical repetition rates of hundreds of MHz require multiplication methods to reach the microwave domain. Here, we introduce a miniaturized photonic integrated circuit-based interleaver, achieving a 64-fold multiplication of the repetition rate from 216 MHz to 14 GHz in Ku-Band. With the interleaver, the generated microwave power was improved by 35 dB, with a phase noise floor reduced by more than 10 folds by alleviating photodetector saturation. Based on a low-loss and high-density Si3N4waveguides, six cascaded stages of Mach-Zehnder interferometers with optical delay lines up to 33 centimeters long are fully integrated into a compact chip. Our result can significantly reduce the cost and footprint of mode-locked-laser-based microwave generation, enabling field deployment in aerospace and communication applications.
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AbstractIn materials exhibiting photoinduced phase transitions, and in which both charge transfer and spin transitions occur, there has long been a debate about which process drives the phase transition. Herein, we present experimental evidence supporting an optically charge-transfer-induced spin transition (CTIST) process, as demonstrated through femtosecond optical spectroscopy in two-dimensional cyanido-bridged cobalt-tungstate photomagnets. Optical and magnetic studies revealed that the photoexcitation of the ground low-temperature (LT) CoIIILS-WIVstate leads to a photoinduced phase transition towards the CoIIHS-WVstate, which is similar to the high temperature (HT) state. Ultrafast spectroscopy further indicates that this optical excitation of the intermetallic W-to-Co charge-transfer band produces a transient photoexcited (PE) CoIILS-WVstate, which decays within 130 fs through a spin transition towards the CoIIHS-WVstate. Here we show that the CTIST dynamics corresponds to the CoIIILS-WIV(LT) → CoIILS-WV(PE) → CoIIHS-WV(HT) sequence. The present work sheds a new light on understanding optical dynamics underlying the photoinduced phase transitions.
AbstractPeptide-specific PLZF+innate-like T (PILT) cells are a member of the innate-like T cell family utilizing a diverse set of T cell receptor (TCR) Vβ chains. Yet there are no present studies providing clues into the developmental features of PILT cells at a transcriptome level. Here, we performed single-cell transcriptomic analyses of PILT cells and compared them to other members of the innate-like T cell family. We show that PILT cells share similar transcriptional profiles and overlapping developmental trajectories with invariant Natural Killer T (iNKT) cells. However, in contrast to iNKT cells, PILT cells display a polyclonal TCR repertoire closely resembling the one of conventional CD8 T cells, inferring MHC I restriction and a broader range of antigen specificity. We further show that artificial thymic organoid cultures (ATOC) support selection and development of PILT cells in vitro exhibiting similar transcriptional profiles to their counterparts maturing in the thymus. Moreover, using an “on-time” TCR retrogenic ATOC system, we provide evidence for an instructive role of TCR specificity in PILT cell lineage commitment and functional differentiation. Altogether, our findings provide further insights into the PILT cells unique characteristics and molecular mechanisms governing their development.
AbstractStrong coupling between matter and vacuum electromagnetic fields in a cavity can induce novel quantum phases in thermal equilibrium via symmetry breaking. Particularly intriguing is the coupling with circularly polarized cavity fields, which can break time-reversal symmetry (TRS) and lead to topological bands. This has spurred significant interest in developing chiral cavities that feature broken TRS, especially in the terahertz (THz) frequency range, where various large-oscillator-strength resonances exist. Here, we present a design for high-quality-factor THz chiral photonic-crystal cavities (PCCs) that achieve broken TRS using a magnetoplasma in a lightly doped semiconductor. We incorporate ab initio density functional theory calculations into the derived microscopic model, allowing a realistic estimate of the vacuum-induced gap in graphene when coupled to our chiral cavity. Our calculations show an enhancement in the light–matter interaction due to Dirac nodes and predict an energy gap on the order of 1 meV. The THz chiral PCCs offer a promising platform for exploring cavity-dressed condensed matter with broken TRS.
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AbstractWe introduce universal diffractive waveguide designs that can match the performance of conventional dielectric waveguides and achieve various functionalities. Optimized using deep learning, diffractive waveguides can be cascaded to form any desired length and are comprised of transmissive diffractive surfaces that permit the propagation of desired modes with low loss and high mode purity. In addition to guiding the targeted modes through cascaded diffractive units, we also developed various waveguide components and introduced bent diffractive waveguides, rotating the direction of mode propagation, as well as spatial and spectral mode filtering and mode splitting diffractive waveguide designs, and mode-specific polarization control. This framework was experimentally validated in the terahertz spectrum to selectively pass certain spatial modes while rejecting others. Without the need for material dispersion engineering diffractive waveguides can be scaled to operate at different wavelengths, including visible and infrared spectrum, covering potential applications in, e.g., telecommunications, imaging, sensing and spectroscopy.
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AbstractThere is accumulating evidence that the human cerebellum is heavily implicated in adult social cognition. Yet, its involvement in the development of Theory of Mind (ToM), a hallmark of social cognition, remains elusive. Using openly available functional MRI data of children with emerging ToM abilities (N= 41, age range: 3-12 years) and adults (N= 78), we show that children who pass a false-belief assessment of ToM abilities activate cerebellar Crus I-II in response to ToM events during a movie-watching task, similar to adults. This activation is not statistically significant in children who do not pass the ToM assessment. Functional connectivity profiles between cerebellar and cerebral ToM regions differ as a function of children’s ToM abilities. Notably, task-driven connectivity shifts from upstream to downstream connections between cerebellar and cerebral ToM regions from childhood to adulthood. Greater dependence on connections emerging from the cerebellum early in life suggests an important role of the cerebellum in establishing the cognitive processes underlying ToM in childhood and thus for the undisrupted development of social cognition.
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AbstractmRNA localization to specific subcellular regions is common in mammalian cells but poorly understood in terms of its physiological roles. This study demonstrates the functional importance ofNet1mRNA, which we find prominently localized at the dermal-epidermal junction (DEJ) in stratified squamous epithelia.Net1mRNA accumulates at DEJ protrusion-like structures that interact with the basement membrane and connect to a mechanosensitive network of microfibrils. DisruptingNet1mRNA localization in mouse epithelium alters DEJ morphology and keratinocyte-matrix connections, affecting tissue homeostasis. mRNA localization dictates the cortical accumulation of the Net1 protein and its function as a RhoA GTPase exchange factor (GEF). Altered RhoA activity is in turn sufficient to alter the ultrastructure of the DEJ. This study provides a high-resolution in vivo view of mRNA targeting in a physiological context. It further demonstrates how the subcellular localization of a single mRNA can significantly influence mammalian epithelial tissue organization, thus revealing an unappreciated level of post-transcriptional regulation that controls tissue physiology.
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AbstractRelapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4cells did not clearly improve outcomes despite EBV-specific TTCR-C4cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.
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AbstractMetastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis.HLFdepletion enhances ccRCC cell migration and lung metastasis, whereasHLFoverexpression abrogates these effects. In ccRCC patients,HLFexpression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1.HLFlevels negatively correlate with migration potential in collagen. Mechanistically, HLF regulatesLPXNexpression, modulating the integration of collagen’s mechanical cues with the actin cytoskeleton through Paxillin, thereby suppressing cancer cell migration and lung metastasis. Overexpression ofHLFor pharmacological inhibition of BRG1 reduces cell invasion across multiple cancer types. Our findings suggest that targeting the BRG1-HLF axis offers a promising therapeutic strategy for combating metastatic cancers.
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AbstractSaccharomyces cerevisiaeprimarily generates energy through glycolysis and respiration. However, the manifestation of the Crabtree effect results in substantial carbon loss and energy inefficiency, which significantly diminishes product yield and escalates substrate costs in microbial cell factories. To address this challenge, we introduce the sucrose phosphorolysis pathway and delete the phosphoglucose isomerase genePGI1, effectively decoupling glycolysis from respiration and facilitating the metabolic transition of yeast to a Crabtree-negative state. Additionally, a synthetic energy system is engineered to regulate the NADH/NAD+ratio, ensuring sufficient ATP supply and maintaining redox balance for optimal growth. The reprogrammed yeast strain exhibits significantly higher yields of various non-ethanol compounds, with lactic acid and 3-hydroxypropionic acid production increasing by 8- to 11-fold comparing to the conventional Crabtree-positive strain. This study describes an approach for overcoming the Crabtree effect in yeast, substantially improving energy metabolism, carbon recovery, and product yields.
AbstractThe pathogenPseudomonas aeruginosaenhances its virulence and antibiotic resistance upon formation of durable biofilms. The exopolysaccharides Pel, Psl and alginate essentially contribute to the biofilm matrix, but their secretion mechanisms are barely understood. Here, we reveal the architecture of the outer membrane complex PelBC for Pel export, where the essential periplasmic ring of twelve lipoproteins PelC is mounted on top of the nanodisc-embedded β-barrel PelB. The PelC assembly is stabilized by electrostatic contacts with the periplasmic rim of PelB and via the membrane-anchored acyl chains. The negatively charged interior of the PelB β-barrel forms a route for the cationic Pel exopolysaccharide. The β-barrel is sealed at the extracellular side, but molecular dynamic simulations suggest that the short loop Plug-S is sufficiently flexible to open a tunnel for the exopolysaccharide transport. This gating model is corroborated by single-channel conductivity measurements, where a deletion of Plug-S renders a constitutively open β-barrel. Our structural and functional analysis offers a comprehensive view on this pathogenicity-relevant complex and suggests the route taken by the exopolysaccharide at the final secretion step.
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AbstractLactobacillusdisplacement from the vaginal microbiome associates with adverse health outcomes and is linked to increased risk of preterm birth. Glycans mediate bacterial adhesion events involved in colonisation and infection. Using customised glycan microarrays, we establish glycan interaction profiles of vaginal bacteria implicated in reproductive health. Glycan binding signatures of the opportunistic pathogensEscherichia coli,Fusobacterium nucleatumandStreptococcus agalactiaeto oligomannose N-glycans, galactose-terminating glycans and hyaluronic acid, respectively are highly distinct fromLactobacilluscommensals. Binding to sulphated glycosaminoglycans by vaginal bacteria is pH dependent, as is binding to neutral and sialic acid-terminating glycans byF. nucleatum. Adhesion ofLactobacillus crispatus,Lactobacillus iners,Gardnerella vaginalis,S. agalactiaeandF. nucleatumto vaginal epithelial cells is partially mediated by chondroitin sulphate.S. agalactiaebinding to chondroitin sulphate C oligosaccharides is inhibited byL. crispatus. This study highlights glycans as mediators of vaginal bacterial binding events involved in reproductive health and disease.
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AbstractThe fossil record provides direct evidence for the behavior of biological systems over millions of years, offering a vital source for studying how ecosystems evolved and responded to major environmental changes. Using network analysis on a dataset of over 3000 fossil species spanning the past 60 Myr, we find that ungulate continental assemblages exhibit prolonged ecological stability interrupted by irreversible reorganizations associated with abiotic events. During the early Cenozoic, continental assemblages are dominated by mid-sized browsers with low-crowned teeth, which show increasing functional diversity. Around 21 Ma, the formation of a land bridge between Eurasia and Africa triggers the first major global transition towards a new functional system featuring a prevalence of large browsers with mid- to high-crowned molars. Functional diversity continues to increase, peaking around 10 Ma. Shortly after, aridification and the spread of C4-dominated vegetation lead to a second tipping point towards a fauna characterized by grazers and browsers with high and low crowned teeth. A global decline in ungulate functional diversity begins 10 Ma ago and accelerates around 2.5 Ma, yet the functional structure of these faunas remains stable in the latest Cenozoic. Large mammal evolutionary history reflects two key transitions, aligning with major tectonic and climatic events.
AbstractLayered two-dimensional (2D) materials offer many promising avenues for advancing modern electronics, thanks to their tunable optical, electronic, and magnetic properties. Applying a strong electric field perpendicular to the layers, typically at the MV/cm level, is a highly effective way to control these properties. However, conventional methods to induce such fields employ electric circuit - based gating techniques, which are restricted to microwave response rates and face challenges in achieving device-compatible ultrafast, sub-picosecond control. Here, we demonstrate an ultrafast field effect in atomically thin MoS2embedded within a hybrid 3D-2D terahertz nanoantenna. This nanoantenna transforms an incoming terahertz electric field into a vertical ultrafast gating field in MoS2, simultaneously enhancing it to the MV/cm level. The terahertz field effect is observed as a coherent terahertz-induced Stark shift of exciton resonances in MoS2. Our results offer a promising strategy to tune and operate ultrafast optoelectronic devices based on 2D materials.
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AbstractThe design and control of atomic-scale spin structures constitute major challenges for spin-based quantum technology platforms, including quantum dots, color centers, and molecular spins. Here, we showcase a strategy for designing the quantum properties of molecular spin qubits by combining tip-assisted on-surface assembly with electron spin resonance scanning tunneling microscopy (ESR-STM): We fabricate magnetic dimer complexes that consist of an iron phthalocyanine (FePc) molecule and an organometallic half-sandwich complex formed by the FePc ligand and an attached iron atom, Fe(C6H6). The total complex forms a mixed-spin (1/2,1) quantum ferrimagnet with a well-separated correlated ground state doublet, which we utilize for coherent control. As a result of the correlation, the quantum ferrimagnet shows an improved spin lifetime ( > 1.5 μs) as it is partially protected against inelastic electron scattering. Lastly, the ferrimagnet units also enable intermolecular coupling, that can be used to realize both ferromagnetic or antiferromagnetic structures. Thus, quantum ferrimagnets provide a versatile platform to improve coherent control in general and to study complex magnetic interactions.
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AbstractThere has been a recent surge in transformer-based architectures for learning on graphs, mainly motivated by attention as an effective learning mechanism and the desire to supersede the hand-crafted operators characteristic of message passing schemes. However, concerns over their empirical effectiveness, scalability, and complexity of the pre-processing steps have been raised, especially in relation to much simpler graph neural networks that typically perform on par with them across a wide range of benchmarks. To address these shortcomings, we consider graphs as sets of edges and propose a purely attention-based approach consisting of an encoder and an attention pooling mechanism. The encoder vertically interleaves masked and vanilla self-attention modules to learn an effective representation of edges while allowing for tackling possible misspecifications in input graphs. Despite its simplicity, the approach outperforms fine-tuned message passing baselines and recently proposed transformer-based methods on more than 70 node and graph-level tasks, including challenging long-range benchmarks. Moreover, we demonstrate state-of-the-art performance across different tasks, ranging from molecular to vision graphs, and heterophilous node classification. The approach also outperforms graph neural networks and transformers in transfer learning settings and scales much better than alternatives with a similar performance level or expressive power.
AbstractThe exploitation of the strong light-matter coupling regime and exciton-polariton condensates has emerged as a compelling approach to introduce strong interactions and nonlinearities into numerous photonic applications. The use of colloidal semiconductor quantum dots with strong three-dimensional confinement as the active material in optical microcavities would be highly advantageous due to their versatile structural and compositional tunability and wet-chemical processability, as well as potentially enhanced, confinement-induced polaritonic interactions. Yet, to date, exciton-polariton condensation in a microcavity has neither been achieved with epitaxial nor with colloidal quantum dots. Here, we demonstrate room-temperature polariton condensation in a thin film of monodisperse, colloidal CsPbBr3quantum dots, placed in a tunable optical resonator with a Gaussian-shaped deformation serving as wavelength-scale potential well for polaritons. The onset of polariton condensation under pulsed optical excitation is manifested in emission by its characteristic superlinear intensity dependence, reduced linewidth, blueshift, and extended temporal coherence.
AbstractMultivalent proteins can form membraneless condensates in cells by liquid-liquid phase separation, and significant efforts have been made to study their biochemical properties. Here, we demonstrate the emergent mechanics of a functional multivalent condensate reconstituted with six postsynaptic density proteins, using atomic-force-microscopy-based mesoscale rheology and quantitative fluorescence measurements. The measured relaxation modulus and protein mobility reveal that the majority (80%) of the proteins in the condensate are mobile and diffuse through a dynamically cross-linked network made of the remaining (20%) non-mobile scaffold proteins. This percolating structure gives rise to a two-mode mechanical relaxation with an initial exponential decay followed by a long-time power-law decay, which differs significantly from simple Maxwell fluids. The power-law rheology with an exponentα≃ 0.5 is a hallmark of weak bonds’ binding/unbinding dynamics in the multivalent protein network. The concurrent molecular and mechanical profiling thus provides a reliable readout for characterizing the mechanical state of protein condensates and investigating their physiological functions and associations with diseases.
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AbstractOver three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMeBiobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores modify phenotypes amongst pathogenic carriers and that genetic background additionally alters the effects of pathogenic variants through interactions.
AbstractAmygdala hyperexcitability is a hallmark of stress-induced anxiety disorders. Stress-associated changes in both principal neurons and interneurons contribute to the increased excitability, but how exactly these mechanisms interact to regulate the function of behaviorally relevant circuits in the amygdala remains unclear. Here, we show that GluK1 subunit-containing kainate receptors in parvalbumin (PV) interneurons maintain high GABA release and control excitability of lateral amygdala (LA) principal neurons via tonic GABAB-receptor-mediated inhibition. Downregulation of GluK1 expression in PV interneurons after chronic restraint stress (CRS) releases the tonic inhibition and increases excitability of LA principal neurons. Stress-induced LA hyperexcitability was associated with increased glutamatergic transmission to central amygdala PKCδ-expressing neurons, implicated in fear generalization. Consistent with significance in anxiogenesis, absence of GluK1-GABABregulation confers resilience against CRS-induced LA hyperexcitability and anxiety-like behavior. Our data reveal a unique novel mechanism involving an interplay between glutamatergic and GABAergic systems in the regulation of amygdala excitability in response to chronic stress.
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AbstractEpigenetic responses to cannabis use could link cannabis use to health problems. We examined the DNA-methylation profiles of long-term cannabis users in midlife, re-evaluating a set of 246 cannabis-associated methylation markers that were previously identified in other studies. Data were from the Dunedin Study, a five-decade longitudinal study of a birth cohort (analyticn= 787). Peripheral whole blood was drawn when the cohort was age 45, and DNA methylation was assayed using the EPIC 850 K BeadChip. Analyses compared long-term cannabis users with non-users and, for a benchmark comparison, long-term tobacco users. Results showed that long-term cannabis use was associated with sixteen of the previously published 246 cannabis-related methylation markers. Methylation markers that were associated with long-term cannabis use were also associated with long-term tobacco use. However, after adjusting for long-term tobacco use and other covariates, long-term cannabis use was robustly associated with hypomethylation of nine markers: cg05575921, cg21566642, cg03636183, cg21161138, cg01940273, cg17739917, cg05086879, cg02978227, cg23079012. Cannabis-related hypomethylation was associated with higher gene expression in the Dunedin Cohort, suggesting meaningful biological associations. A comparison of long-term cannabis users with cannabis quitters revealed that quitters showed less extreme DNA hypomethylation. Long-term cannabis use could affect the epigenome similarly to tobacco use, possibly at least partly though smoke inhalation. Cannabis cessation, like tobacco cessation, may reverse altered DNA methylation.
AbstractTreatment-resistant depression (TRD), defined as major depressive disorder (MDD) with multiple failed responses to antidepressant treatments, has been suggested to be heritable, but identifying its genetic component is challenging. Using a restrictive TRD definition based on antidepressant medication followed by electroconvulsive therapy (ECT), which may represent a severe subset of TRD cases, we investigated both common variants and rare copy number variations (CNVs) associated with a) TRD risk (2 062 TRD vs. 441 037 healthy controls) and b) treatment resistance in MDD (2 062 TRD vs. 38 544 non-TRD) across three Nordic countries. We observed a significant SNP-based heritability for TRD risk at 26% (SE = 5%). Genome-wide association analysis identified one locus on chromosome 3 (intronic region ofSPATA16) for TRD risk and one suggestive locus for treatment resistance in MDD. TRD risk showed positive genetic correlations (rg) with other psychiatric disorders, with notablyrgwith bipolar disorder (0.86, SE = 0.20) and schizophrenia (0.57, SE = 0.13), as well as a negativergwith intelligence (−0.13, SE = 0.07). Analyses using PRS showed that TRD had higher common-variant burdens of various psychiatric disorders compared to non-TRD. Furthermore, TRD carried a higher CNV deletion burden in total and average lengths than healthy controls or non-TRD cases and was associated with a group of 54 known neuropsychiatric CNVs (ORs = 1.74–2.86). Given that our definition of TRD involves the use of ECT, our findings may reflect a severe form of treatment resistance. This work adds evidence on a genetic basis and provides insights into the genetic architecture of TRD, underscoring the need for further genomic research into this ‘difficult-to-treat’ condition.
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AbstractIndividuals with mood disorders present with cognitive impairment and functional disability, and small-scale studies underline aberrant cognitive control and default mode network activity as potential neuronal correlates underlying these deficiencies. The objectives of this large-scale, cross-sectional functional magnetic resonance imaging (fMRI) study were (I) to investigate the replicability of cognitive control network (CCN) hypo-activity and default mode network (DMN) hyper-activity in patients with mood disorders, and (II) to explore brain activity related to cognition and daily functioning across patients and controls. We pooled data from three studies conducted at the same study site, which resulted in a sample of 213 fully or partially remitted patients with mood disorders (189 with bipolar disorder, 24 with major depressive disorder) and 60 healthy controls (HC). All participants underwent fMRI, during which they performed a verbal working memory N-back task, as well as comprehensive neurocognitive testing and assessment of daily functioning. Patients showed task-related hypo-activity within the left dorsolateral prefrontal cortex as well as frontal and parietal nodes of the CCN, which correlated with poorer outside-scanner cognitive performance. Within the DMN, patients showed hyper-activity in the frontal medial cortex compared to HC. Cognitive performance was positively associated with task activity within the right middle frontal gyrus (p= 0.0005), located in the CCN, whereas daily functioning was negatively associated with activity within the cingulate gyrus, a key hub in the DMN (p= 0.007). In the largest study of its kind, we identified CCN and DMN abnormalities in mood disorders and associations with cognition and functioning. The findings highlight plausible neurocircuitry targets for enhancing cognitive and functional recovery in mood disorders.
AbstractFOXG1 (Forkhead Box G1) is a critical transcription factor for brain development, regulating progenitor cell proliferation, neuronal migration, and cortical circuit assembly. PathogenicFOXG1variants lead to FOXG1 syndrome, a neurodevelopmental disorder characterized by severe brain anomalies and cognitive impairments. Despite efforts to correlate genetic variants with clinical outcomes, the precise relationship remains elusive. Here, we analyzed clinical severity and brain anomalies in 14 individuals withFOXG1variants, investigating how these variants impact FOXG1’s properties and functions. We uncovered a strong correlation between the severity of brain anomalies in affected individuals and functional alterations of these variants. Variants with very low protein expression were associated with moderate-to-severe brain anomalies. A luciferase reporter assay was used to assess the ability of FOXG1 variants to repressCOUP-TFI(NR2F1) expression-a function of FOXG1 validated through single-cell RNA-sequencing (scRNA-seq). Variants losingCOUP-TFIrepression ability by binding toCOUP-TFI’s enhancer region consistently caused moderate-to-severe brain anomalies. Furthermore,in uteroelectroporation (IUE) in embryonic mouse brains was employed to study their impact on neuronal migration and differentiation. Electroporation of wild-typeFoxg1delayed neuronal migration and altered their cell fate. Remarkably, variants associated with moderate-to-severe brain anomalies impaired these functions, while those with mild brain anomalies caused partial impairment. Thus, by combining protein expression,COUP-TFIrepression, and neuronal migration assays, we developed a patient stratification paradigm for predicting the severity of FOXG1 syndrome. This workflow successfully differentiated 92.3% of cases, facilitating early diagnosis and guiding future therapeutic interventions.
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AbstractPeripartum depression can have severe impact on the mother’s and the infant’s health. Yet, its biological underpinnings are largely unknown. The present study sought to identify transcriptomic signatures of depressive symptoms during pregnancy and postpartum. Blood samples were collected during late pregnancy or early postpartum for mRNA isolation and sequencing, while depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Based on the timepoint when the samples were collected, differentially expressed genes (DEGs) were identified by (1) comparing mRNA levels between the depression symptom trajectory groups, and (2) correlating with EPDS scores. DEGs for samples collected during late pregnancy, but not postpartum, were associated with depressive symptoms occurring only during pregnancy or persisting postpartum, compared with controls. There were 16 upregulated and 109 downregulated DEGs significantly associated with EPDS score at week 32 among samples collected during late pregnancy. Gene Set Enrichment Analysis identified immune response and cell motility as processes linked to these DEGs. Hypothesis-based analysis on previously identified postpartum depressive symptoms-related DEGs replicated a positive association between expression of immune-related genesISG15andRSAD2with postpartum-onset depressive symptoms, both in samples taken during late pregnancy and postpartum. The present findings point to transcriptomic signatures associated with peripartum depressive symptoms, mostly related to immune system dysregulation.
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Conventional drug delivery methods for chronic disease often suffer from low potency and poor patient compliance, while current advanced devices face limitations because of bulkiness, frequent implantation needs, inflammation risk, and lack of precise control. To overcome these challenges, we developed the SUSTAIN—a smart, ultra-long-lasting, sequentially triggerable, and artfully implantable nozzle system. The SUSTAIN integrates an osmotic pressure–triggered module, an airflow-generated T-pipe (AGT), and a drug infusion pump (DIP) for controlled subcutaneous drug release. The AGT enables tunable dosing by varying NaHCO3/KH2PO4powder amounts, while shear thinning of the β-cyclodextrin/Pluronic F-127 hydrogel in the DIP ensures sustained drug infusion. In vivo studies show that the SUSTAIN delivers at least four doses of levothyroxine sodium over 10 days and three doses of semaglutide over 42 days, maintaining effective blood drug levels with minimal invasiveness. This system presents a highly promising solution for improving therapeutic outcomes and convenience in chronic disease management.
Cardiotoxicity, especially human ether-a-go-go–related gene (hERG)–related toxicity, is a leading cause of drug failure or market withdrawal. Reducing hERG binding to obviate potential cardiac toxicity is crucial. Nanotechnology has been applied to drug delivery for reducing drug toxicity and improving efficacy, but few studies have addressed hERG-related cardiotoxicity. We report the use of self-assembling dendrimer nanosystems for drug formulation and delivery, which effectively reduced hERG binding and associated toxicity while promoting therapeutic efficacy. Specifically, these dendrimer nanosystems efficiently encapsulated the antimalarial drug chloroquine, the anticancer agent doxorubicin, and the NUPR1 inhibitor ZZW115, all three having high affinity to hERG channels. These nanoformulations showed three- to eightfold reduced hERG binding affinity, which, in animal models, translated to abolished toxicity. These nanodrugs exhibited prolonged circulation, leading to enhanced accumulation at disease sites and improved treatment outcomes. This study highlights the potential of nanotechnology to reduce hERG binding and related toxicity while improving drug efficacy, offering valuable perspectives for drug development.
Skeletal harboring of hematopoietic stem cells (HSCs) is generally considered as vertebrate-specific innovation during water-to-land transition. However, this long-standing view has not been rigorously evaluated as hematopoietic sites remain poorly understood in most invertebrate groups. We report, to our knowledge, the first discovery of abundant HSCs in adult mollusk shells, an invertebrate hematopoietic niche resembling vertebrate bone marrow (BM). Cell-lineage analysis and functional assays reveal the developmental origin of HSCs during larval shell formation and their participation in hemocyte-mediated shell regeneration and soft-body blood supply. Widespread skeleton-related HSC-like cells are found in diverse invertebrate groups and bony fish group, suggesting skeletons as a universal niche for animal HSCs and HSC-skeleton association preceding vertebrate water-to-land transition. Comparison of invertebrate and vertebrate skeletal HSCs enables the macroevolutionary profiling of a core-set of animal HSC regulators. Our findings would boost fundamental paradigm shifts for hematopoiesis and stem cell research in invertebrates and provide the redefined understanding of vertebrate BM evolution and water-to-land transition.
Living organisms use intricate strategies to adapt and survive in response to potentially lethal environment changes. Inspired by cryptobiosis in nature, researchers have pioneered approaches to create cell-in-shell nanobiohybrids, aiming to endow cells with enhanced protection and exogenous functions. Yet, these methods still lack the biological autonomy intrinsic to natural cellular responses. Here, we present an innovative chemo-metabolically coupled strategy for the autonomous construction of cell-in-shell structures in cell growth medium. Our system harnesses ethanol fermentation bySaccharomyces cerevisiae, chemically coupled with an enzymatic cascade involving alcohol oxidase and horseradish peroxidase, to drive the nanoshell formation of polydopamine. The integration of autonomous shell formation with cellular proliferation produces anisotropic cell-in-shell structures, which can serve as enzyme-powered cell microrobots, upon conjugation with urease. Our autonomous system enables the creation of cell-in-shell nanobiohybrids with dynamic and adaptive environmental interactions, paving the way for transformative applications in synthetic biology, such as artificial cells, as well as advancements in cell-based therapies.
Identifying previously unknown targets for pathological cardiac hypertrophy and understanding its mechanisms are crucial. Here, we observed that the deubiquitinating enzyme YOD1 was moderately elevated in human hypertrophic myocardium and mouse models. Cardiomyocyte-specific knockout of YOD1 reduced Ang II– and TAC-induced cardiac hypertrophy. Subsequently, we used multiple proteomic analyses to identify and confirm STAT3 as a substrate protein for YOD1. Mechanistically, our findings revealed that the C155 site of YOD1 removes K48-linked ubiquitin chains from K97 on STAT3, stabilizing STAT3 levels and enhancing its nuclear translocation in cardiomyocytes under Ang II stimulation. Notably, inhibiting STAT3 reversed the antihypertrophic effects of YOD1 deficiency in Ang II–challenged mice. In addition, pharmacological inhibition of YOD1 mitigated Ang II–induced pathological ventricular remodeling in mice. This study clarifies the role of YOD1 and introduces a previously unidentified YOD1-STAT3 axis in regulating pathological cardiac hypertrophy, providing valuable insights for drug development targeting this condition.
CD4+T cells are crucial in shaping response and resistance to immunotherapy. To enhance our understanding of their multifaceted functions, we developed copper-64–radiolabeled nanobodies targeting the human CD4 receptor (64Cu-CD4-Nb1) for positron emission tomography (PET). In human CD4-receptor knock-in mice,64Cu-CD4-Nb1 specifically accumulated in different orthotopic tumors, correlating with histological CD4+cell densities. Based on intratumoral CD4+cell distribution patterns within the core and periphery, we distinguished responders to combined αPD-1/4-1BB antibodies early on-treatment. CD4-PET identified resistance to αPD-1 monotherapy, which was mitigated by adding regulatory T cell–depleting α4-1BB antibodies. Patients with early-stage non–small cell lung cancer who relapsed after neoadjuvant αPD-L1 therapy revealed low CD4+T cell densities in the tumor core. In human and mouse tumor tissues, regulatory T cells correlated with CD4+cell densities. Thus, visualizing the spatial distribution patterns of CD4+cells by PET offers mechanistic insights into CD4-mediated therapy efficacy, with great potential for guiding combinatorial immunotherapies in patients with cancer.
Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn2+release and inhibit pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP channel 1 (MTC1)–related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic reactive oxygen species, inhibiting macrophage pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing other inflammatory diseases.
Vesta, the only differentiated rocky protoplanet explored by a spacecraft, offers insight into early planetary formation. The Divalia Fossae, surface troughs comparable in size to the Grand Canyon, encircle two-thirds of the equator. Two giant impacts reshaped the southern hemisphere, where an older basin is partially superposed by the younger Rheasilvia basin. The origin of the Divalia Fossae is widely accepted as directly linked to the Rheasilvia impact, either by tectonics caused immediately by the impact, up-spinning, or secondary cratering. We present several geologic constraints that support a tectonic origin of the troughs due to the adjustment of Vesta’s spin axis to a geoid changed by both large impacts. The best fit to Vesta’s gravitational field corresponds to a spin axis reorientation of 3° that, when coupled with despinning, induces a stress state that predicts Divalia Fossae’s established location, fracture type, and orientation. These insights underline the importance of tectonic processes in the early evolution of protoplanets.
Porphyry copper deposits (PCDs) are the main source of copper globally, with the metals transported in and deposited from aqueous magmatic fluids. Processes that define the volume of magma and concentration of copper in the magma required to form PCDs, however, are not well understood. Here, we present the results of quantitative modeling of the behavior of Cu and Cl during magma evolution in the upper crust. We show that fractional crystallization is the most important process promoting efficient Cu extraction, and that high concentrations of Cu in the ore-forming hydrothermal fluids can be reached with moderate Cl concentrations. Unusually high concentrations of Cl and Cu in the magma and large magma volumes are not required. Arc magmas of modest volume (<103km3) and modest initial Cu and Cl concentrations can generate large PCDs, if a sufficient mass of magmatic fluid is exsolved at an advanced stage of crystallization.
Manipulation of polar functional groups to extend the druggability and developability space is an important approach in the current field of drug discovery. Here, we report an editing method that enables the direct insertion of anthranilyl units into inert amides to form versatile oligoamides and cyclic peptides under exceptionally mild reaction conditions. We showcase a diverse array of pharmaceuticals, natural products, and bioactive molecules involving the mentioned scaffold insertion. The synthesis of the secondary metabolites from marine-derived fungi, the expedited construction of bioactive molecules, and the assembly of functionalized peptide macrocycles through iterative insertions highlight the synthetic utility of this method. Computational tools and experimental measurements indicate that a hydrogen bond network formed by reacting and catalytic amide enables the insertion of the anthranilyl unit into a C─N bond.
Most baleen whales were severely overexploited during the past century, but many populations have received near-complete protection from exploitation for more than a half-century. Some of these populations have made remarkable recoveries and are now approaching pre-exploitation levels of abundance. Contrary to expectations of baleen whales making minor oscillations around equilibrium abundances, several populations that have made the strongest recoveries have experienced major mortality events. We review examples from the literature showing increasing demographic variability in recovering populations of baleen whales and present a simulation study on the expected response of recovered versus depleted whale population to environmental variability and climate impacts. We propose that baleen whales are more sensitive to environmental variability than previously recognized; that major demographic fluctuations will become the norm as baleen whales recover; and that climate-driven disruptions to whale population dynamics will be most dramatic in populations with the lowest rates of anthropogenic mortality.
Harmful algal blooms (HABs) of the toxigenic haptophyteChrysochromulinaare known to cause fish mortalities and collateral ecosystem damage. The ichthyotoxic mechanisms are poorly understood but likely dependent on toxigenesis by polyketide synthases (PKSs). We hypothesize that induction of PKS activity facilitates mixotrophic behavior during nutrient-depleted bloom conditions. To identify potential in situ stimuli for growth, toxigenicity, and bloom persistence, we compared environmental factors and biological processes identified by metaomics toChrysochromulina leadbeateriHABs between two fjords in northern Norway. We identified the polyketide ichthyotoxin leadbeaterin-1 from theC. leadbeateribloom and found potentially associated candidate PKS genes of which most were higher expressed at bloom stations. A relative depletion of inorganic nitrogen and phosphate during the bloom was correlated with higher expression of genes involved in endocytosis, autophagy, and lysosomal activity. Mixotrophy is evidently a compensatory nutritional strategy coupled to induction of toxigenesis and other metabolomic processes as biotic factors linked toChrysochromulinabloom dynamics.
Oriented electric currents in metals are routinely driven by applying an external electric potential. Although the response of electrons to the external electric fields occurs within attoseconds, conventional electronics do not use this speed potential. Ultrashort laser pulses with controlled shapes of electric fields that switch direction at petahertz frequencies open perspectives for driving currents in metals. Light field–driven currents were demonstrated in various media including dielectrics, semiconductors, and topological insulators. Now, our research question is whether we can drive and control orders of magnitude more charge carriers in metals enabling ultrafast switching with practically low-energy, picojoule-level pulses. Here, we demonstrate the interaction of light with nanometer-thick metallic layers, which leads to a generation of light field–controlled electric currents. We show that the implantation of metallic layers into a dielectric matrix leads to up to 40 times increase of the sensitivity in contrast to a bare dielectric, decreasing the intensity threshold for lightwave electronics.
Interleukin-4 (IL-4) plays a central role in type 2 immune responses. Despite its potential use for allergic and autoimmune diseases, its pleiotropic receptor binding complicates selective targeting of IL-4 signaling pathways. We developed a chemical synthesis of (i) IL-4 variants with atomically tailored side-chain modifications that deter specific receptor interactions and (ii) conditionally activatable IL-4 variants uncaged with 365-nanometer light. In primary cell studies, different variants elicited selective STAT5 or STAT6 phosphorylation in lymphocytes or neutrophils. In murine studies, photocaged IL-4 suppressed inflammation only upon UV irradiation, demonstrating precise on demand control. We accomplished the synthesis and folding of IL-4, a hydrophobic cytokine with three disulfide bonds, using the alpha-ketoacid–hydroxylamine (KAHA) ligation to assemble three segments. We introduced further conjugations, including PEGylation for half-life extension, through orthogonal ligations enabled by functionalized amino acid building blocks. This work highlights the flexibility of chemical protein synthesis to produce therapeutically valuable cytokines, including receptor-biased and spatiotemporally activatable IL-4 variants.
Human language is unique among communication systems since many elements are learned and transmitted across generations. Previous research suggests that this process is best predicted by infant-directed communication, i.e., a mode of communication directed by caregivers to children. Despite its importance for language, whether infant-directed communication is unique to humans or rooted more deeply in the primate lineage remains unclear. To assess this, we investigated directed and surrounding vocal communication in human infants and infants of wild nonhuman great apes. Our findings reveal that human infants receive dramatically more infant-directed communication than nonhuman great ape infants. These data suggest that the earliest hominins likely relied more on surrounding communication to become communicatively competent, while infant-directed vocal communication became considerably more prominent with human language.
Several inhibitory interneuron subtypes have been identified as critical in regulating sensory responses. However, the specific contribution of each interneuron subtype remains uncertain. In this work, we explore the contributions of cell type–specific activity and synaptic connections to the dynamics of a spatially organized spiking neuron network. We find that the firing rates of the somatostatin (SOM) interneurons align closely with the level of network synchrony irrespective of the target of modulatory input. Further analysis reveals that inhibition from SOM to parvalbumin interneurons must be limited to allow gradual transitions from asynchrony to synchrony and that the strength of recurrent excitation onto SOM neurons determines the level of synchrony achievable in the network. Our results are consistent with recent experimental findings on cell type–specific manipulations. Overall, our results highlight common dynamic regimes achieved across modulations of different cell populations and identify SOM cells as the main driver of network synchrony.
Climate change is altering marine ecosystems, driving shifts in sea turtle distributions and challenging conservation efforts. Our study examines how climate change affects the global sea distribution of all seven sea turtle species, intersecting with marine protected areas (MPAs) and shipping corridors. Using species distribution models and environmental data from 2000 to 2024, we project sea turtle habitats under current conditions and three future climate scenarios (SSP1-2.6, SSP2-4.5, and SSP5-8.5) for 2050 and 2100. Our results show substantial habitat redistributions, with poleward shifts and contractions, particularly under the SSP5-8.5 scenario. Over 50% of sea turtle hotspots may disappear by 2050, with many new habitats in high shipping intensity areas. Alarmingly, only 23% of current hotspots are within MPAs, highlighting the need for adaptive conservation strategies.
Methane is a major greenhouse gas and a key component of global biogeochemical cycles. Microbial methane often deviates from isotope and isotopolog equilibrium in surface environments but approaches equilibrium in deep subsurface sediments. The origin of this near-equilibrium isotopic signature in methane, whether directly produced by methanogens or achieved through anaerobic oxidation of methane (AOM), remains uncertain. Here, we show that, in the absence of AOM, microbial methane produced from deep-sea sediments exhibits isotopolog compositions approaching thermodynamic equilibrium due to energy limitation. In contrast, microbial methane from salt marsh and thermokarst lakes exhibits significant hydrogen and clumped isotopic disequilibrium due to high free-energy availability. We propose that clumped isotopologs of methane provide a proxy for characterizing the bioenergetics of environments for methane production. Together, these observations demonstrate methane clumped isotopes as a powerful tool to better understand the relation between methane metabolisms and the energy landscape in natural environments.
The maritime migration to the South Ryukyu Islands of southwestern Japan, which occurred approximately 30,000 years ago, was one of the most difficult sea crossings accomplished by the Late PleistoceneHomo sapiens. This study performs numerical simulations to investigate the conditions that were needed to cross between Taiwan and Yonaguni Island, where one of the world’s strongest ocean currents, the Kuroshio, remains active. We combined simulations based on three ocean models with data from an actual experimental voyage conducted in 2019. The results showed that travel across this sea would have been possible on both the modern and Late Pleistocene oceans if a dugout canoe was used with a suitable departure place and paddling strategy. Recognizing the Kuroshio, paddling to counteract this current, and using high-level navigation were crucial to success. This suggests that the Paleolithic maritime expansion in the Western Pacific involved both advanced technologies and strategic challenges.
Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
Achieving accurate locating of perforating arteries (PAs) has great clinical value in various biomedical applications, such as free flap transfer. However, the anatomical variability of these arteries presents a major challenge in PA locating, and existing methods have various disadvantages, limiting their applications. Here, we propose a reusable and flexible hydrogel biosensor array for noninvasive, precise, and efficient PA locating. Particularly, we develop electrically responsive hydrogels to establish rapidly detachable device/hydrogel interfaces, endowing the reusability of the biosensor array. Meanwhile, the adhesion of hydrogel/skin interfaces is also enhanced to facilitate high-fidelity signal acquisition. By analyzing the photoplethysmography (PPG) infrared (IR) signals, the biosensor array can accurately and responsively locate PAs across different types of free flaps in clinical cases, outperforming existing techniques. This biosensor array represents a promising platform for PA locating. The strategy of hydrogel interface design paves the way for the development of reusable flexible electronics in biomedical applications to avoid cross-infection and reduce device costs.
Archeological evidence indicates that full-scale expansion ofHomo sapiensacross the oceans began about 50,000 years ago in the Western Pacific, yet how this was achieved remains unclear. The Ryukyu Islands in southwestern Japan, where archaeological sites suddenly appeared 35,000 to 30,000 years ago, are of particular interest in this regard because of the apparent difficulty in crossing the surrounding waters. In this study, we test if a non-sailing dugout canoe can be produced with Upper Paleolithic tools, and if it can cross the 110-kilometer-wide strait at the western entrance of the Ryukyus, where one of the world’s strongest ocean currents intervenes. Our 7.5-meter-long dugout, manufactured with edge-ground stone axes, was speedy and durable enough to cross this strait. This supports the early development of functional boats, such as dugouts, while our experiment also highlighted that this type of sea travel was possible only for experienced paddlers with advanced navigational skills.
Robot collectives offer a promising solution for complex assignments that are nearly impossible for individual robots to execute. In microscopic scenarios, organizing microrobot collectives is now governed by agent-agent physical interactions. However, the existing methods are insufficient to produce robust connections and fail to tolerate harsh environments. We propose a strategy to efficiently program microrobots into reconfigurable robust collectives to operate in various dynamic environments. Magnetic collectives are produced to achieve reconfigurable pattern transformation with considerable structural enhancement via well-designed gradient magnetic fields. The strong gradient magnetic field–induced connections among individual microrobots enable a record-breaking 700-fold output force enhancement, and 0.2-gram microrobot collectives generate Newton-level output forces. The proposed reconfigurable microrobot collectives provide a stable and promising approach to executing droplet, fluid, and solid manipulations via powerful output forces. These results may have implications for further understanding of self-assembly, particle systems, microrobot collectives, smart dust, and related microscopic multiagent behaviors.
The spontaneous emergence of tissue patterns is often attributed to biochemical reaction-diffusion systems. InHydratissue regeneration, the formation of a Wnt signaling center exemplifies this process. However, a strictly biochemical mechanism for self-organization inHydraremains elusive. In this study, we investigated mechanical stimuli and identified a positive feedback loop between Wnt signaling and tissue stretching. We developed a mathematical model of mechanochemical pattern formation in a closed elastic shell, representing regeneratingHydraepithelial spheroids. Our model explains how mechanical forces drive axis formation and predict the organizer’s location under various perturbations. Validation by partially confining regenerating tissues showed that the organizer forms in regions with the greatest stretching potential. This work highlights a versatile mechanochemical mechanism for luminal epithelium patterning, which is relevant across various biological systems.
Overfishing is one human-driven perturbation driving major evolutionary pressure on marine populations. Fishing is often highly selective for particular traits and elicits marked phenotypic changes, while the evolutionary basis of such trait change remains unresolved. Here, we used a unique time series of the overexploited Eastern Baltic cod (Gadus morhua) to investigate growth trends during 25 years of heavy fishing along with hypothesized genetic changes at the full genome level. A growth analysis demonstrated a 48% decrease in asymptotic body length from 1996 to 2019 while a genome-wide association analysis revealed outlier loci and gene candidates linked to growth performance. The contributing loci showed signals of directional selection with high autocovariance of allele frequency change and significant overlap with regions of high genetic differentiation. Our findings suggest a genomic basis of fisheries-driven growth impairment and underscore implications for conservation policy regarding the adaptive potential of marine populations.
Detecting photon echoes from superconducting Higgs modes is challenging due to the necessity of preserving and retrieving phase coherence encoded in multiple Higgs and quasiparticle (QP) excitations. Here, we demonstrate the emergence of a Higgs echo in niobium superconductors. This approach disentangles unique quantum pathways involving the Higgs mode and QP excitations. Using Higgs echo spectroscopy, we also uncover unconventional echo formation caused by inhomogeneous broadening and “soft” QP bands, which dynamically evolve under terahertz (THz) driving. Specifically, THz pulse pairs modulate the superconducting gap, imprinting coherence and forming a temporal “Higgs grating.” This grating produces echoes with distinctive characteristics: (i) echo rephasing spectral peaks at superconducting gap frequencies, (ii) asymmetric echo formation delays unlike those observed in atoms or semiconductors, and (iii) negative-time echo signals stemming from Higgs-QP anharmonic interactions. Combined with advanced time-frequency analysis, these findings distinguish Higgs from QP responses and clarify their intricate interactions in THz-driven superconductivity.
Endothermy has independently evolved in several vertebrate lineages but remains rare among fishes. Using an integrated approach combining phylogenomic and ecomorphological data for 1051 ray-finned fishes, a time-dependent evolutionary model, and comparative genomic analyses of 205 marine vertebrates, we show that ecological interactions with modern cetaceans coincided with the evolution of endothermy in ray-finned fishes during the Eocene-Miocene. This result is supported by evidence of temporal and geographical overlap between cetaceans and endothermic fish lineages in the fossil record, as well as correlations between cetacean diversification and the origin of endothermy in fishes. Phylogenetic comparative analyses identified correlations between endothermy, large body sizes, and specialized swimming modes while challenging diet specialization and depth range expansion hypotheses. Comparative genomic analyses identified several genes under selection in endothermic lineages, includingcarnmt1(involved in fatty acid metabolism) anddcaf6(associated with development). Our findings advance the understanding of how ecological interactions and genomic factors shape key adaptations.
Adapting to change is a fundamental feature of human learning, yet its developmental origins remain elusive. We developed an experimental and computational approach to track infants’ adaptive learning processes via pupil size, an indicator of tonic and phasic noradrenergic activity. We found that 8-month-old infants’ tonic pupil size mirrored trial-by-trial fluctuations in environmental volatility, while phasic pupil responses revealed that infants used this information to dynamically optimize their learning. This adaptive strategy resulted in successful task performance, as evidenced by anticipatory looking toward correct target locations. The ability to estimate volatility varied significantly across infants, and these individual differences were related to infant temperament, indicating early links between cognitive adaptation and emotional responsivity. These findings demonstrate that infants actively adapt to environmental change, and that early differences in this capacity may have profound implications for long-term cognitive and psychosocial development.
Rice was a staple crop in the ancestral Austronesian regions of Taiwan and Island Southeast Asia, but it was unknown in any of the Pacific Islands at the time of European encounters, with the exception of the unique case of Guam and the Mariana Islands. Through multiple methodologies, including phytolith analysis, micro–computed tomography scanning, and thin-section petrography, this recent research confirms the presence of abundant rice husk and leaf phytoliths adhering to red-slipped pottery (“Marianas Red”) at the Ritidian Site Complex in Guam, dated by radiocarbon to 3500 to 3100 years ago. This study addresses the long-standing question of whether the first Pacific Islanders transported rice with them from the Philippines across 2300 kilometers of open sea, representing the longest known ocean voyage of the time. During this early period, rice was restricted to special ritual events in the Marianas. The early voyage apparently was planned with provisions of rice at 3500 years ago.
In every menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an inflammatory decidual reaction, rendering it poised for embryo implantation and transformation into the decidua of pregnancy. Here, we show that the sequential functions of the decidual reaction—implantation and decidualization—pivot on the time-sensitive loss of progesterone-resistantDIO2+stromal cells that form a specialized implantation niche and reciprocal expansion of progesterone-dependentPLA2G2A+predecidual cells. Simultaneously, uterine natural killer (uNK) cell proliferation results in the accumulation of immunotolerant subsets. Examination of endometrial biopsies from 924 women revealed that the recurrence risk of miscarriage closely aligns with the incidence of a weakened or stalled decidual reaction, more so than poor uNK cell expansion. Analysis of paired biopsies obtained in different cycles and modeling in assembloids intimated that prior miscarriages disrupt intercycle endometrial homeostasis and calibration of the decidual reaction. Our findings show that erosion of the decidual reaction following a miscarriage drives the recurrence risk irrespective of maternal age.
Sea level change is an important forcing on lowland fluvial systems. Although its impact is suggested to extend up to hundreds of kilometers inland, this impact is often considered confined to deltaic regions. We present luminescence dating of cores from the Jianghan Plain in the middle Yangtze River that demonstrates the influence of the last glacially driven sea level fall extended over 1000-kilometers inland. Luminescence ages reveal a common sedimentary hiatus from ~26 to ~17 thousand years ago (ka), reflecting fluvial incision of >35 meters triggered by sea level fall. Subsequent rapid aggradation occurred within these incised valleys during deglaciation between ~17 and ~9 ka and then slowed down afterward. A further synthesis on global continental rivers shows that sea level change affects large, low-gradient lowland fluvial systems farther upstream than generally recognized, with postperturbation geomorphologic equilibrium reachable in timescales comparable to the length of Quaternary glacial cycles.
The dorsal raphe nucleus (DRN) is an important source of serotonin in the brain, but fundamental aspects of its function remain elusive. Here, we present a combination of minimally invasive recording and disruption studies to show that DRN brings about changes in motivation states. We use recently developed methods for identifying temporal patterns in behavior to show that monkeys change their motivation depending on the availability of rewards in the environment. Distinctive patterns of DRN activity occur when monkeys transition between a high-motivation state occupied when rewards are abundant, to a low-motivation state engendered by reward scarcity. Disrupting DRN diminishes sensitivity to the reward environment and perturbs transitions in motivational states.
Movement of pedestrian crowds is ubiquitous in human society. However, it is unclear what dynamical regimes pedestrian crowds can exhibit at different crowd densities, how pedestrians move in these different dynamical regimes, and in which dynamical regime the movement synchronization of pedestrians is most likely to occur. Here, we conducted a unidirectional crowd movement experiment, in which we tracked the movement of pedestrian crowds through foot tracking. We find experimentally that pedestrian crowds can exhibit three distinct dynamical regimes (free regime, slow-moving regime, and jammed regime) depending on the crowd density. In the free regime, pedestrians’ movement is not constrained; in the slow-moving regime, pedestrians’ speed is constrained, but pedestrians’ movement direction in each step is not influenced; and in the jammed regime, both pedestrians’ speed and movement direction in each step are constrained. We also demonstrate that pedestrians are most likely to synchronize their movements spontaneously at the onset of jamming. Our findings provide important insights into crowd dynamics.
Cerebrospinal fluid (CSF) contains inflammatory cues that enable peripheral immune surveillance of the central nervous system (CNS). While some cranial nerves allow for CSF efflux, the immune environment around CSF-interfacing cranial nerves during neuroinflammation is still poorly understood. Using a mouse model of multiple sclerosis [experimental autoimmune encephalomyelitis (EAE)] and CNSMycobacterium tuberculosisinfection (CNS-Mtb), we examined immune responses around olfactory nerve bundles near the cribriform plate, a key CSF efflux route. During neuroinflammation, we found increased perineural immune cells that had access to intracranial injected beads, dye, and bacteria. Additionally, we identified osseous channels connecting the environment surrounding olfactory nerves to bone marrow in the cribriform plate (cpBM). Notably, the cpBM undergoes myelopoiesis during EAE, has access to components of intracranial drainage, and is vulnerable to Mtb bacteria invasion during CNS-Mtb infection. Our findings improve the understanding of how the environments of CSF-interfacing cranial nerves and bone marrow are altered within the skull during neuroinflammatory disease.
Emerging artificial intelligence for science (AI-for-Science) algorithms, such as the Fourier neural operator (FNO), enabled fast and efficient scientific simulation. However, extensive data transfers and intensive high-precision computing are necessary for network training, which challenges conventional digital computing platforms. Here, we demonstrated the potential of a heterogeneous computing-in-memristor (CIM) system to accelerate the FNO for scientific modeling tasks. Our system contains eight four-kilobit memristor chips with embedded floating-point computing workflows and a heterogeneous training scheme, representing a heterogeneous CIM platform that leverages precision-limited analog devices to accelerate floating-point neural network training. We demonstrate the capabilities of this system by solving the one-dimensional Burgers’ equation and modeling the three-dimensional thermal conduction phenomenon. An expected nearly 116 times to 21 times increase in computational energy efficiency was achieved, with solution precision comparable to those of digital processors. Our results extend in-memristor computing applicability beyond edge neural networks and facilitate construction of future AI-for-Science computing platforms.
Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca2+channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human CaV1.3A749Gmutation that causes low-voltage Ca2+channel activation. We demonstrate activation of Ca2+influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of CaV1.3A749G/A749Gmice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca2+channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of CaV1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.
Electrochemical carbon dioxide (CO2) capture and utilization, powered by renewable energy, are essential to achieving net-zero emissions and CO2valorization. While remarkable progress has been made in catalysts, solution design, and system engineering, recent breakthroughs reveal that nitrogen-containing molecules—specifically sp2-hybridized structures (e.g., pyridine) and sp3-hybridized moieties (e.g., ethanolamine) —hold untapped potential to revolutionize both CO2capture and conversion. These structures have been demonstrated as the Holy Grail in facilitating CO2activation, stabilizing key intermediates, and streamlining reaction pathways—capabilities rarely achievable with conventional strategies. However, limited mechanistic understanding of their physicochemical properties and interactions with CO2hampers broader application. This review highlights recent advances in leveraging sp2/sp3-hybridized nitrogen structures, unpacks their molecular roles in electrochemical CO2management, and offers a unifying framework for their dual-functionality across capture and conversion. By illuminating these nitrogen-based motifs, we uncover practical design principles and open avenues for integrating expanded N-containing compounds into energy technologies—paving the way for next-generation carbon management strategies.
Northern African climate is characterized by strongly contrasting wet summers and dry winters. Dust exported by the northeasterly trade (Harmattan) winds creates marine sedimentary records that have been long interpreted to show that northern African climate became drier and more variable across the Pliocene-Pleistocene boundary [2.58 million years ago (Ma)], when global climate cooled and high-latitude glacial-interglacial cycles intensified. However, questions about the impact of summer rainfall on winter dust fluxes and thus the history of the African summer monsoons remain. We present a leaf wax hydrogen isotope record from offshore northwestern Africa that demonstrates that rainfall regimes remained stable and varied solely in response to 21,000-year cycles in summer insolation from 3.5 to 2.5 Ma. We infer that the summer rains and winter winds respond to different climate forcings, with summer rainfall driven by solar radiation over the northern African landmass and the winter trades affected by high-latitude climate and meridional temperature gradients.
Sustaining the growth of the data volume generated by artificial intelligence and the internet of things demands to develop schemes for data storage and processing operating at terahertz frequencies, unrestrained by thermal throttling. The optical drive of coherent magnetic collective excitations, namely magnons, represents a promising route. The ability to arbitrarily and nonthermally increase the magnon frequencies with laser pulses could enable this progress. However, this effect has not been reported to date. To achieve it, here, we explore the optical resonant excitation of high-momentum magnons, which experimentally are observed to couple to low-momentum magnons, modifying the frequencies and amplitudes thereof. This evidence, not caused by laser heating, is explained with a resonant light-scattering mechanism coupling high- and low-momentum eigenmodes across momentum space. Our results disclose routes to inducing instabilities and phase transitions via mode softening and potentially even light-driven Bose-Einstein condensation of magnons and superconductivity mediated by high-momentum spin-fluctuations.
Hexagonal boron nitride (h-BN) has emerged as a promising platform for generating room temperature single photons exhibiting high brightness and spin-photon entanglement. However, improving emitter purity, stability, and scalability remains a challenge for quantum technologies. Here, we demonstrate highly pure and stable single-photon emitters (SPEs) in h-BN by directly growing carbon-doped, centimeter-scale h-BN thin films using the pulsed laser deposition (PLD) method. These SPEs exhibit room temperature operation with polarized emission, achieving ag(2)(0) value of 0.015, which is among the lowest reported for room temperature SPEs and the lowest achieved for h-BN SPEs. It also exhibits high brightness (~0.5 million counts per second), remarkable stability during continuous operation (>15 min), and a Debye-Waller factor of 45%. First-principles calculations reveal unique carbon defects responsible for these properties, enabled by PLD’s low-temperature synthesis and in situ doping. Our results demonstrate an effective method for large-scale production of high-purity, stable SPEs in h-BN, enabling robust quantum optical sources for various quantum applications.
Phytophagous mites, includingTetranychus cinnabarinus, are arthropods known for their wide infestation of host plants and pesticide resistance. We found that fenpropathrin-resistant female mites (YN-FeR, with target resistance: F1538Ikdrmutation) exhibited significantly enhanced adaptability to various stress conditions, including exposure to different acaricides and high-temperature (34°C) and low-humidity environments (40% relative humidity). This evolution was attributed to cuticle thickening in resistant female mites. Cuticle proteinCPR25was identified as a critical gene mediating cuticle thickening.CPR25regulated its own overexpression by producing a circular RNA, namedcircCPR25, which acted as a decoy to selectively sequester and bind to the miR-34~317 cluster. This study revealed a distinctive mechanism underlying the evolution of stress resistance in spider mites. Specifically, a cuticle protein in spider mites regulates its own overexpression by producing a decoy circRNA, thereby promoting cuticle thickening and facilitating rapid adaptation to adverse conditions.
The health sciences largely focus on disease. However, the interconnected determinants of diseases suggest that we need a science of health, a framework to examine the biology of homeodynamics in a changing environment and how this affects the health we value. We build on first principles and recent discoveries on biological system dynamics to develop the concept of intrinsic health, a field-like state emerging from the dynamic interplay of energy, communication, and structure within the organism, giving rise to robustness/resilience, plasticity, performance, and sustainability. Intrinsic health is a quantifiable property of individuals that declines with age and interacts with context. We propose a measurement framework and describe how it will contribute to achieving the shared goals of medicine and public health.
Calcium carbonate dissolution is the dominant negative feedback in the ocean for neutralizing the acidity from rising atmospheric carbon dioxide. Mimicking this natural process, the accelerated weathering of limestone (AWL) can store carbon as bicarbonate in the ocean for tens of thousands of years. Here, we evaluate the potential of AWL on ships as a carbon sequestration approach. We show a successful prediction of laboratory measurements using a model that includes the most recent calcite dissolution kinetics in seawater. When simulated along a Pacific shipping lane in the Estimating the Circulation and Climate of the Ocean–Darwin ocean–general circulation model, surface alkalinity and dissolved inorganic carbon increase by <1.4% after 10 years of continuous operation, leaving a small pH and partial pressure of carbon dioxide impact to the ocean while reducing 50% carbon dioxide emission in maritime transportation.
We present a strategy to achieve absolute asymmetric catalysis that is effectively controlled by an external magnetic field via a spin-exchange reaction leveraging the chirality-induced spin selectivity effect. Using an external magnetic field to achieve asymmetric synthesis has long been desired. Here, we demonstrate 90% enantiomeric excess (ee) in [3 + 2] cycloadditions and 89% ee in aldol reactions, where the handedness of the product is determined by the ~±150 mT external magnetic polarization of a ferromagnet (FM). Our approach uses an enantioselective crystallization of racemic catalysts on a FM surface, using a small-scale crystallization vial connected to a bulk racemic solution. Racemic catalysts controllably crystallize into their respective enantiopure forms and are directly used in asymmetric reactions. Thus, we demonstrate that an external magnetic field can serve as a versatile symmetry-breaking tool to achieve highly enantioselective organic synthesis eliminating the need of any enantioenriched reagents.
Diaplectic glass and maskelynite in shocked plagioclase serve as key diagnostic features for high level of shock metamorphism in impact craters and meteorites. However, their formation mechanisms remain unclear and have long been argued, mainly due to the lack of phase diagram for plagioclase with extended pressure-temperature conditions. We report the stabilities of labradorite and anorthite at pressure up to 65 gigapascals and temperature up to 4000 kelvin. Our experimental results reveal the pressure-temperature conditions for amorphization, decomposition, and melting of labradorite and anorthite. The boundary between amorphous plagioclase and crystalline high-pressure phases in our phase diagram indicate diaplectic glass can form at 1300 to 1500 kelvin, and the melting line suggests that maskelynite can be generated above 3000 kelvin at high pressures. Formation conditions of diaplectic glass and maskelynite in plagioclase-bearing rocks are also suggested by the combination of phase diagram and shock Hugoniot data. These findings will advance our understanding of the bombardment history on rocky planetary surfaces.
Protein and peptide aggregation poses substantial challenges in disease pathology and therapeutic development. While natural glycosylation may mitigate aggregation, its efficacy and underlying mechanisms remain poorly understood due to limited access to homogeneous samples with complex glycans. This study addresses these knowledge gaps by investigating the natural glycosylation of islet amyloid polypeptide (IAPP), a peptide with therapeutic potential for type 2 diabetes but problematic aggregation. An optimized chemical synthesis enabled preparation of diverse IAPP glycoforms with complex glycan structures, allowing systematic evaluation of their effects on aggregation, cytotoxicity, and solubility. Sialylated glycans at Thr30completely inhibited IAPP aggregation, eliminated cytotoxicity toward pancreatic β cells, and enhanced solubility by up to 280-fold. Replica exchange molecular dynamics simulations revealed that glycosylation impedes adoption of a four-stranded β-sheet conformation in IAPP dimers. These findings advance the understanding of the role of natural glycosylation in aggregation and highlight its potential as an evolutionarily inspired strategy to enhance the therapeutic utility of IAPP.
Valley Hall photonic crystals (VPCs) offer the potential for creating topological waveguides capable of guiding light through sharp bends on a chip, enabling seamless integration with functional components in compact spaces, making them a promising technology for terahertz topological photonic integrated circuits. However, a key limitation for terahertz-scale integrated VPC-based devices has been the absence of arbitrary bend interconnects, as traditional VPC-designs restricted to principal lattice axes (i.e., only 0°, 60°, or 120°) due to crystalline symmetry. Here, we present an on-chip, all-silicon implementation of deformed VPCs that enable robust transmission along arbitrary shapes and bends. Although the lattice is amorphous and lacks long-range periodicity, the topological protection is sustained by short-range order. Furthermore, we show an amorphous lattice functioning as a frequency-dependent router, splitting input signals into two perpendicular output ports. We also demonstrate on-chip terahertz communication, achieving data rates of up to 72 Gbps. Our findings show that amorphous topological photonic crystals enhance interconnect adaptability while preserving performance.
Colletotrichumfungi cause destructive diseases among a wide range of hosts worldwide. We found that effector CfEC92 fromC. fructicolaspecifically binds ATP through an unidentified ATP-binding domain, leading to changes in the protein secondary structure. The residues Cys26, Asn38, and Cys39were critical for ATP binding with CfEC92, and mutations at these sites impaired the ability to suppress host immunity. CfEC92 interacted with MdNDPK2, a negative immune regulator in apple. The CfEC92-ATP complex altered the conformation of MdNDPK2, enhancing its affinity for ATP, and further increasing its autophosphorylation and kinase activity. The activated MdNDPK2 phosphorylated MdMPK3 to suppress host immunity. Homology and functional tests showed that the Cx11NC motif was highly conserved amongColletotrichumspecies, suggesting that CNC effectors represent a class of broad-spectrum virulence factors. Our findings revealed a mechanism by whichColletotrichumeffectors cooperate with helper ATP to promote target protein phosphorylation and suppress host immunity.
Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments.
Protein sequence similarity search is fundamental to biology research, but current methods are typically not able to consider crucial genomic context information indicative of protein function, especially in microbial systems. Here, we present Gaia (Genomic AI Annotator), a sequence annotation platform that enables rapid, context-aware protein sequence search across genomic datasets. Gaia leverages gLM2, a mixed-modality genomic language model trained on both amino acid sequences and their genomic neighborhoods to generate embeddings that integrate sequence-structure-context information. This approach allows for the identification of functionally and/or evolutionarily related genes that are found in conserved genomic contexts, which may be missed by traditional sequence- or structure-based search alone. Gaia enables real-time search of a curated database comprising more than 85 million protein clusters from 131,744 microbial genomes. We compare the homolog retrieval performance of Gaia search against other embedding and alignment-based approaches. We provide Gaia as a web-based, freely available tool.
Microbes use signaling molecules to regulate multiple physiological processes and mediate chemical interactions. Decoding these chemical languages is instrumental in comprehending microbial regulatory mechanisms within complex microbiota. Here, we discover previously unidentified autoinducing peptides (AIPs) derived from the plant probiotic bacteriumPaenibacillus polymyxa, identified as Pp-AIPs. Omics analyses coupled with genetic manipulations revealed that Pp-AIP1 could effectively modulate the production of multiple antimicrobial secondary metabolites at nanomolar concentration, expanding known AIP functions. Furthermore, through inoculatingP. polymyxain the natural rhizosphere microbiome and analyzing its antagonistic interactions against root microbes, we suggest that Pp-AIPs may influence the microbial community composition through modulating the antimicrobial spectrum. Global analysis of biosynthetic gene clusters (BGCs) reveal widespread co-occurrence of uncharacterized AIPs with secondary metabolite BGCs. This study underscores the unreported roles of AIPs in antibiotic regulation and the microbiome interactions, advancing knowledge of quorum-sensing mechanisms in microbial ecosystems.
We propose a general principle for the formation of topological structures in ferroelectrics, demonstrating that the fundamental formation mechanism of ferroelectric vortex is the superposition of two orthogonal dipole waves, which has also been validated by the mathematical deduction, phase-field simulations, and angle-resolved piezoelectric force microscopy. Moreover, it is demonstrated that this principle can also be extended to a range of nontrivial topological structures, including Ising, Néel, and Bloch domain walls, merons, skyrmions, Hopf rings, Solomon rings, and others. These findings not only improve our understanding of the fundamental formation mechanism of existing topological structures but also enable the prediction of topological structures, such as Star of David rings, in ferroelectric/ferromagnetic materials, liquid crystals, and Bose-Einstein condensate states (superconductors and superfluids).
Cell behavior emerges from the intracellular distribution of properties such as protrusion, contractility, and adhesion. Thus, characteristic emergent rules of collective migration can arise from cell-cell contacts locally tweaking architecture, orchestrating self-regulation during development, wound healing, and cancer progression. TheDrosophilatestis-nascent-myotube system allows dissection of contact-dependent migration in vivo at high resolution. Here, we describe a role for the axon guidance factor Plexin A in collective cell migration: maintaining cell-cell interfaces at a precise point on the mesenchymal-to-epithelial continuum. This is crucial for testis myotubes to migrate as a continuous sheet, allowing normal sculpting-morphogenesis. Cells must maintain filopodial N-cadherin–based junctions and remain ECM-tethered near cell-cell contacts to spread while collectively moving. Our data further suggest Semaphorin 1b is a Plexin A antagonist, fine-tuning activation. This reveals a contact-dependent mechanism to maintain sheet integrity during migration, driving organ morphogenesis. This is relevant for mesenchymal organ sculpting in other migratory contexts such as angiogenesis.
Linkage drag can hinder the integration of resistance genes from wild crop relatives into breeding programs. We used a chromosome-scaleNicotiana alatagenome assembly and a segregating population exceeding 160,000 plants to dissect the complex genetic architecture and overcome the tight linkage between resistance and deleterious loci to produce plants free from linkage drag. We clonedN. alata RTSW, encoding an immune receptor that confers broad-spectrum resistance to orthotospoviruses through the interaction of its carboxyl-terminal domain with an orthotospovirus-encoded protein. Notably, despite recognizing the same avirulence factor,RTSWgenes fromN. alataandSw-5bfromSolanum peruvianumhave evolved independently of adjacent nonorthologous ancestral loci. Our work illustrates the potential of wild relative genomes as resources from which to precisely introduce disease resistance into cultivated crops.
Intracellular parasites, includingBabesiaandPlasmodium, the agents of human babesiosis and malaria, depend on the salvage or de novo synthesis of critical nutrients for survival within human erythrocytes. Among these, polyamines play a pivotal role, but their specific requirements and molecular functions in intraerythrocytic parasites remain poorly understood. We identify spermidine as a key polyamine forBabesia duncaniandPlasmodium falciparumfor intraerythrocytic development. We demonstrate that spermidine is indispensable for regulating protein translation through hypusination of the eukaryotic translation initiation factor eIF5A, and its depletion leads to increased production of reactive oxygen species. Disruption of spermidine biosynthesis or its conversion from spermine results in parasite death. We also show thatB. duncaniand otherBabesiaspecies use an ancestral spermidine synthase–like enzyme, highlighting a distinct evolutionary adaptation fromP. falciparum. Our results reveal the spermidine’s dual role in oxidative stress defense and translation regulation, positioning spermidine biosynthesis as a critical vulnerability and a promising therapeutic target.
The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson’s disease (PD), contributes to dopaminergic cell death. Injection of PD patient–derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable α-syn pathology. We demonstrate that distinct assemblies of α-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.
Emulating complex neural computations like solving linearly inseparable tasks within single artificial neurons has remained an elusive goal in neuromorphic engineering. Here, we report a dendritic organic electrochemical neuron (d-OECN) capable of achieving anticoincidence detection by classifying the exclusive-OR (XOR) problem—a quintessential linearly inseparable task—within an individual neuron. Inspired by human cortical neurons that perform XOR through dendritic calcium spikes, the d-OECN leverages ion-tunable antiambipolarity in mixed ionic-electronic conducting polymers to mimic voltage-gated dendritic calcium dynamics. By integrating this dendritic component with a tunable spiking circuit representing the soma, the d-OECN achieves XOR classification through its inherent nonlinear activation profile, with decision boundaries that are both ionically and electrically tunable. Moreover, we demonstrate the d-OECN’s ability to perform edge detection using XOR in a tactile sensing system, showcasing its potential for event-based sensing and processing. The d-OECNs, replicating key aspects of biological intelligence, pave the way for next-generation bioelectronics and robotics requiring complex neural computation.
A universal quantum computer can simulate diverse quantum systems, with electronic structure for chemistry offering challenging problems for practical use cases around the hundred-qubit mark. Although current quantum processors have reached this size, deep circuits and a large number of measurements lead to prohibitive runtimes for quantum computers in isolation. Here, we demonstrate the use of classical distributed computing to offload all but an intrinsically quantum component of a workflow for electronic structure simulations. Using a Heron superconducting processor and the supercomputer Fugaku, we simulate the ground-state dissociation of N2and the ground state properties of [2Fe-2S] and [4Fe-4S] clusters, with circuits up to 77 qubits and 10,570 gates. The proposed algorithm processes quantum samples to produce upper bounds for the ground-state energy and sparse approximations to the ground-state wave functions. Our results suggest that, for current error rates, a quantum-centric supercomputing architecture can tackle challenging chemistry problems beyond sizes amenable to exact diagonalization.
Imagine being able to study the human brain in real-world scenarios while the subject displays natural behaviors such as locomotion, social interaction, or spatial navigation. The advent of ultrafast ultrasound imaging brings us closer to this goal with functional ultrasound imaging (fUSi), a mobile neuroimaging technique. Here, we present real-time fUSi monitoring of brain activity during walking in a subject with a clinically approved sonolucent skull implant. Our approach uses personalized 3D-printed fUSi helmets for stability, optical tracking for cross-modal validation with functional magnetic resonance imaging, advanced signal processing to estimate hemodynamic responses, and facial tracking of a lick licking paradigm. These combined efforts allowed us to show consistent fUSi signals over 20 months, even during high motion activities such as walking. These results demonstrate the feasibility of fUSi for monitoring brain activity in real-world contexts, marking an important milestone for fUSi-based insights in clinical and neuroscientific research.
We report evidence that organic aerosols containing carboxylic acids can be spontaneously oxidized in the dark under normal atmospheric conditions due to interfacial hydroxyl radical production. Product formation is negligible under dry conditions and increases with increasing relative humidity. In a dioxygen-free environment, the oxidation efficiency is substantially decreased. Size-resolved measurements show an increase in the reactivity and product formation yields for smaller particles, correlated with their surface-to-volume ratio. Our findings suggest that spontaneous hydroxyl radical production at the air-water interface of organic nanodroplets may be an important pathway in their oxidation, especially during nighttime.
Endovascular interventions require fast access to affected regions, followed by effective treatment. Catheterizations are effective approaches for treating vascular diseases; however, they face challenges in accessibility, efficiency, and invasiveness in narrow, tortuous vascular systems. This study presents a submillimeter magnetically actuated soft rotatable-tipped microcatheter (MSRM) designed to access small blood vessels and provide efficient, minimally invasive therapeutic interventions for blood clot treatment. The MSRM’s rotatable tip design enhances accessibility and navigation speed through a rotation-assisted active steering strategy. Improved blood clot treatment efficiency is achieved through the MSRM’s multifunctionality: It can accelerate drug-blood clot interactions, mechanically break down blood clots, and retrieve clot debris. The low invasiveness is attributed to the soft material design and conservative actuation strategy. The performance of the MSRM is validated in both in vitro phantom studies and in vivo rabbit models, and the invasiveness is evaluated using a human placenta model.
The increasing clinical trials of single-stranded mRNA (ss-mRNA) therapeutics highlight the urgent need to develop efficient, scalable, and economic purification methods. Current diffusion-driven, resin-based purification techniques constrain productivity and rely on expensive oligo(dT) ligands for target ss-mRNA poly(A) tail hybridization. To overcome these challenges, we use interfacial molecular forces, such as charge and hydrogen bonds, between nucleic acid variants and a positively charged synthetic microporous membrane to purify ss-mRNA, a desirable therapeutic, from an undesirable impurity, immunogenic double-stranded RNA (dsRNA). Membranes achieved high binding capacities (1.28 mg/m2) and up to 100% ss-mRNA recovery at ~pH 9.0, with optimized surface density (4000 to 10,000 nmol/m2). Purification was operated at rapid flow rates (1.5 ml/min,1000 MV/min) with reusability (>10 trials) and negligible ligand leaching. The key discovery of this cost-effective ligand-less multimodal surface-modified approach is that the addition of the polyamine spermine, which selectively neutralizes dsRNA charge at amine-to-phosphate ratios >450, enhanced separation efficiency.
As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the health care system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenicEscherichia coli(UPEC), whereasKlebsiella pneumoniaecauses a large portion of non-UPEC UTIs. Both bacteria express type 1 pili tipped with the mannose-binding FimH adhesin critical for UTI pathogenesis. We generated and biochemically characterized 33 murine monoclonal antibodies (mAbs) to FimH. Three mAbs protected mice fromE. coliUTI. Mechanistically, we show that this protection is Fc independent and mediated by the ability of these mAbs to sterically block FimH function by recognizing a high-affinity FimH conformation. Our data reveal that FimH mAbs hold promise as an antibiotic-sparing treatment strategy.
Materials with circumferentially aligned fibers, such as intervertebral discs and arteries, are abundant in nature but challenging to replicate artificially, despite their mechanical advantages. Although ice-templating can create bioinspired materials, the achievable structures remain limited to simple forms, such as honeycomb, lamellar, and radial structures. Here, we developed a unique ice-templating technique that constructs circumferential fibrous structures in hydrogels through slow freezing. Enhanced with rotary compression annealing, these hydrogels exhibit record-breaking features that cannot concurrently be achieved in conventional ice-templated and top-performing tough hydrogels, including high tensile properties, isotropic fatigue threshold of 2320 joules per square meter, ultracompressibility (8% strain after 500 cycles), and extraordinary burst pressure of 1.6 bar while maintaining 85 weight % water content. These properties enable opportunities in robotics, including hydrogel pneumatic grippers and an untethered bioinspired robotic fish that exhibits high-force actuation and long-term robustness. Our approach enriches the diversity of bioinspired structures in artificial materials, establishing exceptional mechanical properties through cross-length scale structural design.
Pain hypersensitivity is associated with increased activity of peripheral and central neurons along the pain neuroaxis. We show that at the peak of acute inflammatory pain, superficial medullary dorsal horn projection neurons (PNs) that relay nociceptive information to the parabrachial nucleus reduce their intrinsic excitability and, consequently, action potential firing. When pain resolves, the excitability of these neurons returns to baseline. Using electrophysiological and computational approaches, we found that an increase in potassium A-current (IA) underlies the decrease in the excitability of medullary dorsal horn PNs in acute pain conditions. In chronic pain conditions, no changes ofIAwere observed, and medullary dorsal horn PNs exhibit increased intrinsic excitability and firing. Our results reveal a differential modulation of the excitability of medullary dorsal horn projection neurons in acute and chronic pain conditions, suggesting a regulatory mechanism that, in acute pain conditions, tunes the output of the dorsal horn and, if lacking, could facilitate pain chronification.
Discovery of human footprints in alluvium dated to the Last Glacial Maximum (LGM) at White Sands, New Mexico, was a notable step in understanding the initial peopling of the Americas, but that work was met with criticism focused on the reliability of the materials used in the radiocarbon dating (seeds ofRuppiaand pollen). This paper reports on an independent study of the chronology of a previously unrecognized stratigraphic record of paleolake Otero that is directly traceable into the track-bearing alluvium. The stratigraphic data along with 26 additional radiocarbon dates on palustrine mud determined by two labs independent of the original investigations document an aggrading lake/wetland/stream record that includes the tracks and spans >23.6 thousand years to ~17.0 thousand calibrated years before present, providing another line of evidence further supporting the validity of an LGM age for the tracks.
Single-walled carbon nanotubes, as prototypical one-dimensional systems, have been extensively studied for their extreme confinement effects and the formation of strongly bound excitons. However, their high surface-to-volume ratio renders their dynamics highly susceptible to variations in the surrounding environment. Yet, visualizing photoinduced dynamics within individual nanotubes has remained a major challenge because of the lack of methods combining sufficient spatial and temporal resolution with sensitivity to an exceedingly small number of electron-hole pairs. Here, we apply ultrafast infrared nanospectroscopic imaging to probe local electron-hole dynamics in both isolated and bundled carbon nanotubes grown by chemical vapor deposition. This approach unravels heterogeneity in electron-hole pair creation and annihilation, arising from disordered stress within a tube and/or interactions with neighboring tubes. The capability to visualize local electron-hole dynamics in real time and space is essential for advancing carbon nanotubes as fundamental building blocks in nanophotonic and optoelectronic devices.
Predation is a major evolutionary driver of life history and morphology. However, whether these traits evolve directly via predation or indirect effects is largely unresolved. We used artificial selection to experimentally test the impact of adult predation on the evolution of life history and morphology in guppies (Poecilia reticulata). We found that, compared to control fish, predation-selected fish produced larger offspring and larger broods early in life. However, other life history parameters, such as interbrood interval and total number of offspring, showed no response. We also found that predation selected for smaller and lighter females and for shorter tails and gonopodia in males, with no effect on body coloration. Our results show that while several traits evolve fast under selection on adult predation, several “classic” predation-dependent traits seem unaffected by predation selection. By comparing our experimental results to those from natural populations, we can disentangle the contribution of direct and indirect effects on trait evolution under predation pressure.
Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations inStk11(which encodes LKB1) display signatures of pathogenic IL-17–producing CD4+T helper 17 (TH17) cells. LKB1 constrains T cell inflammatory potential, asStk11/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17–producing T cell lineages (CD4+TH17 and CD8+Tc17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)–dependent signaling drives pathogenic TH17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17–dependent) T cell responses and identify a CRTC2–IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.
Glutamine reprogramming plays a crucial role in the growth and survival of clear cell renal cell carcinoma (ccRCC), although the mechanisms governing its regulation are still not fully understood. We demonstrate that the RNA demethylase fat mass and obesity-associated gene (FTO) drives glutamine reprogramming to support ccRCC growth and survival. Genetic and pharmacologic inhibition of FTO in ccRCC cells impaired glutamine-derived reductive carboxylation, depleted pyrimidines, and increased reactive oxygen species. This led to increased DNA damage and reduced survival, which could be rescued by pyrimidine nucleobases or the antioxidantN-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter solute carrier family 1 member 5 (SLC1A5) messenger RNA to promote its expression. Restoration of SLC1A5 expression in FTO-knockdown cells rescued metabolic and survival defects. FTO inhibition reduced ccRCC tumor xenograft and PDX growth under the renal capsule. Our findings indicate that FTO is an epitranscriptomic regulator of ccRCC glutamine reprogramming and highlight the therapeutic potential of targeting FTO for the treatment of ccRCC.
HIV-1 uses the microtubule cytoskeleton to reach the host cell nucleus during replication, yet the molecular basis for microtubule-dependent HIV-1 motility is poorly understood. Using in vitro reconstitution biochemistry and single-molecule imaging, we found that HIV-1 binds to the retrograde microtubule-associated motor, dynein, directly and not via a cargo adaptor, as has been previously suggested. The HIV-1 capsid lattice binds to accessory chains on dynein’s tail domain. Further, we demonstrate that multiple dynein motors tethered to rigid cargoes, such as HIV-1 capsids, display reduced motility, distinct from the behavior of multiple motors on membranous cargoes. Our results provide an updated model of HIV-1 trafficking wherein HIV-1 binds to dynein directly to “hijack” the dynein transport machinery for microtubule motility.
Paxillin (PXN) and focal adhesion kinase (FAK) are two major components of the focal adhesion complex, a multiprotein structure linking the intracellular cytoskeleton to the cell exterior. The interaction between the disordered amino-terminal domain of PXN and the carboxyl-terminal targeting domain of FAK (FAT) is necessary and sufficient for localizing FAK to focal adhesions. Furthermore, PXN serves as a platform for recruiting other proteins that together control the dynamic changes needed for cell migration and survival. Here, we show that the PXN N-domain undergoes significant compaction upon FAT binding, forming a 48-kilodalton multimodal complex with four major interconverting states. Although the complex is flexible, each state has unique sets of contacts involving disordered regions that are both highly represented in ensembles and conserved. PXN being a hub protein, the results provide a structural basis for understanding how shifts in the multistate equilibrium (e.g., through ligand binding and phosphorylation) may rewire cellular networks leading to phenotypic changes.
Nonhomologous end joining (NHEJ) is required for repairing DNA double strand breaks (DSBs) generated by the RAG endonuclease during lymphocyte antigen receptor gene assembly by V(D)J recombination. The ataxia telangiectasia–mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) kinases regulate functionally redundant pathways required for NHEJ. Here, we report that loss of the senataxin helicase leads to a strong defect in RAG DSB repair upon inactivation of DNA-PKcs. The NHEJ function of senataxin is redundant with the RECQL5 helicase and the HLTF translocase and is epistatic with ATM. Co-inactivation of ATM, RECQL5, and HLTF results in an NHEJ defect similar to that from the combined deficiency of DNA-PKcs and senataxin or losing senataxin, RECQL5, and HLTF. These data suggest that ATM and DNA-PKcs regulate the functions of senataxin and RECQL5/HLTF, respectively, to provide redundant support for NHEJ.
Bovine pericardium is the tissue of choice for replacing heart valves of human patients in minimally invasive surgery. The tissue has an extraordinarily high toughness of ~100 kilojoules per square meter. Here, we investigate the origin of the toughness through mechanical tests and microscopic observations. In the tissue, crimped, long, strong collagen fibers are embedded in a soft matrix. As a crack grows in the matrix, the fibers decrimp, reorient, slip, and bridge the crack. These microscopic processes enable the fibers to transmit high tension over a long distance. Using two types of experiments, we measure the bridging traction as a function of crack separation, σ(δ). The peak traction is σ0~ 60 megapascals. The maximum separation is δ0~ 6 millimeters, two to four orders of magnitude higher than that of hard tissues. Both the high traction and large separation of the bovine pericardium contribute to its high toughness.
DNA-based storage offers a compelling alternative to traditional optical and magnetic devices. However, random data access usually requires additional noncoding primer DNA as indexes, which substantially reduce the physical data density. Here, we propose an alternative strategy to overcome this barrier by loading different data-encoding DNA files into porous microspheres, each distinguished by unique photonic bandgaps and diameters, allowing for 105types of indexing. With the two features as the addressing indexes, the physical separation of subsets from a diverse pool of DNA files is achieved, thereby facilitating the selective retrieval of stored data. The interconnected nanopore arrays and uniformly distributed positive charges within the microspheres enhance DNA enrichment, achieving a storage density of up to 22.6 exabytes per gram, far exceeding that of previous random access storage methods. This work outlines a simple and scalable method for creating nonfading photonic indexes, enabling long-term random access while maintaining high storage capacity.
The circadian system provides a temporal framework for animals to anticipate environmental events, including threats. However, the effects of stressors on the circadian system remain poorly understood. Here, we demonstrate that, in mice, stressors shift the phase of the central pacemaker, housed in the suprachiasmatic nucleus (SCN), through glutamatergic inputs from the anterior paraventricular nucleus of the thalamus (aPVT). Unlike light, which can phase delay or advance the central pacemaker, stressors consistently induce delays, effects attenuated by inhibiting aPVT neurons. Stressors robustly activate AVP-expressing neurons within the SCN and are associated with inhibition of VIP-expressing neurons, whereas light strongly activates VIP-expressing neurons with minimal effects on AVP-expressing neurons. Pairing stressors with light reveals distinct time-dependent interactions, enhancing phase delays at early night but abolishing phase advances at late night. Our findings uncover distinct SCN microcircuits that differentially encode light and stressors, providing insights into how environmental cues modulate circadian timing.
The fossil record provides the only direct evidence of changes in biodiversity over time. Patterns in more inclusive taxonomic levels (e.g., families and orders) often become more complex because of interactions between biological traits and environmental conditions across different evolutionary lineages. Using supercomputing and artificial intelligence algorithms, we analyzed a high-resolution global dataset of fusuline foraminifera—the most diverse marine fossil group from the Carboniferous to the Permian (~340 to 252 million years ago)—at an unprecedented temporal resolution of <45 thousand years. Our unbinned diversity reconstruction reveals unexpectedly simple diversity dynamics in this exceptionally well-preserved clade. We identify two (and likely a third) truncated exponential diversifications and four major diversity declines. During this interval, long-term cooling consistently promoted biodiversification, whereas warming events were closely linked to extinctions. These findings imply that the current rapid global warming, driven by anthropogenic CO2emissions, represents a critical threat to modern ecosystems.
While occupying an influential position within one’s social network brings many advantages, it is unknown how certain individuals rise in social prominence. Leveraging a longitudinal dataset that tracks an entirely new network of college freshmen (N= 187), we test whether “climbing the social ladder” depends on knowing how other people are connected to each other. Those who ultimately come to occupy the most influential positions exhibit early and accurate representations of their network’s general, abstract structure (i.e., who belongs to which communities and cliques). In contrast, detailed, granular representations of specific friendships do not translate into gains in social influence over time. Only once the network stabilizes do the most influential individuals exhibit the most accurate representations of specific friendships. These findings reveal that those who climb the social ladder first detect their emerging network’s general structure and then fine-tune their knowledge about individual relationships between their peers as network dynamics settle.
A nematic phase lacks translation order but has orientational order. Nematic phases have been discovered in a variety of systems, including liquid crystals, correlated materials, and superconductors. Here, we report on a magnetic nematic phase, where the basis components are composed of magnetic helices. We directly probed the order parameters associated with the magnetic helices using resonant soft x-ray scattering and find two distinct nematic phases with complex spatiotemporal signatures. Using x-ray correlation spectroscopy, we find that near the phase boundary between the two nematic phases, fluctuations coexist on multiple disparate timescales. Our micromagnetic simulations and density functional theory calculations show that the fluctuations occur concomitantly with a reorientation of the magnetic helices, indicating spontaneous symmetry breaking and the emergence of additional degrees of freedom. Our results provide a framework for characterizing exotic phases that can be extended to a broad class of physical systems.
Ocean waves have long been a hazard to marine operations, making water wave isolation critical in ocean engineering. Traditional methods suffer from large area requirements, high costs, and incomplete isolation. We design a water wave isolation device using periodic gear arrays (PGAs), which overcomes these drawbacks and achieves perfect water wave isolation across a wide frequency band. Water wave isolation occurs by effectively creating a negative water depth, which fills a major gap in the field of manipulating water waves using metamaterial concept. We demonstrate the water wave isolation of PGAs through analytical methods, simulations, and experiments, proving that effective negative water depth is key to achieving the isolation of water waves. The PGAs perform well across a wide frequency band, with potential applications in port and ocean wave isolation. This discovery enriches water wave manipulation techniques and advances the development of water wave metamaterials.
Bioinspired piezoelectricity is extensively explored for diverse bio-machine interface and biomedical engineering applications. Nevertheless, state-of-the-art bio-piezoelectricity mainly focuses on crystallization. Yet, crystalized structures exhibit several shortcomings, including limited biocompatibility or biodegradability along with intrinsic non-stretchability. Herein, peptides fibrillization is reported to present inherent bio-piezoelectricity. Upon forming double-network framework with silk fibroin, fibrous peptide piezogels of innate biocompatibility and biodegradability are achieved, showing a programmable piezoelectricity. In particular, the bioinspired supramolecular piezogel can linearly respond to external compression and stretching in large force regions, extensively expanding the application potential bio-piezoelectricity. Upon designing a “W”-shaped structural conformation, a peptide fibrous piezogel–based piezoelectric sensor is shown to be used for detection of limb movements and subcutaneous implantation of the bioinspired piezoelectric electronics, realizing in situ and real-time monitoring of stimuli responses. The findings suggest the promising potential of peptide fibrillization–based bio-piezoelectricity for diverse bio-machine interface and biomedical engineering applications.
The advancement of molecular junction transistors relies heavily on precise modulation of molecular orbitals, yet this is hindered by a limited transmission window and reduced bias stability, which typically restricts the range of active channel molecules adopted to those with orbital levels near Fermi level of the contacts. In this study, we demonstrate an effective orbital gating of prototypical alkanethiol–based molecules with deeper orbital levels in vertical large-area mixed self-assembled monolayers (SAMs) configuration that offers enhanced electrical bias stability and gating efficiency. By using ion gel gating in Au-molecule-graphene junction, the channel conductance could be modulated notably according to a clear transition from direct tunneling to Fowler-Nordheim tunneling regime. The mixed SAM molecular transistors also showed a superior gating efficiency due to the suppressed field screening effect by the net molecular dipole. This work is expected to contribute toward developing reliable three-terminal molecular device platform extended to molecules with deep orbital levels.
The cellular networks that maintain genome stability encompass numerous pathways involved in all aspects of nucleic acid metabolism. Through bioinformatic analysis, we identified the Zinc Finger CCCH-Type Containing 4 protein (ZC3H4), a suppressor of noncoding RNA (ncRNA) production, as a pivotal player in this system. Experimentally, ZC3H4 deficiency led to increased DNA damage, abnormal mitosis, and cellular senescence. Biochemical analysis and super-resolution microscopy revealed that the loss of ZC3H4 increased replication stress (RS)—a major driver of genome instability—by inducing a hypertranscription state that promoted R loop formation and transcription-replication conflicts (TRCs), both of which drive RS. Further bioinformatic analysis demonstrated that ZC3H4 preferentially binds to genomic regions prone to TRCs and R loops, where it suppresses ncRNA bursts, functioning as part of the Restrictor complex. Our findings identify ZC3H4 as a crucial factor in maintaining genome integrity, strategically positioned at the critical intersection of DNA and RNA synthesis.
R2 retrotransposons are site-specific eukaryotic non–long terminal repeat retrotransposons that copy and paste into gene loci encoding ribosomal RNAs. Recently, we demonstrated that avian A-clade R2 proteins achieve efficient and precise insertion of transgenes into their native safe-harbor loci in human cells. The features of A-clade R2 proteins that support gene insertion are not well characterized. Here, we report high-resolution cryo–electron microscopy structures of two vertebrate A-clade R2 proteins at the initiation of target-primed reverse transcription and after cDNA synthesis and second-strand nicking. Using biochemical and cellular assays, we illuminate the basis for high selectivity of template use and unique roles for each of the three zinc-finger domains in nucleic acid recognition. Reverse transcriptase active site architecture is reinforced by an unanticipated insertion motif specific to vertebrate A-clade R2 proteins. Our work provides the first insights into A-clade R2 protein structure during gene insertion and may enable future improvement and adaptation of R2-based systems for precise transgene insertion.
In living tissues, collagen networks rarely exist alone because they are embedded within other biological matrices. When combined, collagen networks rigidify via synergistic mechanical interactions and stiffen only with higher mechanical loads. However, how cells respond to the nonlinear elasticity of collagen in hybrid networks remains largely unknown. Here, we demonstrate that when collagen rigidifies by the interpenetration of a second polymer, the amount of force that initially stiffens the network (onset of stiffening, σc) increases and is sufficient to stimulate an increase in intracellular tension. We investigated this effect by precisely controlling the nonlinear elasticity of collagen with the synthetic semiflexible polymer, polyisocyanopeptides. We find that small increases in σcinduce a biphasic response in cell-matrix interactions, influencing how cells migrate, proliferate, and generate contractile force. Our results suggest that cells adaptively respond to changes in the nonlinear mechanics of collagen, which may be a mechanistic behavior used during tissue homeostasis or when collagen rigidifies during pathological conditions.
Despite their large environmental impact and multiple independent emergences, the processes leading to the evolution of anaerobic methanotrophic archaea (ANME) remain unclear. This work uses comparative metagenomics of a recently evolved but understudied ANME group, “CandidatusMethanovorans” (ANME-3), to identify evolutionary processes and innovations at work in ANME, which may be obscured in earlier evolved lineages. We identified horizontal transfer ofhdrAhomologs and convergent evolution in carbon and energy metabolic genes as potential early steps inMethanovoransevolution. We also identified the erosion of genes required for methylotrophic methanogenesis along with horizontal acquisition of multiheme cytochromes and other loci uniquely associated with ANME. The assembly and comparative analysis of multipleMethanovoransgenomes offers important functional context for understanding the niche-defining metabolic differences between methane-oxidizing ANME and their methanogen relatives. Furthermore, this work illustrates the multiple evolutionary modes at play in the transition to a globally important metabolic niche.
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Elevated levels of asparagine, catalyzed by asparagine synthetase (ASNS), have been identified as a prerequisite for lung metastasis in breast cancer. However, the roles and regulatory mechanisms of ASNS in breast cancer brain metastasis (BCBM) are not well understood. Our study revealed that the family with sequence similarity 50 member A (FAM50A) gene substantially modulates the brain metastatic potential of breast cancer by up-regulating ASNS and promoting asparagine biosynthesis. We demonstrated that FAM50A forms a complex with chromosome 9 open reading frame 78 (C9ORF78), specifically at the S121 residue, to enhance ASNS transcription. This interaction accelerates the rate of ASNS-mediated asparagine synthesis, which is essential in facilitating metastatic cascades to the brain. From a therapeutic perspective, both the genetic suppression of FAM50A and pharmacological inhibition of asparagine synthesis effectively counteract BCBM. Our results highlight the importance of the FAM50A-ASNS signaling pathway in BCBM therapy.
Expanded polytetrafluoroethylene (e-PTFE) is extensively used in medical implants for its excellent bioinertness. Existing methods to fix e-PTFE implants on host tissues mainly use invasive anchorage such as sutures, spiral tacks, or metal skeletons, which has limitations such as being time-consuming and causing leakage and tissue damage. To overcome these limitations, we introduce a bioadhesive interface to realize the adhering fixation of e-PTFE implants. We integrate a hydrophilic and bioadhesive hydrogel layer on the hydrophobic and bioinert e-PTFE by designing a facile approach of freezing-induced micromechanical interlocking. The integration is robust enough as pulling hydrogel out of the interlocked pores on e-PTFE requires large energy dissipation. This bioadhesive interface enables instant (operating time < 10 seconds) and secure (adhesion energy >200 joules per square meter) adhering fixation of e-PTFE implants to wet tissue. The advantages for reducing inflammatory response, fibrogenesis, and the resultant postoperative adhesion are further demonstrated in a reconstructive surgery of an abdominal wall defect in rabbits.
The ecological and evolutionary success of multicellular lineages stems substantially from their increased size relative to unicellular ancestors. However, large size poses biophysical challenges, especially regarding nutrient transport: These constraints are typically overcome through multicellular innovations. Here, we show that an emergent biophysical mechanism—spontaneous fluid flows arising from metabolically generated density gradients—can alleviate constraints on nutrient transport, enabling exponential growth in nascent multicellular clusters of yeast lacking any multicellular adaptations for nutrient transport or fluid flow. Beyond a threshold size, the metabolic activity of experimentally evolved snowflake yeast clusters drives large-scale fluid flows that transport nutrients throughout the cluster at speeds comparable to those generated by ciliary actuation in extant multicellular organisms. These flows support exponential growth at macroscopic sizes that theory predicts should be diffusion limited. This demonstrates how simple physical mechanisms can act as a “biophysical scaffold” to support the evolution of multicellularity by opening up phenotypic possibilities before genetically encoded innovations.
Roadbed tribological energy (RTE) is a promising recoverable resource with an estimated potential on the terawatt scale, generated annually by the interaction between tires and road surfaces. However, RTE remains underutilized due to the lack of effective energy harvesting technologies that can address its high-entropy characteristics. Here, we present a revolutionary harvester formed by a freestanding layer triboelectric nanogenerator array embedded in the road. The harvester effectively converts low-grade vibratory RTE into electrical energy. It demonstrates the potential to achieve a peak power of 16.409 milliwatts and an average power of 2.2 milliwatts from a compact 78–square centimeter road area under a single tire impact, with a triboelectric conversion efficiency of 11.723%. In addition, we developed a self-powered intelligent and connected transportation system (SP-ICTS), integrating a five-in-one harvesting array. Experimental findings show that the system can meet the SP-ICTS’s electricity requirements along a 1-kilometer segment with a 50-meter harvester.
Competition among news sources over public opinion can incentivize them to resort to misinformation. Sharing misinformation may lead to a short-term gain in audience engagement but ultimately damages the credibility of the source, resulting in a loss of audience. To understand the rationale behind news sources sharing misinformation, we model the competition between sources as a zero-sum sequential game, where news sources decide whether to share factual information or misinformation. Each source influences individuals based on their credibility, the veracity of the article, and the individual’s characteristics. We analyze this game through the concept of quantal response equilibrium, which accounts for the bounded rationality of human decision-making. The analysis shows that the resulting equilibria reproduce the credibility-opinion distribution of real-world news sources, with hyperpartisan sources spreading the majority of misinformation. Our findings provide insights for policymakers to mitigate the spread of misinformation and promote a more factual information landscape.
Plexiform neurofibromas (PNFs) are benign tumors of the peripheral nervous system that represent a major source of morbidity in neurofibromatosis type 1 (NF1). A substantial proportion of patients do not respond to current therapies or experience intolerable side effects. Transcriptomic characterization of murine and human PNF at bulk and single-cell resolution identified transforming growth factor–β (TGFβ) signaling as a key upstream regulator, driving aberrant basement membrane (BM) protein production by neoplastic Schwann cells and Fbs. Conditional TGFβ1 overexpression inNf1-deficient Schwann cells driven byHoxb7-Cre promoted PNF growth and malignant transformation in vivo. Conversely, pharmacologic inhibition of the type I TGFβ receptor (TGFβRI) reduced PNF tumor burden inNf1mutant mice. Proteomic characterization of the extracellular matrix (ECM) showed reduced BM proteins upon TGFβRI inhibition. These findings implicate TGFβ as a potential therapeutic target in PNF and provide insights into the role of TGFβ signaling in orchestrating ECM dynamics in the PNF microenvironment.
The heterotrimeric G protein–coupled serotonin receptor 5-HT1Areceptor (5-HT1AR) mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, we evolved ST171, a bitopic 5-HT1AR agonist that revealed highly potent and functionally selective Gi/osignaling without Gsactivation and marginal β-arrestin recruitment. ST171 is effective in acute and chronic pain models. Cryo–electron microscopy structures of ST171 bound to 5-HT1AR in complex with the Giprotein compared to the canonical agonist befiradol bound to complexes of 5-HT1AR with Gior Gsrevealed that the ligands occupy different exo-sites. The individual binding poses are associated with ligand-specific receptor conformations that were further studied by molecular dynamics simulations, allowing us to better understand ligand bias, a phenomenon that may be crucial to the discovery of more effective and safe G protein–coupled receptor drugs.
The Argonaute CSR-1 is essential for germline development inC. elegans. Loss of CSR-1 leads to the down-regulation of thousands of germline-expressed genes, supporting a model in which CSR-1 “licenses” gene expression via a poorly understood mechanism. In contrast, a small subset of genes is up-regulated incsr-1mutants, includingmorc-1, which encodes a conserved GHKL-type ATPase. We show thatmorc-1is overexpressed incsr-1mutants and accumulates over CSR-1 licensed targets, coinciding with aberrant gain of H3K9me3, reduced H3K36me3, and transcriptional repression. Notably, loss ofmorc-1fully rescues these chromatin defects and partially restores gene expression and fertility incsr-1mutants. Conversely, ectopic overexpression of MORC-1 in the wild-type germ line is sufficient to repress CSR-1 licensed targets and severely compromise fertility. These findings support a model in which CSR-1 prevents MORC-1 overexpression and consequent misregulation of CSR-1 licensed genes.
Evolution of Archean continental crust involved partial melting of mafic crust to form the tonalite-trondhjemite-granodiorite (TTG) series. However, crustal generation remains enigmatic with both plate tectonic and non-plate tectonic modes proposed. In this study, we show that zircons from the ~2.5–billion years ago TTGs in the Eastern Block (EB) of the North China Craton have low water contents (median of 263 parts per million) and high δ18O values (median of 6.22‰) and a negative correlation between them, which suggest a thick hybridized and hydrated mafic source. By contrast, zircon water contents of the adjoining coeval TTGs in the Trans-North China Orogen, formed in a supra-subduction zone setting, are notably higher. These results support a two-stage mantle plume-sagduction process for TTG formation. Our study suggests that Archean continental crust, such as that in the EB, most likely originated from plume-related oceanic plateaus, rather than subduction-related island arc magmatism under a plate tectonic regime.
Capturing the intricate dynamics of neural activity in freely behaving animals is essential for understanding the neural mechanisms underpinning specific behaviors. Miniaturized microscopy enables investigators to track population activity at the cellular level, but the field of view (FOV) of these microscopes has often been limited and do not support multi-brain region imaging. To fill this technological gap, we have developed the eXtra Large FOV Miniscope (MiniXL) for mice, a 3.5-gram miniaturized microscope with an FOV measuring 3.5 mm in diameter. We demonstrate the capabilities of the MiniXL through large-scale neuronal population records in hippocampal dorsal CA1. We also demonstrate simultaneous multi-brain region imaging across bilateral medial prefrontal cortex (mPFC) and mPFC and nucleus accumbens (NAc) during complex social behavior and stably track cells across multiple days. As with all microscopes in the UCLA Miniscope ecosystem, the MiniXL is fully open-source and designed to be shared with the neuroscience community to lower the barriers for adoption of this technology.
Ferroelectric domain walls (FDWs) exhibit exotic structural and electronic properties, positioning them as a promising functional element for next-generation nanoelectronics. However, achieving the deterministic creation of FDWs with nanoscale precision and controlled polarization of domains remains a substantial challenge for the scalable FDW-device fabrication and circuit design. Here, we demonstrate a strategy for FDW engineering by tailoring the interfacial electrostatic profile. Using SrRuO3islands as “nano-masks,” we spatially modulate the interfacial atomic termination to generate alternating positive and negative built-in electric fields. The boundaries where the electric field switches polarity drive the formation of 180° FDWs in BiFeO3thin films. This mechanism is validated through theoretical calculations and direct experimental observations. Furthermore, atomic-scale analysis reveals localized lattice distortions, structural chirality of the FDWs, as well as the edge effect of SrRuO3islands on the position precision of FDW nucleation. Our findings pave the way toward a scalable and controllable bottom-up FDW-growth technique for future FDW nanoelectronics.
To gain insight into the root causes of metabolic dysfunction, it is essential to understand how tissues communicate and coordinate their metabolic functions. Here, we sought to address this in the context of cold exposure, a well-studied metabolic perturbation. We performed proteomics across six metabolic tissues and plasma, quantifying 11,394 proteins. Beginning our investigation in brown adipose tissue (BAT), we identified a mechanism to explain enhanced glucose utilization in cold-adapted BAT. This was characterized by select remodeling of upper glycolysis and pentose cycling to increase oxygen consumption, likely by increasing uncoupling protein 1 activity through the production of reactive oxygen species. Cold-induced remodeling of the plasma proteome appeared to underpin the ability of BAT to modify its fuel preference, stimulating lipolysis in white adipose tissue and glucose production in the liver. These findings emphasize the importance of considering metabolic adaptations in the context of the whole body and suggest overlap between the mechanisms of cold adaptation and obesity.
Rapid, millennial-scale changes in sea level have been proposed for the beginning, middle, and/or end of the Last Interglacial (LIG) [~129 to 116 thousand years ago (ka)]. Each of these scenarios has different implications for polar ice sheet behavior in a warming world. Here, we present a suite of230Th ages for fossil corals in the Seychelles within a detailed sedimentary and stratigraphic context to evaluate the evolution of sea level during this past warm period. The rise to peak sea level at ~122 to 123 ka was punctuated by two abrupt stratigraphic discontinuities, defining three distinct generations of reef growth. We attribute the evidence of episodic reef growth and ephemeral sea-level fall to the competing influence of Northern Hemisphere ice melt and Antarctic ice regrowth. Asynchronous ice sheet contributions would mask the full extent of retreat for individual ice sheets during the LIG and imply greater temperature sensitivity of ice sheets than previously inferred.
Prediction of peptide secondary structure is challenging because of complex molecular interactions, sequence-specific behavior, and environmental factors. Traditional design strategies, based on hydrophobicity and structural propensity, can be biased and could indeed prevent discovery of interesting, diverse, and unconventional peptides with desired nanostructure assembly. Using β sheet formation in pentapeptides as a case study, we used an integrated high-throughput experimental workflow and an artificial intelligence–driven active learning framework to improve prediction accuracy of self-assembly. By focusing on sequences where machine learning (ML) predictions deviate from conventional design strategies, we synthesized and tested 268 pentapeptides, successfully finding 96 forming β sheet assemblies, including unconventional sequences (e.g., ILFSM, LMISI, MITIY, MISIW, and WKIYI) not predicted by traditional methods. Our ML models outperformed conventional β sheet propensity tables, revealing useful chemical design rules. A web interface is provided to facilitate community access to these models. This work highlights the value of ML-driven approaches in overcoming the limitations of current peptide design strategies.
T cells targeting epitopes in infectious diseases or cancer play a central role in spontaneous and therapy-induced immune responses. Epitope recognition is mediated by the binding of the T cell receptor (TCR), and TCRs recognizing clinically relevant epitopes are promising for T cell–based therapies. Starting from a TCR targeting the cancer-testis antigen NY-ESO-1157–165epitope, we built large phage display libraries of TCRs with randomized complementary determining region 3 of the β chain. The TCR libraries were panned against NY-ESO-1, which enabled us to collect thousands of epitope-specific TCR sequences. Leveraging these data, we trained a machine learning TCR-epitope interaction predictor and identified several epitope-specific TCRs from TCR repertoires. Cellular assays revealed that the predicted TCRs displayed activity toward NY-ESO-1 and no detectable cross-reactivity. Our work demonstrates how display technologies combined with TCR-epitope interaction predictors can effectively leverage large TCR repertoires for TCR discovery.
Prostate cancer risk is influenced by various factors, including exposure to heavy metals like cadmium (Cd). The study reveals that the autophagy-regulating gene PLAC8 (placenta-specific 8) is significantly involved in Cd-induced prostate carcinogenesis, and NF-κB acts as the upstream transcriptional activator of PLAC8, which then selectively up-regulates BCL-xL, providing a survival advantage to Cd-transformed cells. NF-κB activation stabilizes PLAC8 in the cytosol, disrupting autophagy by allowing PLAC8 to colocalize with LC3B instead of LAMP1. Silencing NF-κB down-regulates PLAC8 and its survival function while inhibiting NF-κB or PLAC8, which restores autophagy and decreases tumor growth in xenograft models. In addition, targeting BCL-xL confirmed this signaling pathway. The findings suggest that sustained NF-κB activation regulates PLAC8 and highlights the NF-κB–PLAC8–BCL-xL axis as a potential target for early detection and therapies in metal-induced prostate cancer.
Unique electrical properties emerging at nanoscale ferroelectric interfaces originate from the polarization induced charges. However, real-space characterization of polarization induced charges at nanoscale ferroelectric interfaces has been extremely challenging. Here, directly observing the nanoscale electric field by tilt-scan averaged differential phase contrast scanning transmission electron microscopy enables us to measure the spatially varying total charge density profiles across both head-to-head and tail-to-tail domain walls in a ferroelectric crystal. Combined with atomic column displacement measurements, the spatial distribution of polarization bound charges and screening charges across the domain walls can be disentangled. Our results reveal the true charge states of the nanoscale ferroelectric interfaces, providing an opportunity for experimentally exploring the interplay between atomic-scale local polarization structures and their charge states in ferroelectric interfaces.
The integration of high strength, super toughness, damage resistance, body-temperature shape memory, and biosafety into a single skin-mimic material system has been a notable challenge in the realm of material science and biomedical applications. In this study, “Lego-like” polyurethane (PU) was selected to amalgamate multiple properties through the design of multilevel structures. By comprehensively designing the chemical and sequence structures of blocks, coordinating weak/strong hydrogen bonds, and achieving rational microphase separation and crystallization, an elastomer was obtained with an exceptional true tensile strength of 1.42 gigapascal, a high fracture energy of 384.7 ± 18.9 kJ/m2, and a skin-like nonlinear mechanoresponse. The coordination of crystallization and physical cross-linking also guaranteed excellent body-temperature shape memory properties, which are applicable in 4D printing. Moreover, the obtained elastomer is biosafe and has the potential to promote cell proliferation and DNA repair, which will find wide applications in the biomedical field including minimally invasive surgery.
Brain geometry affects brain function. A quantitative encoding of form is provided by the Laplace-Beltrami operator’s spectrum of eigenvalues (LBS). We examined LBS genetics of 22 subcortical brain structures and cerebellum in 19,862 healthy White-British UK Biobank participants by multivariate genome-wide association study on the first 49 eigenvalues each. Controlling for surface and volume, we identified 80 unique variants influencing the shapes of one or several structures, with the highest yield (37 variants) for brain stem. The previously known influence of several of these loci on basic morphology, such as volume, is thus shown to also influence complex shape. Known associations of observed loci with blood pressure, neurodegeneration, alcohol consumption, and mental disorders hint at preclinical stages of these conditions potentially mediating the genetic effect on brain morphology. Significant correlations between LBS of several brain structures and the polygenic risks of hypertension, ischemic stroke, and schizophrenia evince brain shapes as early biomarkers.
Exciton dissociation in organic solar cells (OSCs) is primarily achieved through interfacial charge-transfer (CT) states, leading to a trade-off between open-circuit voltage (VOC) and short-circuit current (JSC). Spatially dispersed delocalized singlet excitons (DSEs) in nonfullerene acceptors (NFAs) provide an alternative channel to promote charge generation without interfacial CT state. Here, we manipulate intermolecular interactions, carrier dynamics, and photovoltaic properties through selective asymmetric fluorination. Two asymmetric molecules, Z12 and Z13, were synthesized by substituting the terminal group with different fluorine atoms compared with the symmetrical molecule, Z11. Z12 showed enhanced molecular interactions, promoting to more compact and ordered stacking, which in turn promotes the DSE formation, benefiting the synergistic enhancement ofVOCandJSC. The D18:Z12-based device achieved a remarkable power conversion efficiency of 19.5%, notably outperforming the other two devices. Our study indicates that controlling the molecular configuration by selective fluorination to enhance the DSE formation in NFAs is an effective strategy to achieve efficient OSCs.
Widespread application of bacterial-based cancer therapy is limited because of the need to increase therapeutic bacteria specificity to the tumor to improve treatment safety and efficacy. Here, we harness the altered tumor metabolism and specifically elevated kynurenine accumulation to target engineered bacteria to the cancer site. We cloned and leveraged kynurenine-responsive transcriptional regulator (KynR) with its cognate promoter inEscherichia coli. Optimizing KynR expression coupled with overexpressing kynurenine transporter and amplifying the response through plasmid copy number–based signal amplification enabled the response to kynurenine at the low micromolar levels. Knocking out genes essential for cell wall synthesis and supplying these genes via kynurenine-controlled circuits allowed tuningSalmonella entericagrowth in response to kynurenine. Our kynurenine-controlledS. enterica(hereafter named AD95+) showed superior tumor specificity in breast and ovarian cancer murine models compared toS. entericaVNP20009, one of the best characterized tumor-specific strains. Last, AD95+ showed anticancer properties compared to vehicle controls, demonstrating the potential as an anticancer therapeutic.
Sound is a crucial sensing element for many organisms in nature, with various species evolving organic structures that produce complex acoustic scattering and dispersion phenomena to emit and perceive sound clearly. To date, designing artificial scattering structures that match the performance of these organic structures has proven challenging. Typically, sound manipulation relies on active transduction in fluid media rather than passive scattering principles, as often observed in nature. In this work, we use computational morphogenesis to create complex, energy-efficient, wavelength-sized single-material scattering structures that passively decompose radiated sound into its spatio-spectral components. Specifically, we design an acoustic rainbow structure with “above unity” efficiency and an acoustic wavelength splitter. Our work demonstrates what is possible when using computational morphogenesis to tailor the emission and reception of sound fields, with relevance to disciplines concerned with the sensing and emission of wave fields.
In magnetic pyrochlore materials, the interplay of spin-orbit coupling, electronic correlations, and geometrical frustration gives rise to exotic quantum phases, including topological semimetals and spin ice. While these phases have been observed in isolation, the interface-driven phenomena emerging from their interaction have never been realized previously. Here, we report on the discovery of interfacial electronic anisotropy and rotational symmetry breaking at a heterostructure consisting of the Weyl semimetal Eu2Ir2O7and spin ice Dy2Ti2O7. Subjected to magnetic fields, we unveil a sixfold anisotropic transport response that is theoretically accounted by a Kondo-coupled heterointerface, where the spin ice’s field-tuned magnetism induces electron scattering in the Weyl semimetal’s topological Fermi-arc states. Furthermore, at elevated magnetic fields, we reveal a twofold anisotropic response indicative of the emergence of a symmetry-broken many-body state. This discovery showcases the potential of pyrochlore frustrated magnet/topological semimetal heterostructures in search of emergent interfacial phenomena.
The nucleolus is essential for ribosome biogenesis and stress regulation. However, because of its dynamic nature, there is still a lack of methods to specifically visualize nucleolar localization in living cells and to study dynamic changes in protein interaction networks within the cell nucleolus. In this study, we identified and engineered a signal peptide sequence, termed nucleolar beacon, which exhibits robust nucleolar localization and universal applicability across various mammalian cell types. Using this sequence, we established nucleolar indicator cell lines and demonstrated their practicality in studying nucleolar functions in living cells. In addition, by combining the signal peptide with proximity labeling technology, we developed an effective approach for capturing the nucleolar proteome and successfully identified nucleolar-associated proteins. These techniques provide effective and versatile tools for investigating nucleolar functions in living cells and offer a potential strategy for drug delivery applications.
Amyloid aggregates are pathological hallmarks of many human diseases, but how soluble proteins nucleate to form amyloids is poorly understood. Here, we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid-β (Aβ42), the protein that aggregates in Alzheimer’s disease. In total, we measure the nucleation rates of >140,000 variants of Aβ42 to accurately quantify the changes in free energy of activation of the reaction for all possible amino acid substitutions in a protein and, in addition, to quantify >600 energetic interactions between mutations. Strong energetic couplings suggest that the Aβ42 nucleation reaction transition state is structured in a short C-terminal region, providing a structural model for the reaction that may initiate Alzheimer’s disease. Using this approach it should be possible to reveal the energetic structures of additional amyloid transition states and, in combination with additional selection assays, protein transition states more generally.
Optoretinography is an emerging method for detecting and measuring functional responses from neurons in the living human retina. Its potential applications are compelling and broad, spanning clinical assessment of retinal disease, investigation of fundamental scientific questions, and rapid evaluation of experimental therapeutics for blinding retinal diseases. Progress in all these domains hinges on the development of robust methods for quantifying observed responses in relation to visible stimuli. In this work, we describe an optoretinographic imaging platform: full-field swept-source optical coherence tomography with adaptive optics, measure cone responses in two healthy volunteers to a variety of stimulus patterns, and propose a simple model for predicting and quantifying responses to those stimuli.
Eosinophil-rich granulomas, formed around tissue-trapped parasite eggs, are hallmarks of schistosomiasis mansoni, a prevalent neglected tropical disease. How eosinophils populate and affect the complexSchistosomagranulomas remains unclear. Here, we mapped eosinophils across evolutional hepatic granulomas in a mouse model and in a primary wild reservoir for human schistosomiasis in Brazil (water ratNectomys squamipes). With in-depth quantitative image analysis and three-dimensional histological reconstructions of entire granulomas, we find that eosinophils are spatially organized and occupy a major, peripheral niche conserved across space and time in all granuloma stages and both experimental and natural infections. Within this niche, immature and mature eosinophils coinhabit, compartmentalize their major basic protein-1 content, robustly interact with other immune cells, and secrete through piecemeal degranulation. This unveiled niche, unrelated to parasite eggs, challenges the concept of eosinophil as a “helminth killer” cell and invigorates its view as an immunoregulatory cell of the tissue microenvironment inSchistosomagranulomas.
Trial-and-error approaches in chemistry generate abundant unsuccessful experiments, yet the potential of these so-called negative results remains largely underutilized. Here, we demonstrate that information from negative chemical reactions can be leveraged to improve reactivity-prediction models, offering advantages in scenarios with a limited volume of successful data. We extend the tuning of language models with reinforcement learning to the chemistry domain, training a transformer model for chemical reaction prediction. Our approach is evaluated using both a rigorously controlled dataset and a realistic high-throughput dataset comprising extensive reaction screenings across diverse catalysts sets and experimental conditions. The model achieves state-of-the-art performance by leveraging information from as few as 20 positive data points in the controlled dataset, supported by a negative dataset at least 40 times larger. Consistent results on both datasets demonstrate that, with an appropriate optimization strategy and the inclusion of unsuccessful experimental data, models can be effectively trained even when successful reactions are underrepresented.
The electrified interface between a liquid and a solid underpins diverse phenomena, from ion-transfer during battery operation to action potentials enabling biological communication. However, conventional tools are blind to the nanoscale dynamics of this metastable interface. Here, we leverage electrified cryo–electron microscopy (eCryo-EM), a technique that rapidly freezes and kinetically traps these dynamic, nonequilibrium states during battery operation for nanoscale characterization. Collective snapshots of the electrified interface at controlled time intervals quantifies early-stage growth kinetics of the solid electrolyte interphase (SEI), a passivation film that governs electron and ion transport. Unexpectedly, the diffusivity of charged species of the two SEI films with differing chemistry and performance are estimated to be within 10% of the other, indicated by the slope of their diffusion-limited SEI growth regimes. Instead, the slope of the reaction-limited SEI growth regimes differs by a factor of 3, suggesting that lowered reactivity of the high-performance electrolyte is largely responsible for its high coulombic efficiency.
Earth is the only known rocky planet to support complex life forms that use oxygen and to have a strong intrinsic magnetic field in much of its history, prompting speculation that Earth’s magnetic field and habitability are related on geological timescales. We search for possible observational evidence for such a relationship by examining evolutions of the virtual geomagnetic axial dipole moment and the atmospheric oxygen level over the past 540 million years. We find that both exhibit strong linearly increasing trends, coupled with a large surge in magnitude between 330 and 220 million years ago. Our time series analysis and statistical tests show that both are highly correlated, with the maximum correlation reached when there is no time lag between the two. Our findings suggest unexpected strong connections between the geophysical processes in Earth’s deep interior, the surface redox budget, and biogeochemical cycling.
DNA damage arises from various environmental stresses, and ABA is well known for its roles in plant stress resistance. However, its function in plant DNA damage tolerance remains unclear. In this study, we showed that ABA supplementation significantly enhances plant tolerance to DNA-damaging treatments. SnRK2.2 and SnRK2.3 kinases in the ABA signaling pathway are pivotal in this process. These kinases interact with clathrin light chain 2 (CLC2), facilitating its phosphorylation and nuclear translocation in response to Zeocin and ABA treatment. In the nucleus, CLC2 interacts with ADA2b, an adaptor protein crucial for recruiting SMC5/6 complex to the double-strand break (DSB) sites. The enhanced nuclear localization of CLC2 is essential for the accurate localization of ADA2b at DSB sites. Collectively, our study uncovers that ABA enhances plant DNA damage tolerance with a distinct function of CLC2 in genomic stability maintaining, thereby improving our understanding of DNA damage tolerance mechanisms in plants.
It is widely held that identical systems tend to behave similarly under comparable conditions. Yet, for systems that interact through a network, symmetry breaking can lead to scenarios in which this expectation does not hold. Prominent examples are chimera states in multistable phase-oscillator networks. Here, we show that for a broad class of such networks, asynchronous states can be converted into frequency-synchronized states when identical oscillators are detuned to have different intrinsic frequencies. We show that frequency synchronization is achieved over a range of intrinsic frequency detuning and is thus a robust effect. These results, which are supported by theory, simulations, and electrochemical oscillator experiments, reveal a counterintuitive opportunity to use parameter heterogeneity to promote synchronization.
Noninvasive transcranial neuromodulation of deep brain regions is a longstanding goal in neuroscience. While optogenetics enables remote neural control, it is constrained by shallow tissue penetration of visible light and delayed onset due to required opsin expression. Here, we introduce a neuromodulation technique using hybrid upconversion and photovoltaic (HUP) nanoparticles, which eliminates the need for genetic modification and affords near-infrared (NIR) activation of neurons in wild-type mice. This method converts deeply penetrating NIR light into localized electrical stimuli, enabling immediate and precise modulation in deep brain. In vitro patch-clamp experiments confirm neuronal activation upon HUP application. In vivo, we achieve remote NIR neuromodulation in the medial septum and ventral tegmental area 7 days postinjection, effectively modulating neuronal activity, suppressing seizures, and triggering dopamine release. This minimally invasive approach offers a versatile tool kit for investigating neural processes in mammals, with potential applications across diverse brain regions through customizable nanoparticle engineering.
In plants, ATP-binding cassette (ABC) transporters are crucial for nutrient uptake, phytohormone transport, and environmental response. It is of great interest to understand the mechanisms of these transporters and develop small-molecule modulators to regulate plant growth.ArabidopsisABCB19 was recently shown to transport brassinosteroid, shaping hormone dynamics and plant architecture. However, the conformational cycle and inhibitor mechanism of ABCB transporters remain elusive. We reconstituted ABCB19 into lipid nanodiscs, where activity was drastically higher than in detergents, and determined its cryo–electron microscopy structures in substrate-free, substrate-bound, vanadate-trapped, and inhibitor-bound states. Inward-facing ABCB19 moved inward upon substrate binding and fully closed with vanadate trapping, unexpectedly temperature dependent. Two inhibitor molecules locked ABCB19 in the inward-facing conformation. Mutagenesis identified key residues for substrate and inhibitor binding, revealing differential contributions to transporter function and inhibition. These results deepen knowledge of plant ABCB transporters, laying a foundation for targeted manipulation to enhance plant resilience and productivity.
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Maintaining reactive oxygen species (ROS) homeostasis is essential for balancing growth-defense trade-offs in plants. Although the transcription factors (TFs) that regulate ROS production and scavenging genes have been studied, the regulation of these TFs to control ROS accumulation remains poorly understood. Here, we demonstrate that during N nucleotide-binding leucine-rich repeat–mediated immunity, Alfin-like 7 (AL7) is ubiquitinated by the ubiquitin protein ligase E3 component N-recognin 7 (UBR7). UBR7 interacts with AL7 and acts as a molecular brake to mediate the ubiquitination of AL7 at lysine-20, leading to its subsequent proteasomal degradation. UBR7 functions upstream of AL7 to reduce AL7-induced ROS accumulation duringN-mediated defense. The phosphorylation of AL7 at serine-174 enhances its interaction with UBR7, thereby increasing AL7 ubiquitination and reducing AL7 stability. Our findings reveal a mechanism by which ROS accumulation is regulated through the phosphorylation and ubiquitination of a TF during the immune response. This ensures precise switching of ROS signaling to prevent excessive defense responses.
Resolving partial waves, including their amplitudes and phases, is crucial for understanding the intricate structure and dynamics of the photoelectron released. However, the knowledge is limited because of the complexities of the multiphoton interactions with molecules in the nonperturbative regime. Here, we address these challenges using an orthogonal two-color (OTC) scheme, which combines different photon energies and polarizations of the laser fields to produce characteristic photoelectron angular distributions (PADs) that vary with the laser phase. By analyzing the phase-dependent PADs, the partial waves, including their individual amplitudes and phases, involved in the nondissociative and dissociative single ionization of H2are unambiguously resolved. In addition, the interaction phases accumulated during the absorption of multiple photons of different polarizations are revealed. The OTC scheme works as a powerful tool to achieve a partial-wave decomposition of the photoelectron wave packet launched via multiphoton ionization and explore attosecond electron dynamics in strong laser fields.
α-Chiral phosphorus compounds have broad applications as organic catalysts or ligands in organic chemistry and related areas. Herein, we disclose a Ni-catalyzed enantioselective cross-hydrodimerization of alkenyl phosphine sulfides with unactivated alkenes to access α-chiral phosphine sulfides, representing the first example of asymmetric hydrodimerization of electron-deficient alkenes with electron-rich alkenes. Key to success is the precise recognition between electron-deficient alkenes and electron-rich alkenes and streamlined alkyl-alkyl bond forming with the control of chemo-, regio-, and enantioselectivity. This strategy requires alkenes as sole precursors for asymmetric alkyl-alkyl cross-coupling, circumventing the use of stoichiometric amounts of alkyl electrophiles or alkyl nucleophiles as coupling partners. The mild conditions tolerate a wide range of functional groups, providing direct access to α-chiral phosphines through a carbon-carbon bond-forming process without prefunctionalized coupling precursors.
Bone morphogenetic protein (BMP) signaling patterns secondary body axes throughout Bilateria and in the bilaterally symmetric corals and sea anemones. Chordin-mediated “shuttling” of BMP ligands is responsible for the BMP signaling gradient formation in many bilaterians and, possibly, also in the sea anemoneNematostella, making BMP shuttling a candidate ancestral mechanism for generating bilaterality. However,NematostellaChordin might be a local inhibitor of BMP rather than a shuttle. To choose between these options, we tested whether extracellular mobility of Chordin, a hallmark of shuttling but dispensable for local inhibition, is required for patterning inNematostella. By generating localized Chordin sources in the Chordin morphant background, we showed that mobile Chordin is necessary and sufficient to establish a peak of BMP signaling opposite to Chordin source. These results provide evidence for BMP shuttling in a bilaterally symmetric cnidarian and suggest that BMP shuttling may have been functional in the potentially bilaterally symmetric cnidarian-bilaterian ancestor.
Materials with low thermal conductivity are important for a variety of applications such as thermal barrier coatings and thermoelectrics, and understanding the underlying mechanisms of low heat transport, as well as relating them to structural features, remains a central goal within material science. Here, we report on the ultralow thermal conductivity of the quarternary crystalline silver chalcogenide AgGaGe3Se8, with a remarkable value of only 0.2 watts per meter per kelvin at room temperature and an unusual glass-like thermal behavior from 2 to 700 kelvin. The ultralow thermal conductivity is linked to a disordered nature of silver in the structure, displaying extremely large silver atomic displacement parameters obtained from multitemperature synchrotron powder x-ray scattering measurements and silver ionic conductivity at elevated temperatures. In addition, a low-temperature Boson peak in the heat capacity and a low Debye temperature of 158 kelvin reveal signs of structural anharmonicity and soft bonding.
Effective memory formation declines in human aging. Diminished neural selectivity—reduced differential responses to preferred versus nonpreferred stimuli—may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer’s disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During learning, neural selectivity in place- and, to a lesser extent, face-selective regions was greater for subsequently remembered than forgotten events; positively scaled with variability in dorsal attention network activity, within and across individuals; and negatively related to AD pathology, evidenced by elevated plasma phosphorylated Tau181(pTau181). Path analysis revealed that neural selectivity mediated the effects of age, attention, and pTau181on memory. These data reveal multiple pathways that contribute to memory differences among older adults—AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.
Spatial transcriptomics enables multiplex profiling of gene cellular expression and location within the tissue context. Although large volumes of spatial transcriptomics data have been generated, the lack of systematic curation and analysis limits biological discovery. We present Spatial transcriptOmics Analysis Resource (SOAR), a comprehensive spatial transcriptomics platform with 3461 uniformly processed samples across 13 species, 42 tissue types, and 19 different spatial transcriptomics technologies. Using SOAR, we found thatCXCL16/SPP1macrophage polarity characterizes the coordination of immune cell polarity in the tumor microenvironment. SOAR’s integrative approach toward drug discovery revealed sirolimus and trichostatin A as potential anticancer agents targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin growth and proliferation pathway and identified Janus kinase/signal transducers and activators of transcription inhibitors for ulcerative colitis treatment. SOAR’s results demonstrate its broad application to data generated from diverse spatial technologies and pathological conditions. SOAR will support future benchmarking studies and method development, facilitating discoveries in molecular functions, disease mechanisms, and potential therapeutic targets.
Josephson junctions (JJs) are key to superconducting quantum technologies and the search for self-conjugate quasiparticles potentially useful for fault-tolerant quantum computing. In topological insulator (TI)–based JJs, measuring the current-phase relation (CPR) can reveal unconventional effects such as Majorana bound states (MBS) and nonreciprocal transport. However, reconstructing CPR as a function of magnetic field has not been attempted. Here, we present a platform for field-dependent CPR measurements in planar JJs made of NbSe2and few-layer Bi2Se3. When a flux quantumΦ0threads the junction, we observe anomalous peak-dip CPR structure and nonreciprocal supercurrent flow. We show that these arise from a nonuniform supercurrent distribution that also leads to a robust and tunable Josephson diode effect. Furthermore, despite numerous previous studies, we find no evidence of MBS. Our results establish magnetic field–dependent CPR as a powerful probe of TI-based superconducting devices and offer design strategies for nonreciprocal superconducting electronics.
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling of host-pathogen interactions has enhanced our understanding of drug resistance. However, how combinations of drug resistance mutations affect dose-response curves remains underappreciated in PK-PD studies. The fitness seascape model addresses this by extending the fitness landscape model to map genotypes to dose-response functions, enabling the study of evolution under fluctuating drug concentrations. Here, we present an empirical fitness seascape inE. coliharboring all combinations of four drug resistance mutations. Incorporating these data into PK-PD simulations of antibiotic treatment, we find that higher mutation supply increases the probability of resistance, and early adherence to the drug regimen is critical. In vitro studies further support the finding that the second dose in a drug regimen is important for preventing resistance. This work bridges empirical fitness seascapes and computational PK-PD studies, revealing insights into drug resistance.
Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of function or increased levels of the essential activation factorAscl1reveal thatAscl1promotes the activation of hippocampal neural stem cells by driving these cells out of deep quiescence, despite its low protein expression in this state. Subsequently, during the transition from deep to shallow quiescence,Ascl1induces the expression ofMycn, which drives progression through shallow quiescent states toward a proliferating state. Together, these results define the required sequence of transcription factors during hippocampal neural stem cell activation and establish a combinatorial code for classifying these cells into deep and shallow quiescence.
Self-powered sensing related to triboelectric nanogenerator (TENG) as a sustainable self-sufficient power source for environmental monitoring by harvesting energy from a living environment is critical in the field of energy and environmental science. However, features of small energy-density and irregularity of environmental energy make it difficult to use directly for real-time environmental monitoring. Here, we report a self-powered and self-calibrated environmental monitoring system (SSEMS) composed of TENG, a calibration resistor, and a sensor network in parallel for real-time temperature and humidity monitoring. The calibration resistor can monitor in real time the irregular output of TENG from the irregularity of rainfalls. SSEMS uses this calibrating signal to calibrate the sensing signal in real time, achieving accurate sensing with an error margin less than 5.0%. We applied SSEMS under waterfalls and rainfalls to monitor in real time the environmental temperature and relative humidity with a sensing error as low as 1.0%. This work promotes self-powering technology one step further to practical applications.
The impact of anaerobic oxidation of methane (AOM) coupled with denitrification on the emission of the denitrification intermediate N2O remains poorly understood. Here, we investigated the influence of AOM coupled with nitrate and nitrite reduction on soil N2O emissions and the associated microbial interactions. We show that AOM coupled with denitrification markedly reduces soil N2O emissions, with the type I methanotrophMethylobacterspecies collaborating with the Methylophilaceae and Gemmatimonadaceae families to perform key roles. The suppression of N2O emissions by AOM primarily stems from its role in supplying electrons and carbon sources, fueling complete denitrification by associated bacteria. In addition, we uncovered distinct microbial interaction strategies for AOM-coupled nitrate and nitrite reduction. While nitrite reduction necessitates both bacterial cooperation and extracellular electron transfer during its initial stages, nitrate reduction predominantly depends on methanotrophic bacteria alone at the outset. These findings advance our understanding of carbon-nitrogen cycle coupling and underscore AOM’s potential to simultaneously mitigate both CH4and N2O emissions.
Unraveling the mechanisms underlying the maintenance of species diversity is a central pursuit in ecology. It has been hypothesized that ectomycorrhizal (EcM) in contrast to arbuscular mycorrhizal fungi can reduce tree species diversity in local communities, which remains to be tested at the global scale. To address this gap, we analyzed global forest inventory data and revealed that the relationship between tree species richness and EcM tree proportion varied along environmental gradients. Specifically, the relationship is more negative at low latitudes and in moist conditions but is unimodal at high latitudes and in arid conditions. The negative association of EcM tree proportion on species diversity at low latitudes and in humid conditions is likely due to more negative plant-soil microbial interactions in these regions. These findings extend our knowledge on the mechanisms shaping global patterns in plant species diversity from a belowground view.
Scattering-type scanning near-field optical microscopy (s-SNOM) allows for the observation of the optical response of material surfaces with a resolution far below the diffraction limit. Based on amplitude-modulation atomic force microscopy (AFM) with typical tapping amplitudes of tens of nanometers, a spatial resolution of 10 to 100 nm is routinely achieved in s-SNOM. However, optical imaging and spectroscopy of atomic-scale structures remain a substantial challenge. Here, we developed ultralow tip oscillation amplitude s-SNOM (ULA-SNOM), where the ultraconfined field localized at a 1-nm-scale gap between a plasmonic tip and sample is combined with frequency-modulation (noncontact) AFM in a stable cryogenic ultrahigh vacuum environment. Using a silver tip under visible laser illumination with a constant 1-nm amplitude oscillation, we obtain a material-contrast image of silicon islands on a silver surface with 1-nm lateral resolution, which surpasses the conventional limits of s-SNOM. ULA-SNOM paves the way for the acquisition of optical information from atomic-scale structures, such as single photo-active defects and molecules.
The coherent vibrational dynamics of gold nanorods with varying aspect ratios have been extensively studied by time-resolved spectroscopy to reveal their mechanical properties, but quantum-sized rods (transverse diameter < 2 nanometers) remain unexplored. Here, we present a comprehensive study on the coherent vibrations of atomically precise gold quantum rods with distinct energy gaps (0.6 to 1.3 electron volts), all sharing the same radial dimension but with increasing aspect ratios. Time-resolved spectroscopy reveals ultrafast internal conversion and intersystem crossing, along with oscillatory features superimposed on transient signals that unveil coherent vibrational dynamics. Two dominant modes are identified: a longitudinal mode scaling with rod length and a transverse mode independent of aspect ratio. Theoretical simulations support these findings and clarify the structural origins of the observed vibrational behavior. Our study provides a framework for designing atomically precise gold quantum rods with tailored optical and vibrational properties, advancing the understanding and application of anisotropic quantum materials.
Flat optical components, or metasurfaces, have transformed optical imaging, data storage, information processing, and biomedical applications by providing unprecedented control over light-matter interactions. These nano-engineered structures enable compact, multidimensional manipulation of light’s amplitude, phase, polarization, and wavefront, producing scalar and vector beams with unique properties such as orbital angular momentum and knotted topologies. This flexibility has potential applications in optical communication and imaging, particularly in complex environments such as atmospheric turbulence and undersea scattering. However, designing metasurfaces for shorter wavelengths, such as visible and ultraviolet light, remains challenging due to fabrication limitations and material absorption. Here, we introduce an innovative concept called topology imprinting using judiciously designed all-dielectric nonlinear optical metasurfaces to replicate desired waveforms at fundamental and harmonic frequencies, opening promising avenues for advanced photonic applications.
Programming microorganism adhesions to engineer multicellular microbial communities holds promise for synthetic biology and medicine. Current chemical and genetic engineering approaches often lack specificity or require engineered bacteria, making the design of responsive interactions challenging. Here, we demonstrate the use of functional DNA as programmable surface receptors to regulate the patterns and behaviors of microbial communities. Using metabolic labeling and hydrophobic insertion, we modified various microorganisms with DNA, including Gram-positive and Gram-negative bacteria, and dormant spores. By incorporating distinct sequences, we achieved precise spatial control of bi- and tricomponent microbial assemblies, forming diverse morphologies like core-shell and selective clusters. Stimuli-responsive clustering was successfully realized using aptamers, strand displacement, and reverse-Hoogsteen base pairing, with oligonucleotides or small molecules as exogenous cues. This work extends the use of functional DNA to control microbial interactions, enabling living communities with dynamic biofunctions, such as biofilm formation, antibiotic sensitivity, and quorum sensing, in response to biological triggers.
The accurate targeting of proteins to their designated cellular compartments is essential for maintaining proper cellular architecture and function. However, interpreting and sorting the highly variable targeting sequences in secreted and membrane proteins present a substantial challenge for achieving precise localization within the secretory pathway. In this study, we demonstrate that atypical signal sequences, characterized by high hydrophobicity and/or the absence of characteristic charges, are recognized by the signal recognition particle and targeted to the endoplasmic reticulum in a reverse orientation. These misoriented signal sequences are subsequently dislocated by the P5A-ATPase ATP13A1 and delivered to SEC61 for further translocation. Using cryo–electron microscopy, we determined the structures of human ATP13A1 in multiple conformations (3.40- to 3.87-angstrom resolution), revealing key residues within its substrate-binding pocket that engage signal sequences through polar interactions. Collectively, our findings elucidate a comprehensive, substrate-specific translocation pathway that ensures both high efficiency and fidelity in protein subcellular localization.
PIEZOs form trimeric calcium-permeable nonselective cationic channels that serve mechanical sensing needs across eukaryotic biology. Forces act on the channels by causing their curved blades to flatten and decompact, leading to an activated state, but it is unclear how this is regulated to enable the channels to adapt to different contexts. To identify potential mechanisms, we performed coarse-grained and all-atom molecular dynamics simulations on human PIEZO1. We observed an interblade handshake interaction mediated by basic amino acid residues in two flexible helices coordinated with regulated anionic lipid phosphatidylinositol 4,5-bisphosphate. The interaction determined the resting configuration of the channel, blade curvature, compactness, and ion pore structure. In experiments, disruption of the handshake by neutralization of helix amino acids or phosphatidylinositol 4,5-bisphosphate depletion increased the channel’s sensitivity to membrane tension. Structural and amino acid sequence analysis for multiple PIEZOs predicted helix amino acid arrangements for varied handshaking intensity. We suggest a dynamic interaction in PIEZO channels that regulates force sensitivity.
Bacteria, the smallest and most abundant life forms on Earth, have been a source of insights that have had a considerable impact on human health.Helicobacter pylorihas captured substantial attention due to its role in provoking an array of gastrointestinal ailments and other human diseases. Here, we report thatH. pylorireleases the protein CagA (cytotoxin-associated gene A) that strongly inhibits formation of both functional (bacterial biofilm) and pathogenic amyloid assemblies by targeting various stages during fibril formation. CagA’s broad substrate specificity reveals a mechanism wherebyH. pyloriinterferes with other bacteria and humans, offering approaches to combat bacterial infections and human protein misfolding diseases.
Influenza A virus (IAV) enters host cells via endocytosis, and fusion of the viral particles (VPs) at endosomes releases the viral ribonucleoproteins (vRNPs) into the cytoplasm. This uncoating step that is vital for IAV infection remains to be fully understood. The aggresome processing machinery (APM) plays a relevant but not essential role in this. Here, we reveal a mechanism in which light chain 3 proteins (LC3s) and pericentrin (PCNT) form an adaptor complex that is required for vRNPs binding to the dynein 1 and IAV uncoating at endosomes. This function of LC3s and PCNT is independent from their established role in autophagy and centrosome assembly, respectively. LC3s or PCNT depletion severely impairs IAV cytoplasm entry and infection, which can be further inhibited by additional silencing of histone deacetylase 6, an APM component. Collectively, our results show that IAV has adopted two redundant strategies to hijack the dynein biomolecular motors and facilitate VP uncoating.
Behavioral fever, a thermoregulatory response in which ectothermic animals seek warmer environments to elevate body temperature and combat parasite infections, is well documented against microparasites. However, its role and mechanisms against macroparasites remain largely unknown. Here, we show thatDrosophilahosts use behavioral fever to defend againstLeptopilinaparasitoid wasps. This thermal preference increases wasp mortality and enhances host survival. We find that behavioral fever is mediated by up-regulation ofHeat shock protein 70(Hsp70) genes in infected hosts asHsp70loss abolishes behavioral fever, whereas its overexpression induces heat-seeking behavior. We further find that behavioral fever up-regulates immune genes in infected hosts, including 12antimicrobial peptide(AMP) genes, which disrupt the gut microbiota homeostasis of parasitoid wasps and, in turn, lead to substantial wasp mortality. Our findings elucidate the detailed mechanisms of behavioral fever inDrosophilahosts, advancing our understanding of ectothermic animal defenses against macroparasites.
The proper assembly of light-harvesting complexes (LHCs) is critical for photosynthesis and requires the biogenesis of light-harvesting chlorophylla,b-binding proteins (LHCPs) to be coordinated with chlorophyll (Chl) biosynthesis. The mechanism underlying this coordination is not well understood. Here, we show that a conserved molecular chaperone, chloroplast signal recognition particle 43-kDa protein (cpSRP43), provides a molecular thermostat that helps maintain this coordination. cpSRP43 undergoes a conformational rearrangement between a well-folded closed state and a partially disordered open state. Closed cpSRP43 is dedicated to the biogenesis of LHCPs, whereas open cpSRP43 protects multiple Chl biosynthesis enzymes from heat-induced destabilization. Rising temperature shifts cpSRP43 to the open state, enabling it to protect heat-destabilized Chl biosynthesis enzymes. Our results reveal the molecular basis of a posttranslational mechanism for the thermoadaptation of LHC biogenesis. They also demonstrate how an adenosine triphosphate–independent chaperone uses conformational dynamics to switch its activity and client selectivity, thereby adapting to different proteostatic demands under shifting environmental conditions.
An emerging family of metal-halide perovskite semiconductors is highly attractive for optoelectronic applications because of their tunable light absorption, long-lived photogenerated carriers, and high defect tolerance. However, their inherent bandgaps limiting the photoabsorption below 1000 nanometers greatly constrain the further development of these materials and their optoelectronic devices. Here, we reported a straightforward strategy to achieving visible-to-infrared photoabsorption covering 630 to 2000 nanometers in inorganic perovskites by incorporating supramolecular crown ethers. Crown ethers enable supramolecular host-guest complexation and the formation of self-organizing Turing structures composed of original perovskites and supramolecular hybrid crystals. The visible-to-infrared photoabsorption is attributed to the interphase electron transitions in the Turing-structured perovskite hybrid matter system. Such visible-to-infrared photoabsorption is successfully translated into a photoelectronic response in an interdigitated photodetector. Our research extends the light absorption and detection capabilities of the perovskite hybrid semiconductors into the infrared region.
Billions of people rely upon groundwater for drinking water and agriculture, yet predicting how climate change may affect aquifer storage remains challenging. To gain insight beyond the short historical record, we reconstruct changes in groundwater levels in western North America during the last glacial termination (LGT, ~20 to 11 thousand years ago) using noble gas isotopes. Our reconstructions indicate remarkable stability of water table depth in a Pacific Northwest aquifer throughout the LGT despite increasing precipitation, closely matching independent Earth system model (ESM) simulations. In the American Southwest, ESM simulations and noble gas isotopes both suggest a pronounced LGT decline in water table depth in in response to decreasing precipitation, indicating distinct regional groundwater responses to climate. Despite the hydrologic simplicity of ESMs, their agreement with proxy reconstructions of past water table depth suggests that these models hold value in understanding groundwater dynamics and projecting large-scale aquifer responses to climate forcing.
The origin and function of chirality in DNA, proteins, and other building blocks of life represent a central question in biology. Observations of spin polarization and magnetization associated with electron transport through chiral molecules, known collectively as the chiral induced spin selectivity effect, suggest that chirality improves electron transfer. Using reconfigurable nanoscale control over conductivity at the LaAlO3/SrTiO3interface, we create chiral electron potentials that explicitly lack mirror symmetry. Quantum transport measurements on these chiral nanowires reveal enhanced electron pairing persisting to high magnetic fields (up to 18 tesla) and oscillatory transmission resonances as functions of both magnetic field and chemical potential. We interpret these resonances as arising from an engineered axial spin-orbit interaction within the chiral region. The ability to create one-dimensional electron waveguides with this specificity creates opportunities to test, via analog quantum simulation, theories about chirality and spin-polarized electron transport in one-dimensional geometries.
Regulatory T cell (Tregcell) therapy has been transformed through the use of chimeric antigen receptors (CARs). We previously found that human Tregcells minimally produce IL-10 and have a limited capacity to control innate immunity compared to type 1 regulatory T cells (Tr1 cells). To create “hybrid” CAR Tregcells with Tr1 cell-like properties, we examined whether thePDCD1locus could be exploited to endow Tregcells with CAR-regulated IL-10 expression. CRISPR-mediated PD1 deletion increased CAR Tregcell activation, and knock-in ofIL10under control of the PD1 promoter resulted in CAR-induced IL-10 secretion.IL10knock-in improved CAR Tregcell function, as determined by increased suppression of dendritic cells and alloantigen- and islet autoantigen–specific T cells. In vivo,IL10knock-in CAR Tregcells were stable, safe, and suppressed dendritic cells and xenogeneic graft-versus-host disease. CRISPR-mediated engineering to simultaneously remove an inhibitory signal and enhance a suppressive mechanism is a previously unexplored approach to improve CAR Tregcell potency.
Endothelial barrier dysfunction and the resulting vascular injury are responsible for multiorgan failure in sepsis. Myeloid C-type lectin domain family 5 member A (CLEC5A) is a pattern recognition receptor involved in host defense against infection. Mice lacking CLEC5A were resistant to cecal ligation and puncture (CLP)–induced polymicrobial sepsis and lipopolysaccharide (LPS)–induced endotoxemia, as observed by decreased mortality. Single-cell RNA sequencing revealed transcriptomic heterogeneity of vascular endothelial cells in CLEC5A-deficient lungs following CLP. Endothelial-specific knockdown of CLEC5A improved survival of CLP-challenged mice, which was completely ineffective with reexpression of endothelial CLEC5A. The survival benefits were attributed to alleviated inflammatory storm and vascular leakage. Furthermore, endothelial CLEC5A deficiency protected mice againstEscherichia coli–induced pneumonia. In vitro, CLEC5A deletion maintained trans-endothelial electrical resistance, and inhibited adhesion and trans-endothelial migration of monocytes/neutrophils under LPS stimulation. The study unveils the importance of CLEC5A in regulating endothelial barrier function and suggests endothelial CLEC5A as a therapeutic target for pneumonia or sepsis-causing bacterial infection.
Mineral-associated organic carbon (MAOC) is the largest terrestrial pool of organic carbon, yet controls on its formation remain unresolved. Existing MAOC is thought to preclude additional C storage on minerals, but this perspective is difficult to reconcile with observations that MAOC stacks in multilayers, suggesting that existing MAOC could promote greater C retention. Here, in a manipulative experiment using 118 soils from 15 agricultural sites across the United States, we show that MAOC formation is promoted by both existing MAOC and its counterpart—MAOC saturation deficit. The positive effect of existing MAOC on the formation of new MAOC persists after accounting for soil physicochemical properties that covary with MAOC. In contrast with current theory, we found that MAOC formation was not clearly influenced by microbial carbon-use efficiency (CUE). Our findings demonstrate that existing MAOC and saturation deficit, not microbial CUE, are key to determining new MAOC formation in agricultural soils.
The impact of chemotherapy-induced tumor cell pyroptosis on fibroblasts, a key stromal cell type within the tumor microenvironment (TME), remains unexplored. Here, we report morphologically and molecularly distinct subtypes of cancer-associated fibroblasts (CAFs) in bladder cancer, including αSMA+IL-6−myofibroblastic CAFs (myCAFs), αSMA−IL-6+inflammatory CAFs (iCAFs), and hybrid i/myCAFs. Caspase-1–dependent tumor pyroptosis releases several inflammatory chemokines, converting αSMA+CAF into iCAFs in a CCR6-dependent manner. This is clinically relevant, as a fibroblast gene signature driven by iCAF markers and collagen type III is enriched in patients with chemoresistant bladder cancer after neoadjuvant chemotherapy. Contrary to the current notion, iCAFs, rather than myCAFs, produce collagen III in response to chemotherapy, supporting the expansion of cancer stem cells (CSCs). Thus, tumor cell pyroptosis initiates an iCAF-CSC feedforward loop that drives chemoresistance, indicating that inflammatory cell death is not universally beneficial to anticancer therapy, depending on the target cell type.
Earth’s continental margins are dissected by submarine canyons that convey sediments, carbon, and nutrients to the deep ocean, regulating global biogeochemical fluxes. Despite their importance in the Earth system, the controls on canyon occurrence remain poorly understood. We report results from a spatial statistical model that explains global canyon distribution. By analyzing >2000 canyons, we show that canyon occurrence correlates with the inclination of continental slopes. Onshore orogeny and associated surface processes, long considered key controls on canyon formation, play a subordinate role. Instead, our results suggest slope inclination as the primary control on submarine canyon density. Because continental slope morphology is fundamentally shaped by marine tectonic and thermal processes, these large-scale forces indirectly govern canyon formation and distribution globally. As a result, they influence the presence of pathways that facilitate the transfer of sediments, carbon, and nutrients to the deep ocean, with implications for biogeochemical cycles over geological timescales.
Femtosecond lasers with extremely high peak intensity have driven remarkable advancements in manufacturing across science, medicine, and industry. However, the problem of notably low machining speed remains unsolved. Here, we demonstrate that by transiently exciting electrons in a transparent material, the laser drilling speed is increased by a factor of 1 million compared to that in multishot percussion drilling. By irradiating with a single shot of a spatially shaped ultrashort laser pulse, the optical properties are momentarily changed on the picosecond scale, making the material considerably easier to machine by a successive laser pulse. The selective absorption of laser energy in regions with excited electrons leads to the rapid heating and evaporation of material at an extraordinarily high speed. Furthermore, the machining is achieved using a low-power light source, four orders of magnitude lower than conventional femtosecond lasers. The concept of transiently altering material properties is expected to usher in a paradigm shift in research and development for manufacturing.
Edholm’s law predicts exponential growth in data rate and spectrum bandwidth for communications. Owing to exponentially increasing deep neural network computing demands and the slowing of Moore’s law, new computing paradigms are required for future advanced communications like 6G. Optical neural networks (ONNs) are promising accelerators but struggle with scalability and system overhead. Here, we introduce our multiplicative analog frequency transform optical neural network (MAFT-ONN), an artificial intelligence hardware accelerator that experimentally computes fully analog deep learning on raw radio frequency (RF) signals, performing modulation classification that quickly converges to 95% accuracy. MAFT-ONN also exhibits scalability with nearly 4 million fully analog operations for MNIST digit classification. Because of the Shannon capacity–limited analog data movement, MAFT-ONN is also hundreds of times faster than traditional RF receivers.
B cell epitope prediction tools are crucial for designing vaccines and disease diagnostics. However, predicting which antigens a specific antibody binds to and their exact binding sites (epitopes) remains challenging. Here, we present AbEpiTope-1.0, a tool for antibody-specific B cell epitope prediction, using AlphaFold for structural modeling and inverse folding for machine learning models. On a dataset of 1730 antibody-antigen complexes, AbEpiTope-1.0 outperforms AlphaFold in predicting modeled antibody-antigen interface accuracy. By creating swapped antibody-antigen complex structures for each antibody-antigen complex using incorrect antibodies, we show that predicted accuracies are sensitive to antibody input. Furthermore, a model variant optimized for antibody target prediction—differentiating true from swapped complexes—achieved an accuracy of 61.21% in correctly identifying antibody-antigen pairs. The tool evaluates hundreds of structures in minutes, providing researchers with a resource for screening antibodies targeting specific antigens. AbEpiTope-1.0 is freely available as a web server and software.
Pacinian corpuscles are among the most sensitive mechanoreceptors found in vertebrates, and they are tuned to vibrations in the highest perceptible frequency range (100 to 2000 Hz). One of their anatomical hallmarks is the onion-like cell layers surrounding the central axon. The innermost layers consist of ~60 densely packed lamellar Schwann cells (LSCs), whose function remains largely unknown. Using high-resolution three-dimensional electron microscopy, we found that LSCs do not form concentric rings, but complex, multilayered, and intertwining assemblies that are connected via a high density of desmosomes and gap junctions. LSCs make multiple converging contacts with the afferent axon via desmosomes. Using optogenetic manipulations of LSCs, we demonstrate not only that their activation drives reliable time-locked spiking in the axon but also that their inactivation significantly elevates the thresholds in situ and increases perceptual thresholds behaviorally. Together, these findings provide evidence that LSCs are a key element of somatosensory processing, actively potentiating mechanosensitivity in Pacinian corpuscles.
Mercury compounds are potent neurotoxins that pose threats to human health, primarily through fish consumption. Rivers, critical for drinking water and food supply, have seen rapid increases in mercury concentrations and export to coastal margins since the Industrial Revolution (~1850). However, patterns of these changes remain understudied, limiting assessments of environmental policies. Here, we develop a global model to simulate preindustrial riverine total mercury and assess human perturbations by comparing it to present-day conditions. We find that global rivers transported ~390 megagrams annually of mercury to the oceans in the preindustrial era, with spatial variability. Human activities have elevated riverine mercury budgets by two to three times in the present day. Establishing a baseline riverine mercury level, our findings reveal rapid responses of riverine mercury to human perturbations and could be used to inform targets for global riverine mercury restoration. Total riverine mercury concentrations could also be used as indicators to comprehensively understand the effectiveness of mercury pollution governance.
Carbon cycling between surface and mantle reservoirs is pivotal in fostering habitability of Earth. A critical yet poorly constrained parameter is whether crustal carbon can “survive” devolatilization processes that accompany slab subduction and therefore influence deep carbon budgets. Carbonatites provide a key record to address this important topic. Here, we present high-precision potassium isotope data for a large set of carbonatite samples from both continental and oceanic settings, spanning from 2 billion years ago to the present. Modeling suggests that the heavy potassium isotopic compositions of carbonatites are inherited from their mantle sources, rather than resulting from magmatic and postmagmatic processes. Our results demonstrate a strong link between the subduction of oceanic crust and the recycling of carbonates into the mantle sources of carbonatites. These findings support the hypothesis that subduction of carbonate-bearing altered oceanic crust has been a critical mechanism for transferring carbon into the deep Earth through time.
Tissue atlases provide foundational knowledge on the cellular organization and molecular distributions across molecular classes and spatial scales. Here, we construct a comprehensive spatiomolecular lipid atlas of the human kidney from 29 donor tissues using integrated multimodal molecular imaging. Our approach leverages high-spatial-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry for untargeted lipid mapping, stained microscopy for histopathological assessment, and tissue segmentation using autofluorescence microscopy. With a combination of unsupervised, supervised, and interpretable machine learning, the atlas provides multivariate lipid profiles of specific multicellular functional tissue units (FTUs) of the nephron, including the glomerulus, proximal tubules, thick ascending limb, distal tubules, and collecting ducts. In total, the atlas consists of tens of thousands of FTUs and millions of mass spectrometry measurements. Detailed patient, clinical, and histopathologic information allowed molecular data to be mined on the basis of these features. As examples, we highlight the discovery of how lipid profiles are altered with sex and differences in body mass index.
Oceanic mesoscale eddies play a crucial but underexplored role in regulating carbon fluxes and climate change. While they redistribute heat, salt, nutrients, and other tracers, their effects on CO2uptake remain uncertain. Using observation-based machine learning to estimate CO2fluxes throughout the lifetimes of thousands of eddies, we show that anticyclonic eddies substantially enhance CO2uptake on average, while cyclonic eddies marginally diminish it. This asymmetry yields an overall net increase in CO2absorption by 9.98 ± 2.28 and 13.82 ± 9.94% in the Kuroshio Extension and Gulf Stream, respectively, major carbon sequestration regions. The primary driver of this enhanced uptake is the downward pumping of dissolved inorganic carbon within anticyclonic eddies. Asymmetric biological responses between anticyclonic and cyclonic eddies contribute to the overall eddy-induced CO2flux imbalance. The finding suggests a potential underestimation of the ocean’s capacity for carbon sequestration because of insufficient incorporation of eddies in current observations, emphasizing the need for expanded monitoring in eddy-rich, undersampled regions.
Biomolecular condensates formed via phase separation of proteins, and nucleic acids regulate crucial cellular processes. However, such liquid-like membraneless bodies can undergo aberrant liquid-to-solid transitions into amyloid-like pathological species, which necessitates their efficient clearance by the cellular protein quality control machinery comprising molecular chaperones. We present a unique case to demonstrate that a heat shock protein 40 (Ydj1) promotes the heterotypic phase separation of intrinsically disordered tau via a multitude of interactions. Using multicolor imaging, time-resolved fluorescence anisotropy, vibrational Raman spectroscopy, and single-molecule Förster resonance energy transfer, we unmask the crucial molecular events associated with heterotypic phase separation of tau. We show that the presence of Ydj1 within condensates abolishes phase transitions into amyloids, unlike tau-only droplets that spontaneously mature into amyloid fibrils. We identify the amyloidogenic hexapeptide motifs located in the hydrophobic microtubule-binding region of tau that interacts with the peptide-binding regions of Ydj1 promoting tau-Ydj1 condensate formation. Our results provide mechanistic underpinnings of condensate-mediated protein homeostasis.
Disruption in neuronal and synaptic metabolic homeostasis is a key driver of neurodegeneration in Parkinson’s disease (PD). Mitochondrial activity, biomass, and efficiency are critical to this balance. While activity and biomass are well characterized in PD pathology, mitochondrial metabolic efficiency remains insufficiently explored. Our previous studies showed that the protein product of PD-associated gene DJ-1 modulates metabolic efficiency through its interaction with the F1Fo-ATP-synthase β subunit (β-sub). Here, using proximity ligation assay (PLA), we compared mitochondrial DJ-1-β-sub association in distinct mesencephalic dopaminergic (mesDA) neuronal subpopulations and their intracellular compartments of PD and control postmortem brains. In PD brains, DJ-1-β-sub-PLA was lower than control in substantia nigra pars compacta (SNpc) somata and neurites but unchanged in ventral tegmental area (VTA) neurons. In PD and control cases, the PLA signal was reduced in distal neurites of SNpc compared to VTA neurons. These intracellular and region-specific differences suggest that impaired mitochondrial efficiency may contribute to the differential vulnerability of mesDA neurons in PD.
Many animals can regenerate tissues after injury. While the initiation of regeneration has been studied extensively, how the damage response ends and normal gene expression returns is unclear. We found that inDrosophilawing imaginal discs, the pioneer transcription factor Zelda controls the exit from regeneration and return to normal gene expression. Optogenetic inactivation of Zelda during regeneration disrupted patterning, induced cell fate errors, and caused morphological defects yet had no effect on normal wing development. Using Cleavage Under Targets & Release Using Nuclease, we identified targets of Zelda important for the end of regeneration, including genes that control wing margin and vein specification, compartment identity, and cell adhesion. We also found that GAGA factor and Fork head similarly coordinate patterning after regeneration and that chromatin regions bound by Zelda increase in accessibility during regeneration. Thus, Zelda orchestrates the transition from regeneration to normal gene expression, highlighting a fundamental difference between developmental and regeneration patterning in the wing disc.
Conventional dendritic cells (cDCs) regulate adaptive immunity. Although most cDCs are of myeloid origin (M-cDCs), some cDCs originate from pro–plasmacytoid DCs (pro-pDCs) via pDC-like cells [lymphoid cDCs (L-cDCs)]. Using lymphoid progenitor–tracking systems, we report tissue segregation, a unique differentiation pathway, and the functions of L-cDCs. Notably, L-cDC2s are predominantly distributed in barrier tissues such as the lungs and skin. Single-cell RNA-sequencing analysis revealed the enrichment of lymphocyte signature genes in L-cDCs. We identified lymphocyte-primed cDC precursors, which are distinct from pDC-like cells, as sources of L-cDCs. Compared with M-cDC2s, L-cDC2s weakly primed T cells under low-dose antigen stimulation and preferentially promoted T helper 2 (TH2) differentiation under sufficient antigenic stimulation. These results suggest the diverse developmental pathways of L-cDCs and imply the contribution of L-cDCs to tolerance and hyperresponses to TH2-related antigens in barrier tissues.
Photocatalytic hydrogen production has emerged as a promising strategy to mitigate the environmental impact of carbon-intensive chemical industries. Loading single atoms is known to enhance photocatalytic efficiency, as their activity is heavily influenced by the microenvironment. Therefore, achieving precise control over the microenvironment of single atoms is crucial but remains a substantial challenge. Here, we reported a unique Pt–C/TiO2photocatalyst with Pt quantum dots (PtQD) and C-coordinated Pt single atoms (PtSA). Under the given experimental conditions, the hydrogen production rate reaches 43.2 mmol hour−1with 70 mg of the photocatalyst. Notably, the hydrogen molecules generated per incident photon (H2/photon) reach 0.92. The special coordination environment influenced by C not only provides a direct transmission channel for photogenerated electrons but also activates surrounding Ti, thus improving the separation of the electron-hole pairs and H2production performance. This research provides a prospect of efficient on-site hydrogen production.
Ocean change leaves a potentially important imprint on ocean colorimetry. Here, we present an overview and current evaluation of the global ocean color variability from 1998 to 2022, and satellites observe that 36% of oceans (~122 million square kilometers, derived from valid observations) have experienced changes (P< 0.1). In this context, 25% of the area (formerly blue hue) is turning light blue or green, while the remaining 11% becomes bluer, mainly concentrating in the low-latitude oceans. This study further identifies a “direct” notable impact of both sea surface temperature (SST) and climate on ocean colorimetry tendency and anomaly, especially in the low-latitude oceans. Extreme SST events cause “distinct” ocean colorimetry anomalies, although 94% of cases involve relatively small SST fluctuations. Causal analysis reveals important impacts of climate change on equatorial ocean dynamics, particularly ENSO events. Our findings prove the low-latitude oceans as one of the core changing regions that respond to climate change in the early 21st century.
Membrane-based processes, such as reverse osmosis (RO) and nanofiltration (NF), are widely used for water purification and desalination due to their high energy efficiency and exceptional solute-water selectivity. Nevertheless, the fundamental, molecular-level mechanisms governing ion selectivity are still not fully understood. This study explores ion selectivity in polyamide desalination membranes, focusing on the partitioning and diffusion mechanisms of co-ions and counterions. Our experimental and molecular simulation results reveal that electrostatic interactions play a key role in impeding co-ion partitioning while enhancing their diffusion. The results further suggest that ion selectivity is predominantly controlled by the partitioning step, particularly the selective partitioning of co-ions. This finding highlights the importance of focusing on ion partitioning at the water-membrane interface to improve membrane ion-ion selectivity. In addition, our results point out to a trade-off between partitioning and diffusion, requiring careful tuning of these processes. Overall, this study provides the scientific foundation for molecular design of membranes with high ion-ion selectivity.
Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing group of virus-encoded transmembrane oligomeric proteins that allow passage of small molecules across the membrane. Despite sparsity in viroporin structures, recent work has revealed diversity in both the number of transmembrane helices and oligomeric states. Here, we provide evidence that the small hydrophobic protein (SH) from mumps virus is a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracellular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expression of wild-type SH and variants inXenopus laevisoocytes reveals the viroporin as a chloride channel, with transport facilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by the small-molecule BIT225, highlighting the potential for antiviral targeting through SH.
Tropical cyclones regularly form above the ocean’s largest subsurface oxygen minimum zone (OMZ) in the eastern tropical North Pacific Ocean (ETNP), yet how these powerful storms affect this biogeochemically important region remains unknown. We captured multiple direct and potentially interactive oceanographic effects of a Category 4 hurricane (Bud) during a 2018 research cruise in the ETNP. Profiles and samples collected directly beneath Bud’s wake revealed rapid OMZ shoaling of 29 to 50 meters, reaching depths as shallow as 41 meters. Untargeted mass spectrometry–based characterization of organic matter, along with elevated particulate organic carbon and chlorophyll concentrations, demonstrated production and accumulation of distinct organic compounds—including phytoplankton biomarkers—within a hurricane-generated phytoplankton bloom. 16SrRNA transcripts from active microbes were dominated by degraders of phytoplankton-derived organic matter near the surface and by anaerobic bacteria (including sulfate-reducing bacteria) within the shoaled OMZ—indicating rapid microbial responses. Tropical cyclones therefore severely disrupt OMZ biogeochemistry through vertical OMZ expansion and altered carbon cycling.
In contrast to global warming, the subpolar North Atlantic has experienced long-term cooling throughout the 20th century. This cooling, known as the North Atlantic cold blob, has been hypothesized to arise from reduced poleward oceanic heat transport associated with a slowdown of the Atlantic meridional overturning circulation (AMOC). Here, by diagnosing historical simulations from multiple coupled climate models, we find that ocean heat transport is not the only pathway through which the AMOC modulates sea surface temperature variability. A weakened AMOC is also associated with colder, drier lower atmospheric conditions, which lead to a reduction in surface warming expected from increasing amounts of heat-trapping gases by reducing downward clear-sky longwave radiation at the surface. This radiative pathway and the oceanic processes contribute equally to the North Atlantic cold blob. These results highlight the importance of the AMOC’s impact on atmospheric properties and their radiative effects.
Structural materials for protective applications are exposed to complex environments including impacts under a wide range of loading velocities. Bioinspired Bouligand-type structural materials show high impact resistance under quasi-static and low-velocity impacts. However, their protective performance under high-velocity impact is lacking investigation. Herein, we expand the Bouligand-type structure family by synergistically considering structural design and compositional regulation and highlight a double-twisted Bouligand structure with gradient composition (DT-Bou-G) for enhancing impact resistance under a wide range of loading velocities. As one demonstration, the DT-Bou-G structural material was fabricated by multimaterial fused deposition with stiff polylactic acid and soft thermoplastic polyurethane as raw materials. Experimental investigations show its superior impact-resistant capability under multiple loading velocities (0.5 millimeters per minute, 2.1 meters per second, 4.3 meters per second, and 120 meters per second). Finite element simulations further prove the mechanical result and reveal the underlying mechanisms. The DT-Bou-G structure will inspire the design of engineering protective materials capable of withstanding complex working conditions.
The excitation-inhibition ratio is a key functional property of cortical microcircuits which changes throughout an individual’s lifespan. Adolescence is considered a critical period for maturation of excitation-inhibition ratio. This has primarily been observed in animal studies. However, there is limited human in vivo evidence for maturation of excitation-inhibition ratio at the individual level. Here, we developed an individualized in vivo marker of regional excitation-inhibition ratio in human adolescents, estimated using large-scale simulations of biophysical network models fitted to resting-state functional imaging data from both cross-sectional (n= 752) and longitudinal (n= 149) cohorts. In both datasets, we found a widespread decrease in excitation-inhibition ratio in association areas, paralleled by an increase or lack of change in sensorimotor areas. This developmental pattern was aligned with multiscale markers of sensorimotor-association differentiation. Although our main findings were robust across alternative modeling configurations, we observed local variations, highlighting the importance of methodological choices for future studies.
The escalating data volume and complexity resulting from the rapid expansion of artificial intelligence (AI), Internet of Things (IoT), and 5G/6G mobile networks is creating an urgent need for energy-efficient, scalable computing hardware. Here, we demonstrate a hypermultiplexed tensor optical processor that can perform trillions of operations per second using space-time-wavelength three-dimensional optical parallelism, enabling O(N2) operations per clock cycle with O(N) modulator devices. The system is built with wafer-fabricated III/V micrometer-scale lasers and high-speed thin-film lithium niobate electro-optics for encoding at tens of femtojoules per symbol. Lasing threshold incorporates analog inline rectifier (ReLU) nonlinearity for low-latency activation. The system scalability is verified with machine learning models of 405,000 parameters. A combination of high clock rates, energy-efficient processing, and programmability unlocks the potential of light for low-energy AI accelerators for applications ranging from training of large AI models to real-time decision-making in edge deployment.
We assess how quantum-mechanical effects associated with high-frequency chromophore vibrations influence excitation energy transfer in biological light-harvesting complexes. After defining a classical nuclear limit that is consistent with the quantum-classical equilibrium, we include nuclear quantum effects through a variational polaron transformation of the high-frequency vibrational modes. This approach is validated by comparison with fully quantum-mechanical benchmark calculations and applied to three prototypical light-harvesting complexes. For light-harvesting complex 2 of purple bacteria, the inter-ring transfer is 1.5 times slower in the quantum treatment than in the classical treatment. For the Fenna-Matthews-Olson complex, the transfer rate is the same in both cases, whereas for light-harvesting complex II of spinach, the transfer is 1.7 times slower in the quantum treatment. The effect is most pronounced for systems with large excitonic energy gaps and strong vibronic coupling to high-frequency modes. In all cases, nuclear quantum effects are found to be unimportant for the directionality of energy transfer.
High-entropy oxides (HEOs) have attracted attention due to their unique elemental synergistic effect and lattice distortion. However, mixing elements’ vastly different radii and valences leads to substantial element segregation during the reaction. In addition, the requirement for a harsh temperature (1100°C) to achieve entropy stabilization results in the volatilization of low–melting point components. Here, we propose a strategy for synthesizing functionalized Ga-based HEOs (GHEOs) at a low temperature (400°C) by the Ga integration mechanism. The negative mixing enthalpy between Ga and other metals reduces the Gibbs free energy, enabling the creation of homogeneous GHEOs through a hydrothermal process at a lower temperature. The Ga integration mechanism is supported by thermodynamic and density functional theory analyses. In particular, the perovskite, spinel, and rock salt crystal can be precisely tuned by choosing metal ions, enabling tailored applications in electrocatalysis, energy-saving materials, and methane sensors. Hence, this GHEOs strategy can be extended to realize many ideal GHEOs adjusted for specific applications.
Bacteriophages use receptor-binding proteins (RBPs) to adhere to bacterial hosts, yet their sequence and structural diversity remain poorly understood. Tail fibers, a major class of RBPs, are elongated and flexible trimeric proteins, making their full-length structures difficult to resolve experimentally. Advances in deep learning–based protein structure prediction, such as AlphaFold2-multimer (AF2M) and ESMFold, provide opportunities for studying these challenging proteins. Here, we introduce RBPseg, a method that combines monomeric ESMFold predictions with a structural-based domain identification approach, to divide tail fiber sequences into manageable fractions for high-confidence modeling with AF2M. Using this approach, we generated complete tail fiber models, validated by single-particle cryo–electron microscopy of five fibers from three phages. A structural classification of 67 fibers identified 16 distinct classes and 89 domains, revealing patterns of modularity, convergence, divergence, and domain swapping. Our findings suggest that these structural classes represent at least 24% of the known tail fiber universe, providing key insights into their evolution and functionality.
Itaconate, derived from the tricarboxylic acid cycle, is recognized as a key regulator of the immune response in mammals. Despite this well-characterized role, its presence and functions within plants have remained largely unexplored. Here, we identify itaconate as an endogenous metabolite in maize andArabidopsisand investigate its impact on development. Itaconate treatment has dose-dependent effects on growth in maize andArabidopsisseedlings. To characterize the mechanisms responsible for itaconate’s regulation of plant development, we investigated its effects onArabidopsisroots using analysis of mutants and reporter lines, RNA sequencing, and two forms of protein-metabolite interaction assays. Our results demonstrate that itaconate covalently binds to proteins and substantially influences critical pathways in plants, including central carbon metabolism, phytohormone signaling, and oxidative stress response. This study expands the current understanding of itaconate’s roles beyond the animal kingdom, providing a foundation for further research into its complex functions in plants.
The two-dimensional (2D) thermoacoustic emitter excels in producing a flat sound spectrum above 5 kilohertz but struggles with reduced sound pressure at lower frequencies. To address this, we designed a wearable acoustic device that combines graphene with a 3D-printed cavity, enabling tunable resonant frequency and enhanced sound amplification based on thermoacoustic resonance. The design features laser-scribed graphene as a 2D flexible thermoacoustic source attached onto the cavity, with a specialized chamber above to facilitate air vibration through Joule heat release. The inversely proportional relationship between the operating resonant frequency and the path distance of sound propagation is verified, the sound pressure level increases from 32 to 71 decibels at 5.4 kilohertz when the cavity height increases from 0 to 10 millimeters. Last, a wearable conch-like spiral cavity with graphene is tested under a commercial artificial ear system, demonstrating an effective amplification at approximately 1 and 10 kilohertz, offering insights for developing flexible loudspeakers.
Classically, chemokines coordinate leukocyte trafficking; however, many chemokines also have direct antibacterial activity. The bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. We report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill bacteria and that they exert rapid bacteriostatic and bactericidal effects with a higher potency than the antimicrobial peptide β-defensin 3. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics,Escherichia colifailed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as binding partners for chemokines responsible for chemokine antimicrobial action.
We present the class of extreme nuclear transients (ENTs), including the most energetic single transient yet found, Gaia18cdj. Each ENT is coincident with its host-galaxy nucleus and exhibits a smooth (<10% excess variability), luminous (2 × 1045to 7 × 1045erg per second), and long-lived (>150 days) flare. ENTs are extremely rare (≥1 × 10–3cubic gigaparsec per year) compared to any other known class of transients. They are at least twice as energetic (0.5 × 1053to 2.5 × 1053erg) as any other known transient, ruling out supernova origins. Instead, the high peak luminosities, long flare timescales, and immense radiated energies of the ENTs are most consistent with the tidal disruption of high-mass (≳3M⊙) stars by massive (≳108M⊙) supermassive black holes (SMBHs). ENTs will be visible to high redshifts (z~ 4 to 6) in upcoming surveys, providing an avenue to study the high-mass end of the SMBH mass distribution, complementing recent studies of actively accreting SMBHs at high redshifts with the James Webb Space Telescope.
Two kinds of multidimensional atom interferometers are demonstrated that are capable of measuring both the magnitude and direction of applied inertial forces. These interferometers, built from ultracold Bose-Einstein condensed rubidium atoms, use an original design that operates entirely within the Bloch bands of an optical lattice. Through time-dependent lattice position control, we realize Bloch oscillations in two dimensions and a vector atomic Michelson interferometer. Fits to the observed Bloch oscillations demonstrate the measurement of an applied acceleration of 2galong two axes, wheregis Earth’s gravitational acceleration. For the Michelson interferometer, we perform Bayesian inferencing from a 49-channel output by repeating experiments for two-axis accelerations and demonstrate vector parameter estimation. Accelerations can be measured from single experimental runs and do not require repeated shots to construct a fringe. The performance of our device is near the quantum limit for the interferometer size and quantum detection efficiency of the atoms.
Despite advances in machine learning and computer vision for biomedical imaging, machine reading and learning of colors remain underexplored. Color consistency in computer vision, color constancy in human perception, and color accuracy in biomedical imaging are intertwined, complicating digital color–based diagnostics. Existing color reference charts and correction algorithms are inadequate for mobile health (mHealth) and telemedicine in digital health applications where detecting subtle color changes is critical. We present a machine reading and learning platform for color recognition and quantification to extract diagnostic information from colors. A unique combination of spectroscopic gamut determination, reference color optimization, nonsubjective quantification metrics, and neural network–based color recovery retrieves absolute colors of biological tissue. Studies on inflammation bioimaging of photocarcinogenesis and mHealth blood hemoglobin assessment demonstrate accuracy and precision in color recovery across diverse acquisition scenarios. The reported framework overcomes limitations of conventional colorimetric detection, enabling machine-compatible color-based bioassays and bioimaging, advancing digital diagnostics.
Quantum light sources, especially single-photon emitters, are crucial for advancing quantum technologies. Despite extensive research, the behavior of defect-localized excitons in monolayer WSe2under external perturbations, such as magnetic fields, remain underexplored. This study investigates the nature and dynamics of defect-localized excitons under in-plane magnetic fields using steady-state and time-resolved photoluminescence (PL) spectroscopy. Observations reveal a sharp PL peak, indicative of single-photon emission, with doublet peaks from hybridized spin–state excitons. Notably, magnetic brightening of the PL peak was detected at a low magnetic field (<1 tesla), and the dynamics of hybridized-state excitons under magnetic fields indicated field-induced state mixing, explaining the magnetic brightening. These findings advance tunable single-photon emitters controlled by magnetic fields, with implications for quantum optics applications.
The subcellular localization of neurotransmitter receptors is strictly regulated in neurons. Changes in the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–type glutamate receptors (AMPARs) play an essential role in synaptic plasticity, which is the cellular basis of learning and memory. To explore receptor trafficking, genetically encoded approaches (e.g., the fusion of fluorescent proteins to receptors) are often used. However, concerns remain that genetic approaches cannot fully reproduce the receptor functions that are inherent to neurons. Herein, we report on PFQX1(AF488), a fluorescent probe for the visualization of cell-surface AMPARs without any genetic manipulation to neurons. The rapid and reversible staining features of this probe enabled snapshot imaging, which showed the accumulation of native AMPARs in dendritic spines during synaptic plasticity. Moreover, the mechanism of this synaptic accumulation, for which genetically encoded approaches have given controversial results, was revealed by integrating two chemical methods: PFQX1(AF488) and covalent chemical labeling.
Alloys, solid solutions, and doped systems are essential in technologies such as energy generation and catalysis, but predicting their properties remains challenging because of compositional disorder. As the concentration of components changes in a binary solid solutionA(1−x)Bx, the number of possible configurations becomes computationally intractable. Algorithms used in classical optimization methods cannot avoid assessing high-energy states where, for example, simulated annealing is designed to initially spend computational effort. We introduce a scalable, practical, and accurate approach using quantum annealing to efficiently sample low-energy configurations of disordered materials, avoiding the need for excessive high-energy calculations. Our method includes temperature and simulates large unit cells, producing a Boltzmann-like distribution to identify thermodynamically relevant structures. We demonstrate this by predicting bandgap bowing inAl1−xGaxNand bulk modulus variations inTa1−xWx, with results in excellent agreement with experiments.
Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons is known to reduce maladaptive host responses during endotoxemia, only selective vagal afferent neuron stimulation inhibited TLR7-induced macrophage activation and neutrophil recruitment to the lung. These anti-inflammatory actions are dependent on adrenal gland–derived epinephrine, as adrenalectomy or inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the β2-adrenergic receptor (β2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in β2AR knockout mice and with pharmacological inhibition of the β2AR. These findings demonstrate a previously unidentified neuroimmune circuit elicited by VNS that can control acute lung inflammation.
Laser-induced air fluorescence in the ultraviolet regime is primarily attributed to transitions between the C and B states in excited neutralN2molecules and between the B and X states inN2+ions. However, the mechanism underlying the former remains contentious, as direct population to the C state by light fields is forbidden by electron spin constraints. In this work, we investigate the mechanism of air fluorescence from excited neutralN2molecules by carrier-envelope phase–stabilized sub–4 femtosecond pulses. Our results show that fluorescence fromN2+ions reaches a maximum with cosine-like pulses, while fluorescence from excited neutralN2molecules peaks with sine-like pulses. In addition, by scanning the chirp of the driving pulse, we find that ionic fluorescence is maximized with chirp-free pulses, whereas neutral fluorescence favors negatively chirped pulses. These observations, supported by classical trajectory Monte Carlo simulations, support the mechanism of intersystem crossing from excited spin-singlet states, which are populated via recollision-induced strong-field excitation.
Several landmark studies over the past decade have uncovered a critical role of the CRL3KBTBD4ubiquitin ligase complex in regulating stability of corepressor of repressor element 1 silencing transcription factor (CoREST) complex proteins and normal hematopoietic stem cell self-renewal. There is now mounting evidence that the CoREST complex plays oncogenic roles, although the contributions of its catalytic versus noncatalytic functions remain unclear. Here, we summarize and discuss mechanisms whereby the CoREST complex coopts tissue-specific transcription factors to elicit pathogenic activity in cancer and neurodegenerative disease. We also identify tumor types with selective dependencies on the scaffolding properties of the CoREST complex. We argue that these tumor types may benefit from a KBTBD4-activating/CoREST complex degrader therapy, which could also enhance antitumor immunity and sensitize resistant tumors to immunotherapy. Overall, understanding how the CoREST complex operates abnormally and differences between its targeting through catalytic inhibitors or protein degraders will help discern all possible applications for targeting therapies now in clinical development.
The autophagosomal SNARE (solubleN-ethylmaleimide–sensitive factor attachment protein) Syntaxin17 (Syx17) plays a pivotal role in autophagosome-lysosome fusion, yet the broader impact of its loss remains elusive. Our investigation of Syx17 function inDrosophilanephrocytes and salivary gland cells revealed unexpected effects. We find that Syx17 loss induces the formation of autophagosome-lysosome clusters in a HOPS (homotypic fusion and vacuole protein sorting)–dependent manner, entrapping this tether, autophagosomes, and lysosomes. While locked in clusters, these organelles cannot participate in other vesicle fusions, impeding endosomal progression and autophagosome secretion. Therefore, the absence of Syx17 not only inhibits autophagosome-lysosome fusion but also prevents HOPS release from autophagosome-lysosome tethering sites causing a “tethering lock.” Preventing autophagosome formation or removing the HOPS adaptor Plekhm1 (pleckstrin homology domain–containing family M member 1) leads to release of HOPS and lysosomes from these clusters, thus rescuing secondary effects of Syx17 loss. Our findings show that a tethering lock can disrupt multiple vesicle trafficking routes.
Fibroblastic reticular cells (FRCs) are specialized fibroblasts that construct secondary lymphoid organs where they provide crucial signals for immune cell homeostasis and migration. While splenic FRCs are thought to support antiviral T cell responses, their role remains unclear. Here, we found that ablation of splenic FRCs impaired virus-specific CD8+T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Immunofluorescence imaging revealed that FRCs promote CD8+T cell clustering with type 1 conventional dendritic cells (cDC1) in the T cell zone before migration to the infected marginal zone. Without FRCs, T cells instead clustered with cDC1 and virus-infected cells in the marginal zone, leading to suboptimal priming. Mechanistically, FRCs coordinated early viral replication and the inflammatory milieu for optimal DC activation, and an intact FRC network was crucial for generating effector T cells and maintaining protective memory T cells. Thus, splenic FRCs provide essential lymphoid niches for antiviral T cell responses.
More than 90% of the world’s hydrogen (H2) is produced from fossil fuel sources, which requires energy-intensive separation and purification to produce high-purity H2fuel and to capture the carbon dioxide (CO2) by-product. While membranes can decarbonize H2/CO2separation, their moderate H2/CO2selectivity requires secondary H2purification by pressure swing adsorption. Here, we report hyperselective carbon molecular sieve hollow fiber membranes showing H2/CO2selectivity exceeding 7000 under mixture permeation at 150°C, which is almost 30 times higher than the most selective nonmetallic membrane reported in the literature. The membrane is able to maintain an ultrahigh H2/CO2selectivity over 1400 under mixture permeation at 400°C. Pore structure characterization suggests that highly refined ultramicropores are responsible for effectively discriminating the closely sized H2and CO2molecules in the hyperselective carbon molecular sieve membrane. Modeling shows that the unprecedented H2/CO2selectivity will potentially allow one-step enrichment of fuel-grade H2from shifted syngas for decarbonized H2production.
The Fe-Ni alloy is believed to be the main component of Earth’s core. Yet, a comprehensive understanding of phase equilibria near the melting point of this alloy under core conditions is still lacking, leaving the effect of nickel inconclusive. Using ab initio simulations, we computed Gibbs free energy and phase diagram for liquid and solid solutions of the Fe-Ni alloy under conditions close to the inner core. The Fe-Ni phase diagram provides crucial insights for understanding previous experimental observations and crystallization simulations of the Fe-Ni alloy under core conditions. It also presents complex scenarios for inner core structures, suggesting body-centered cubic (bcc)–liquid coexistence at the inner core boundary and the possibility of multilayer structures consisting of bcc–hexagonal close-packed (hcp) composites within the inner core. Our work clarifies nickel’s substantial impact on the inner core structure, providing additional constraints for studying the core’s composition and formation.
Climate change is decimating habitat-forming species in ecosystems around the world. Yet, the impacts of habitat loss on the energetics of the wider food web remain uncertain for many iconic ecosystems, including cold-water kelp forests. Here, we assessed how the loss of kelp forests and the subsequent proliferation of low-lying turf algae in the Gulf of Maine have altered the trophic niches of, and energy acquired by, predatory reef fishes. Bulk tissueδ13C andδ15N analysis showed that fishes in kelp forests had larger trophic niches and greater interspecific niche separation than fishes on turf reefs. Moreover,δ13C analysis of essential amino acids revealed that kelp-derived energy accounted for most of the energy used by kelp forest fishes (> 50% on average), whereas fishes on turf reefs compensated for kelp decline via greater reliance on a phytoplankton-based energy channel. Therefore, ecosystem state shifts to turf algae—now a global phenomenon—may have far-reaching impacts on food web energetics and resilience.
Anemotaxis behaviors inspired by rats have tremendous potential in efficiently processing perilous search and rescue operations in the physical world, but there is still lack of hardware components that can efficiently sense, encode, and recognize wind signal. Here, we report an artificial vibrissal system consisting of a self-powered carbon black sensor and threshold-switching HfO2memristor. By integrating a forming HfO2memristor with a self-powered angle-detecting hydro-voltaic sensor, the spiking sensory neuron can synchronously perceive and encode wind, humidity, and temperature signals into spikes with different frequencies. Furthermore, to validate the self-powered artificial vibrissal system with anemotaxis behavior, a robotic car with equipped artificial vibrissal system tracks trajectory toward the air source has been demonstrated. This design not only addresses the high energy consumption and low computing issues of traditional sensory system but also introduces the multimode functionalities, therefore promoting the construction of neuromorphic perception systems for neurorobotics.
Past coral range expansions suggest that high-latitude environments may serve as refugia, potentially buffering coral biodiversity loss due to climate change. We explore this possibility for corals globally, using a dynamic metacommunity model incorporating temperature, photosynthetically available radiation, pH, and four distinct, interacting coral assemblages. This model reasonably reproduces the observed distribution and recent decline of corals across the Indo-Pacific and Caribbean. Our simulations suggest that there is a mismatch between the timescales of coral reef decline and range expansion under future predicted climate change. Whereas the most severe declines in coral cover will likely occur within 40 to 80 years, large-scale coral reef expansion requires centuries. The absence of large-scale coral refugia in the face of rapid anthropogenic climate change emphasizes the urgent need to reduce greenhouse gas emissions and mitigate nonthermal stressors for corals, both in the tropics and in higher latitudes.
SalmonellaTyphi assembles and secretes two forms of typhoid toxin by using two receptor-binding subunits, PltB and PltC. Unlike PltB typhoid toxin, little is known about the tropism and functional consequences of PltC typhoid toxin. Here, we report that PltC typhoid toxin has hepatobiliary tropism through the binding of PltC subunit to sulfated glycans on liver sinusoidal endothelial cells and gallbladder epithelial cells. Critical bacterial and mammalian cell factors involved are PltC R109 residue and carbohydrate sulfotransferases CHST2/4. One notable effect associated with the hepatobiliary tropism of PltC typhoid toxin is a reduction in bile acids, consequently promotingS.Typhi pathogenicity in infected mice. Similarly, bile acids serve as anti–S.Typhi infectivity agents at the cellular level, as bile acids inhibit invasion of mammalian cells. These findings highlight a distinct mechanism used by a bacterial exotoxin promoting the pathogenicity of the cognate bacteria and offer insights into the development of antivirulence agents against PltC typhoid toxin and/orS.Typhi.
The endolysosomal pathway plays an evolutionarily conserved role in pathogen clearance, and viruses have evolved complex mechanisms to evade this host defense system. Here, we describe a previously unidentified aspect of coronaviral infection, whereby the master transcriptional activator of lysosomal homeostasis—TFEB—is targeted for proteasomal-mediated degradation upon viral infection. Through mass spectrometry analysis and an unbiased small interfering RNA screen, we identify that TFEB protein stability is coordinately regulated by the E3 ubiquitin ligase subunit DCAF7 and the PAK2 kinase. We derive a series of novel small molecules that interfere with the DCAF7-TFEB interaction. These agents inhibit virus-induced TFEB degradation and demonstrate broad antiviral activities including attenuating severe acute respiratory syndrome coronavirus 2 infection in two animal models. Together, these results delineate a virally triggered pathway that impairs lysosomal homeostasis in the host. Small molecule E3 ubiquitin ligase DCAF7 inhibitors that restore lysosomal function represent a novel class of host-directed, antiviral therapies useful for current and potentially future coronaviral variants.
Learning disabilities affect a substantial proportion of children worldwide, with far-reaching consequences for their academic, professional, and personal lives. Here we develop digital twins—biologically plausible personalized deep neural networks (pDNNs)—to investigate the neurophysiological mechanisms underlying learning disabilities in children. Our pDNN reproduces behavioral and neural activity patterns observed in affected children, including lower performance accuracy, slower learning rates, neural hyperexcitability, and reduced neural differentiation of numerical problems. Crucially, pDNN models reveal aberrancies in the geometry of manifold structure, providing a comprehensive view of how neural excitability influences both learning performance and the internal structure of neural representations. Our findings not only advance knowledge of the neurophysiological underpinnings of learning differences but also open avenues for targeted, personalized strategies designed to bridge cognitive gaps in affected children. This work reveals the power of digital twins integrating artificial intelligence and neuroscience to uncover mechanisms underlying neurodevelopmental disorders.
Ice-jam floods are a unique yet understudied hydrological hazard, occurring in cold-region rivers when upstream thawing and downstream freezing create ice blockages. Despite their severe impacts, their atmospheric drivers and future trends remain unclear. Using a 160-year documentary record, historical reanalysis datasets, and statistical modeling, we examine the climatic and hydrological controls of ice-jam floods in the lower Yellow River, one of the world’s most flood-prone rivers. Our findings show that ice-jam floods are strongly influenced by large-scale atmospheric teleconnections, including the Arctic Oscillation, Siberian High, and Ural Blocking, which regulate regional thermal contrasts and cold-air intrusions. Over the past century, ice-jam flood frequency has declined, with hot spots shifting toward the river estuary due to weakening upstream-to-downstream temperature gradients under climate warming. Projections using bias-corrected CMIP6 multimodel ensemble indicate a continued decline in ice-jam flood occurrences by 2100. Our study bridges historical and future perspectives, emphasizing the need for adaptive flood management as climate change shifts hydrological risks worldwide.
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Scarmeas & Noriega De La Colina use the ancient Greek concepts of nosos (biological disease) and asthenia (functional decline) to frame the shift in Alzheimer’s disease diagnosis from clinical symptoms to biomarkers, calling for better public understanding of both biological presence and lived experience.
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AbstractEssential tremor (ET) is a highly prevalent movement disorder characterized by high heritability. However, the genetic basis of this disease remains largely unknown. Understanding the genetic causes of ET is crucial for unraveling its pathogenesis and developing targeted therapies. In this study, we aimed to investigate tandem repeats in a Chinese cohort of ET pedigrees.To explore the genetic causes of ET, we enrolled 165 Chinese ET pedigrees and performed whole-exome sequencing (WES) as well as long-read sequencing (LRS) within this cohort. Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analyses were employed to assess HSF1 expression levels. Transgenic Drosophila model and induced pluripotent stem cells (iPSCs) were constructed to investigate the pathogenic role of HSF1 in ET.Our study identified the expanded variable number of tandem repeats (VNTRs) in intron 10 of HSF1. LRS revealed two repeat configurations consisting of CCCCGCNCCGCCT and CCNCGCCT in this VNTR loci. Expanded VNTRs alleles were highly enriched in ET affected individuals, and VNTRs length was positively correlated with disease severity. We found the intronic repeat expansions downregulated HSF1 expression in affected individuals, indicating its loss-of-function in ET. Consistently, RNAi knockdown of HSF1 homolog in Drosophila led to leg and head shaking and age-dependent movement deficits, recapitulating the ET phenotype in fly model. iPSCs derived from the ET affected individual carrying expanded VNTRs in the HSF1 gene exhibited significantly reduced expression of HSF1 compared to control iPSCs. Bulk RNA-sequencing analysis of these iPSCs revealed that diminished HSF1 expression resulted in the downregulation of genes associated with GABAergic synapse function.In conclusion, our study suggests that impaired GABAergic signaling may play a critical role in the pathogenesis of HSF1-related ET. These findings provide new information on the etiology of ET and highlight the role of HSF1 in human genetic disorder.
AbstractAssessing disease progression and informing clinical trials in peripheral neuropathy would benefit from objective and responsive fluid biomarkers closely linked to disease biology. This is particularly important in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS), the most common inflammatory neuropathies, where reliable biomarkers of peripheral demyelination would help identify, and potentially measure, active disease and responses to treatment. We postulated that periaxin, a protein exclusively expressed by myelinating Schwann cells, could serve as a fluid biomarker of demyelinating peripheral neuropathy.We developed a Simoa-based immunoassay to measure plasma periaxin in patients with CIDP (n = 45, including longitudinal samples across a discovery cohort and a validation cohort, for a total of 77 time points), GBS (n = 30, 66 time points), Charcot-Marie-Tooth disease (CMT, n = 20), central nervous system (CNS) disease controls with multiple sclerosis (MS, n = 30), and healthy controls (HC, n = 30). We also evaluated whether periaxin is released in myelinating cocultures following immune-mediated demyelination and axonal damage, comparing results with uninjured cultures.Plasma periaxin effectively distinguishes peripheral from central nervous system diseases, with significantly elevated levels in CIDP, GBS, and CMT, but not in CNS disease or healthy controls (all P < 0.01). In CIDP, periaxin discriminates patients with active disease from those with inactive disease (P < 0.0001), and plasma levels decrease following treatment with intravenous immunoglobulin (IVIg). Elevated periaxin strongly predicts clinical worsening at 1 year [sensitivity 99%, specificity 72%, area under the curve (AUC) 0.86 (95% C.I. 0.67–1)]. In GBS, peak levels of plasma periaxin and the ratio of periaxin to axonal biomarkers [neurofilament light chain (NfL) and peripherin] discriminate most cases of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) from acute motor axonal neuropathy (AMAN), as classified by electrophysiology (sensitivity 100%, specificity 86%, AUC = 0.94, 95% CI 0.81-1). Serial measurements showed that plasma periaxin levels peak 2 to 3 weeks after GBS symptom onset, followed by a gradual decline in the weeks thereafter. In vitro, periaxin is higher following immune-mediated demyelination compared to axonal damage and control conditions.Plasma periaxin is a biomarker of peripheral nerve demyelination. Combined with axonal fluid biomarkers and existing clinical scales, periaxin has the potential to improve the clinical management of peripheral neuropathies, accelerating advances in care and experimental research.
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AbstractTemporal lobe epilepsy is the most common focal epilepsy in adults. While temporal lobe epilepsy was historically perceived to have a largely acquired aetiology, growing evidence points to important genetic contributions. There are several temporal lobe epilepsy subtypes, including mesial temporal lobe epilepsy with or without hippocampal sclerosis, but the relative genetic contributions to each of these subtypes have not been directly studied.In this study, we use the classical twin model in 80 twin pairs where at least one twin had temporal lobe epilepsy. We assessed the genetic contribution to various subtypes [lesional temporal lobe epilepsy, non-lesional temporal lobe epilepsy, mesial temporal lobe epilepsy (with or without hippocampal sclerosis), lateral temporal lobe epilepsy, and non-localized temporal lobe epilepsy], by analysing the concordance for temporal lobe epilepsy in monozygotic twins compared to dizygotic twins. In the 10 monozygotic pairs where at least one twin had hippocampal sclerosis, we searched for within-pair acquired differences between affected and unaffected individuals.There was an excess of monozygotic pairs concordant for temporal lobe epilepsy compared to dizygotic pairs (17/47 concordant monozygotic vs 0/33 concordant dizygotic, p<0.05). This supports a genetic contribution to temporal lobe epilepsy, but notably this concordance was driven by non-lesional temporal lobe epilepsy cases, particularly mesial temporal lobe epilepsy without hippocampal sclerosis (14/22 concordant monozygotic vs 0/11 concordant dizygotic, p<0.05). No concordant monozygotic or dizygotic pairs were observed in the lesional temporal lobe epilepsy (n=8) and non-localized temporal lobe epilepsy (n=15) groups.The concordance for temporal lobe epilepsy in monozygotic twins with mesial temporal lobe epilepsy with hippocampal sclerosis was much lower (2/10 concordant monozygotic vs 0/9 concordant dizygotic, p=1), suggesting a lesser contribution from germline genetic causes to mesial temporal lobe epilepsy with hippocampal sclerosis. Eight monozygotic twin pairs were discordant for hippocampal sclerosis. In four of these pairs, both twins had febrile seizures, but hippocampal sclerosis was only present in the twin who had prolonged seizures.The two monozygotic twin pairs concordant for hippocampal sclerosis had clinical neurofibromatosis type 1 with pathogenic germline NF1 variants.Our findings confirm a germline genetic component in temporal lobe epilepsy, strongest in mesial temporal lobe epilepsy without hippocampal sclerosis and present in lateral temporal lobe epilepsy but absent in lesional and non-localized temporal lobe epilepsy. In our mesial temporal lobe epilepsy with hippocampal sclerosis twins, we found both genetic factors (NF1) and prolonged febrile seizures contributed to the aetiology of hippocampal sclerosis.
Neuroscientific research into mental imagery often relies on David Hume’s view of visual imagination as weak perception. Arcangeli & Bartolomeo argue that Jean-Paul Sartre’s alternative framework—supported by recent findings on aphantasia—offers a more conceptually and empirically robust approach.
AbstractAmyotrophic lateral sclerosis (ALS) is thought to be caused by interaction between genetic and environmental factors leading to motor neuron (MN) degeneration. Physical exercise has been linked to ALS but controversy remains. A key question is to determine which individuals might be at risk of exercise-associated ALS, because unnecessary avoidance of exercise could be harmful.We implemented complementary strategies including Mendelian randomization and multiple questionnaire-based measures of physical exercise in different cohorts. We include a prospective study in UK Biobank participants where we could test for a relationship between exercise and the timing of future ALS symptom onset. To interrogate the molecular basis of our observations we performed a genetic association study of ‘extreme’ exercise, equivalent to >6 hours of strenuous exercise or >12 hours of any leisure-time exercise per week.Our data suggest that the link between increased physical exercise and ALS is particularly important for males who perform the most activity; with no evidence of a link in females. We determined that extreme exercise in males is associated with loss-of-function genetic variants within a number of mammalian target of rapamycin (mTOR) signalling genes that are also differentially expressed in ALS spinal cord.Activity-induced mTOR signalling has been shown to selectively benefit MN. Therefore, our findings could imply that moderate exercise is neuroprotective via enhanced mTOR signalling, but extreme exercise in men is associated with neurotoxicity and ALS via a failure of this mechanism. There was no significant overlap between genes associated with extreme exercise and those associated with ALS risk, consistent with a true gene-environment interaction rather than a shared genetic basis. We are not yet able to make individual-level recommendations regarding exercise and risk of ALS, but our conclusions should focus future investigation.
AbstractLearning is a fundamental aspect of human behaviour and is essential for adapting to new environments and situations. The ventral tegmental area is a critical brain area containing neurons that release dopamine to signal reward, drive learning, and bias decision-making. Human data on ventral tegmental area’s effects on cognition are scarce, and no studies have causally manipulated the human ventral tegmental area. Here we studied a unique group of patients who had deep brain stimulation surgery in the ventral tegmental area, to improve pain due to trigeminal autonomic cephalalgias refractory to medical therapy.In this study, we asked how deep brain stimulation, which aimed to inhibit the ventral tegmental area, affected reward-related learning and decision-making. Patients performed a reversal learning task while their deep brain stimulation was switched on vs. off, in a powerful within-subject design. In the task, patients learned to choose between two options to win money, based on previous outcomes, but also made post-decision bets based on whether they thought they were likely to win. This allowed us to also investigate the effect of electrical stimulation within the ventral tegmental area on betting behaviour.We found that stimulation did not affect learning in this group of patients but led to a more strategic betting behaviour. First, stimulation reduced the bias where healthy people tend to bet similarly to the previous trial. Second, when on stimulation, bets were more strongly linked to the actual value of the choice. The data indicate that disrupting ventral tegmental area signals by electrical stimulation reduces the perseverative betting bias, permitting more strategic decision-making. We interpret this to mean that mesolimbic dopaminergic signals in humans may be important in producing persistence of reward-driven behaviours over time.
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AbstractLimbic-predominant age-related TAR-DNA binding protein (TDP-43) encephalopathy neuropathological change (LATE-NC) refers to the aberrant accumulation of TDP-43 in the brains of aging individuals either in isolation or in combination with neurodegenerative disease. LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease. Since LATE-NC can only be diagnosed post-mortem, there is a need for pathology-validated neuroimaging biomarkers for LATE-NC. In the current study we assessed MRI-measured amygdalar and hippocampal volume in brain donors with Alzheimer’s disease or Lewy Body diseases with and without co-occurring LATE-NC pathology.Post-mortem in-situ 3D-T1 3T-MRI data were collected for 51 cases (27 Alzheimer’s disease and 24 Lewy Body Disease) of whom 17 had post-mortem confirmed LATE-NC and 34 were non-LATE-NC (matched on age, sex, and neurodegenerative disease). Amygdalar and hippocampal volumes were calculated using FreeSurfer. Within-subject amygdalar and hippocampal tissue sections were immunostained for TDP-43 (pTDP-43), phosphorylated tau (AT8), amyloid-β (4G8) and α-synuclein (pSer129). Positive cell density (TDP-43 and α-synuclein) and area percentage immunoreactivity (p-tau and amyloid-β) outcome measures were quantified using QuPath. Group differences between LATE-NC and non-LATE-NC donors were assessed with univariate analyses and correlations were assessed with linear regression models, all adjusting for intracranial volume and post-mortem delay and if applicable for primary pathology.Brain donors with LATE-NC showed significantly lower amygdalar (-26%, p=.014) and hippocampal (-19%, p=.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden. These group differences remained significant in the Alzheimer’s disease group (amygdala -24%, p=.028; hippocampus -21%, p=.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared to non-LATE-NC donors (18%, p=.030). These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology. This study proposes that exceptionally low amygdalar and hippocampal volumes could indicate LATE-NC and that this may serve as a potential biomarker for in-vivo studies.
AbstractGait problems in people with Parkinson’s (PD) are increasingly common as disease progresses. Symptoms include freezing of gait (FoG), and a predisposition to falls. The causative pathophysiology is still not completely understood. In this study, Positron Emission Tomography (PET) with 18F-fluoro-ethoxy-benzovesamicol (18F-FEOBV), a presynaptic marker of cholinergic terminal density, and 18F-fluoro-deoxy-glucose (18F-FDG) was performed in a cohort of people with PD and gait disorder to derive spatial covariance networks of cholinergic and metabolic activity, and to evaluate the correlation of such networks against frequency of FoG and other gait measures.Fourteen patients with PD and FoG in the ON motor state underwent PET using 18F-FEOBV and 18F-FDG on two separated days. Following spatial normalization, functional networks were derived by Principal Component Analysis (PCA). The individual expression of linear combinations of principal components (PCs) was subsequently correlated with measures of FoG in the ON motor state (ON-FoG) and a lower body and gait (LBG) subsection of the Unified Parkinsons Disease Rating Scale (UPDRS) part III. Gait measures were derived from home-worn measures using a triaxial accelerometer.We found a derived pattern of 18F-FEOBV binding that correlated with ON-FoG (R2= 0.46975, p = 0.045) as well as other lower body and gait signs (R2 = 0.78591, p = 0.0077). Lower levels of cholinergic activity in the thalamus, hippocampus, striatum, anterior cingulate as well as areas of the brainstem consistent with the mesencephalic locomotor region were associated with worse ON-FoG and gait disturbances. The derived pattern was not associated with overall disease duration or progression as assessed by standard motor scores. There was no correlation between 18F-FEOBV and OFF-FoG. For 18F-FDG, no correlation between covariance patterns and gait assessments could be found. However, a statistically significant correlation was found for a subset of lower body and gait symptoms (R2 = 0.78306, p = 0.002).These results exhibit a correlation between lower levels of cholinergic function in locomotor-related areas of the brainstem and objective measures of dopamine medication ON-FoG, potentially indicating a causative link between the two. No association was found with OFF-FoG. Taken together our results provide support for the role of the cholinergic system in the occurrence of dopamine medication ON-FoG.
AbstractPerineuronal nets are specialized extracellular matrix structures forming preferentially around parvalbumin interneurons to regulate plasticity. While cortical perineuronal nets have been implicated in sensory plasticity and memory modulation, perineuronal nets of the primary motor cortex have been largely overlooked. We found that transient reduction of primary motor cortex perineuronal nets by ChABC treatment in otherwise healthy adult mice resulted in temporary deficits in motor function. In a mouse model of Parkinson's disease based on unilateral 6-hydroxydopamine lesions of the midbrain, perineuronal net levels were decreased in both primary motor cortex hemispheres 2 weeks post-lesion, yet returned to baseline within 5 weeks. We discovered that subsequent transient reduction of primary motor cortex perineuronal nets through ChABC treatment could unlock motor recovery when coupled with motor stimulation. This recovery was associated with a bilateral increase in perineuronal-net-enwrapped parvalbumin interneurons and a rebalancing of parvalbumin cell soma excitatory synaptic markers. These findings reveal distinct roles of perineuronal net plasticity – first in response to the initial midbrain lesion and then during rescue after ChABC treatment – suggesting that primary motor cortex perineuronal nets play a nuanced role in regulating motor function. This duality positions perineuronal nets as potential therapeutic targets for motor rehabilitation strategies in Parkinson's disease.
AbstractIn the intensive care unit (ICU), management of unresponsive patients with brain injury focuses on preventing secondary brain damage. Therapeutic strategies that directly promote the recovery of consciousness are urgently needed. In an investigator-initiated, randomized, placebo-controlled, double-blind, cross-over trial, we studied the effects of apomorphine and methylphenidate in ICU patients with acute disorders of consciousness (DoC). We hypothesized that these stimulants would improve consciousness biomarkers assessed by automated pupillometry (primary outcome) and clinical signs of consciousness (secondary outcome).We randomized 50 ICU patients with DoC (14 women; mean age 63 ± 10 years; 48 with non-traumatic brain injuries) to strata consisting of three consecutive treatment sessions during which apomorphine, methylphenidate or placebo were administered. In total, we administered 112 study medications, including 36 doses of apomorphine, 39 doses of methylphenidate and 37 doses of placebo. Missing administrations were due to death, ICU discharge, or spontaneous consciousness recovery. Plasma concentrations of stimulants confirmed drug exposure. We found no adverse events related to the trial drugs.Pupillometry recordings of sufficient quality (n = 590) were available from 48 (96%) patients. A pupillary response to a verbal arithmetic command (i.e., ≥3 pupillary dilations on five verbal arithmetic tasks) was identified during 70 (12%) of these recordings. Seven (15%) patients without any other observable response to spoken commands also passed a stricter threshold of ≥4 pupillary dilations, suggesting cognitive motor dissociation. Apomorphine (OR 1.35, 95% CI: 0.93 to 1.96) and methylphenidate (OR 1.29, 95% CI: 0.89 to 1.86) did not significantly increase pupillary responses. However, after study drug administration, 10 (20%) patients showed improved clinical arousal at least once. Signs of arousal were noted after one dose of placebo, four doses of apomorphine (OR 5.04, 95% CI: 0.56 to 120.7), and seven doses of methylphenidate (OR 9.96, 95% CI: 1.36 to 235.8). Changes toward higher consciousness level categories were observed once after placebo, four times after apomorphine (OR 5.67, 95% CI 0.63 to 169.46), and three times after methylphenidate (OR 3.41, 95% CI 0.34 to 88.00). In a post-hoc analysis, patients with greater pupillary responsiveness showed better arousal, suggesting that this condition may predict stimulant drug effects.In conclusion, while pupillometry revealed no direct drug effects on overall pupillary responses, stimulants may have triggered clinical arousal in some patients, particularly in those with greater pupillary responsiveness. These findings require replication but should guide future pharmacological trials aimed at improving consciousness recovery after brain injury.
AbstractIndividuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear.Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings, and behavioral analysis of zebrafish and multiple mouse models.We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein, and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within down-regulated genes. Lastly using both zebrafish and mouse models, we found behavioral disruptions that include developmental deficits and sex-specific social behavioral changes.Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology, and behavior across multiple models and systems.
AbstractDystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e).We investigated patients diagnosed with congenital myopathy using exome or genome sequencing. In 19 affected individuals from 14 unrelated families, we identified nine different variants in biallelic state located in exons 40-41, specific to DST-b. Affected individuals presented with severe neonatal myopathy characterized by arthrogryposis, hypotonia, and dilated cardiomyopathy. Postnatal CPAP ventilation was required in nine patients, and seven died within the first three years of life. Survivors showed an improvement of symptoms, with the oldest three patients, now over 25 years old, exhibiting normal cognition and being ambulatory.RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue, and cultured fibroblasts, but not in brain matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Muscle biopsies from four patients aged 1 month to 3 years revealed mild, non-specific myopathic changes. Ultrastructural analysis in three individuals showed mild and focal myofibrillar disruption and non-specific undulating nuclear membranes, with these changes observed in two cases each.Additionally, we identified two homozygous variants affecting both DST-a and DST-b isoforms in four patients from two unrelated families; all presented with severe arthrogryposis and died intrauterine or shortly after birth. Genotype-Phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome.Our findings demonstrate that biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. The location of the variant within DST allows for phenotype prediction. We propose redefining DST as a disease-associated gene linked to four distinct allelic disease phenotypes.
AbstractLoss-of-function mutations in the transcription factor POU3F2 have been identified in individuals with neurodevelopmental disorders.To elucidate the mechanistic role of POU3F2 in human neurodevelopment, we induced POU3F2 disruption in human neural progenitor cells (NPCs).Mutation of POU3F2 in NPCs causes reduced baseline canonical Wnt signalling and decreased proliferation, resulting in premature specification of radial glia. Additionally, POU3F2 levels across genetically diverse NPCs significantly associate positively with baseline canonical Wnt signalling and negatively with markers of radial glia specification. Through a series of unbiased analyses, we show that SOX13 and ADNP are transcriptional targets of POU3F2 which mediate POU3F2’s effects on Wnt signalling in human NPCs. Finally, we describe five individuals with autism spectrum disorder that harbor loss-of-function mutations in POU3F2, enhancing the genetic evidence for its critical role in human neurodevelopment.Together, these studies define POU3F2 as an activator of canonical Wnt signalling and mechanistically link two high-confidence autism genes, ADNP and POU3F2, in the regulation of neurodevelopment.
AbstractDe novo or autosomal dominant BAG3 gene variants cause a wide range of skeletal and cardiac muscle diseases encompassing Charcot–Marie–Tooth disease, myofibrillar myopathy, cardiomyopathy or a combination of them. Given the severity and rarity of BAG3-neuromuscular diseases (NMD), series of patients are lacking. Our aim was to characterize the clinical and genetic spectrum as well as the natural history of BAG3-NMD in Europe.In this multicentre retrospective study, we collected clinical, ancillary, and genetic data of patients with NMD and BAG3 variants, identified from European paediatric and adult neuromuscular reference centres from May to December 2023 following a call circulated through the European Reference Network EURO-NMD and other partners. Responses were received from 35 centres in 17 countries. Twenty-six patients (65.4% males, 34.6% females) with BAG3-NMD from 18 different families were included in the study. The c.626C>T p.(Pro209Leu) variant, carried by 16 patients, was the only recurrent variant and was associated with a homogeneous and severe phenotype, with predominantly lower-limb motor weakness (n=13, 81.25%) or heart failure (n=3, 18.75%) as the presenting feature, and a mean age at symptom onset of 7.8±3.4 years. Where available (n=13), electroneuromyography showed a polyneuropathy with demyelinating features and a frequently associated myopathy. Eleven (68.8%) patients had restrictive cardiomyopathy on initial assessment. Orthopaedic manifestations were common, with contractures (n=15, 93.8%), foot deformities (n=11, 84.6%), and scoliosis and/or rigid spine (n=12, 80%). At last follow-up (age 21.5±8.6 years), of the patients carrying the p.(Pro209Leu) variant, 10 (62.5%) had lost ambulation, 14 (93.3%) had respiratory insufficiency (11 requiring ventilation), and 12 (75%) had a restrictive cardiomyopathy, leading to heart failure and heart transplantation in five and four patients, respectively. Eight (50%) patients died prematurely at a mean age of 22.5±9.6 years, most frequently from sudden death (n=5). The other 10 patients carried three other BAG3 variants, and showed a milder disease course, with all patients remaining ambulatory, without cardiorespiratory manifestations at last follow-up. The p.(Arg309*) nonsense variant, known to cause isolated dilated cardiomyopathy, as well as the p.(Val505Glyfs*6) frameshift variant resulting in a premature stop codon, caused distal hereditary motor neuropathy.This is the largest study of patients with BAG3-NMD, delineating the frequency, specific presentation, and the natural history in patients with the recurrent BAG3 p.(Pro209Leu) missense variant, crucial for informing patient management in the context of a rapidly progressive disease. All other BAG3 variants were rare and caused milder clinical presentations.
AbstractRemote digital monitoring of Huntington’s disease (HD) has potential to enhance the development of therapeutics, but no data-driven digital motor score exists to quantify the diversity of disease manifestations and track their progression.The HD Digital Motor Score (HDDMS), co-designed with people with HD and neurologists, is a composite score for measuring motor progression of HD in clinical research. It is derived from smartphone sensor-based motor tests included in a remote HD digital monitoring platform. Developing the HDDMS involved selecting features that quantify test performance according to desired measurement properties and combining these features in a weighted composite score using factor analysis. It was developed and subsequently validated using data from four separate studies [HD Natural History Study (NCT03664804), open-label extension (OLE) of the tominersen phase I/IIa study (NCT03342053), GENERATION HD1 (NCT03761849) and Digital-HD].Based on data from 1048 (the total number of individuals whose data contributed to the construction of the score includes the 40 gene-negative volunteers) individuals, the HDDMS encompasses balance, chorea, speeded tapping and gait. It has favourable characteristics, including reliability (intraclass correlation coefficient > 0.95), correlation with the composite Unified Huntington’s Disease Rating Scale (cUHDRS) (r = −0.5), and better sensitivity to change (STC) than the cUHDRS. In a post hoc analysis of GENERATION HD1, the STC of HDDMS at Week 20 was comparable to that of the cUHDRS at Week 68. The HDDMS promises substantial reduction in sample size in clinical trials.
This scientific commentary refers to ‘The association of seizure control with neuropathology in dementia’ by Zawar et al. (https://doi.org/10.1093/brain/awaf017).
Pansieri et al. argue that bureaucracy is suffocating research, as an ever increasing administrative burden consumes researchers’ time and diverts focus from discovery to compliance. They highlight ways in which red tape delays progress, wastes funding, and drives researchers out of academia, and call for systemic change.
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AbstractCharcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E.Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity.Twenty-four presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes.Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.
This scientific commentary refers to ‘Interferon-γ causes myogenic cell dysfunction and senescence in immune myopathies’ by Hou et al. (https://doi.org/10.1093/brain/awaf153).
AbstractAlzheimer’s disease (AD) is characterized by the accumulation of pathogenic proteins, notably amyloid-beta and hyperphosphorylated tau, which disrupt neuronal function and contribute to cognitive decline. Although proteotoxic stress is well-established in AD, the role of the ubiquitin-proteasome system (UPS) in maintaining neuronal proteostasis, and how it becomes compromised during disease progression remains incompletely understood.Here we integrated multiple approaches to characterize proteasome function, composition, and regulation in post-mortem human AD brain tissue compared to age-matched controls. These included proteasome kinetic assays, affinity purification of intact 26S proteasomes, in-gel activity assays and proteomics. According to Braak staging, we further interrogated bulk RNA-seq and single-nucleus RNA-seq (sn-RNA-seq) datasets spanning the progression of AD pathology. Finally, we examined Nrf1/NFE2L1 binding and subcellular localization to understand the transcriptional regulation of proteasome genes in AD.We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes. This reduction in proteolytic capacity persisted after proteasome purification, implicating intrinsic defects within the proteasome complex. Proteomic profiling of isolated proteasomes revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g., tau, α-synuclein and SQSTM1/p62), suggesting proteasome entrapment in pathological aggregates. Transcriptomic analyses showed progressive downregulation of constitutive proteasome subunit genes in individuals along the Braak stage axis, with downregulation apparent even at the earliest Braak stages, in tissue without overt tau aggregation. Neurons were disproportionately affected, whereas non-neuronal cells did not show substantial differences in proteasome-related gene expression, possibly through immunoproteasome induction. Despite elevated NFE2L1 expression, a key transcription factor normally driving proteasome gene transcription, AD brains exhibited impaired Nrf1 nuclear localization, preventing the expected compensatory upregulation of proteasome components.Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course. Intrinsic alterations in proteasome complexes, coupled with early transcriptional downregulation of proteasome subunits and disrupted Nrf1-mediated regulatory pathways, contribute to a vicious cycle of proteotoxic stress and neuronal vulnerability. Restoring proteasome function and enhancing Nrf1-driven transcriptional responses may represent promising therapeutic strategies to preserve proteostasis and mitigate neurodegeneration in AD.
AbstractRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an incurable microvascular disease caused by C-terminus truncation of the TREX1 exonuclease. There is a pressing need to understand disease mechanisms and identify therapeutic targets.We evaluated TREX1 sequencing data from 469 229 UK Biobank participants together with RVCL-S-related microvascular clinical and imaging outcomes. We show that mono-allelic truncating mutations in TREX1 require intact nuclease activity in order to cause endothelial disease. Differential proteomics identifies loss of interaction with endoplasmic reticulum insertion proteins such as Guided Entry of Tail-Anchored Proteins Factor 3 as a major consequence of pathogenic TREX1 truncation, and this altered trafficking results in the unregulated presence of enzymatically active TREX1 in the nucleus. In endothelial cells with a patient mutation, mislocalized yet enzymatically active TREX1 causes accumulation of a spectrum of DNA damage. These pathological changes can be rescued by inhibiting exonuclease activity.In summary, our data implicate exonuclease-dependent DNA damage in endothelial cells as a key therapeutic target in the pathogenesis of RVCL-S.
AbstractHow do brain networks limit seizure activity? In the Interictal Suppression Hypothesis, we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression. If broad networks appear to be responsible for interictal SOZ suppression, what changes during seizure initiation, spread, and termination? For patients with drug-resistant epilepsy, intracranial monitoring offers a view into the electrographic networks which organize around and in response to the SOZ.In this manuscript, we investigate network dynamics in the peri-ictal periods to assess possible mechanisms of seizure suppression and the consequences of this suppression being overwhelmed. Peri-ictal network dynamics were derived from stereo electroencephalography recordings from 75 patients with drug-resistant epilepsy undergoing pre-surgical evaluation at Vanderbilt University Medical Center. We computed directed connectivity from 5-second windows in the periods between, immediately before, during, and after 668 seizures. We aligned connectivity matrices across seizures and patients, then calculated net connectivity changes from the SOZ, propagative zone, and NIZ.Across all seizure types, we observed two phases: a rapid increase in directed communication towards the SOZ followed by a collapse in network connectivity. During this first phase, SOZs could be distinguished from all other regions (One-Way ANOVA, P-value = 8.32x10-19-2.22x10-7). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (One-Way ANOVA, P-value = 2.58x10-10-1.66x10-2). NIZs appeared to drive increased SOZ connectivity while intra-NIZ connectivity concordantly decreased. Stratifying by seizure subtype, we found that consciousness-impairing seizures decrease inward connectivity from the NIZ earlier than consciousness-sparing seizures (one-way ANOVA, p<0.01 after false discovery correction). Tracking network reorganization against a surrogate for seizure involvement highlighted a possible antagonism between seizure propagation and the NIZ’s ability to maintain high connectivity to the SOZ. Finally, we found that inclusion of peri-ictal connectivity improved SOZ classification accuracy from previous models to a combined area under the curve of 93%.Overall, NIZs appear to actively increase inhibitory signaling towards the SOZ during seizure onset, possibly to thwart seizure activity. While inhibition appears insufficient to prevent seizure onset, the inability to restrict seizure propagation may contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work may: i) facilitate accurate delineation of surgical targets in focal epilepsy, ii) reveal why interictal suppression of SOZs may be insufficient to prevent all seizures, and iii) provide insight into mechanisms of loss of consciousness during certain seizures.
AbstractT-type/Cav3 calcium channels are key in neuronal excitability and pain processing with Cav3.2 being the prominent isoform in primary sensory neurons of the dorsal root ganglion (DRG). Cav3.2 pharmacological inhibition or gene silencing induces analgesia in several preclinical models of inflammatory and neuropathic pain. However, the presence of Cav3.2, encoded by the CACNA1H gene, in human DRG neurons remains unresolved.Using RNA in-situ hybridization and electrophysiological recordings, we show that human DRGs express Cav3.2 in a subset of neurons positive for the neurotrophic factor receptor TrkB (NTRK2 gene). The Cav3.2 current exhibits typical biophysical and pharmacological properties, including inhibition by a low concentration of nickel and by Z944, a specific T-type calcium channel blocker in advanced clinical development. Conversely, ABT-639, a T-type calcium channel inhibitor that failed in Phase 2 trials for pain relief, does not inhibit Cav3.2 currents in human DRG neurons. Importantly, Cav3.2 currents are prominent in neurons from female organ donors, supporting the presence of sex differences in pain mechanisms in humans.These findings underscore the potential of continued exploration of Cav3.2 as a therapeutic target for pain treatment and highlight a specific subset of human neurons that likely rely on this channel to modulate their excitability.
AbstractPathogenic variants in GABAA receptor subunits genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations, and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review. Our cohort included 19 individuals (7 males, 12 females) from 15 families harboring 13 different GABRB1 variants (11 missense, 1 indel, 1 stop). Functional analysis was performed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes. For all eleven missense variants, α1β1γ2 GABAA receptors with a single mutant β1 subunit were used. Four missense variants were selected for further functional analysis using α5β1γ2 GABAA receptors with two mutant β1 subunits.Gain-of-function (GoF) effects, characterised by increased GABA-sensitivity, were observed for eight missense variants. Loss-of-function (LoF) effects were observed for one, and no functional effects for two variants. Clinically, GoF variants were only observed in individuals with severe early-onset disease including profound intellectual disability, hypotonia, and early mortality. Additionally, cortical visual impairment, dysmorphisms and cortical atrophy were exclusive to this cohort. By integrating previously reported clinical data for variants in other GABR* genes we validated that these features were associated with GoF variants more broadly. The only LoF variant was identified in a nuclear family with the relatively milder syndrome of genetic epilepsy with febrile seizures plus.Seizures were therapy-resistant in all individuals with GoF variants, and in a single individual with a LoF variant. The GABAergic anti-seizure medication (ASM) vigabatrin caused life-threatening side-effects in two individuals with GoF variants, while the sodium-channel blocker (SCB) lamotrigine exacerbated seizures in a single individual carrying a LoF variant. By integrating data from literature on all GABR* variants, we observed a potential dichotomy in treatment responses: GABAergic and broad-spectrum ASMs, such as valproate and levetiracetam, were more effective for individuals with LoF variants in GABR* genes, while SCBs showed greater benefit for GoF variants. Additionally, there is an increased risk of adverse effects of SCBs in LoF and vigabatrin in GoF variants. Our results highlight the importance of functional characterisation of variants and clinical predictors in guiding treatment strategies for individuals with GABRB1 and other GABR* variants, though larger prospective studies are needed to confirm these observations.
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AbstractThere has been a rapid growth in research on peripheral fluid biomarkers for Alzheimer’s Disease and Alzheimer’s Disease related dementias (AD/ADRD) because they are non-invasive, relatively inexpensive, and easily accessible. The most commonly used plasma biomarkers include β-amyloid (Aβ), phosphorylated tau (p-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The extent to which distinct profiles of multiple plasma biomarkers correlate with common neuropathologies is unclear.Using clinicopathologic data from 405 community-dwelling older adults, we applied latent profile analysis on 4 plasma biomarkers, i.e., Aβ42/40 ratio, p-tau217, NfL and GFAP, and examined the correlates of the latent profiles with 4 degeneration measures of AD, Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy (LATE), hippocampal sclerosis, and 5 vascular measures including chronic macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriosclerosis.On average, participants died at the age of 89 and blood samples for plasma biomarkers were measured 3.9 years before death. Over 75% were female and 24% were non-Latino Black. We observed 3 distinct biomarker profiles. Profile #1, characterized by low p-tau217, low GFAP, low NfL and high Aβ42/40, represents most participants (55.6%) with better than average biomarker levels. Both Profile #2 and Profile #3 showed worse than average biomarker levels. Profile #2, representing 34.8% of the participants, was high in p-tau217 and GFAP. By contrast, Profile #3, representing 9.6% of the participants, was high in NfL and GFAP. Examination of neuropathologic correlates of these plasma biomarker profiles revealed that Profile #2 exemplifies older adults with a high burden of neurodegeneration; almost all participants (92.9%) in Profile #2 had a diagnosis of pathologic AD, and the group also had the highest percentage of participants with Lewy bodies (41.1%). In comparison, Profile #3 exemplifies older adults with more severe vascular conditions; participants in this group had the highest percentage of macroscopic infarcts (31.6%) and moderate or severe atherosclerosis (42.1%).Together, these findings suggest that common plasma biomarkers may exhibit profiles reflective of distinct pathophysiologic processes.
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AbstractMonoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture of LGI1–ADAM22/23 pathway-related diseases remains incompletely understood.Through international genetic data sharing, we identified the first ultra-rare biallelic LGI1 variants in six individuals from four consanguineous families. Affected individuals presented DEE with neonatal/infantile-onset epilepsy (6/6), global developmental delay/intellectual disability (6/6), and infant/premature death (5/6). Brain MRI showed mild cerebral atrophy in a subset of patients (3/6).Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes. Further, we observed epileptic discharges from the isolated whole hippocampus of Lgi1–/– knockout mice, experimentally modelling the hippocampal origin of LGI1-related epilepsy. Automated behavioural analysis of a mouse model for ADAM22-related DEE revealed its impaired cognitive function. Furthermore, we report the first ADAM23 variant associated with lethal neonatal-onset epilepsy and myopathy. Collectively, this study defines the LGI1–ADAM22/23 pathway-related disease spectrum.
AbstractApathy is a common neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD) but can emerge earlier in prodromal and even preclinical stages as part of mild behavioural impairment (MBI-apathy), a syndrome defined by emergent and persistent NPS. In dementia, apathy is associated with higher morbidity, mortality, and caregiver distress. However, the significance of MBI-apathy in dementia-free persons, including its associations with AD biomarkers, remains unclear. This study aimed to determine whether MBI-apathy is associated with biomarker evidence of amyloid beta (Aβ) and tau (phosphorylated [p-tau], total [t-tau]) in CSF. Because MBI predicts incident dementia better than NPS without MBI, we aimed to determine the association between apathy and AD biomarkers when it occurred as part of the MBI syndrome and when it did not.Dementia-free participants with mild cognitive impairment (MCI) or normal cognition from the Alzheimer’s Disease Neuroimaging Initiative were stratified by NPS status – MBI-apathy, non-apathy MBI, non-MBI NPS, and no-NPS – based on the Neuropsychiatric Inventory (NPI) or NPI-Questionnaire (NPI-Q). Linear regressions modelled cross-sectional associations between NPS status (predictor) and CSF biomarker ratios (Aβ42/Aβ40, p-tau181/Aβ42, and t-tau/Aβ42; primary outcomes) and levels (Aβ40, Aβ42, p-tau181, t-tau; exploratory outcomes), adjusting for age, sex, Apolipoprotein E4, education, Mini Mental State Examination, and NPI version. Hierarchical linear mixed-effects (LME) models assessed longitudinal associations over two years incorporating random intercepts and slopes to account for repeated measures. Fixed effects included NPS status, all covariates from the linear regression model, as well as an interaction term between NPS status and time.Among 477 participants (176 cognitively normal), 52 had MBI-apathy. Primary cross-sectional analyses showed that, compared to the no-NPS group, MBI-apathy was associated with higher CSF p-tau181/Aβ42 (11.25% [2.56% – 20.68%]; adjusted p = 0.018) and t-tau181/Aβ42 (10.26% [2.42% – 18.70%]; adjusted p = 0.018). Exploratory analyses revealed that MBI-apathy was associated with higher CSF p-tau181 (5.98% [0.50% – 11.77%]; p = 0.032). Primary LMEs showed that MBI-apathy was associated with higher CSF p-tau181/Aβ42 (11.34% [2.55% – 20.88%]; adjusted p = 0.022) and t-tau181/Aβ42 (10.34% [2.41–18.88%]; adjusted p = 0.022) over two years. Exploratory LMEs revealed that MBI-apathy was associated with higher CSF p-tau181 (6.03% [0.56% – 11.81%]; p = 0.032) and t-tau (4.96% [0.07% – 10.09%]; p = 0.049) over two years.MBI-apathy was significantly associated with core AD biomarkers cross-sectionally and longitudinally, over two years, underscoring its relevance as a marker of AD pathological burden. An overall MBI composite score may reflect a broader spectrum of pathology and warrants further investigation.
AbstractFragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a preCGG repeat expansion in the FMR1 gene. Individuals with the FMR1 premutation often exhibit neuropsychiatric symptoms before FXTAS onset, leading to the identification of fragile X-associated neuropsychiatric disorders (FXAND). Rodent models of FXTAS show motor impairments, pathological intranuclear inclusions, and heightened anxiety. However, the early onset of neuropsychiatric features and underlying mechanisms remain poorly understood.To address the above issues, we used the doxycycline (dox)-inducible 90CGG mouse model, with transgene activation at two developmental stages: adolescence and young adulthood. Mice were evaluated in a behavioural battery to assess anxiety-like behaviour, exploration, and motor coordination and learning. Next, we conducted a combination of ex vivo extracellular local field potential recordings to measure synaptic physiology and oscillatory activity in the limbic system, particularly in the basolateral amygdala (BLA) and ventral hippocampus (vH) regions. Parvalbumin interneurons and intranuclear inclusions in the amygdala and hippocampus were investigated by immunofluorescence, while mass spectrometry and gene set enrichment were used to identify differentially expressed proteins molecular pathways.Adolescent 90CGG mice displayed early-onset hyperactivity, transitioning to heightened anxiety in young adulthood, coinciding with the accumulation of intranuclear inclusions in the BLA and vH. Electrophysiological analysis revealed augmented gamma oscillations in the vH, emerging during adolescence and persisting in young adulthood. These changes correlated with a reduction in parvalbumin interneurons in these regions, and together likely contribute to enhanced BLA excitability and impaired vH plasticity. Finally, proteomic analysis of the vH revealed altered proteins linked to attention deficit hyperactivity disorder in adolescence and anxiety/depression in adulthood, aligning well with behavioural findings. Importantly, these behavioural, electrophysiological, and cellular alterations were reversible upon transgene inactivation.This study reveals a temporal progression of CGG premutation effects on behaviour, from hyperactivity to heightened anxiety to late onset motor dysfunction. Moreover, these findings provide altered network activity in the limbic system as a putative mechanism in neuropsychiatric features of premutation carriers.
AbstractThe historical understanding of cerebrospinal fluid (CSF) production and flow comprises CSF production primarily in the choroid plexus of the 1st-3rd ventricles, flow through the aqueduct of Sylvius en route to the 4th ventricle, circulation around the subarachnoid space, and ultimately resorption into the blood circulation through arachnoid granulations. Since the discovery of a perivascular CSF clearance system in 2012 and in 2015 of lymphatic vessels localized to the dura mater of mice, there has been a growing interest in characterizing the structure and function of the tissues surrounding the dural sinuses, or the parasagittal dural (PSD) space. This work is now being pursued with increasing frequency to understand how the PSD space may relate to impaired neurofluid egress or neuroimmune function, with the intent of further informing our understanding of neurodegenerative proteinopathies and associated therapeutic avenues in disease. This review summarizes (i) our current understanding of neurofluid (comprised of CSF and interstitial fluid) circulation within the brain, as well as the (ii) anatomy and (iii) function of the PSD space in the context of neurofluid circulation and neuroimmune surveillance. With this context in place, we report on recent (iv) abilities to quantify the PSD volume and function in humans, (v) large-scale studies of PSD evolution across the human lifespan, and (vi) evidence for PSD structural variation in the setting of neurodegenerative disease.
Matt Butler, runner up in the Brain Essay Competition 2024, considers what happens when memories fragment and certainties fade in this fictional tale of a professor of literature who loses her grasp on time.
Drawing on two decades of clinical experience with affective disorders, Jesús Ramírez-Bermúdez— runner up in the Brain Essay Competition 2024—explores the cultural significance of melancholy, with the aid of historical archives from the Inquisition and the introspections of a 17th century poet.
The response of an atom to external electric and magnetic fields can reveal fundamental atomic properties. It has long been verified that, in a static magnetic field, those atomic energy levels with hyperfine interactions shift according to the Breit–Rabi formula, which introduces nonlinear dependence on the magnetic field. On the other hand, the corresponding Breit–Rabi dependence on a static electric field has not been observed before due to a combination of experimental challenges. Here, we precisely measure the Stark shift of the6s21S0↔6s6p1P1transition of171Yb (I= 1/2) with cold atoms held by an optical dipole trap in a static electric field up to 120 kV/cm. We observe the electric Breit–Rabi effect displaying high-order (E4andE6) DC Stark shifts. These effects arise from the influence of the strong electric field on hyperfine interactions.
Collective cooperation maintains the function of many natural and social systems, making understanding the evolution of cooperation a central question of modern science. Although human interactions involve complex contact networks, current explorations are limited to static networks, where social ties are permanent and do not change over time. In reality, human activities often involve temporal interactions, where links are impermanent, and understanding the evolution of cooperation on such temporal networks is an open problem. Here, we systematically analyze how cooperation spreads on arbitrary temporal networks, and we distill our results down to a concise condition, which integrates evolutionary game dynamics with both static and temporal interactions. We find that the emergence of cooperation is facilitated by a simple rule of thumb: Hubs (individuals with many social ties) should be temporally deprioritized in interactions. For empirical applications, we further provide a quantitative metric capturing the priority of hubs, which is validated on empirical datasets based on its effectiveness in orchestrating the ordering of interactions to best promote cooperation. Our findings unveil the fundamental advantages conferred by temporal interactions for promoting collective cooperation, transcending the specific insights gleaned from studying static networks.
D-peptides hold great promise as therapeutics by alleviating the challenges of metabolic stability and immunogenicity in L-peptides. However, current D-peptide discovery methods are severely limited by specific size, structure, and the chemical synthesizability of their protein targets. Here, we describe a computational method for de novo design of D-peptides that bind to an epitope of interest on the target protein using Rosetta’s hotspot-centric approach. The approach comprises identifying hotspot sidechains in a functional protein–protein interaction and grafting these side chains onto much smaller structured peptide scaffolds of opposite chirality. The approach enables more facile design of D-peptides and its applicability is demonstrated by design of D-peptidic binders of influenza A virus hemagglutinin, resulting in identification of multiple D-peptide lead series. The X-ray structure of one of the leads at 2.38 Å resolution verifies the validity of the approach. This method should be generally applicable to targets with detailed structural information, independent of molecular size, and accelerate development of stable, peptide-based therapeutics.
Light controls important biological processes in fungi by regulating transcriptional gene activation. Here, we found that beyond the regulation of mRNA transcript abundance, light regulates alternative splicing (AS) in the filamentous fungiAspergillus nidulans,Trichoderma guizhouense,andNeurospora crassa. Blue light-regulated AS was involved in ergothioneine biosynthesis and conidiation inT. guizhouense, which required the blue light receptor BLR1. Blue light activated the MAPK HOG (Sak) pathway which then transmitted the signal via the serine/threonine kinase SRK1 to the AS key regulator SRP1. SRK1 and SRP1 are important for light-induced conidiation. The light-activated HOG pathway led to an increase of the SRK1 protein level and its phosphorylation status. Phosphorylated SRK1 translocated from the cytoplasm to the nucleus to interact with SRP1, thereby regulating AS efficiency. This study unravels another level of complexity of fungal environmental sensing and responses and also first describes the entire cascade from an environmental signal to the splicing machinery.
Multiple sclerosis (MS) is an immune-mediated disease with no current cure. Drug discovery and repurposing are essential to enhance treatment efficacy and safety. We utilized summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma and 1,443 brain proteins, a genome-wide association study of MS susceptibility with 14,802 cases and 26,703 controls, both bulk and cell-type specific transcriptome data, and external pQTL data in blood and brain. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization to determine potential causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing all analyses were prioritized as potential drug targets. We further conducted pathway annotations and protein–protein interaction network analysis (PPI) and verified our findings at mRNA and protein levels. We tested hundreds of MS-associated proteins and confirmed 18 potential causal proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also identified intricateAQ PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. We identified two targets using bulk mRNA expression data and four targets expressed in MS-related cell types. We finally verified 10 targets using external pQTL data. We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for potential drug discovery and repurposing in MS.
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A long-standing fundamental open problem in mathematical fluid dynamics and nonlinear partial differential equations is to determine whether solutions of the 3D incompressible Euler equations can develop a finite-time singularity from smooth, finite-energy initial data. Leonhard Euler introduced these equations in 1757 [L. Euler,Mémoires de l’Académie des Sci. de Berlin11, 274–315 (1757).], and they are closely linked to the Navier–Stokes equations and turbulence. While the general singularity formation problem remains unresolved, we review a recent computer-assisted proof of finite-time, nearly self-similar blowup for the 2D Boussinesq and 3D axisymmetric Euler equations in a smooth bounded domain with smooth initial data. The proof introduces a framework for (nearly) self-similar blowup, demonstrating the nonlinear stability of an approximate self-similar profile constructed numerically via the dynamical rescaling formulation.
Retinoic acid (RA) is a morphogen that contributes to inner ear development. Gain and loss of function experiments have indicated retinoic acid’s critical role in cochlear hair cell development. However, the underlying molecular mechanisms are unclear. Here, we hypothesized that RA receptor alpha (RARA) has a dual role in cochlear organogenesis: First, during embryonic development, in the presence of RA, RARA functions as a transcriptional activator that induces prosensory gene expression in progenitor cells and supports differentiation of the organ of Corti; later during postnatal development, when RA is absent, the function of RARA switches, thereby repressing prosensory genes in postnatal hair cells and hindering trans-differentiation into supporting cells. This hypothesis was supported by demonstration that RARA forms a complex with either the coactivator NCOA1 or the corepressor NCOR1 depending on the developmental stage. In addition, modulation of RA levels was found to govern recruitment of the coactivator and corepressor to the RARA complex, and the expression of prosensory genes was validated to depend on RARA complex composition. Together, our results provide insights supporting the potential of harnessing RA signaling to induce prosensory progenitors in stem cell–based strategies for hearing loss.
The formation of bilateral testes in animals is critical for puberty, reproductive capacity, and testosterone production across the life course. In humans, testis development begins in embryonic life in the first trimester, with considerable effort focused on the cell and developmental events associated with testis cell specification, leaving limited knowledge on testicular organogenesis during the second and third trimesters. To fill this knowledge gap, we evaluated testicular cell maturation at weeks 5 (W5), W6, W8, W15, and W19 postconception using a rhesus macaque model. Our data identify a major transcriptional change in the somatic cells of the testis (Sertoli cells, interstitial cells and fetal Leydig cells) between W8 and W15, and this is associated with the maturation of seminiferous cords and maturation of PGCs into fetal spermatogonia. Through this work, we identified cellular changes and differential protein expression between W5 and W19 that can be used to holistically define testis development across the time course of embryonic and fetal life. This study provides important insights necessary to recreate the testicular niche from stem cells for biomedical research.
Darwinian evolution results from an interplay between stochastic diversification of heritable phenotypes, impacting the chance of survival and reproduction, and fitness-based selection. The ability of populations to evolve and adapt to environmental changes depends on rates of mutational diversification and the distribution of fitness effects of random mutations. In turn, the distribution of fitness effects of stochastic mutations can be expected to depend on the adaptive state of a population. To systematically study the impact of the interplay between the adaptive state of a population on the ability of asexual populations to adapt, we used a spatial agent-based model of a neoplastic population adapting to a selection pressure of continuous exposure to targeted therapy. We found favorable mutations were overrepresented at the extinction bottleneck but depleted at the adaptive peak. The model-based predictions were tested using an experimental cancer model of an evolution of resistance to a targeted therapy. Consistent with the model’s prediction, we found that enhancement of the mutation rate was highly beneficial under therapy but moderately detrimental under the baseline conditions. Our results highlight the importance of considering population fitness in evaluating the fitness distribution of random mutations and support the potential therapeutic utility of restricting mutational variability.
The rapid evolution of RNA viruses implies that their evolutionary and ecological processes occur on the same time scale. Genome sequences of these pathogens therefore can contain information about the processes that govern their transmission and dispersal. Landscape phylogeographic approaches use phylogeographic reconstructions to investigate the impact of environmental factors and variables on the spatial spread of viruses. Here, we extend and improve existing approaches and develop three novel landscape phylogeographic methods that can test the impact of continuous environmental factors on the diffusion velocity of viral lineages. In order to evaluate the different methods, we also implemented two simulation frameworks to test and compare their statistical performance. The results enable us to formulate clear guidelines for the use of three complementary landscape phylogeographic approaches that have sufficient statistical power and low rates of false positives. Our open-source methods are available to the cientific community and can be used to investigate the drivers of viral spread, with potential benefits for understanding virus epidemiology and designing tailored intervention strategies.
Drimenol synthase fromAquimarina spongiae(AsDMS) is a highly unusual chimera that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol. The AsDMS structure exhibits a didomain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase-like phosphatase domain, with two distinct active sites located on opposite sides of the protein. Mechanistic studies show that dephosphorylation of the drimenyl diphosphate intermediate proceeds through stepwise hydrolysis such that two equivalents of inorganic phosphate rather than inorganic pyrophosphate are coproducts of the reaction sequence. When the AsDMS reaction is performed in H218O,18O is not incorporated into drimenol, indicating that the hydroxyl oxygen of drimenol originates from the prenyl oxygen of FPP rather than a water molecule from bulk solution. These results correct a mechanistic proposal previously advanced by another group. Surprisingly, AsDMS exhibits substrate promiscuity, catalyzing the conversion of the slowly reactive substrate mimic farnesyl-S-thiolodiphosphate into cyclic and linear sesquiterpene products. Structural and mechanistic insights gained from AsDMS illustrate the functional diversity of terpene biosynthetic enzymes and provide a foundation for engineering “designer cyclase” assemblies capable of generating a wide variety of terpenoid products.
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Insects frequently form associations with maternally transmitted symbiotic bacteria. This transmission mode ensures that symbiont-conferred effects, both beneficial and negative, are passed onto offspring. Here, we report an extreme example of symbiont-mediated temperature sensitivity imposed by a vertically transmitted, defensive symbiont. Pea aphids infected with the bacterial endosymbiont,Fukatsuia symbiotica,resist infection by fungal pathogens but produce few or no offspring when moved from cool (15 °C) to mildly warmer temperatures (20 °C). This temperature-dependent reduction in host fitness is associated with increased symbiont abundance, disordered symbiont localization, and high expression of a horizontally acquired nonribosomal peptide synthetase (NRPS) locus. This NRPS operon is syntenic with the locus responsible for the production of Herbicolin A, a known antifungal produced by some plant-associatedErwiniaceae. Activity of chemical extracts from infected aphids is predictive of in vivo protection against entomopathogenic fungi, indicating that an Herbicolin A–like molecule is the likely source ofFukatsuia’sprotective effects against fungal pathogens. Injection of the same chemical extracts into naive aphids partially recapitulates developmental defects observed in natural infections at 20 °C, suggesting that increased levels of this compound contribute to disrupted embryonic development. Finally, the purification of the causal agent revealedFukatsuiaproduces a compound similar but not identical to Herbicolin A, that exhibits both antifungal and hemolytic activity. These results suggest thatF. symbioticainfection imposes a trade-off between antifungal defense and disrupted embryonic development, mediated by a single genetic locus.
Antagonistic interactions are critical determinants of microbial community stability and composition, offering host benefits such as pathogen protection and providing avenues for antimicrobial control. While the ability to eliminate competitors confers an advantage to antagonistic microbes, it often incurs a fitness cost. Consequently, many microbes only produce toxins or engage in antagonistic behavior in response to specific cues like quorum sensing molecules or environmental stress. In laboratory settings, antagonistic microbes typically dominate over sensitive ones, raising the question of why both antagonistic and nonantagonistic microbes are found in natural environments and host microbiomes. Here, using both theoretical models and experiments with killer strains ofSaccharomyces cerevisiae, we show that “boom-and-bust” dynamics—periods of rapid growth punctuated by episodic mortality events—caused by temporal environmental fluctuations can favor nonantagonistic microbes that do not incur the growth rate cost of toxin production. Additionally, using control theory, we derive bounds on the competitive performance and identify optimal regulatory toxin-production strategies in various boom-and-bust environments where population dilutions occur either deterministically or stochastically over time. Our mathematical investigation reveals that optimal toxin regulation is much more beneficial to killers in stochastic, rather than deterministic, boom-and-bust environments. Overall, our findings show how both antagonistic and nonantagonistic microbes can thrive under varying environmental conditions.
Polyploid organisms evolve from their initial doubled genomic condition through a number of processes collectively termed diploidization, whose tempo and mode remain poorly understood mainly due to the difficulty of discriminating de novo evolution subsequent to polyploidy from variation inherited from progenitors. Here, we generated chromosome-scale genome assemblies for the wild rice allopolyploidOryza minutaand its two diploid progenitors,Oryza punctataandOryza officinalis, and employed a population genomic approach to investigate the diploidization process inO. minutaat the sequence and transcriptomic level. We show that this wild rice allopolyploid originated around 0.7 Mya, and during subsequent diploidization, its two subgenomes have retained highly conserved synteny with the genomes of its extant diploid progenitors. This populational approach allowed us to distinguish parental legacy of inherited variation from postpolyploidy evolution, and our analyses revealed that whereas gene fractionation occurred in an early burst, accumulation of transposable elements (TEs) and homoeologous exchanges has been gradual. Patterns of homoeolog expression bias are highly variable across tissues, with no consistent subgenome expression bias. Our assessments of the impact of DNA methylation, TE distribution, and parental legacy on expression patterns provide some support for the TE load theory (the theory that the TE densities in flanking regions surrounding genes strongly influence expression levels), while also illustrating the complexity of transcription regulation.
Currently, catalytic recycling of polyethylene (PE) into high-value chemicals using solar energy often faces poor product selectivity and low efficiency. This is mainly due to the difficulty in effectively controlling the intermediates during PE photoreforming and the long-standing challenge of inefficient charge dynamics. Here, we present a solar-driven photothermal catalytic approach for the selective conversion of PE waste into propionic acid and hydrogen under ambient conditions. Atomically dispersed Ni sites supported on CeO2(NiSA/CeO2) achieve a propionic acid yield of 331 μmol h–1with 94.8% selectivity in the photothermal reaction. This performance is 1.6 times higher than that of catalysts supported by Ni clusters (NiNP/CeO2). Additionally, NiSA/CeO2exhibits a hydrogen yield of 0.23 mmol h–1with stable long-term performance. Mechanistic studies reveal that single Ni atoms form linear coordination with oxygen atoms in CeO2, introducing unoccupied mid-gap states that effectively capture hot electrons and enhance the photothermal effect through local hotspot formation. In contrast, Ni clusters suffer from inefficient heat accumulation due to multistep phonon scattering. Furthermore, site isolation of Ni single atoms spatially separates the reaction intermediates and suppresses dimerization of the key intermediate COOHCH2CH2*, thereby greatly improving the selectivity for propionic acid. In contrast, closely packed Ni cluster sites promote intermediate coupling and the formation of undesirable byproducts, reducing selectivity. This work provides mechanistic insights into the advantages of atomic-scale catalyst design for selective chemical transformations.
The basal ganglia play a crucial role in action selection by facilitating desired movements and suppressing unwanted ones. The substantia nigra pars reticulata (SNr), a key output nucleus, facilitates movement through disinhibition of the superior colliculus (SC). However, its role in action suppression, particularly in primates, remains less clear. We investigated whether individual SNr neurons in three male macaque monkeys bidirectionally modulate their activity to both facilitate and suppress actions and examined the role of glutamatergic inputs in suppression. Monkeys performed a sequential choice task, selecting or rejecting visually presented targets. Electrophysiological recordings showed that SNr neurons decreased firing rates during target selection and increased firing rates during rejection, demonstrating bidirectional modulation. Pharmacological blockade of glutamatergic inputs to the lateral SNr disrupted saccadic control and impaired suppression of reflexive saccades, providing causal evidence for the role of excitatory input in behavioral inhibition. These findings suggest that glutamatergic projections, potentially originating from sources including the subthalamic nucleus, contribute to the increased SNr activity during action suppression. Our results highlight conserved basal ganglia mechanisms across species and offer insights into the neural substrates of action selection and suppression in primates, with implications for understanding disorders such as Parkinson’s disease.
Chronic pain arises from maladaptive changes in both peripheral and central nervous systems, including the anterior cingulate cortex (ACC), a key region implicated in descending pain modulation. Chronic pain increases the excitability of pyramidal neurons in the ACC. Although a reduction in inhibitory inputs onto pyramidal neurons has been observed in neuropathic conditions, the identity of the specific interneurons responsible remains unclear. We show that chronic pain selectively impairs parvalbumin (PV), but not somatostatin, interneurons in the rostral ACC. This is characterized by a decrease in the density of PV interneuron processes, a reduction in their surrounding perineuronal net, and a lower expression of PV. Functionally, PV interneurons display diminished inhibitory efficacy in vitro and reduced phasic activation in response to aversive stimuli in vivo. Dopamine (DA) fibers preferentially contact PV interneurons and excite them via D1 dopamine receptor activation, increasing their excitability and enhancing the frequency of inhibitory postsynaptic currents on pyramidal neurons in healthy, but not neuropathic, conditions. Furthermore, we show that this pathway is involved in hunger-induced analgesia: Food deprivation increases DA release in the ACC and consequently decreases pain thresholds in neuropathic mice. Conversely, when mice are not food deprived, neuropathic pain significantly reduces DA release in the ACC. We conclude that the loss of PV interneuron inhibitory efficacy, alongside convergent hypodopaminergic signaling, synergistically contributes to pathological ACC dysfunction and associated symptoms of chronic pain.
Regulation of proteome homeostasis is crucial for the survival and adaptation to changing environments for all species. In eukaryotes, this process is finely tuned through regulation at the level of transcription, translation, protein modification, and protein degradation. The phospholipase A2 activating protein (PLAA) is present in all eukaryotes and believed to be a key player in ubiquitin-dependent protein sorting and degradation via its interactions with ubiquitin and/or the AAA+ ATPase, valosin-containing protein (VCP/p97). PLAA’s molecular targets and interaction network remain unclear. We usedCaenorhabditis elegansand unbiased proteome-scale approaches to investigate neuronal specific interactors of theC. elegansPLAA ortholog UFD-3 (ubiquitin fusion degradation 3), its effect on ubiquitinated proteins, and global protein expression changes in anufd-3mutant. We found that PLAA may play a unique role in cytoplasmic messenger ribonucleic acid (mRNA) processing bodies (P-bodies). Using biochemical analysis in vitro and fluorescence imaging inC. elegans, we show that UFD-3 directly interacts with the mRNA decapping complex regulatory subunit DCAP-1. UFD-3's intrinsic disordered region (IDR), which contains conserved amino acid motifs, is important for the recruitment of DCAP-1 to P-bodies. Finally, we show that loss of the IDR does not affect UFD-3's role in sorting ubiquitinated proteins through the multivesicular body pathway. Collectively, our results suggest that UFD-3's role in P-bodies is distinct from its role in the ubiquitin-dependent protein degradation pathway and the IDR is only critical for UFD-3-regulated P-bodies pathways. Thus, PLAA/UFD-3 might regulate the proteome via two distinct pathways: ubiquitinated protein turnover, as well as mRNA regulation through P-bodies.
In recent years, trust in US public health and science institutions has faced unprecedented declines, particularly among Republicans/conservatives. To what extent might institutional criticism on social media be responsible for such politically polarized declines in institutional trust? Two online survey experiments (totalN= 6,800), using samples roughly reflective of the US adult population, examined the effects of key types of criticism against the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention (CDC). The results suggest that just a single exposure to any of the key types of criticism was sufficient to undermine institutional trust. While an institutional rebuttal was partially able to reverse these effects, residual declines in trust were substantial enough to cause decreased intentions to adhere to the AHRQ/CDC health recommendation featured in the experiments. While institutions should, therefore, be concerned about all types of social media criticism, those featuring morally charged trust-undermining narratives attacking the integrity of the AHRQ/CDC generated dramatically more anger (i.e., moral outrage), which in turn attracted social media engagement preferences likely to promote viral spread and exacerbate preexisting institutional politicization and issue polarization. These results suggest that efforts to bolster institutional trust should pay special attention to criticisms featuring integrity-based trust-undermining narratives.
Hydrocephalus, a neurological condition characterized by an excessive buildup of cerebrospinal fluid (CSF) in the brain, affects millions worldwide and leads to severe consequences. Current treatments, such as ventriculoperitoneal shunts, divert excess CSF from the brain but often face complications, mainly due to shunt obstructions caused by biological matter accumulation. While previous shunt designs aimed to improve fluid flow and reduce occlusion, they often lacked the precision needed for real-world applications due to simplified simulation models that did not fully capture the dynamics of the cerebral ventricular system. Here, we introduce BrainFlow, a computational model that integrates detailed anatomical and physiological features to simulate CSF dynamics in the presence of shunt implants. BrainFlow incorporates patient-specific medical imaging data, pulsatile flow to mimic cardiac cycles, adjustable parameters for various hydrocephalus conditions, and a biomolecule tracking feature to evaluate the long-term risk of shunt occlusion due to flow-mediated biomolecular transport. This model provides a more nuanced understanding of the factors contributing to shunt obstruction, offering insights into optimal shunt placement, design, and materials choice. Through validation against four-dimensional MRI flow data, BrainFlow demonstrates robust accuracy across multiple flow metrics. Our work lays the groundwork for the development of next-generation shunts tailored to individual patient anatomy and pathology, ultimately aiming to improve hydrocephalus treatment through informed, patient-specific design strategies.
Adhesive interfaces store significant energy due to interlocking molecular chain entanglement and van der Waals forces. When two adhesive surfaces are separated, triboelectric effects induce charge transfer, generating a strong electric field at the peeling interface. This effect offers different opportunities for initiating chemical reactions. Here, we report that the stick–slip friction involved in peeling tape produces electric fields on the order of 109V/m, as measured by the vibrational Stark shift observed by confocal Raman spectroscopy during tape peeling. This field is sufficiently strong to ionize water and produce the H4O2+cation, a hydroxyl radical adduct with a hydronium ion. We further demonstrate that this electric field can drive a variety of electron transfer reactions. Our findings suggest that tribocharging presents a promising, energy-efficient avenue for electric-field-driven green chemistry.
Generative AI is poised to revolutionize how humans work, and has already demonstrated promise in significantly improving human productivity. A key question is how generative AI affects learning—namely, how humans acquire new skills as they perform tasks. Learning is critical to long-term productivity, especially since generative AI is fallible and users must check its outputs. We study this question via a field experiment where we provide nearly a thousand high school math students with access to generative AI tutors. To understand the differential impact of tool design on learning, we deploy two generative AI tutors: one that mimics a standard ChatGPT interface (“GPT Base”) and one with prompts designed to safeguard learning (“GPT Tutor”). Consistent with prior work, our results show that having GPT-4 access while solving problems significantly improves performance (48% improvement in grades for GPT Base and 127% for GPT Tutor). However, we additionally find that when access is subsequently taken away, students actually perform worse than those who never had access (17% reduction in grades for GPT Base)—i.e., unfettered access to GPT-4 can harm educational outcomes. These negative learning effects are largely mitigated by the safeguards in GPT Tutor. Without guardrails, students attempt to use GPT-4 as a “crutch” during practice problem sessions, and subsequently perform worse on their own. Thus, decision-makers must be cautious about design choices underlying generative AI deployments to preserve skill learning and long-term productivity.
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Prostate cancer is a global health challenge, particularly for patients resistant to the second-generation anti-androgen receptor pathway inhibitors. The steroidogenic enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) has emerged as a promising therapeutic target and the corresponding inhibitors, biochanin-A (BCA) and its derivatives, suppress tumor growth in preclinical models and patients. However, the poor oral bioavailability of BCA hinders its clinical application. Here, we employed a sophisticated computational approach to refine the structural design of 3βHSD1 inhibitors. AlphaFold2 was utilized to construct detailed models of 3βHSD1 binding to various substrates. These models, in conjunction with the elucidated enzymatic mechanism of 3βHSD1, guided the optimization of a series of BCA-related compounds. Our structure–activity relationship studies identified HEAL-116 as a potent 3βHSD1 inhibitor. HEAL-116 exhibited enhanced binding specificity to the substrate-binding pocket of 3βHSD1 and effectively neutralized the local charge environment. The incorporation of hydrophilic groups in its structure also markedly enhanced its oral bioavailability. HEAL-116 robustly inhibited 3βHSD1 activity and exerted pronounced antitumor effect in biochemical, cellular, and mouse models. Our findings lay the foundation for the clinical translation of 3βHSD1 inhibitors, offering a promising therapeutic strategy for the management of prostate cancer and potentially other diseases.
Trichomonas vaginalisis a common, extracellular, sexually transmitted parasite which is often found in symbiosis with the intracellular bacteriumMycoplasma hominis(Mh), an opportunistic pathogen of the female reproductive tract. How this symbiosis affects infection outcomes and the host cell innate immune response is poorly understood. Here, we show that infection withT. vaginalisin symbiosis withM. hominisorM. hominisalone triggers a noncanonical type I interferon, interferon-epsilon (IFNε), but infection withT. vaginalisalone does not. We also demonstrate that extracellular vesicles (TvEVs) produced by the parasite downregulate host cell IFNε, counteracting this symbiont-driven response and elevating infection. We further demonstrate that IFNε, a hormonally regulated cytokine produced in the human reproductive system, is protective againstT. vaginaliscytoadherence and cytolysis of host cells. These studies provide insight into how a parasite and its bacterial symbiont work in concert to regulate host cell innate immune responses to drive infection.
The aggregation ofα-synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation ofα-synuclein. Using this framework, we find thatα-synuclein fibrils form via a two-step primary nucleation mechanism and that lipid molecules are directly involved in both the nucleation and fibril elongation steps, giving rise to lipid–protein coaggregates. To illustrate the applicability of this kinetic approach to drug discovery, we identify the mechanism of action of squalamine, a known inhibitor of lipid-inducedα-synuclein aggregation, revealing that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design ofα-synuclein aggregation inhibitors.
There is overwhelming evidence that forest trees are locally adapted to climate. Thus, genecological models based on population phenotypes have been used to measure local adaptation, infer genetic maladaptation to climate, and guide assisted migration. However, instead of phenotypes, there is increasing interest in using genomic data for gene resource management. We used whole-genome resequencing and common-garden experiments to understand the genetic architecture of adaptive traits in black cottonwood. We studied the potential of using genome-wide association studies (GWAS) and genomic prediction to detect causal loci, identify climate-adapted phenotypes, and inform gene resource management. We analyzed population structure by partitioning phenotypic and genomic (single-nucleotide polymorphism) variation among 840 genotypes collected from 91 stands along 16 rivers. Most phenotypic variation (60 to 81%) occurred among populations and was strongly associated with climate. Population phenotypes were predicted well using genomic data (e.g., predictive abilityr> 0.9) but almost as well using climate or geography (r> 0.8). In contrast, genomic prediction within populations was poor (r< 0.2). We identified many GWAS associations among populations, but most appeared to be spurious based on pooled within-population analyses. Hierarchical partitioning of linkage disequilibrium and haplotype sharing suggested that within-population genomic prediction and GWAS were poor because allele frequencies of causal loci and linked markers differed among populations. Given the urgent need to conserve natural populations and ecosystems, our results suggest that climate variables alone can be used to predict population phenotypes, delineate seed zones and deployment zones, and guide assisted migration.
Chloroplast division, a process tightly linked to the energy demands of plants, is initiated by the formation of the stromal filamenting temperature-sensitive Z (FtsZ) ring. The Z ring is highly dynamic, and its constriction provides the essential force for chloroplast division. However, the regulatory mechanisms governing Z-ring dynamics and constriction remain poorly understood. Here, we report that the chloroplast inner envelope membrane (IEM) protein ACCUMULATION AND REPLICATION OF CHLOROPLASTS6 (ARC6) interacts with the chloroplast stromal protein ARC3, and this interaction is negatively regulated by the conserved J-like domain of ARC6. ARC3 is found both distributed throughout the stroma and localized to a ring-like structure at the chloroplast division site. We demonstrate that ARC6 recruits ARC3 to the division site to form a ring-like structure, likely through direct interaction. This ARC6–ARC3 interaction enables ARC3 to bind FtsZs. Furthermore, we show that the ARC6–ARC3 complex significantly promotes the dynamics of chloroplast Z rings reconstituted in a heterologous system. Finally, the constriction of these reconstituted Z rings is markedly enhanced by ARC6–ARC3. Our findings reveal a regulatory mechanism that governs Z-ring dynamics and constriction, shedding light on the molecular mechanisms underlying chloroplast division.
Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance remains a major hurdle. Metabolic reprogramming is a notable phenotype associated with the acquisition of drug resistance. Here, we develop a computational framework that predicts metabolic gene targets capable of reverting the metabolic state of drug-resistant cells to that of drug-sensitive parental cells, thereby sensitizing the resistant cells. The computational framework performs single-gene knockout simulation of genome-scale metabolic models that predicts genome-wide metabolic flux distribution in drug-resistant cells, and clusters the resulting knockout flux data using uniform manifold approximation and projection, followed byk-means clustering. From the clustering analysis, knockout genes that lead to the flux data near that of drug-sensitive cells are considered drug sensitization targets. This computational approach is demonstrated using doxorubicin- and paclitaxel-resistant MCF7 breast cancer cells. Drug sensitization targets are further refined based on proteome and metabolome data, which generateGOT1for doxorubicin-resistant MCF7,GPIfor paclitaxel-resistant MCF7, andSLC1A5as a common target. These targets are experimentally validated where treating drug-resistant cancer cells with small-molecule inhibitors results in increased sensitivity of drug-resistant cells to doxorubicin or paclitaxel. The applicability of the developed framework is further demonstrated using drug-resistant triple-negative breast cancer cells. Taken together, the computational framework predicts drug sensitization targets in an intuitive and cost-efficient manner and can be applied to overcome drug-resistant cells associated with various cancers and other metabolic diseases.
Cancer therapy would benefit from suppressing cancer cell motility in the process of metastasis. Such directed cell migration relies on the propulsive force established by the filamentous actin network within lamellipodia. Proteins of the Ena/VASP family and the WAVE regulatory complex orchestrate lamellar protrusions and therefore provide promising targets for pharmacological interventions. Here, we report a cross-talk between Ena/VASP proteins and WAVE2 that is important for cancer cell extravasation. Mutating the EVH1 domain recognition motif in WAVE2 abrogates chemotaxis of triple-negative MDA-MB-231 breast cancer cells and reduces their extravasation in a zebrafish model. In pilot experiments, orthotopic implantation of these cells into mice led to a reduction in macrometastasis, resulting in prolonged survival. Similarly, intervention by an Ena/VASP-EVH1 inhibitor also reduced metastasis in vivo. Our results suggest that pharmacological interference with the Ena/VASP–WAVE2 interaction may thus reduce metastasis.
The Hantzsch ester (HEH2) has found considerable utility as a photoreductant in synthesis, with photodriven transfer hydrogenation reactions typically limited to activated substrates. We recently established that the addition of an organic buffer of collidinium triflate [(ColH)OTf] and collidine (Col) allows photodriven transfer hydrogenation from HEH2to N2forming NH3(nitrogen reduction; N2R) in the presence of a Mo catalyst. Given the requirements for Mo-catalyzed thermally driven N2R, this result suggested the generation of a significant driving force for proton-coupled electron transfer (PCET) when irradiating HEH2in the presence of Col-buffer. In this study, we probe how Col-buffer enables efficient photodriven proton-coupled reductions with HEH2. Wavelength-dependent NH3yields are consistent with HEH2photoexcitation, and the combination of HEH2with Col-buffer is privileged. Data are presented, suggesting that HEH2is statically quenched via ET to [ColH]OTf through an H-bonded association complex to release ColH•and [HEH2]•+. Transient absorbance data and EPR studies establish that the resulting [HEH2]•+intermediate is rapidly deprotonated by Col to yield HEH•, in net furnishing HEH•and ColH•as potent H-atom donors. Broader utility of this reagent combination is demonstrated in the photoreduction of a range of C=O and N=O π-bonds by HEH2, with a significant boost in rates and yield, and altered reactivity, observed on addition of Col-buffer. ColH•is posited as the most potent PCET donor generated (BDFEN−Hof 28 kcal mol−1).
Perception is fallible. Humans know this, and so do some nonhuman animals like macaque monkeys. When monkeys report more confidence in a perceptual decision, that decision is more likely to be correct. It is not known how neural circuits in the primate brain assess the quality of perceptual decisions. Here, we test two hypotheses. First, that decision confidence is related to the structure of population activity in the sensory cortex. And second, that this relation differs from the one between sensory activity and decision content. We trained macaque monkeys to judge the orientation of ambiguous stimuli and additionally report their confidence in these judgments. We recorded population activity in the primary visual cortex and used decoders to expose the relationship between this activity and the choice-confidence reports. Our analysis validated both hypotheses and suggests that perceptual decisions arise from a neural computation downstream of visual cortex that estimates the most likely interpretation of a sensory response, while decision confidence instead reflects a computation that evaluates whether this sensory response will produce a reliable decision. Our work establishes a direct link between neural population activity in the sensory cortex and the metacognitive ability to introspect about the quality of perceptual decisions.
The contact between two rough surfaces has been a topic of significant interest since early studies on Coulombic friction and remains crucial for numerous technological applications. However, theoretical progress has outpaced experiments due to the challenges in measuring contact areas across scales ranging from subnanometers to macroscopic dimensions. Here, we demonstrate the use of commonly available infrared-based (IR) spectroscopy in combination with finite-difference time-domain (FDTD) optical simulations to measure separation gaps and contact areas for glassy polymers ranging in roughness over two orders in magnitude. With the combined IR and FDTD simulations, we can overcome the optical diffraction limits and take advantage of the chemical specificity of IR spectroscopy to overcome limitations due to scattering. The scaling of the contact area ratio as a function of pressure illustrated the limitations of using pure elastic or plastic deformation in explaining the results. At both low and high pressures, the contact area ratios scale linearly with pressure as expected for purely elastic deformations at low pressures or plastic deformations at high pressures. However, if analyzed over a broad range of pressure, the power laws we observe are much larger than 1, exemplifying the need to consider elastoplastic models in explaining results for softer polymer contacts compared to other brittle, glassy materials. In comparison, the separation gaps scale exponentially with pressure, as expected. These results have important implications for the interpretation of properties such as friction, adhesion, and conductivity for softer, glassy contact interfaces.
RNA recognition motif (RRM) domain proteins are crucial RNA-binding proteins across all domains of life. In cyanobacteria, single RRM domain proteins are involved in mRNA targeting to the thylakoid membrane and acclimation to certain stress conditions, but many details of their physiological functions and molecular targets have remained unknown. The model cyanobacteriumSynechocystissp. PCC 6803 has a family of three genes encoding the RRM domain–containing proteins Rbp1, Rbp2, and Rbp3. Here, we verified the RNA-binding activity of Rbp3 in vivo and show that cells of a Δrbp3deletion strain had a lower photosystem (PS) I:PSII ratio and decreased pigment content and were significantly smaller than wild-type cells. To identify the set of interacting molecules, coimmunoprecipitation experiments were performed with a strain expressing a C-terminally FLAG-tagged Rbp3. Mass spectrometry of the elution fraction suggested physical proximity between Rbp3, ribosomes, and a very small number of other proteins. The most highly enriched transcript in the coeluting RNA fraction was thepsaABmRNA. This was corroborated by fluorescent in situ hybridization analyses showing decreasedpsaAmRNA signals in Δrbp3, and colocalization with Rbp3 fusions to the green fluorescent protein (GFP) in the wild type. Other mRNAs coenriched with Rbp3 encode thylakoid, plasma membrane, and carboxysome proteins. Binding assays using Bio-layer Interferometry validated the Rbp3-psaABmRNA interaction, indicating a preference for folded RNA segments near or overlapping the respective stop codons.
Liquid–liquid phase transitions (LLPTs) are typically characterized as two-state systems, where transitions occur between two distinct liquid phases driven by local structural rearrangements. In this study, we observed a continuous LLPT with an inversion of electronegativity in a K–Rb binary alloy. This uniquely exhibits a three-state system behavior. The transition, induced by pressure-driven reordering of electronic orbital energies, progresses through a sequence froms-metal to electride tod-metal, accompanied by a valence reversal: Potassium transitions from a negative to a positive valence, while rubidium undergoes the opposite shift. This process is marked by two successive anomalies in the alloy’s optical, thermodynamic, and dynamic properties over a broad pressure range. The observation of similar LLPT phenomena in other alkali and alkaline earth metal liquids suggests that this three-state system mechanism may provide broader insights into the nature of continuous phase transitions.
PIK3CA-related disorders are rare genetic disorders due to somatic gain-of-function mutations inPIK3CAduring embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients withPIK3CA-related disorders indicates that peripheral nerves are frequently affected, leading to severe neurological symptoms. However, the exact underlying mechanism of these disorders remains unclear. To address this, we developed a mouse model with aPIK3CAgain-of-function mutation specifically in Schwann cells, which successfully mirrored the clinical features observed in patients. In this model, we observed thatPIK3CA-mutated cells communicate with neighboring healthy cells, such as adipocytes and hair follicles, through a unique crosstalk mechanism that triggers their growth, proliferation, and anagen phase expansion. Additionally, we demonstrated thatPIK3CAmutation in peripheral nerves leads to a metabolic shift through glycolytic activation. We investigated the effects of alpelisib, an approved pharmacological inhibitor of PIK3CA, in the model. Early administration of alpelisib significantly improved the signs and symptoms in the mice. However, when treatment was delayed, its efficacy was diminished due to the drug’s inability to penetrate the myelin sheath effectively. In summary, our study offers a valuable mouse model for studyingPIK3CA-related neuropathy, uncovers a unique communication between healthy and affected tissues, and highlights the potential benefits of early pharmacological intervention using alpelisib.
Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. In this study, we focused on the stability of SAM levels in the fat body (FB) ofDrosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin–proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt level reduction by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated reduction helps maintain SAM levels under SAM shortage conditions.
The outer membrane vesicles (OMVs) produced by diderm bacteria have important roles in cell envelope homeostasis, secretion, interbacterial communication, and pathogenesis. The facultative intracellular pathogenSalmonella entericaTyphimurium (STm) activates OMV biogenesis inside the acidic vacuoles of host cells by upregulating the expression of the OM protein PagC, one of the most robustly activated genes in a host environment. Here, we used solid-state nuclear magnetic resonance (NMR) and electron microscopy (EM), with native bacterial OMVs, to demonstrate that three histidines, essential for the OMV biogenic function of PagC, constitute a key pH-sensing motif. The NMR spectra of PagC in OMVs show that they become protonated around pH 6, and His protonation is associated with specific perturbations of select regions of PagC. The use of bacterial OMVs is a key aspect of this work enabling NMR structural studies in the context of the physiological environment. PagC expression upregulates OMV production inEscherichia coli, replicating its function in STm. Moreover, the presence of PagC drives a striking aggregation of OMVs and increases bacterial cell pellicle formation at acidic pH, pointing to a potential role as an adhesin active in biofilm formation. The data provide experimental evidence for a pH-dependent mechanism of OMV biogenesis and aggregation driven by an OM protein.
Island populations of large vertebrates have experienced higher extinction rates than mainland populations over long timescales due to demographic stochasticity, genetic drift, and inbreeding. While being more susceptible to extinction and as such potentially targeted for conservation interventions such as genetic rescue, small-island populations can experience relatively less anthropogenic habitat degradation than those on larger islands. Here, we determine the consequences and conservation implications of long-term isolation and recent human activities on genetic diversity of island populations of two forest-dependent mammals endemic to the Wallacea archipelago: the anoa (Bubalusspp.) and babirusa (Babyrousaspp.). Using genomic analyses and habitat suitability models, we show that, compared to closely related species, populations on mainland Sulawesi exhibit low heterozygosity, high inbreeding, a high proportion of deleterious alleles, and experience a high rate of anthropogenic disturbance. In contrast, populations on smaller islands occupy higher-quality habitats, possess fewer deleterious mutations despite exhibiting lower heterozygosity and higher inbreeding. Site frequency spectra indicate that these patterns reflect stronger, long-term purging in smaller-island populations. Our results thus suggest that conservation efforts should focus on protecting small-island high-quality habitats and avoiding translocations from mainland populations. This study highlights the crucial role of small offshore islands for the long-term survival of Wallacea’s iconic and indigenous mammals in the face of development on the mainland.
Tissue fibrosis is commonly associated with organ malfunction and is strongly associated with the development of chronic rejection, cardiovascular diseases, and other chronic diseases. Fibrosis also contributes to immune exclusion in tumor tissues. Targeting fibrosis might be a strategy for prolonging allograft survival while suppressing cancer development. Here, single-cell transcriptomes of human and mouse heart allografts showed that macrophages accumulated in grafts with fibrosis were reprogrammed via histone methylation regulated by Setdb1, an H3K9 methyltransferase. Myeloid-specific deletion of Setdb1 prolonged heart allograft survival but reversed immune exclusion in tumor tissues. Interestingly, myeloid-specific Setdb1-knockout led to lower fibrosis in heart allografts and tumor tissues in mice. Our single-cell sequencing data showed that Setdb1 ablation impaired Fn1+and SPP1+profibrogenic macrophage reprogramming. Mechanistically, Fn1, which was induced by the CCR2-Creb/Setdb1 axis, upregulated the expression of genes related to fibrosis in fibroblasts and macrophages via ITGA5 and PIRA receptors. Blocking the interaction between FN1 and these receptors inhibited fibrosis in allograft and tumor tissues. Our results reveal a target, histone methylation in macrophages, for the treatment of fibrosis-related disease.
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The Late Paleozoic Ice Age (~340 to 260 Ma) occurred under peak atmospheric O2(1.2 to 1.7 PIAL, pre-industrial atmospheric levels) for Earth history and CO2concentrations comparable to those of the preindustrial to that anticipated for our near future. The evolution of the marine redox landscape under these conditions remains largely unexplored, reflecting that oceanic anoxia has long been considered characteristic of carbon cycle perturbation during greenhouse times. Despite elevated O2, a 105-y period of CO2-forced oceanic anoxia was recently identified, but whether this short-term interval of widespread oceanic anoxia was anomalous during this paleo-ice age is unexplored. Here, we investigate these issues by building a high-resolution record of carbonate uranium isotopes (δ238Ucarb) from an open-marine succession in South China that permits us to reconstruct the global marine redox evolution through the deep glacial interval (310 to 290 Ma) of near peak O2. Our data reveal repeated, short-term decreases in δ238Ucarbcoincident with negative C isotopic excursions and rises in paleo-CO2, all superimposed on a longer-term rise in δ238Ucarb. A carbon–phosphorus–uranium biogeochemical model coupled with Bayesian inversion is employed to quantitatively explore the interplay between marine anoxia, carbon cycling, and climate evolution during this paleo-glacial period. Although our results indicate that protracted, enhanced organic carbon burial can account for the long-term O2increase, seafloor oxygenation, and overall low CO2, episodic pulses of C emissions had the potential to drive recurring short-term periods of marine anoxia (with 4 to 12% of seafloor anoxia) despite up to 1.7 times higher atmospheric O2than present day.
Inspired by Nature, we present a polypeptide-based organic redox-active material constructed from renewable feedstocks, L-glutamic acid (an amino acid) and riboflavin (vitamin B2), to address challenges with start-to-end-of-life management in energy storage systems (ESSs). The amino acid was utilized to establish a degradable polymer backbone, along which many copies of riboflavin were incorporated to serve as the redox-active pendant groups that enabled energy storage. The overall synthesis involved the ring-opening polymerization (ROP) of anl-glutamic acid-derivedN-carboxyanhydride (NCA) monomer, followed by side chain activation with azides and, finally, click coupling to achieve installation of alkyne-functionalized riboflavin moieties. The steric bulkiness and rich chemical functionality of riboflavin resulted in synthetic complexities that required reaction optimization to achieve the desired polymer structure. Electrochemical characterization of the resultant riboflavin polypeptide, in organic electrolyte, showed quasireversible redox activity with a half-wave potential (E1/2) ofca.−1.10 Vvs.ferrocene/ferrocenium (Fc/Fc+). Cell viability assays revealed biocompatibility, as indicated by negligible cytotoxicity for fibroblast cells. The polypeptide design, consisting of labile amide backbone linkages and side-chain ester functionalities that tethered the riboflavin units to the backbone, enabled hydrolytic degradation to recover building blocks for future upcycling or recycling. This bioinspired strategy advances the development of degradable redox-active polymers and promotes sustainable materials design for circular energy storage technologies.
Equine infectious anemia virus (EIAV) is an important model for the study of pathogenesis in lentiviruses. Studies of viral genome organization and replication mechanisms are fundamental to the understanding of virus pathogenicity. In this study, we identified an unique transcript from EIAV in vivo and in vitro by Sanger sequencing and Northern blotting. The transcript contains a complete open reading frame and has length 369 nt. We named the protein encoded by this transcript S4 and demonstrated its expression in EIAV-infected cells. An S4-deficient EIAV infectious clone displayed obviously impaired virion release and attenuated virus replication in vitro, demonstrating that S4 plays a role in the release step of EIAV. The host restriction factor tetherin has broad-spectrum antiviral activity and prevents the release of a wide range of enveloped viruses, including lentiviruses. Here, we demonstrated that S4 enhances the release of the EIAV-like particle by counteracting the equine tetherin (eqTHN). S4 interacts with the eqTHN and sequesters it within intracellular membrane compartments, attenuating eqTHN expression on the cell surface and thereby disrupting its antiviral activity. Further investigation revealed that S4 retains eqTHN in the endoplasmic reticulum and trans-Golgi network through impacting its anterograde transport to the cell surface and may interfere with the posttranslational modification of this membrane protein. Collectively, our findings uncover an accessory protein, S4, of EIAV and reveal its ability to promote virion release by antagonizing the antiviral activity of the host restriction factor tetherin.
Scholars have long been concerned about gender representation in scientific research but there has been little work on gender differences in participation and performance in climate science, a field that engages with both male-majority disciplines (e.g., geosciences, engineering) and female-majority disciplines (e.g., life sciences, medical science). This has implications for both gender equity and viewpoint representation. Sampling over 400,000 publications and a similar number of authors, we examine gender differences in several scholarly outcomes including publication count, career survival, coauthor gender, journal status, and mean citation count. We find men and women are similarly productive, successful, and connected, though women have shorter research careers and thus fewer papers. We also find gender homophily effects in collaboration, but no evidence of gender bias in peer review.
Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
Freshwater resources are fundamental to supporting humanity, and measures of water scarcity have been critical for identifying where water requirements and water availability are imbalanced. Existing water scarcity metrics typically account for blue water withdrawals (i.e., from surface-/groundwater), while the contribution of green water (i.e., soil moisture) and water quality—dimensions with important implications for multiple societal sectors—to water scarcity remains unclear. Here, we introduce the concept of multidimensional water scarcity that explicitly assesses all three of these dimensions of water scarcity and evaluates their individual and combined effects. We find that 22 to 26% of the global land area and 58 to 64% of the global population are exposed to some form of water scarcity annually, with multidimensional (i.e., blue, green, and quality) water scarcity particularly high in India, China, and Pakistan. Examining seasonal water scarcity, we estimate that 5.9 billion people (or 80% of the world’s population in 2015) were exposed to at least one dimension of water scarcity for at least 1 mo per year and that 1-in-10 people (10%) were exposed to multidimensional water scarcity at least 1 mo per year. Our findings demonstrate that the challenges of water scarcity are far more widespread than previously understood. As such, our assessment provides a more holistic view of global water scarcity issues and points to overlooked scarcity where action needs to bring human pressure on freshwater resources into balance with water quantity and quality.
The Qinghai–Tibet Plateau (QTP) harbors extraordinarily high levels of biodiversity and endemism. The region is warming at a rate twice the global average, yet the evolutionary dynamics of its unique biota are poorly understood. Here, we used the endemic land plant genera of the QTP to investigate how its floristic endemism was shaped over time by Cenozoic geoclimatic changes. We first clarified that the QTP hosts 82 endemic land plant genera; we found that the origins of these endemic genera were most likely driven by ecological niche and elevation differentiation, caused by the uplift of the QTP and associated climate change. By sampling 37 land plant clades that together encompass 1,740 species, covering all 82 endemic genera, we show that QTP floristic endemism had emerged by the Early Eocene. Furthermore, the unique biodiversity of the QTP comprises a mix of indigenous elements and immigrants. Among the three subregions of the QTP (Plateau Platform, Himalaya, and the Hengduan Mountains), the processes associated with floristic endemism are asynchronous, reflecting different geoclimatic events with the Miocene as a particularly critical period. The relative contributions of in situ speciation and immigration to the unique biodiversity of the three subregions are also markedly different; in situ speciation dominated in the Hengduan Mountains, which hosts the oldest endemic components of the flora and has served as an important “pump” and “sink” of unique biodiversity. These findings provide insights into how past geoclimatic events may have shaped floristic endemism on the QTP and also have important conservation implications.
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Indirect reciprocity is a compelling explanation for stable cooperation in a large society: Those who cooperate appropriately earn a good standing, so that others are more likely to cooperate with them. However, this mechanism requires a population to agree on who has good standing and who has bad standing. Consensus can be provided by a central institution that monitors and broadcasts reputations. But how might such an institution be maintained, and how can a population ensure that it is effective and incorruptible? Here, we explore a simple mechanism to sustain an institution for judging reputations: a tax collected from each member of the population. We analyze the possible tax rate that individuals will rationally pay to sustain an institution of judgment, which provides a public good in the form of information, and we derive necessary conditions for individuals to resist the temptation to evade their tax payment. We also consider the possibility that institution members may be corrupt and subject to bribery, and we analyze how strong the incentives against corruption need to be. Our analysis has implications for establishing robust public institutions that provide social information to support cooperation in large populations—and the potential negative consequences associated with wealth or income inequality.
Cyclin F, a noncanonical member of the cyclin protein family, plays a critical role in regulating transitions in the cell division cycle. Unlike canonical cyclins, which bind and activate cyclin-dependent kinases (CDKs), Cyclin F functions as a substrate receptor protein within the Skp1–Cullin-F-box E3 ubiquitin ligase complex, enabling the ubiquitylation of target proteins. The structural features that distinguish Cyclin F as a ligase adaptor and the mechanisms underlying its selective substrate recruitment over Cyclin A, which functions in complex with CDK2 at a similar time in the cell cycle, remain largely unexplored. We utilized single-particle cryoelectron microscopy to elucidate the structure of a Cyclin F–Skp1 complex bound to an E2F1 peptide. The structure and biochemical analysis reveal important differences in the substrate-binding site of Cyclin F compared to Cyclin A. Our findings expand on the canonical cyclin-binding motif (Cy or RxL) and highlight the importance of electrostatics at the E2F1 binding interface, which varies between Cyclin F and Cyclin A. These results advance our understanding of E2F1 regulation and may inform strategies for selectively targeting Cyclin F in cancer or neurodegeneration.
Thiamine (vitamin B1) deficiency in marine systems is a globally significant threat to marine life. In 2020, newly hatched Chinook salmon (Oncorhynchus tshawytscha) fry in California’s Central Valley (CCV) hatcheries swam in corkscrew patterns and died at unusually high rates due to a lack of this essential vitamin. We subsequently investigated the impacts and causes of thiamine deficiency in California’s anadromous salmonids. Our laboratory studies defined the relationship between thiamine concentrations in Chinook salmon eggs and early life-stage survival in offspring; we used these data to develop a model that estimated 26 to 48% thiamine-dependent fry mortality across consecutive years (2020–2021) for winter-run Chinook salmon. We established an egg surveillance effort that found widespread thiamine deficiency in CCV Chinook salmon in 2020 and 2021, and emerging thiamine deficiency in Klamath River and Trinity River coho salmon (Oncorhynchus kisutch) in 2021. We determined that thiamine injections into adults raised egg thiamine concentrations above levels found to impact early life-stage survival and swimming behavior. Ocean surveys, prey nutrition, salmon gut contents, and stable isotope data link thiamine deficiency to an ocean diet dominated by a booming population of northern anchovy (Engraulis mordax). This forage fish had low thiamine, high lipid, and high thiaminase activity levels consistent with both a thiaminase and oxidative stress hypothesis for causing thiamine deficiency in California salmon. Our research suggests California’s already stressed anadromous salmonids will continue to be impacted by thiamine deficiency as long as their ocean forage base and diet are dominated by northern anchovy.
Salt marshes provide valuable ecosystem services but are vulnerable to drowning with accelerated sea-level rise (SLR). Marsh belowground biomass (BGB) production helps avoid drowning by building marsh surface elevation. Reductions in BGB can serve as an early warning sign of marsh deterioration, as they often precede decreases in aboveground biomass (AGB). However, landscape-scale BGB assessments to predict broad trends in marsh deterioration have not been previously available. We applied the Belowground Ecosystem Resiliency Model (BERM) to assess standing stocks and trends in both BGB and AGB over the past decade (2014–2023) across US Georgia coastSpartina alternifloramarshes (691 km2). Over this time period, BGB and AGB averaged 841 ± 323 and 221 ± 14 g m−2, respectively, but showed opposite trends. BGB decreased on average by 0.94% per year and over most of the marsh area (72%), while AGB increased on average by 0.66% per year and showed a net increase across most of the marsh area (88%). This disconnect suggests that AGB is not a good indicator of marsh resilience, and we highlight two areas with similar AGB but different BGB. Inundation intensity, an important predictor of BGB, rose through time and was negatively related to BGB. SLR trends suggest continuing increases in inundation, which will result in further declines in BGB followed by widespread marsh drowning. Landscape BGB assessments are a valuable tool to identify ecosystem vulnerability and proactively manage salt marshes and the services they provide under rising sea levels.
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Fire is a pivotal aspect of human involvement in the carbon cycle. However, the precise timing of the large-scale human fire use remains uncertain. Here, we report a pyrogenic carbon record of East Asian fire history over the past 300,000 y from the East China Sea. This record suggests a rapid increase in fire activity since approximately 50,000 y ago, indicating a decoupling from the monsoon climate, and this pattern is consistent with fire histories in Europe, Southeast Asia, and Papua New Guinea-Australia regions. By integrating extensive archaeological data, we propose that the intensified global expansion of modern human and population growth, coupled with the rising demand for fire use during cold glacial periods, resulted in a significant increase in fire utilization from 50,000 y onward. This suggests that a measurable human imprint on the carbon cycle via fire likely predates the Last Glacial Maximum.
Each new mammalian life begins with the fusion of an oocyte and a sperm to produce a fertilized egg containing two sets of genomes, one from the mother and one from the father. Androgenesis, a way for producing offspring solely from male genetic material, is limited in mammals, presumably due to barriers arising from genomic imprinting, an epigenetic mechanism leading to monoallelic gene expression. Here, we report adult mammalian offspring derived from the genetic material of two sperm cells. These mice, which we refer to as androgenetic mice, were produced via targeted DNA methylation editing of seven imprinting control regions (ICRs) through CRISPR-based epigenome engineering. Two sperm cells were injected into an enucleated oocyte to form putatively diploid embryos. Allele-specific epigenetic editing was achieved by injecting guide RNAs with protospacer adjacent motif (PAM) sequences designed to match one allele but not the other. The birth of androgenetic mice that were able to develop to adulthood demonstrates that mammalian androgenesis is achievable by targeted epigenetic remodeling of a few defined ICRs.
Tree species worldwide face increasing exposure to unprecedented macroclimatic conditions due to anthropogenic climate change, which may trigger biome shifts and ecosystem disruptions. We quantified climate change exposure–shifts to species’ currently unoccupied climate zones–for 32,089 tree species globally by 2100, assessing both species-level and local tree diversity risks. On average, 69% of species are predicted to experience macroclimatic shifts in at least 10% of their range, while 14% face exposure in over 50% of their range under a high-emission (4 °C warming) future scenario. This suggests that most species retain substantial climate refugia within their current range. However, local tree diversity exposure is predicted to be severe in vast regions, including Eurasia, the northwestern United States and Canada, northern Chile, and the Amazon Delta. Under a moderate (2 °C warming) scenario, high tree diversity exposure is mostly restricted to taiga regions in the Northern Hemisphere. These findings provide conservative estimates of climate-driven biodiversity risk, as our approach focuses solely on macroclimate and does not account for additional stressors such as land-use change or species interactions. Identifying tree species and areas of high macroclimatic shift exposure allows for targeted conservation strategies, including species stability monitoring, assisted migration, and the protection of climate refugia. Our results offer a foundation for prioritizing conservation actions in a rapidly changing climate, ensuring long-term ecosystem resilience.
TheHTLV-1 bZIP factor(HBZ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia–lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1–infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1–infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-β activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-β stimulation.JUNBknockdown inhibits cell proliferation in vitro and in vivo and promotes apoptosis in ATL cells but not in HTLV-1–infected nonleukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-β-induced nuclear translocation of HBZ–JunB complexes is associated with ATL oncogenesis.
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A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA—leaked from mitochondria or nuclei during infection—remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid–sensing pathways.
Estrogen receptor β (ERβ) plays an important role in both the mouse and human prostate. The endogenous ligand for ERβ is the dihydrotestosterone metabolite, 5β-androstane-3β, 17β-diol (3β-Adiol). Thus, treatment with 5-α reductase inhibitor (5-ARI) should produce a phenotype similar to that seen in ERβ−/−mice. By comparing RNA-Seq of the ventral prostates (VP) of ERβ knockout mice (ERβcrispr−/−) and wild-type (WT) mice, we confirmed that ERβ modulates androgen receptor (AR) signaling indirectly by suppressing AR coactivators. Compared to WT mice, basal cell genes from ERβcrispr−/−mouse VP were significantly upregulated. A population of abnormal basal cells coexpressing P63 and AR was identified in the ERβcrispr−/−mouse VP by immunohistochemistry. In men treated with 5-ARI for treatment of benign prostatic hyperplasia (BPH), there was induction of a P63-positive intermediate cell population characterized by down regulation of Krt14 without significant change in the expression of Krt15, upregulation of AR and NKX3.1, and increased proliferation. In both VP of aging ERβcrispr−/−mice and in human prostates after 5-ARI treatment, there was substantial immune infiltration. Testosterone treatment inhibited immune infiltration in the VP of ERβcrispr−/−mice. We conclude that ERβ is a gene critical in maintaining normal basal cells and modulating immune environment in the prostate. Its loss leads to histological changes suggesting prostatitis and increases the number of intermediate cells, which are considered to be the cells of origin of prostate cancers. We suggest that an ERβ agonist could protect against 5-ARI-induced inflammatory cell infiltration and defects in the basal cell layer in BPH.
Motivated by recent data pointing to the existence of homo-oligomeric assemblies of membrane proteins called higher-order transient structures, and their apparent role in connecting components of membrane signal pathways, we examine here by cryoelectron microscopy some of the protein–protein interactions that occur in cluster formation. Metabotropic glutamate receptors and HCN ion channels inside clusters contact their neighbors through structured extracellular and intracellular domains, respectively. Other ion channels, including Kv2.1 and Slo1, appear to form clusters through prominent intrinsically disordered sequences in the cytoplasm. These distinct modes of interaction are associated with clusters exhibiting varying degrees of compactness and order. We conclude that nature utilizes a variety of ways to form connections between membrane proteins in self-assembled clusters.
Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we demonstrate a role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings reveal that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.
Recently, extensive evidence has demonstrated that the brain operates close to a critical state, characterized by dynamic patterns known as neuronal avalanches. The critical state, reflecting the delicate balance between neural excitation and inhibition, offers numerous advantages in information processing. However, the role of genetics in shaping brain criticality is not fully understood. Whether there is any shared genetic factor influencing the critical state and cognitive functions remains elusive. Here, we aimed to address these questions by examining the heritability of brain criticality and its relation to cognitive function by analyzing resting-state functional magnetic resonance imaging (rs-fMRI) in 250 monozygotic twins, 142 dizygotic twins, and 437 Not-twin subjects. We found that genetic factors substantially influenced brain criticality across various scales, encompassing brain regions, functional networks, and the whole brain. These genetic influences exhibited heterogeneity, with the criticality of the primary sensory cortex being more strongly influenced by genetic factors compared to that of the association cortex. Furthermore, we combined rs-fMRI data with transcriptional microarray data from the Allen Brain Atlas: Human Brain (ABHB) dataset and found that the organization of regional critical dynamics was highly explained by a specific gene expression profile. Finally, our results showed that the critical state was correlated with total cognition and had a genetic link with it. These findings provide empirical evidence that brain criticality is a biological phenotype and suggest a shared genetic foundation underlying brain criticality and cognitive functions. Our results pave the way toward revealing specific biological mechanisms contributing to critical dynamics and their associations with brain function and dysfunction.
The mutual antagonistic signaling of abscisic acid (ABA) and ROP GTPases highlights an intersection between stress responses and pattern formation. Previously, we have shown that signaling of ABA in the endodermis leads to protoxylem (PX) differentiation. In this study, we demonstrate that ROPs suppress PX differentiation in the roots of bothArabidopsisand tomato. Fourier transform and Shannon’s entropy show that endodermal ABA signaling controls the periodicity and overall order of PX secondary cell wall (SCW) coils in an ROP-dependent manner. Correspondingly, in the PX, GFP-ROP11 is initially dispersed and gradually becomes distributed in an oscillatory fashion with a periodicity corresponding to that of the SCW coils. Oryzalin treatments disrupt the frequency and increase the entropy of the GFP-ROP11 signal, suggesting that microtubules delimit ROP distribution. Signaling of ABA in the endodermis encourages the enlargement of metaxylem SCW pits, while ABA signaling in the stele limits this enlargement. Pit size and density are decreased in ROP mutants while ABA enhances ROP11 expression in the stele and broadens its distribution in the endodermis. Taken together, non-cell-autonomous and cell-autonomous interactions between ABA and ROPs regulate xylem differentiation and SCW patterning.
Gastrointestinal (GI) neuroimmune interactions are crucial sensors and regulators of tissue homeostasis. Most enteric neurons reside within the myenteric plexus of the enteric nervous system in the muscular region, forming a structure called themuscularis externa. Despite established interactions between muscularis macrophages and neurons, the presence and function of other immune cell types remains poorly characterized. Here, we mapped the muscularis immune cell landscape, revealing that diverse cell types are present within distinct locations of the GI tract, and they lie in proximity to neuronal cell bodies and their axons. Using a hypothesis-free computational approach, we identify putative ligand–receptor interactions from publicly available single-cell RNA datasets and further validate one of these (App-CD74). This study provides a valuable reference to encourage new avenues of research underpinning enteric neuroimmune interactions as key contributors to GI homeostasis and diseases.
Climate change pushes species toward higher latitudes and altitudes, but the proximate drivers of range expansions vary, and it is unclear whether evolution facilitates climate change–induced range changes. In a temporally replicated field experiment, we translocated wall brown butterflies (Lasiommata megera) descending from range interior and range margin populations to sites at 1) the range interior, 2) the range margin, and 3) beyond the current northern range edge. Thereby, we tested for local adaptation in seasonal timing and winter survival and evaluated to what extent local adaptation influences the ongoing, climate-driven range expansion. Almost all individuals from all populations entered diapause at an appropriate time, despite previously identified among-population variation in diapause induction thresholds. Caterpillars of northern descent, however, grew faster than those from southern populations at all field sites. This may be a countergradient adaptation to compensate for the short, northern growing seasons, but we found no evidence for prewinter body mass affecting winter survival. In fact, winter survival was low overall—extremely so at the beyond range site—regardless of population origin, indicating that the primary constraint to range expansion is an inability to adapt to winter conditions. Hence, although range-expanding wall browns show clear local evolution of two traits related to seasonal timing, these putative local adaptations likely do not contribute to range expansion, which is instead limited by winter survival. To predict future range changes, it will be important to distinguish between the traits that evolve during range expansion and those that set the range limit.
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Neisseria meningitidisis a human commensal bacterium that can opportunistically invade the bloodstream and cross the blood–brain barrier, where it can cause septicemia and meningitis. These diseases, if left untreated, can be lethal within hours. HyperinvasiveN. meningitidisstrains often express a genomically encoded filamentous bacteriophage called MDAΦ, which promotes colonization of mucosal host surfaces to facilitate bacterial invasion. How this phage is organized and how it promotes biofilm formation and infection at the molecular level is unclear. Here, we present an electron cryomicroscopy structure of the MDA phage, showing that MDAΦ is a class I filamentous inovirus, with the major capsid protein (MCP) arranged within the phage as a highly curved and densely packed α-helix. Comparison with other filamentous bacteriophages offers clues about inoviral genome encapsidation mechanisms, providing a framework for understanding the evolutionary diversity of inoviruses. A disordered, N-terminal segment in the MCP presents hydrophobic patches on the surface of assembled phage particles, which, together with electron cryotomography data of phage bundles, furnishes a structural rationale for phage–phage interactions that were seen previously in an epithelium adhesion infection model ofN. meningitidis. Taken together, our results shed light on the structure, organization, and higher-order assembly of a biomedically relevant phage encoded in the genome of a human pathogen. Molecular insights gleaned from this study increase our understanding of phage evolution, phage-mediated bacterial adhesion, and pathogenicity.
It is increasingly recognized that participation bias can pose problems for genetic studies. Recently, to overcome the challenge that genetic information of nonparticipants is unavailable, it is shown that by comparing the IBD (identity by descent) shared and not-shared segments between participating relative pairs, one can estimate the genetic component underlying participation. That, however, does not directly address how to adjust estimates of heritability and genetic correlation for phenotypes correlated with participation. Here, we demonstrate a way to do so by adopting a statistical framework that separates the genetic and nongenetic correlations between participation and these phenotypes. Crucially, our method avoids making the assumption that the effect of the genetic component underlying participation is manifested entirely through these other phenotypes. Applying the method to 12 UK Biobank phenotypes, we found eight that have significant genetic correlations with participation, including body mass index, educational attainment, and smoking status. For most of these phenotypes, without adjustments, estimates of heritability and the absolute value of genetic correlation would have underestimation biases.
Water molecules at the solid–liquid interface display intricate behaviors sensitive to small changes. The presence of different interfacial components, such as cations or functional groups, shapes the physical and chemical properties of the hydrogen-bond network. Understanding such interfacial hydrogen-bond networks is essential for a large range of applications and scientific questions. To probe the interfacial hydrogen-bond network, atmospheric water capture is a powerful tool. Here, we experimentally observe that a calcium ion on a calcium-intercalated graphene oxide aerogel (Ca-GOA) surface captures 3.2 times more water molecules than in its freestanding state. From experimental Van’t Hoff estimation and density functional theory (DFT) calculations, we uncover the synergistically enhanced hydrogen-bond network of the calcium ion–epoxide complex due to significantly larger polarizations and hydrogen bond enthalpies. This study reveals valuable insights into the interfacial water hydrogen-bond network on functionalized carbon–cation complexed surfaces and potential pathways for future atmospheric water generation technologies.
The gut microbiome has emerged as a key factor influencing a wide range of host physiological processes and behaviors, though the mechanisms behind these effects remain only partially understood. In this study, we explored the role of the gut microbiome in memory regulation using a parasitoid wasp-induced oviposition depression paradigm inDrosophila melanogaster. Our findings show that flies with depleted gut microbiota, either through axenic culture or antibiotic treatment, exhibited significant memory impairments. However, reintroducing the commensal bacteriumLactobacillus plantarumalone was sufficient to restore memory, while coinoculation withAcetobacter pomorumfurther enhanced memory performance. Hemolymph metabolomic analyses revealed reduced amino acid levels in antibiotic-treated flies, which were linked to impairedDrosophilatarget of rapamycin (dTOR) signaling. Additionally, genetic manipulation of dTOR or dietary supplementation with branched-chain amino acids either mimicked or rescued the memory deficits caused by antibiotic treatments. These results suggest that the gut microbiome is essential for regulating memory function by maintaining amino acid homeostasis and proper dTOR signaling, with profound implications for advancing knowledge of cognitive regulation.
The vertical transport of solid material in a stratified medium is fundamental to a number of environmental applications, with implications for the carbon cycle and nutrient transport in marine ecosystems. In this work, we study the diffusion-limited settling of highly porous particles in a density-stratified fluid through a combination of experiment, analysis, and numerical simulation. By delineating and appealing to the diffusion-limited regime wherein buoyancy effects due to mass adaptation dominate hydrodynamic drag, we derive a simple expression for the steady settling velocity of a sphere as a function of the density, size, and diffusivity of the solid, as well as the density gradient of the background fluid. In this regime, smaller particles settle faster, in contrast with most conventional hydrodynamic drag mechanisms. Furthermore, we outline a general mathematical framework for computing the steady settling speed of a body of arbitrary shape in this regime and compute exact results for the case of general ellipsoids. Using hydrogels as a highly porous model system, we validate the predictions with laboratory experiments in linear stratification for a wide range of parameters. Last, we show how the predictions can be applied to arbitrary slowly varying background density profiles and demonstrate how a measured particle position over time can be used to reconstruct the background density profile.
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As large language models (LLMs) become more widely used, people increasingly rely on them to make or advise on moral decisions. Some researchers even propose using LLMs as participants in psychology experiments. It is, therefore, important to understand how well LLMs make moral decisions and how they compare to humans. We investigated these questions by asking a range of LLMs to emulate or advise on people’s decisions in realistic moral dilemmas. In Study 1, we compared LLM responses to those of a representative U.S. sample (N= 285) for 22 dilemmas, including both collective action problems that pitted self-interest against the greater good, and moral dilemmas that pitted utilitarian cost–benefit reasoning against deontological rules. In collective action problems, LLMs were more altruistic than participants. In moral dilemmas, LLMs exhibited stronger omission bias than participants: They usually endorsed inaction over action. In Study 2 (N= 474, preregistered), we replicated this omission bias and documented an additional bias: Unlike humans, most LLMs were biased toward answering “no” in moral dilemmas, thus flipping their decision/advice depending on how the question is worded. In Study 3 (N= 491, preregistered), we replicated these biases in LLMs using everyday moral dilemmas adapted from forum posts on Reddit. In Study 4, we investigated the sources of these biases by comparing models with and without fine-tuning, showing that they likely arise from fine-tuning models for chatbot applications. Our findings suggest that uncritical reliance on LLMs’ moral decisions and advice could amplify human biases and introduce potentially problematic biases.
AI is increasingly replacing human decision-makers across domains. AI-based tools have become particularly common in assessment decisions, such as when recruiting employees or admitting students. Calls for transparency and new legislation require organizations to disclose the use of AI assessment tools, thus making people under assessment aware of its use. We investigate whether this shift from human to AI assessment affects people’s behavior during the assessment. We propose that people emphasize their analytical characteristics and downplay their intuitive and emotional ones under AI (vs. human) assessment, a phenomenon we label “the AI assessment effect.” Twelve studies (eight in text and four in the Supporting Information;N= 13,342) document the AI assessment effect and its underlying mechanism: the lay belief that AI prioritizes analytical characteristics in its assessment. Whereas prior work has studied perceptions of AI assessment tools and their productivity gains, the current research demonstrates systematic behavioral changes because of AI assessment. The findings offer theoretical contributions to the psychology of AI and practical insights for organizations using AI assessment.
Determining how people behave in contexts governed by social norms can clarify both how norms influence human behavior and how norms evolve. We examined cooperative farming harvest division among the Derung, a Tibeto-Burman-speaking horticultural society in southwestern China. In the village of Dizhengdang, the norm dictates that cofarming harvests should be divided equally among participating households. This contrasts with an alternative norm followed in some other Derung villages that holds that harvests should be divided equally among participating laborers. Rational choice theory and evolutionary models of norm-based cooperation assume that individuals weigh the material and social payoffs of different actions and follow norms because doing so maximizes their payoff. However, the behavior of the Derung in Dizhengdang is not consistent with payoff maximization. Using interviews on co-farming behaviors and attitudes, along with an ultimatum game experiment framed as co-farming harvest division, we found that most respondents preferred divisions based on labor contribution. They also accurately guessed that others shared this preference and would approve of such divisions. Nonetheless, they still followed the prevailing norm of dividing by household. Their self-reported explanation for this behavior was that they desired to follow their traditional practices. Such a normative decision-making algorithm can allow individually consequential norms to persist without costly policing by other group members.
Despite over a century of studies, fundamental questions remain about the processes governing crystal nucleation from melts or solutions. Research over the past three decades has presented mounting evidence for kinetic pathways of crystal nucleation that are more complex than envisioned by the simplest forms of classical theory. Such observations have been presented for colloidal and elemental systems with covalent and metallic bonding. Despite the technological and geochemical importance of molten salts, similar studies for these ionically bonded systems are currently lacking. Here we develop a machine learning interatomic potential for a model ionic system: LiF. The potential features quantum-level accuracy for both liquid and multiple solid polymorphs over wide temperature and pressure ranges and accurately reproduces experimentally measured properties. Thanks to the efficiency of the potential, which enables microsecond-scale molecular dynamics simulations, induction times for nucleation of LiF solids from their melts are computed over a range of undercoolings. With the aid of a set of robust local order parameters established here, the simulations reveal that homogeneous crystal nucleation in undercooled melts preferentially initiates from liquid regions showing slow dynamics and high bond orientational order simultaneously, and the second-shell order of both precritical nuclei and the surface of postcritical nuclei is dominated by hexagonal close packing and body-centered cubic local structure, even though the nucleus core is dominated by face-centered cubic structure corresponding to the stable rocksalt crystal structure. Finally, we establish a connection between the crystallization pathway and the equilibrium crystal–melt interface structure.
We investigate the hypothesis that family resemblance on school performance can be fully explained by additive genetic effects and assortative mating. Our sample consists of all schoolchildren who took Norwegian national standardized tests between 2007 and 2019 (N = 936,708). These tests measure aptitude in math and reading comprehension, and are taken the years children turn 10, 13, and 14 y old. We identify millions of pairs of relatives within our sample (82 different kinds, in total), including not only conventional biological relatives such as siblings and cousins, but also relatives-in-law, relatives through adoption, twins, and relatives connected through twins. When fitting models which assume that family resemblance arises solely from additive genetic effects and assortative mating, we find that they describe much of our data well, but that they systematically underestimate the similarity of close relatives (particularly monozygotic twins), maternal relatives, relatives-in-law, and relatives through adoption. We discuss potential explanations for these deviations, including shared-environmental effects, nonadditive genetic effects, and gene–environment interplay.
Negative feedback of the cochlear efferent system plays a critical role in control of hearing sensitivity and protection from noise trauma. Type II auditory nerves (ANs) innervate outer hair cells (OHCs) in the cochlea and provide an input to the cochlear efferent system to achieve hearing sensitivity controlling and protection; in particular, medial olivocochlear efferent nerves innervate OHCs to control OHC electromotility, which is an active cochlear amplifier in mammals. However, little is known about channel information underlying type II AN activity and consequent function. Here, we report that ATP-gated P2x7 receptor had a predominant expression at type II spiral ganglion (SG) neurons and the synaptic areas under inner hair cells and OHCs with lateral and medial olivocochlear efferent nerves. Knockout (KO) of P2x7 increased hearing sensitivity with enhanced acoustic startle response, auditory brainstem response, and cochlear microphonics by increasing OHC electromotility. P2x7 KO also increased susceptibility to noise and exacerbated ribbon synapse degeneration. Middle-level noise exposure could impair active cochlear mechanics resulting in hearing loss in P2x7 KO mice. These data demonstrate that P2x7 receptors have a critical role in type II SG neuron’s function and the cochlear efferent system to control hearing sensitivity; deficiency of P2x7 receptors can impair type II SG neuron’s function and the cochlear efferent suppression leading to increase of active cochlear amplification and hearing oversensitivity, i.e., hyperacusis, and susceptibility to noise, which may also associate with other hearing disorders, such as tinnitus.
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The thymus is one of the most important organs of the immune system. It is responsible for both the production of T cells and the prevention of their autoimmunity. It comprises two types of tissue: The cortex, where nascent T cells (thymocytes) are generated; and the medulla, embedded within the cortex, where autoreactive thymocytes are eliminated through negative selection. In mice, the medulla exhibits a complex, convoluted morphology, which has raised the question of whether its form impacts its function. Intriguingly, experiments also reveal a reverse dependency: The interactions between medullary stroma and thymocytes shape the medullary structure. However, an understanding of the underlying mechanisms of medulla morphogenesis emerging from these interactions remains elusive. Here, we present a conceptual theoretical model showing that central, experimentally verified signaling pathways suffice to shape the convoluted medullary structure. The mathematical analysis of the model explains the observed effects of chemotaxis on thymocyte localization, and the reported morphological changes resulting from the modulation of thymocyte production. Our findings reveal that the cross-talk between medulla growth and negative selection of thymocytes not only regulates medullary volume but also orchestrates the morphology of the thymus medulla. This mechanism of structure formation robustly organizes the medulla in a way that accelerates thymocyte negative selection by improving their chemotactic migration into the medulla. Thereby, we identify a feedback between the function of the thymus medulla and its form. Our theoretical study motivates further experimental analysis of the spatial distribution of thymic cell populations and predicts morphological changes under genetic perturbations.
Computational theories of reinforcement learning suggest that two families of algorithm—model-based and model-free—tightly map onto the classic distinction between automatic and deliberate systems of control: Deliberate evaluative responses are thought to reflect model-based algorithms, which are accurate but computationally expensive, whereas automatic evaluative responses are thought to reflect model-free algorithms, which are error-prone but computationally cheap. This framework has animated research on psychological phenomena ranging from habit formation to social learning, moral decision-making, and cognitive development. Here, we propose that model-based and model-free algorithms may not be as aligned with deliberate and automatic evaluative processing as prevailing theories suggest. Across three preregistered behavioral experiments involving adult human participants (totaln= 2,572), we show that model-based algorithms shape not only deliberate but also automatic evaluations. Experiment 1 numerically replicates past findings suggesting that deliberate (but not automatic) evaluative responses are uniquely shaped by model-based algorithms but, critically, also reveals confounds that render interpretation of this evidence equivocal. Experiments 2 to 3 eliminate these confounds and reveal robust model-based contributions to automatic evaluative processing across two measures of automatic evaluation, supported by multinomial processing tree modeling. Together, these results suggest that dominant frameworks may considerably underestimate both the ubiquity of model-based algorithms and the computational sophistication of automatic evaluative processing.
Using machine learning (ML) to construct interatomic interactions and thus potential energy surface (PES) has become a common strategy for materials design and simulations. However, those current models of machine-learning interatomic potential (MLIP) consider no relevant physical constraints or global scaling and thus may owe intrinsic out-of-domain difficulty which underlies the challenges of model generalizability and physical scalability. Here, by incorporating the global universal scaling law, we develop an ultrasmall parameterized MLIP with superlinear expressive capability, named SUS2-MLIP. Due to the global scaling derived from the universal equation of state (UEOS), SUS2-MLIP not only has significantly reduced parameters by decoupling the element space from coordinate space but also naturally outcomes the out-of-domain difficulty and endows the model with inherent generalizability and scalability even with relatively small training dataset. The non-linearity-embedding transformation in radial function endows the model with superlinear expressive capability. SUS2-MLIP outperforms the state-of-the-art MLIP models with its exceptional computational efficiency, especially for multiple-element materials and physical scalability in property prediction. This work not only presents a highly efficient universal MLIP model but also sheds light on incorporating physical constraints into AI–aided materials simulation.
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A charge density wave (CDW) is a phase of matter characterized by a periodic modulation of valence electron density coupled with lattice distortion. Its formation is closely tied to the dynamical charge susceptibility,χ(q,ω), which reflects the collective electron dynamics of the material. Despite decades of study,χ(q,ω)near a CDW transition has never been measured at nonzero momentum,q, with meV energy resolution. Here, we investigate the canonical CDW transition in ErTe3using momentum-resolved electron energy loss spectroscopy, a technique uniquely sensitive to valence band charge excitations. Unlike phonons, which soften via the Kohn anomaly, we find the electronic excitations exhibit purely relaxational dynamics well described by a diffusive model, with the diffusivity peaking just below the critical temperature,TC1. Additionally, we report for the first time a divergence in the real part ofχ(q,ω)in the static limit (ω→0), a long-predicted hallmark of CDWs. Unexpectedly, this divergence occurs asT→0, with only a weak thermodynamic signature atT=TC1. Our study necessitates a reexamination of the traditional description of CDW formation in quantum materials.
Protein structure–function relationships are critical for understanding molecular mechanisms and the impacts of genetic variation. Mutational scanning approaches can deliver scalable analysis, usually through the study of loss-of-function variants. Rarer dominant negative and gain-of-function variants can be more information rich, as they retain a stable proteoform and can be used to dissect molecular function while retaining biological context. Dominant variant proteoforms can still engage substrates and interact with binding partners. Here, we probe the structure–function relationships of the Mus81 endonuclease by ectopic expression of deep mutational scanning libraries to find amino acid variants that confer dominant sensitivity to genotoxic stress and dominant synthetic lethality. Screening more than 2,200MUS81variants at 100 positions identified 13 amino acids that can be altered to elicit a dominant phenotype. The dominant phenotype of these variants required the presence of the obligate Mus81 binding protein, Mms4. The dominant variants affect amino acids in a contiguous surface on Mus81 and fall into two distinct classes: residues that bind the catalytic magnesium atoms and residues that form the hydrophobic wedge. Most of the variant amino acids were conserved across species and cognate variants expressed in human cell lines resulted in dominant sensitivity to replication stress and synthetic growth defects in cells lacking BLM helicase. The dominant variants in both yeast and humanMUS81resulted in phenotypes distinct from aMUS81knockout. These data demonstrate the utility of dominant genetics using ectopic expression of amino acid site saturation variant libraries to link function to protein structure providing insight into molecular mechanisms.
The surface layer or “S-layer” is a two-dimensional lattice of proteins that coats a wide range of archaea and bacteria in place of a cell wall or capsular polysaccharides. S-layers are thought to play an important role in chemically and physically insulating cells from the external environment. Here, we show that the integrity of the S-layer inSulfolobus acidocaldariusis maintained as cells grow via a process of self-assembly as SlaA monomers fill gaps in the lattice. Although this lattice which is physically tethered to the membrane might be expected to hinder cell division, we show that the S-layer flattens the membrane at cytokinesis to accelerate ESCRT-III-dependent cell division—and is important for robust, successful cell divisions under conditions of mechanical stress. Taken together, these results define the rules governing S-layer self-assembly and show how a flexible lattice coat that is coupled to the underlying membrane can both provide a cell with mechanical support and help to drive rapid and functionally important changes in cell shape.
Regional collectivism has been observed to contribute to better coping with public crises such as the COVID-19 pandemic. This study poses a reverse question: Does the eruption of public crises increase people’s conformity to the collective? To answer this question, we analyzed real-world transactions on Taobao (the largest e-commerce platform in China), each with a purchase decision and a list of candidates considered before purchasing. Conformity to the collective was measured using two indicators: whether the decision-maker opted for the A) most-sold and B) best-rated options within the candidate option set. The results reveal that both conformity variables were significantly higher in the 10 wk subsequent to January 19, 2020 (when the nationwide COVID-19 crisis erupted in China), than in the 8 wk prior. These shifts were common across subpopulations, regions, and product categories and remained significant after strictly matching across weeks and after using a within-person, longitudinal sample. These shifts were more confidently attributed to the pandemic by further conducting difference-in-differences analyses to compare pandemic-affected regions with their unaffected, comparable counterparts using data from six subsequent regional waves in China. Furthermore, regions with larger increases in conformity during the early stage of the pandemic achieved better antipandemic outcomes. These findings provide real-world evidence for previous theories on behavioral immune systems, terror management, and compensatory control. Additionally, cross-regional comparisons of effect sizes offer exploratory insights into cultural psychology. In summary, these findings capture how human societies dynamically adjust their values to better adapt to unanticipated survival challenges.
In Shannon’s seminal paper, the entropy of printed English, treated as a stationary stochastic process, was estimated to be roughly 1 bit per character. However, considered as a means of communication, language differs considerably from its printed form: i) the units of information are not characters or even words but clauses, i.e., shortest meaningful parts of speech; and ii) what is transmitted is principally the meaning of what is being said or written, while the precise phrasing that was used to communicate the meaning is typically ignored. In this study, we show that one can leverage recently developed large language models to quantify information communicated in meaningful narratives in terms of bits of meaning per clause.
Evolutionary adaptation to new environments likely results from a combination of selective sweeps and polygenic shifts, depending on the genetic architecture of traits under selection. While selective sweeps have been widely studied, polygenic responses are thought to be more prevalent but remain challenging to quantify. The infinitesimal model makes explicit the hypothesis about the dynamics of changes in allele frequencies under selection, where only allelic effect sizes, frequencies, linkage, and gametic disequilibrium matter. Departures from this, like long-range correlations of allele frequency changes, could be a signal of epistasis in polygenic response. We performed an Evolve & Resequence experiment inDrosophila melanogasterexposing flies to a high-sugar diet for over 100 generations. We tracked allele frequency changes in >3000 individually sequenced flies and population pools and searched for loci under selection by identifying sites with allele frequency trajectories that differentiated selection regimes consistently across replicates. We estimate that at least 4% of the genome was under positive selection, indicating a highly polygenic response. The response was dominated by small, consistent allele frequency changes, with few loci exhibiting large shifts. We then searched for signatures of selection on pairwise combinations of alleles in the new environment and found several strong signals of putative epistatic interactions across unlinked loci that were consistent across selected populations. Finally, we measured differentially expressed genes (DEGs) across treatments and show that DEGs are enriched for selected SNPs. Our results suggest that epistatic contributions to polygenic selective response are common and lead to detectable signatures.
The utility of a pure population of highly regenerative satellite stem cells (SSCs) is a prerequisite for successful cell-based muscle therapies. Previous works have reported several methods for the SSC isolation. However, the majority of cells isolated using previous methods are fibroblasts and other nonmyogenic cell types, necessitating further expensive and time-consuming purification steps often affecting the regenerative quality of the isolated SSCs. Here, we describe a simple, time-effective, and robust protocol for the isolation of a pure population of SSCs in a single direct step, eliminating the need for further purification steps. By separating the muscle fascicles from the adjacent connective tissues (i.e., epimysium and perimysium) and utilizing a defined dissociation medium, a cell pool enriched in SSCs was successfully obtained. Immunofluorescent staining confirmed the stemness and the myogenic purity of the isolated cells (~97%). Upon myogenic induction, SSCs gave rise to multinucleated myofibers that exhibited spontaneous contraction in the culture dish for up to 21 d. Efforts to optimize the culture conditions revealed that tissue culture plates (TCPs) coated with a tissue-specific extract significantly enhanced SSCs’ attachment, growth, and differentiation compared to collagen I, Matrigel-coated TCPs, or noncoated TCPs. Further studies confirmed the robust myogenic regenerative capacity of the isolated cells, as evidenced by their ability to display key regenerative characteristics, demonstrating the mild effects of our isolation protocol on their regenerative capacity. The isolation protocol presented herein can potentially be used to obtain SSCs with high myogenic purity for skeletal muscle regenerative engineering and clinical indications.
The freezing of droplets on surfaces is closely relevant with various industrial processes such as aviation, navigation, and transportation. Previous studies mainly focus on physiochemically heterogeneous but electrically homogeneous surfaces, on which the presence of vapor pressure gradient between droplets is the predominant mechanism for interdroplet freezing bridging, propagation, and eventual frosting across the entire surface. An interesting yet unanswered question is whether electrostatic charge on surfaces affects freezing dynamics. Here, we find an interdroplet freezing relay (IFR) phenomenon on electrically heterogeneous surfaces that exhibits a three-dimensional, in-air freezing propagation pathway and an accelerated freezing rate. Theoretical and experimental investigations demonstrate that this phenomenon originates from the presence of surface charge gradient established between the frozen droplet and neighboring water droplet, which leads to a spontaneous shooting of desublimated ice needles from the frozen droplet and then triggers the freezing of neighboring water droplet in in-air manner. We further demonstrate its generality across various dielectric substrates, liquids, and droplet configurations. Our work enriches conventional perspectives on droplet freezing dynamics and emphasizes the pivotal role of electrostatics in designing passive anti-icing and antifrosting materials.
Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of theMYCNoncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming in NB, including upregulation of antioxidant enzymes. Here, we identify peroxiredoxin 6 (PRDX6) as a promising therapeutic target in NB. Pharmacological inhibition of PRDX6 reduces MYCN levels, induces apoptosis, and promotes neuronal differentiation accompanied by lipid droplet accumulation, essential for the phenotypic reprogramming. Moreover, combined inhibition of PRDX6 and glutathione S-transferase Pi 1 (GSTP1), a key antioxidant enzyme needed for PRDX6 activation, demonstrated synergistic effects both in vitro and in vivo. This strategy results in neuronal maturation as well as activity and initiates downstream pathways distinct from the ones triggered by retinoic acid, the differentiation-inducing agent currently used in clinical practice for NB. Notably, bothPRDX6andGSTP1are highly expressed in the developing murine adrenal gland, as well as in high-risk,MYCN-amplified NB, correlating with an undifferentiated state and poor prognosis. Together, our results provide insights into the potential of PRDX6 and GSTP1 as therapeutic targets for differentiation induction for children with NB.
Protein–protein interactions (PPIs) are crucial for comprehending the molecular mechanisms and signaling pathways underlying diverse biological processes and disease progression. However, investigating PPIs involving membrane proteins is challenging due to the complexity and heterogeneity of glycosylation. To tackle this challenge, we developed an approach termed glycan-dependent affinity purification coupled with mass spectrometry (GAP–MS), specifically designed to characterize changes in glycoprotein PPIs under varying glycosylation conditions. GAP–MS integrates metabolic control of glycan profiles in cultured cells using small molecules referred to as glycan modifiers with affinity purification followed by mass spectrometry analysis (AP–MS). Here, GAP–MS was applied to characterize and compare the interaction networks under five different glycosylation states for four bait glycoproteins: BSG, CD44, EGFR, and SLC3A2. This analysis identified a network comprising 156 interactions, of which 131 were determined to be glycan dependent. Notably, the GAP–MS analysis of BSG provided distinct information regarding glycosylation-influenced interactions compared to the commonly used glycosylation site mutagenesis approach combined with AP–MS, emphasizing the unique advantages of GAP–MS. Collectively, GAP–MS presents distinct insights over existing methods in elucidating how specific glycosylation forms impact glycoprotein interactions. Additionally, the glycan-dependent interaction networks generated for these four glycoproteins serve as a valuable resource for guiding future functional investigations and therapeutic developments targeting the glycoproteins discussed in this study.
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Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive experience-dependent reciprocal antagonism that gates cortical feedback regulation of feedforward thalamic refinement.
The evolutionary histories of many polyploid plant species are difficult to resolve due to a complex interplay of hybridization, incomplete lineage sorting, and missing diploid progenitors. In the case of octoploid strawberry with four subgenomes designated ABCD, the identities of the diploid progenitors for subgenomes C and D have been subject to much debate. By integrating new sequencing data from North American diploids with reticulate phylogeny and admixture analyses, we uncovered introgression from an extinct or unsampled species in the clade ofFragaria viridis,Fragaria nipponica, andFragaria nilgerrensisinto the donor of subgenome A of octoploidFragariaprior to its divergence fromF. vescasubsp. bracteata. We also detected an introgression event fromF. iinumaeinto an ancestor ofF. nipponicaandF. nilgerrensis.Using an LTR-age-distribution-based approach, we estimate that the octoploid and its intermediate hexaploid and tetraploid ancestors emerged approximately 0.8, 2, and 3 million years ago, respectively. These results provide an explanation for previous reports ofF. viridisandF. nipponicaas donors of the C and D subgenomes and suggest a greater role than previously thought for homoploid hybridization in the diploid progenitors of octoploid strawberry. The integrated set of approaches used here can help advance polyploid genome analysis in other species where hybridization and incomplete lineage sorting obscure evolutionary relationships.
Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis.UBR4knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.
During vertebrate development, the heart primarily arises from mesoderm, with crucial contributions from cardiac neural crest (CdNC) cells that migrate to the heart and form a variety of cardiovascular derivatives. Here, by integrating bulk and single cell RNA-seq with ATAC-seq, we identify a gene regulatory subcircuit specific to migratory cardiac crest cells composed of key transcription factorsegr1, sox9a, tfap2a,andets1.Notably, we show that cells expressing the canonical neural crest genesox10are essential for proper cardiac regeneration in adult zebrafish. Furthermore, expression of all transcription factors from the migratory cardiac crest gene subcircuit are reactivated after injury at the wound edge. Together, our results uncover a developmental gene regulatory network that is important for CdNC fate determination, with key factors of the program reexpressed during regeneration.
On shallow rocky and coral reefs, cultural and recreational values, like aesthetics, are critical aspects of Nature’s Contributions to People (NCP) that support human well-being and provide billions of dollars in tourism revenue. Quantifying the aesthetic value of reef ecosystems and uncovering the conditions that enhance it could support NCP-based management. Here, we combine a global dataset of reef fish surveys, species-level aesthetic values, and causal modeling to assess the global status and drivers of reef fish assemblage aesthetic value. We find that aesthetic value is inherently linked to species richness, displaying a latitudinal gradient with peaks in the tropics, but varies strongly with the presence of exceptionally beautiful or less-beautiful species. Sea surface temperature, primary productivity, human gravity, and protection status are the strongest drivers of assemblage-level aesthetic value. Protection against human impacts consistently enhances aesthetic value by boosting taxonomic and phylogenetic diversity, and this effect is greatest in species-rich, tropical ecoregions. Economic development has little influence, indicating that low-income countries are not constrained from maintaining beautiful fish assemblages. Our results therefore suggest that marine protected areas (MPAs) can support multiple NCPs simultaneously, particularly in developing tropical countries. While we highlight the effectiveness of MPAs, given the low level of marine protection globally and the sensitivity of aesthetic value to environmental conditions, the beauty of the world’s reefs appears severely threatened. Aesthetic value should be immediately integrated into reef conservation and management plans.
Assessing model uncertainty is crucial to quantitative political science. Yet, most available sensitivity analyses focus only on a few modeling choices, most notably the covariate space, while neglecting to jointly consider several equally important modeling choices simultaneously. In this article, we combine the exhaustive and systematic method of the Extreme Bounds Analysis with the more multidimensional logic underpinning the multiverse approach to develop an approach to sensitivity analyses. This allows us to systematically assess the degree and sources of model uncertainty across multiple dimensions, including the control set, fixed effect structures, SE types, sample selection, and dependent variable operationalization. We then apply this method to four prominent topics in political science: democratization, institutional trust, public good provision, and welfare state generosity. Results from over 3.6 bn estimates reveal widespread model uncertainty, not just in terms of the statistical significance of the effects, but also their direction, with most independent variables yielding a substantive share of statistically significant positive and negative coefficients depending on model specification. We compare the strengths and weaknesses of three distinct approaches to estimating the relative importance of different model specification choices: nearest 1-neighbor; logistic; and deep learning. All three approaches reveal that the impact of the covariate space is relatively modest compared to the impact of sample selection and dependent variable operationalization. We conclude that model uncertainty stems more from sampling and measurement than conditioning and discuss the methodological implications for how to assess model uncertainty in the social sciences.
Unraveling the origin(s) of carbon on Earth has remained challenging, not only because of the multiple isotopic fractionation episodes that may have occurred during planet formation processes but also because the end point of these processes, the current isotopic value of Earth’s deep carbon reservoirs remains poorly constrained. Here, we present carbon isotopic measurements on rare undegassed mid-ocean ridge basalts from the Pacific, Atlantic, and Arctic Oceans that have preserved the isotopic signature of their mantle source. We find that Earth’s present-day convecting upper mantle has variable δ13C value from ~−10 to −4‰, significantly different from the δ13C value of peridotitic diamonds and with the highest values being restricted to the Atlantic. Evidence for significant mantle heterogeneity contrasts with previous assumptions and its origin remains puzzling being uncorrelated with geochemical markers associated with either subduction and surficial recycling processes or lower mantle contributions. The data do not preclude other causes such as primordial mantle heterogeneity. We suggest that the δ13C value of the bulk silicate Earth may need to be revised.
Adaptation to novel environments requires genetic variation, but whether adaptation typically acts upon preexisting genetic variation or must wait for new mutations remains a fundamental question in evolutionary biology. Selection during domestication has been long used as a model to understand evolutionary processes, providing information not only on the phenotypes selected but also, in many cases, an understanding of the causal loci. For each of the causal loci that have been identified in maize, the selected allele can be found segregating in natural populations, consistent with their origin as standing genetic variation. The sole exception to this pattern is the well-characterized domestication locustga1(teosinte glume architecture1), which has long been thought to be an example of selection on a de novo mutation. Here, we use a large dataset of maize and teosinte genomes to reconstruct the origin and evolutionary history oftga1. We first estimated the age oftga1-maizeusing a genealogy-based method, finding that the allele arose approximately 42,000 to 49,000 y ago, predating the beginning of maize domestication. We also identifytga1-maizein teosinte populations, indicating that the allele can survive in the wild. Finally, we compare observed patterns of haplotype structure and mutational age distributions neartga1with simulations, finding that patterns neartga1in maize better resemble those generated under simulated selective sweeps on standing variation. These multiple lines of evidence suggest that maize domestication likely drew upon standing genetic variation attga1and cement the importance of standing variation in driving adaptation during domestication.
Pregnancy- and birth-related factors affect offspring brain development, emphasizing the importance of early life exposures. While most previous studies have focused on a few variables in isolation, here we investigated associations between a broad range of pregnancy- and birth-related variables and multivariate cortical brain MRI features. Our sample consisted of 8,396 children aged 8.9 to 11.1 y from the Adolescent Brain Cognitive Development Study. Through multiple correspondence analysis and factor analysis of mixed data, we distilled numerous pregnancy and birth variables into four overarching dimensions; maternal pregnancy complications, maternal substance use, low birth weight and prematurity, and newborn birth complications. Vertex-wise measures of cortical thickness (CT), surface area (SA), and curvature were fused using linked independent component analysis. Linear mixed-effects models showed that maternal pregnancy complications and low birth weight and prematurity were associated with smaller global SA. Additionally, low birth weight and prematurity was associated with complex regional cortical patterns reflecting bidirectional variations in both SA and CT. Newborn birth complications showed multivariate patterns reflecting smaller occipital- and larger temporal area, bidirectional frontal area variations, and reduced CT across the cortex. Maternal substance use showed no associations with child cortical structure. By employing a multifactorial and multivariate morphometric fusion approach, we connected complications during pregnancy and fetal size and prematurity to global SA and specific regional signatures across child cortical MRI features.
Herpesviruses, including Epstein–Barr virus (EBV) – a human oncogenic virus and essential trigger of multiple sclerosis – must bypass host DNA-sensing mechanisms to establish lifelong, latent infection. Therefore, herpesviruses encode viral proteins to disrupt key host factors involved in DNA sensing and viral restriction. The first viral latency protein expressed, EBNA-LP, is essential for transformation of naïve B cells and establishment of viral gene expression, yet its role in evading host defenses remains unclear. Using single-cell RNA sequencing of EBNA-LP Knockout (LPKO)-infected B cells, we reveal an antiviral response landscape implicating the “speckled proteins” as key cellular restriction factors countered by EBNA-LP. Specifically, loss of Sp100 or the primate-specific Sp140L reverses the restriction of LPKO, suppresses a subset of canonically interferon-stimulated genes, and restores transcription of essential latent viral genes and cellular proliferation. Notably, we also identify Sp140L as a restriction target of the herpesvirus saimiri ORF3 protein, implying a role for Sp140L in immunity to other diverse DNA viruses. This study reveals Sp140L as a restriction factor that we propose links sensing and transcriptional suppression of viral DNA to an Interferon-independent innate immune response, likely relevant to all nuclear DNA viruses.
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Emerging theories in cognitive neuroscience propose a third brain pathway dedicated to processing biological motion, alongside the established ventral and dorsal pathways. However, its role in computing dynamic social signals for behavior remains uncharted. Here, participants (N = 10) actively categorized dynamic facial expressions synthesized by a generative model and displayed on different face identities—as “happy,” “surprise,” “fear,” “anger,” “disgust,” “sad”—while we recorded their MEG responses. Using representational interaction measures that link facial features with MEG activity and categorization behavior, we identified within each participant a functional social pathway extending from the occipital cortex to the superior temporal gyrus. This pathway selectively represents, communicates, and integrates facial movements that are essential for the behavioral categorization of emotion, while task-irrelevant identity features are filtered out in the occipital cortex. Our findings uncover how the third pathway selectively computes complex dynamic social signals for emotion categorization in individual participants, offering computational insights into the dynamics of neural activity.
How tick-borne pathogens interact with their hosts has been primarily studied in vertebrates where disease is observed. Comparatively less is known about pathogen interactions within the tick. Here, we report thatIxodes scapularisticks infected with eitherAnaplasma phagocytophilum(causative agent of anaplasmosis) orBorrelia burgdorferi(causative agent of Lyme disease) show activation of the ATF6 branch of the unfolded protein response (UPR). Disabling ATF6 functionally restricts pathogen survival in ticks. When stimulated, ATF6 functions as a transcription factor, but is the least understood out of the three UPR pathways. To interrogate theIxodesATF6 transcriptional network, we developed a custom R script to query tick promoter sequences. This revealedstomatinas a potential gene target, which has roles in lipid homeostasis and vesical transport.Ixodes stomatinwas experimentally validated as a bona fide ATF6-regulated gene through luciferase reporter assays, pharmacological activators, RNA interference transcriptional repression, and immunofluorescence microscopy. SilencingstomatindecreasedA. phagocytophilumcolonization inIxodesand disrupted cholesterol dynamics in tick cells. Furthermore, blockingstomatinrestricted cholesterol availability to the bacterium, thereby inhibiting growth and survival. Taken together, we have identified theIxodesATF6 pathway as a contributor to vector competence through Stomatin-regulated cholesterol homeostasis. Moreover, our custom, web-based transcription factor binding site search tool “ArthroQuest” revealed that the ATF6-regulated nature ofstomatinis unique to blood-feeding arthropods. Collectively, these findings highlight the importance of studying fundamental processes in nonmodel organisms.
The nucleobase queuine (q) and its nucleoside queuosine (Q) are micronutrients derived from bacteria that are acquired from the gut microbiome and/or diet in humans. Following cellular uptake, Q is incorporated at the wobble base (position 34) of tRNAs that decode histidine, tyrosine, aspartate, and asparagine codons, which is important for efficient translation. Early studies suggested that cytosolic uptake of queuine is mediated by a selective transporter that is regulated by mitogenic signals, but the identity of this transporter has remained elusive. Here, through a cross-species bioinformatic search and genetic validation, we have identified the solute carrier family member SLC35F2 as a unique transporter for both queuine and queuosine inSchizosaccharomyces pombeandTrypanosoma brucei. Furthermore, gene disruption in human HeLa cells revealed that SLC35F2 is the sole transporter for queuosine (Km174 nM) and a high-affinity transporter for the queuine nucleobase (Km67 nM), with the additional presence of second low-affinity queuine transporter (Km259 nM). Ectopic expression of labeled SLC35F2 reveals localization to the cell membrane and Golgi apparatus via immunofluorescence. Competition uptake studies show that SLC35F2 is not a general transporter for other canonical ribonucleobases or ribonucleosides but selectively imports q and Q. The identification of SLC35F2, an oncogene, as the transporter of both q and Q advances our understanding of how intracellular levels of queuine and queuosine are regulated and how their deficiency contributes to a variety of pathophysiological conditions, including neurological disorders and cancer.
The host–microbiome interface is rich in metabolite exchanges and exquisitely sensitive to diet. Hydrogen sulfide (H2S) is present at high concentrations at this interface and is a product of both microbial and host metabolism. The mitochondrial enzyme, sulfide quinone oxidoreductase (SQOR), couples H2S detoxification to oxidative phosphorylation; its inherited deficiency presents as Leigh disease. Since an estimated two-thirds of systemic H2S metabolism originates in the gut, it raises questions as to whether impaired sulfide clearance in this compartment contributes to disease and whether it can be modulated by dietary sulfur content. In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells perturbs colon bioenergetics that is reversed by antibiotics, revealing a significant local contribution of microbial H2S to host physiology. We also find that a 2.5-fold higher methionine intake, mimicking the difference between animal and plant proteins, synergizes with intestinal SQOR deficiency to adversely impact colon architecture and alter microbiome composition. In serum, increased thiosulfate, a biomarker of H2S oxidation, reveals that intestinal SQOR deficiency combined with higher dietary methionine affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies. The mice exhibit lower exploratory locomotor activity while brain MRI reveals an atypical reduction in ventricular volume, which is associated with lower aquaporin 1 that is important for cerebrospinal fluid secretion. Our study reveals the dynamic interaction between dietary sulfur intake and sulfide metabolism at the host–microbe interface, impacting gut health, and the potential for lower dietary methionine intake to modulate pathology.
Microscopic robots exhibit efficient locomotion in liquids by leveraging fluid dynamics and chemical reactions to generate force asymmetry, thereby enabling critical applications in photonics and biomedicine. However, achieving controllable locomotion of such robots on terrestrial surfaces remains challenging because fluctuating adhesion on nonideal surfaces disrupts the necessary asymmetry for propulsion. Here, we present a microscopic robot composed of three-dimensional nanomembranes, which navigate diverse terrestrial surfaces with omnidirectional motion. We propose a general mechanism employing nonreciprocal shape morphing to generate stable asymmetric forces on surfaces. This nonreciprocal shape morphing is realized through a laser-actuated vanadium dioxide nanomembrane, leveraging the material's inherent hysteresis properties. We demonstrate that these robots can be fabricated in various shapes, ranging from simple square structures to bioinspired "bipedal" helical designs, enabling them to directionally navigate challenging surfaces such as paper, leaves, sand, and vertical walls. Furthermore, their omnidirectional motion facilitates applications in microassembly and microelectronic circuit integration. Additionally, we developed an artificial intelligence control algorithm based on reinforcement learning, enabling these robots to autonomously follow complex trajectories, such as tracing the phrase "hello world". Our study lays a theoretical and technological foundation for microscopic robots with terrestrial locomotion and paves a way for microscopic robots capable of operating on surfaces for advanced nanophotonic, microelectronic, and biomedical applications.
Gonadotropin-releasing hormone receptor (GnRHR) is critical for reproductive health and a key therapeutic target for endocrine disorders and hormone-responsive cancers. Using high-resolution cryoelectron microscopy, we determined the structures ofSus scrofaandXenopus laevisGnRHRs bound to mammal GnRH, uncovering conserved and species-specific mechanisms of receptor activation and G protein coupling. The conserved “U”-shaped GnRH conformation mediates high-affinity binding through key interactions with residues such as K3.32, Y6.51, and Y6.52. Species-specific variations in extracellular loops and receptor–ligand contacts fine-tune receptor function, while ligand binding induces structural rearrangements, including N terminus displacement and TM6 rotation, critical for signaling. Structure–activity relationship analysis demonstrates how D-amino acid substitutions in GnRH analogs enhance stability and receptor affinity. Distinct binding modes of agonists and antagonists elucidate mechanisms of ligand-dependent activation and inactivation. These insights lay the groundwork for designing next-generation GnRHR therapeutics with enhanced specificity and efficacy for conditions like endometriosis, prostate cancer, and infertility.
Mutations that impact splicing play a significant role in disease etiology but are not fully understood. To characterize the impact of exonic variants on splicing in 71 clinically actionable disease genes in asymptomatic people, we analyzed 32,112 exonic mutations from ClinVar and Geisinger MyCode using a minigene reporter assay. We identify 1,733 splice-disrupting mutations, with the most extreme variants likely being deleterious. We report that these variants are not distributed evenly across exons but are mostly concentrated in the ~8% of exons that are most susceptible to splicing mutations (i.e., hotspot exons). We demonstrate how multiple, splice-disrupting mutations in these exons can be reverted by the same ASOs targeting the splice sites of either their upstream or downstream flanking exons. This finding supports the feasibility of developing single therapeutic ASOs that could revert all splice-altering variants localized to a particular exon.
Human society is coordinated by mechanisms that control how prices are agreed, taxes are set, and electoral votes are tallied. The design of robust and effective mechanisms for human benefit is a core problem in the social, economic, and political sciences. Here, we discuss the recent application of modern tools from AI research, including deep neural networks trained with reinforcement learning (RL), to create more desirable mechanisms for people. We review the application of machine learning to design effective auctions, learn optimal tax policies, and discover redistribution policies that win the popular vote among human users. We discuss the challenge of accurately modeling human preferences and the problem of aligning a mechanism to the wishes of a potentially diverse group. We highlight the importance of ensuring that research into “deep mechanism design” is conducted safely and ethically.
Theories on group-bias often posit an internal preparedness to bias one’s cognition to favor the in-group (often envisioned as a product of evolution). In contrast, other theories suggest that group-biases can emerge from nonspecialized cognitive processes. These perspectives have historically been difficult to disambiguate given that observed behavior can often be attributed to innate processes, even when groups are experimentally assigned. Here, we use modern techniques from the field of AI that allow us to ask what group biases can be expected from a learning agent that is a pure blank slate without any intrinsic social biases, and whose lifetime of experiences can be tightly controlled. This is possible because deep reinforcement-learning agents learn to convert raw sensory input (i.e. pixels) to reward-driven action, a unique feature among cognitive models. We find that blank slate agents do develop group biases based on arbitrary group differences (i.e. color). We show that the bias develops as a result of familiarity of experience and depends on the visual patterns becoming associated with reward through interaction. The bias artificial agents display is not a static reflection of the bias in their stream of experiences. In this minimal environment, the bias can be overcome given enough positive experiences, although unlearning the bias takes longer than acquiring it. Further, we show how this style of tabula rasa group behavior model can be used to test fine-grained predictions of psychological theories.
Inspired by the challenges at the intersection of Evolutionary Game Theory and Machine Learning, we investigate a class of discrete-time multiagent reinforcement learning (MARL) dynamics in population/nonatomic congestion games, where agents have diverse beliefs and learn at different rates. These congestion games, a well-studied class of potential games, are characterized by individual agents having negligible effects on system performance, strongly aligned incentives, and well-understood advantageous properties of Nash equilibria. Despite the presence of static Nash equilibria, we demonstrate that MARL dynamics with heterogeneous learning rates can deviate from these equilibria, exhibiting instability and even chaotic behavior and resulting in increased social costs. Remarkably, even within these chaotic regimes, we show that the time-averaged macroscopic behavior converges to exact Nash equilibria, thus linking the microscopic dynamic complexity with traditional equilibrium concepts. By employing dynamical systems techniques, we analyze the interaction between individual-level adaptation and population-level outcomes, paving the way for studying heterogeneous learning dynamics in discrete time across more complex game scenarios.
Theories of the evolution of cooperation through reciprocity explain how unrelated self-interested individuals can accomplish more together than they can on their own. The most prominent theories of reciprocity, such as tit-for-tat or win-stay-lose-shift, are inflexible automata that lack a theory of mind—the human ability to infer the hidden mental states in others’ minds. Here, we develop a model of reciprocity with a theory of mind, the Bayesian Reciprocator. When making decisions, this model does not simply seek to maximize its own payoff. Instead, it also values the payoffs of others—but only to the extent it believes that those others are also cooperating in the same way. To compute its beliefs about others, the Bayesian Reciprocator uses a probabilistic and generative approach to infer the latent preferences, beliefs, and strategies of others through interaction and observation. We evaluate the Bayesian Reciprocator using a generator over games where every interaction is unique, as well as in classic environments such as the iterated prisoner’s dilemma. The Bayesian Reciprocator enables the emergence of both direct-reciprocity when games are repeated and indirect-reciprocity when interactions are one-shot but observable to others. In an evolutionary competition, the Bayesian Reciprocator outcompetes existing automata strategies and sustains cooperation across a larger range of environments and noise settings than prior approaches. This work quantifies the advantage of a theory of mind for cooperation in an evolutionary game theoretic framework and suggests avenues for building artificially intelligent agents with more human-like learning mechanisms that can cooperate across many environments.
Methane seeps harbor uncharacterized animal–microbe symbioses with unique nutritional strategies. Three undescribed sea spider species (family Ammotheidae; genusSericosura) endemic to methane seeps were found along the eastern Pacific margin, from California to Alaska, hosting diverse methane- and methanol-oxidizing bacteria on their exoskeleton. δ13C tissue isotope values of in situ specimens corroborated methane assimilation (−45‰, on average). Live animal incubations with13C-labeled methane and methanol, followed by nanoscale secondary ion mass spectrometry, confirmed that carbon derived from both compounds was actively incorporated into the tissues within five days. Methano- and methylotrophs of the bacterial families Methylomonadaceae, Methylophagaceae and Methylophilaceae were abundant, based on environmental metagenomics and 16S rRNA sequencing, and fluorescence and electron microscopy confirmed dense epibiont aggregations on the sea spider exoskeleton. Egg sacs carried by the males hosted identical microbes suggesting vertical transmission. We propose that these sea spiders farm and feed on methanotrophic and methylotrophic bacteria, expanding the realm of animals known to harness C1 compounds as a carbon source. These findings advance our understanding of the biology of an understudied animal lineage, unlocking some of the unique nutritional links between the microbial and faunal food webs in the oceans.
In multiple sclerosis (MS), cerebellar gray matter atrophy, white matter demyelination, and Purkinje cell (PC) loss have been linked to tremors, impaired motor control, and loss of coordination. Similar pathologies have been observed in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). This study hypothesized that inflammatory demyelination of the cerebellum alters overall mitochondrial function and is a contributor to axon degeneration and PC loss. Postmortem cerebellar tissue from MS patients, particularly those with secondary progressive MS, showed decreased mitochondrial complex IV (COXIV) activity and significant PC loss. Inflammation, PC axon demyelination, axon degeneration, and parallel fiber loss were also evident. These findings were mirrored in late-stage EAE mice, which also showed increased inflammation and demyelination, reduced PC COXIV activity, and overall PC loss. Further analysis of EAE mice revealed altered mitochondrial structure, modified mitochondrial respiration, and reduced levels of mitochondrial genes involved in energy production. These findings indicate that both human MS and mouse EAE share similar cerebellar changes linked to mitochondrial dysfunction. Thus, late-stage EAE is a valuable model for studying MS-related cerebellar pathology, and mitochondria may be a potential therapeutic target for MS treatment.
Iron (Fe) availability limits photosynthesis at a global scale where Fe-rich photosystem (PS) I abundance is drastically reduced in Fe-poor environments. We used single-particle cryoelectron microscopy to reveal a unique Fe starvation-dependent arrangement of light-harvesting chlorophyll (LHC) proteins where Fe starvation–induced TIDI1 is found in an additional tetramer of LHC proteins associated with PSI inDunaliella tertiolectaandDunaliella salina. These cosmopolitan green algae are resilient to poor Fe nutrition. TIDI1 is a distinct LHC protein that co-occurs in diverse algae with flavodoxin (an Fe-independent replacement for the Fe-containing ferredoxin). The antenna expansion in eukaryotic algae we describe here is reminiscent of the iron-starvation induced (isiA-encoding) antenna ring in cyanobacteria, which typically co-occurs withisiB, encoding flavodoxin. Our work showcases the convergent strategies that evolved after the Great Oxidation Event to maintain PSI capacity.
State-of-the-art ice sheet model simulations used in the Ice Sheet Model Intercomparison Project (ISMIP) that informs the Intergovernmental Panel on Climate Change tend to underestimate observed mass loss from the Greenland Ice Sheet, leading to the question of whether future sea-level rise may be larger than projected. We use one of these models, the Ice-sheet and Sea-level System Model, to investigate how transient calibration impacts historical and projection simulations. Transient calibration is an emerging capability in ice flow models; it uses time series of surface observations and time-dependent physics to constrain uncertain model parameters—in this case, the basal friction coefficient in the sliding law. With more constraints than the common snapshot inversion method, transient calibration has been shown to better capture trends in ice dynamics. Here, we apply both methods to northwestern Greenland, a region undergoing rapid changes. For simulations initialized with the snapshot inversion, we find that subsequent modeled velocities are generally too slow, leading to an underestimation of the mass loss. With transient calibration, however, our simulation better matches a time series of observed velocities, bringing it within observational error for mass loss; however, the fit to observed surface elevation is slightly reduced. Together with the ISMIP results, our simulations show that reproducing the high rates of historical mass loss leads to greater projected sea-level contribution from this region over the coming century. Finally, we suggest a path forward for making transient calibration scalable to the entire Greenland Ice Sheet.
Ralph Holloway pioneered and developed the field of hominin paleoneurology. Although Holloway’s undergraduate degrees were in metallurgical engineering and geology, at graduate school his interests switched to the brain. Holloway and his graduate students explored many aspects of the macro- and microstructure of the brain of extant primates but he focused on the recent evolutionary history of the human brain. The infant skull of the first African early hominin discovered at Taungs by Raymond Dart included a natural brain endocast. Natural endocasts as well-preserved as that of the Taungs infant are rare, but Holloway reasoned that if a way could be found to reproduce the endocranial morphology of early hominin crania then he would be able to track brain evolution within the human clade. Holloway realized that if liquid latex was introduced into the cranial cavity and left to cure, it could be extracted via the foramen magnum and then be used to make a facsimile of that individual’s brain. Modern imaging methods have made Holloway’s technique redundant, but for many years, it was the only way to access the endocranial morphology of fossil hominins.
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Evolutionary game theory (EGT) has been pivotal in the study of cooperation, offering formal models that account for how cooperation may arise in groups of selfish, but simple agents. This is done by inspecting the complex dynamics arising from simple interactions between a few strategies in a large population. As such, the strategies at stake are typically hand-picked by the modeler, resulting in a system with many more individuals in the population than strategies available to them. In the presence of noise and with multiple equilibria, the choice of strategies can considerably alter the emergent dynamics. As a result, model outcomes may not be robust to how the strategy set is chosen, sometimes misrepresenting the conditions required for cooperation to emerge. We propose three principles that can lead to a more systematic choice of the strategies in EGT models of cooperation. These are the inclusion of all computationally equivalent strategies; explicit microeconomic models of interactions, and a connection between stylized facts and model assumptions. Further, we argue that new methods arising in AI may offer a promising path toward richer models. These richer models can push the field of cooperation forward together with the principles described above. At the same time, AI may benefit from connecting to the more abstract models of EGT. We provide and discuss examples to substantiate these claims.
A brief global warming event known as the Pre-Onset Excursion (POE) occurred just before the Paleocene–Eocene Thermal Maximum (PETM, 56 Mya). The deconvolution of the evolutionary consequences of these two hyperthermal events is puzzling because of their close temporal proximity and the lack of comprehensive, well-calibrated paleontological records, especially in terrestrial environments. As a consequence, the impact of the POE on mammalian evolution and its role in shaping PETM faunas remains unclear. Here, we report from France a mammalian fauna, named Albas, which is interpreted to postdate the POE and predate the PETM. The absence of artiodactyls, perissodactyls, and euprimates at Albas lends support to the controversial hypothesis that these “modern” mammal groups appeared in the European fossil record during the PETM. In contrast, Albas yielded the European first definitive Paleocene record of metatherians, paromomyid primates, “creodonts,” and rodents, challenging the assumption that these groups migrated into Europe during the PETM. Because the majority of them originated from North American pre-POE species, we tentatively suggest that these “precursor” dispersers entered Europe during the POE. Similar to the modern orders during the PETM, these “precursor” dispersers likely entered Europe through corridors in the continuous evergreen forest belt at high latitudes. Our findings highlight how a brief warming event in the Arctic during the latest Paleocene, such as the POE (which could result in a release of carbon into the atmosphere similar to cumulative ongoing anthropogenic emissions), significantly influenced the evolutionary dynamics of European mammals.
Multiagent learning is challenging when agents face mixed-motivation interactions, where conflicts of interest arise as agents independently try to optimize their respective outcomes. Recent advancements in evolutionary game theory have identified a class of “zero-determinant” strategies, which confer an agent with significant unilateral control over outcomes in repeated games. Building on these insights, we present a comprehensive generalization of zero-determinant strategies to stochastic games, encompassing dynamic environments. We propose an algorithm that allows an agent to discover strategies enforcing predetermined linear (or approximately linear) payoff relationships. Of particular interest is the relationship in which both payoffs are equal, which serves as a proxy for fairness in symmetric games. We demonstrate that an agent can discover strategies enforcing such relationships through experience alone, without coordinating with an opponent. In finding and using such a strategy, an agent (“enforcer”) can incentivize optimal and equitable outcomes, circumventing potential exploitation. In particular, from the opponent’s viewpoint, the enforcer transforms a mixed-motivation problem into a cooperative problem, paving the way for more collaboration and fairness in multiagent systems.
Choosing social partners is a potentially demanding task which involves paying attention to the right information while disregarding salient but possibly irrelevant features. The resultant trade-off between cost of evaluation and quality of decisions can lead to undesired bias. Information-processing abilities mediate this trade-off, where individuals with higher ability choose better partners leading to higher performance. By altering the salience of features, technology can modulate the effect of information-processing limits, potentially increasing or decreasing undesired biases. Here, we use game theory and multiagent reinforcement learning to investigate how undesired biases emerge, and how a technological layer (in the form of a perceptual intervention) between individuals and their environment can ameliorate such biases. Our results show that a perceptual intervention designed to increase the salience of outcome-relevant features can reduce bias in agents making partner choice decisions. Individuals learning with a perceptual intervention showed less bias due to decreased reliance on features that only spuriously correlate with behavior. Mechanistically, the perceptual intervention effectively increased the information-processing abilities of the individuals. Our results highlight the benefit of using multiagent reinforcement learning to model theoretically grounded social behaviors, particularly when real-world complexity prohibits fully analytical approaches.
Antarctic krill is a keystone species in the Antarctic marine ecosystem and the target of a growing fishery. Given the ecological importance of krill, concerns have been raised about potential negative impacts of fishing on the Southern Ocean ecosystem. Resource-efficient approaches to fisheries monitoring are particularly valuable in this context due to the high costs associated with data collection in Antarctica. In this study, we trained a segmentation model (U-Net) to extract dives of air-breathing krill predators from more than 30,000 h of active acoustic data collected by three krill fishing vessels over six years. We were able to characterize the temporal and spatial dynamics of predator-vessel co-occurrences, which aligned well with the findings from more costly tracking studies. For example, we found that encounters with whales consistently peaked in autumn around the Antarctic Peninsula, when whales are building up fat reserves for their migration to breeding grounds. We also demonstrated that protection measures, introduced to protect breeding penguins at the Antarctic Peninsula, have simply shifted penguin-vessel encounters to the South Orkney Islands, where the affected colonies are not currently monitored. Our approach, results, and application example demonstrate how acoustic data from fishing vessels can provide important information to support fisheries management. As a by-product of fishing operations, these data are cost-effective, offering unique temporal and spatial coverage and providing a useful basis for rapid, low-level assessments of the fishery’s interaction with the wider ecosystem. This is particularly important given the unpredictable dynamics of krill fishery management decision-making.
We use crowd-sourced assessments from X’s Community Notes program to examine whether there are partisan differences in the sharing of misleading information. Unlike previous studies, misleadingness here is determined by agreement across a diverse community of platform users, rather than by fact-checkers. We find that 2.3 times more posts by Republicans are flagged as misleading compared to posts by Democrats. These results are not base rate artifacts, as we find no meaningful overrepresentation of Republicans among X users. Our findings provide strong evidence of a partisan asymmetry in misinformation sharing which cannot be attributed to political bias on the part of raters, and indicate that Republicans will be sanctioned more than Democrats even if platforms transition from professional fact-checking to Community Notes.
Symbioses with microorganisms expand the genetic and metabolic repertoire of many insects. The lac insectKerria lacca(Hemiptera: Sternorrhyncha) is a phloem-feeding scale insect that is brightly colored due to the presence of natural polyhydroxy-anthraquinone pigments called laccaic acids. The deep red pigments possibly provide defense against pathogens and predators and are commercially important as dyes in textiles, lacquerware, and cosmetics. Laccaic acids are categorized as polyketides comprising an anthraquinone backbone decorated with tyrosine or its derivatives. However, the genetic basis of these pigments remains unknown, as insects are not known to produce aromatic polyketides or tyrosine de novo. Here, we sequence the genome of the lac insect and its two endosymbionts—Wolbachiaand a hitherto unidentified, transovarially transmitted yeast-like symbiont (YLS). We found no evidence for the host orWolbachiato be able to synthesize the pigments. The pigments and their precursors were also not detected in the host plant. Genomic, transcriptomic, and metabolomic analyses combined with fluorescence microscopy identified and characterized YLS as the sole producer of the pigment’s polyketide backbone and tyrosine moiety, demonstrating an endosymbiotic origin of the lac pigments. A nonreducing polyketide synthase gene cluster encoding the laccaic acid backbone was identified. Furthermore, the YLS genome encoded essential amino acids and vitamins that are deficient in the insect’s phloem diet. Experimental fungicide-treated insects exhibited reduced concentrations of laccaic acids and tyrosine, along with decreased body size and weight, indicating a mutualistic association between the lac insect and its YLS.
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Vertebrate scavengers play a critical role in ecosystem functioning worldwide. Through the cascading effects of their ecological role, scavengers can also alleviate the burden of zoonotic diseases on people. This importance to human health fuels a growing need to understand how vertebrate scavengers and their ecosystem services are faring globally in the Anthropocene. We reviewed the conservation status of 1,376 vertebrate scavenging species and examined the implications for human health. We uncovered that 36% of these species are threatened or decreasing in population abundance and that apex (large-bodied or obligate) scavengers are disproportionately imperiled. In contrast, mesoscavengers (small-bodied or facultative) are thriving from anthropogenic food subsidies and ecological release. We posit that this global shift in scavenger community structure increases carrion persistence enabling zoonotic pathogens to propagate. Our analysis also indicates that the release of mesoscavengers is associated with reservoir host proliferation, potentially further exacerbating human disease burdens. Urgently tackling the key threats to scavengers—intensive livestock production, land use change, wildlife trade, and the interactions among them—is critical to securing the long-term public health benefits of the world’s diverse scavenger communities.
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Removing CO2from the atmosphere is emerging as a viable strategy to mitigate global warming, yet the responses of the climate system to CO2reduction remain uncertain. One of the most uncertain aspects of El Niño behavior is the change in periodicity in response to CO2forcing [O. Alizadeh,Earth-Sci. Rev.235, 104246 (2022)]. In this study, we show that climate models consistently project an abrupt shortening of El Niño periodicity once CO2reductions commence in ramp-up and ramp-down CO2experiments. Besides the contribution of slow mean state changes, this phenomenon is shown to be driven by a southward shift of the Intertropical Convergence Zone (ITCZ) [J.-S. Kug,et al.,Nat. Clim. Chang.12, 47–53 (2022)] and the consequent narrowing of El Niño’s spatial pattern, which enhances the effectiveness of ocean heat recharge/discharge processes, thereby shortening its periodicity. This suggests that the abrupt shift in El Niño periodicity results from a cascading reaction involving ITCZ dynamics and El Niño’s spatial configuration. These findings highlight the critical role of the global energy balance in shaping El Niño characteristics.
The physics of the heat-trapping properties of CO2were established in the mid-19th century, as fossil fuel burning rapidly increased atmospheric CO2levels. To date, however, research has not probed when climate change could have been detected if scientists in the 19th century had the current models and observing network. We consider this question in a thought experiment with state-of-the-art climate models. We assume that the capability to make accurate measurements of atmospheric temperature changes existed in 1860, and then apply a standard “fingerprint” method to determine the time at which a human-caused climate change signal was first detectable. Pronounced cooling of the mid- to upper stratosphere, mainly driven by anthropogenic increases in carbon dioxide, would have been identifiable with high confidence by approximately 1885, before the advent of gas-powered cars. These results arise from the favorable signal-to-noise characteristics of the mid- to upper stratosphere, where the signal of human-caused cooling is large and the pattern of this cooling differs markedly from patterns of intrinsic variability. Even if our monitoring capability in 1860 had not been global, and high-quality stratospheric temperature measurements existed for Northern Hemisphere mid-latitudes only, it still would have been feasible to detect human-caused stratospheric cooling by 1894, only 34 y after the assumed start of climate monitoring. Our study provides strong evidence that a discernible human influence on atmospheric temperature has likely existed for over 130 y.
We demonstrate a tripling in the frequency of planetary wave resonance events over the past halfcentury, coinciding with the rise in persistent boreal summer weather extremes. This increase aligns with changes in the underlying climate conditions favoring these events, including amplified Arctic warming and land–sea thermal contrast. We also observe increased prevalence of resonant amplification events following the mature phase of strong El Niño events, suggesting that such events may precondition the mean state conditions in ways that favor large-scale quasi-stationary wave patterns and quasi-resonant wave amplification. Since the impact of anthropogenic warming on quasi-resonant amplification is not well captured by current-generation climate models, it is likely that models are underpredicting the potential increase, indicating even greater risk of persistent extreme summer weather events with ongoing warming.
Circulating monocytes are recruited to the tumor microenvironment, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate and migrate through the type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by a higher loss tangent or faster stress relaxation rate. Here, we studied how changes in matrix stiffness and viscoelasticity impact the three-dimensional (3D) migration of monocytes through stromal-like matrices. Interpenetrating networks of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining matrices for 3D culture of monocytes. Increased stiffness and faster stress relaxation independently enhanced the 3D migration of monocytes. Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Matrix adhesions were dispensable for monocyte migration in 3D, but migration did require actin polymerization and myosin contractility. Mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that open a path for the monocytes to migrate through in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal how monocytes use pushing forces at the leading edge mediated by actin polymerization to generate migration paths in confining viscoelastic matrices.
In an era increasingly influenced by autonomous machines, it is only a matter of time before strategic individual decisions that impact collective goods will also be made virtually through the use of artificial delegates. Through a series of behavioral experiments that combine delegation to autonomous agents and different choice architectures, we pinpoint what may get lost in translation when humans delegate to algorithms. We focus on the collective-risk dilemma, a game where participants must decide whether or not to contribute to a public good, where the latter must reach a target in order for them to keep their personal endowments. To test the effect of delegation beyond its functionality as a commitment device, participants are asked to play the game a second time, with the same group, where they are given the chance to reprogram their agents. As our main result we find that, when the action space is constrained, people who delegate contribute more to the public good, even if they have experienced more failure and inequality than people who do not delegate. However, they are not more successful. Failing to reach the target, after getting close to it, can be attributed to precision errors in the agent’s algorithm that cannot be corrected amid the game. Thus, with the digitization and subsequent limitation of our interactions, artificial delegates appear to be a solution to help preserving public goods over many iterations of risky situations. But actual success can only be achieved if humans learn to adjust their agents’ algorithms.
Pure siderite [FeIICO3] was recently discovered in abundant quantities (4.8 to 10.5 wt.%) by the Curiosity rover at Gale crater, Mars. Diagenetic alteration of siderite likely caused the carbonate-sequestered CO2to be released back into the atmosphere and consequently produced ferric [Fe(III)] oxyhydr(oxide) minerals. Here, using laboratory experimentation, we demonstrate that while closed system acid diagenesis—as proposed for Gale crater—is incapable of effective siderite alteration in Mars-relevant fluids, oxyhalogen compounds (chlorate and bromate) can weather siderite not only at acidic pH but also in near-neutral Mars-relevant solutions. The ferric oxyhydroxide minerals produced as a consequence are controlled by the diagenetic fluid composition. While photooxidation is possible, the mutually exclusive products of alteration—magnetite (Fe3O4) during ultraviolet irradiation and ferric oxyhydroxide (FeOOH) by oxyhalogens—demonstrate that siderite at Gale crater underwent chemical weathering by chlorate and bromate brines owing to the complete absence of magnetite in drill samples containing siderite. We propose a top–down oxyhalogen brine percolation model to explain the iron mineralogy of the sulfate-rich unit at Gale crater. We conclude that siderite alteration by acidic fluids alone cannot explain the redox disequilibrium witnessed in Gale crater sediments as promulgated before and siderite weathering by oxyhalogen brines is the most likely explanation. It is highly likely that the halogen cycle on Mars is interlinked to the iron and the carbon cycle on early and current Mars.
Cooperation at scale is critical for achieving a sustainable future for humanity. However, achieving collective, cooperative behavior—in which intelligent actors in complex environments jointly improve their well-being—remains poorly understood. Complex systems science (CSS) provides a rich understanding of collective phenomena, the evolution of cooperation, and the institutions that can sustain both. Yet, much of the theory in this area fails to fully consider individual-level complexity and environmental context—largely for the sake of tractability and because it has not been clear how to do so rigorously. These elements are well captured in multiagent reinforcement learning (MARL), which has recently put focus on cooperative (artificial) intelligence. However, typical MARL simulations can be computationally expensive and challenging to interpret. In this perspective, we propose that bridging CSS and MARL affords new directions forward. Both fields can complement each other in their goals, methods, and scope. MARL offers CSS concrete ways to formalize cognitive processes in dynamic environments. CSS offers MARL improved qualitative insight into emergent collective phenomena. We see this approach as providing the necessary foundations for a proper science of collective, cooperative intelligence. We highlight work that is already heading in this direction and discuss concrete steps for future research.
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Intermediate filaments are key regulators of cell mechanics. Vimentin, a type of intermediate filament expressed in mesenchymal cells and involved in migration, forms a dense network in the cytoplasm that is constantly remodeling through filament transport, elongation/shortening, and subunit exchange. While it is known that filament elongation involves end-to-end annealing, the reverse process of filament shortening by fragmentation remains unclear. Here, we use a combination of in vitro reconstitution, probed by fluorescence imaging and atomic force microscopy, with theoretical modeling to uncover the molecular mechanism involved in filament breakage. We first show that vimentin filaments are composed of two populations of subunits, half of which are exchangeable and half immobile. We also show that the exchangeable subunits are tetramers. Furthermore, we reveal a mechanism of continuous filament self-repair, where a soluble pool of vimentin tetramers in equilibrium with the filaments is essential to maintain filament integrity. Filaments break due to local fluctuations in the number of tetramers per cross-section, induced by the constant subunit exchange. We determine that a filament tends to break if approximately four tetramers are removed from the same filament cross-section. Finally, we analyze the dynamics of association/dissociation and fragmentation to estimate the binding energy of a tetramer to a complete versus a partially disassembled filament. Our results provide a comprehensive description of vimentin turnover and reveal the link between subunit exchange and fragmentation.
The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17–iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.
Positive-strand RNA viruses are important pathogens of humans and plants. These viruses built viral replication organelles (VROs) with the help of co-opted host proteins and intracellular membranes to support robust virus replication in infected cells. Tomato bushy stunt virus (TBSV), a model (+)RNA virus, assembles membranous VROs, which are associated with vir-condensate substructures driven by TBSV p33 replication-associated protein. In this work, we provide evidence that the peroxisome-associated TBSV and the mitochondria-associated carnation Italian ringspot virus hijack the host small ubiquitin-like modifier (SUMO) machinery in yeast model host and plants. Based on knockdown of components of the SUMO pathway, we show that SUMO machinery acts as a cellular proviral dependency factor during TBSV replication. The sumoylation machinery was found to be partially retargeted from the nucleus into vir-condensate associated with membranous VROs through direct interactions with TBSV p33. We developed a yeast-based sumoylation assay that demonstrated p33 sumoylation. Absence of sumoylation or mutations in SIM SUMO-interacting motif in p33 replication protein reduced the ability of p33 to form droplets in vitro via phase separation. We demonstrate that p33 sumoylation and its intrinsically disordered region play noncomplementary roles in droplet formation. Mutations in p33 sumoylation sites and p33-SIM sequence resulted in reduced-sized VROs, which showed diminished protection of TBSV p33 and the viral RNA from degradation and also reduced viral RNA recombination. Altogether, the co-opted host sumoylation machinery promotes viral replication and RNA recombination. This finding could provide opportunities for antiviral interventions via targeting protein posttranslational modifications.
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The wave-like behavior of matter in quantum physics has spurred insightful analogies between the dynamics of particles and waves in classical systems. In this study, drawing inspiration from synchrotrons that resonate to accelerate ions along a closed path, we introduce a synchrowave: a waveguide designed to generate and sustain traveling water waves within an annular channel. In analogy to unavoidable energy losses in conventional particle accelerators due to electromagnetic radiation and inelastic collisions, the system displays undesired water-wave dampening, which we address through the synchronized action of underwater wavemakers. Our analogies extend the resonance mechanisms of synchrotrons to generate and sustain gravity waves in closed waveguides efficiently. A proof-of-concept experiment at a laboratory scale demonstrates the unique capability of this technique to build up anomalously large traveling waves displaying a flat response in the long-wave limit. Besides quantifying the performance of wave generation, our findings offer a framework for both industrial and computational applications, opening up unexplored possibilities in hydraulics, coastal science, and engineering. In a broader context, our experimental apparatus and methods highlight the versatility of a simple yet powerful concept: a closed-path continuous-energy-pumping scheme to effectively harvest prominent resonant responses within wave-supporting systems displaying weak dissipation.
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Many dynamical systems can exist in alternative regimes for which small changes in an environmental driver can cause sudden jumps between regimes. In ecology, predicting the regime of population fluctuations under unobserved levels of an environmental driver has remained an unsolved challenge with important implications for conservation and management. Here, we show that integrating time-series data and information on a putative driver into a Gaussian Process regression model for the system’s dynamics allows us to predict dynamical regimes without the need to specify the equations of motion of the system. As a proof of concept, we demonstrate that we can accurately predict fixed-point, cyclic, or chaotic dynamics under unseen levels of a control parameter for a range of simulated population dynamics models. For a model with an abrupt population collapse, we show that our approach goes beyond an early warning signal by characterizing the regime that follows the tipping point. We then apply our approach to data from an experimental microbial food web and from a lake planktonic food web. We find that we can reconstruct transitions away from chaos in the microbial food web and anticipate the dynamics of the oligotrophic regime in the planktonic food web. These results lay the groundwork for making rational decisions about preventing, or preparing for, regime shifts in natural ecosystems and other dynamical systems.
AI systems, particularly large language models (LLMs), are increasingly being employed in high-stakes decisions that impact both individuals and society at large, often without adequate safeguards to ensure safety, quality, and equity. Yet LLMs hallucinate, lack common sense, and are biased—shortcomings that may reflect LLMs’ inherent limitations and thus may not be remedied by more sophisticated architectures, more data, or more human feedback. Relying solely on LLMs for complex, high-stakes decisions is therefore problematic. Here, we present a hybrid collective intelligence system that mitigates these risks by leveraging the complementary strengths of human experience and the vast information processed by LLMs. We apply our method to open-ended medical diagnostics, combining 40,762 differential diagnoses made by physicians with the diagnoses of five state-of-the art LLMs across 2,133 text-based medical case vignettes. We show that hybrid collectives of physicians and LLMs outperform both single physicians and physician collectives, as well as single LLMs and LLM ensembles. This result holds across a range of medical specialties and professional experience and can be attributed to humans’ and LLMs’ complementary contributions that lead to different kinds of errors. Our approach highlights the potential for collective human and machine intelligence to improve accuracy in complex, open-ended domains like medical diagnostics.
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Reflection and refraction are ubiquitous phenomena with extensive applications, yet minimizing energy loss and information distortion during these processes remains a significant challenge. This study examines the behavior of structurally stable solitons, known as directrons, in nematic liquid crystals interacting with an interface where the director field orientation changes, despite identical physical properties, external potentials, and boundary anchoring in the two regions. During reflection and refraction, the directrons maintain nearly constant structure and velocity, ensuring energy conservation and information integrity. Microscopic analyses of the director field and macroscopic evaluations of effective potential are employed to elucidate the dependence of reflection and refraction probabilities on the directron’s incident angle and the orientation difference across the interface. The findings provide valuable insights into the dynamics of solitary waves in structured liquid crystal systems, offering significant implications for the development of tunable photonic devices, reconfigurable optical systems, and nanoscale material engineering.
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We give an explicit counterexample to the bunkbed conjecture introduced by Kasteleyn in 1985. The counterexample is given by a planar graph on 7,222 vertices and is built on the recent work of Hollom (2024).
Ryanodine receptors (RyRs) are intracellular Ca2+channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca2+. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.
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Lipoprotein retention in Bruch’s membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch’s membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch’s membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.
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The discovery of transgenerational epigenetic inheritance and the unraveling of its molecular mechanisms are currently solving previously puzzling challenges that Mendelian genetics based solely on DNA could not explain, leading to significant paradigm shifts across various fields of biology. There has been a long-standing controversy over the factors determining the caste fate of individuals in social insects. Increasing evidence supports heritable influences on division of labor. Here, we provide evidence that transgenerational epigenetic inheritance influences caste determination in a termite. We demonstrate that the age of the king influences the caste fate of offspring, with young kings’ progeny showing a higher tendency for reproductive differentiation compared to offspring from older kings (under controlled conditions). Then, we conducted a high-quality chromosome-level genome assembly for the Japanese subterranean termiteReticulitermes speratus. Genome-wide methylome analysis of kings’ sperm reveals a drastic change in DNA methylation patterns with aging. Among 39,399,411 CpG sites, 21,611 sites showed significant age differences in methylation levels. We identified 13 genes whose methylation levels are significantly different between young and old kings and suggestively correlated with the offspring’s differentiation into the reproductive pathway. Our results suggest that sperm DNA methylation, which changes with the age of kings, is a potential transgenerational epigenetic factor involved in offspring caste differentiation in a termite. These findings may have broad applicability to caste differentiation in social insects and to phenotypic plasticity more generally.
Resource fluctuations are ubiquitous in nature and yet are generally assumed to play a limited role in the maintenance of biodiversity. We challenge this assumption by analyzing resource competition dynamics under conditions where prevailing theory does not hold. We show that multispecies coexistence can be sustained when species are able to specialize on different temporal patterns of resource variability, including the asymmetries and periodic extremes commonly observed in natural systems. We further show how this partitioning of the statistical moments of the resource distribution provides a unified framework for explaining coexistence in variable resource environments. The multiplicity of niches we find in a single fluctuating resource highlights the potential for anthropogenic changes in resource regimes to drive cascading biodiversity losses.
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Alveolar macrophages (AMs) are indispensable to prevent pulmonary alveolar proteinosis and clear inhaled pathogens. Receptor for activated C kinase 1 (RACK1) is a versatile adaptor protein that regulates multiple signaling pathways. Whether RACK1 is implicated in AM alterations remains elusive. Alveolar type 2 cells-derived granulocyte-macrophage colony-stimulating factor and autocrine transforming growth factor-β1 drive the transcription ofPparg, the gene encoding AM signature transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). The regulation of PPARγ stability during AM development and maintenance remains unexplored. Here, we report that myeloid RACK1 deficiency results in the scarcity of mature AMs and pulmonary alveolar proteinosis. A mixed bone marrow chimera approach reveals a cell-intrinsic role of RACK1 in AM differentiation. Bulk RNA-sequencing indicates a considerable loss of AM identity, impaired PPAR signaling, but a largely unchangedPpargmessenger RNA (mRNA) level in the absence of RACK1. Indeed, myeloid deletion ofRack1halts AM differentiation in vivo and blocks the ability of PPARγ agonist to induce AM-like cells in vitro. Mechanistically, RACK1 directly binds to and stabilizes PPARγ by preventing its ubiquitination and degradation. Moreover, myeloid RACK1 deficiency renders mice susceptible toStreptococcus pneumoniaeinfection.
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Fluorinated compounds are used for agrochemical, pharmaceutical, and numerous industrial applications, resulting in global contamination. In many molecules, fluorine is incorporated to enhance the half-life and improve bioavailability. Fluorinated compounds enter the human body through food, water, and xenobiotics including pharmaceuticals, exposing gut microbes to these substances. The human gut microbiota is known for its xenobiotic biotransformation capabilities, but it was not previously known whether gut microbial enzymes could break carbon–fluorine bonds, potentially altering the toxicity of these compounds. Here, through the development of a rapid, miniaturized fluoride detection assay for whole-cell screening, we identified active gut microbial defluorinases. We biochemically characterized enzymes from diverse human gut microbial classes including Clostridia, Bacilli, and Coriobacteriia, with the capacity to hydrolyze (di)fluorinated organic acids and a fluorinated amino acid. Whole-protein alanine scanning, molecular dynamics simulations, and chimeric protein design enabled the identification of a disordered C-terminal protein segment involved in defluorination activity. Domain swapping exclusively of the C-terminus conferred defluorination activity to a nondefluorinating dehalogenase. To advance our understanding of the structural and sequence differences between defluorinating and nondefluorinating dehalogenases, we trained machine learning models which identified protein termini as important features. Models trained on 41-amino acid segments from protein C termini alone predicted defluorination activity with 83% accuracy (compared to 95% accuracy based on full-length protein features). This work is relevant for therapeutic interventions and environmental and human health by uncovering specificity-determining signatures of fluorine biochemistry from the gut microbiome.
The correlation between synonymous codon usage and secondary structure in translated proteins has been widely demonstrated. This usage plays a capital role in tuning translational rates and protein folding kinetics, indirectly influencing multiple biological processes. A recent report [A. A. Rosenberg, A. Marx, A. M. Bronstein,Nat. Commun.13, 2815 (2022).] suggests that the translated synonymous codon influences the(ϕ,ψ)dihedral angles within secondary structure elements. If true, this conclusion would have strong consequences in several scientific fields, including structural biology and protein design, where results would depend on DNA sequence rather than protein sequence. Here, we show that the original statistical methodology used in the referred study was formally incorrect. Furthermore, when using a correct approach, we demonstrate that the influence of the codon on the distribution of the dihedral angles is not statistically significant for any type of secondary structure.
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The growth of populations and organisms often depends on their previous history of environmental exposure: a phenomenon referred to as “phenotypic memory.” The field of ecology presently lacks a mechanistic theory describing phenotypic memory and, as such, evaluating the ecological consequences of this phenomenon is a major challenge. Here, we show that internal nutrient storage connects past thermal experience to current growth in phytoplankton. We develop a mechanistic model showing that delays in the response of nutrient stores to changing temperatures produces phenotypic memory. By testing this model against experimental data of phytoplankton growth rates following temperature perturbations, we find general patterns in the population consequences of phenotypic memory: Prior exposure to warm temperatures depletes nutrient stores, and, in doing so, slows growth during subsequent temperature exposure and restricts the breadth of the thermal niche (i.e., the range of acute temperature exposures yielding a positive growth rate). Our model reveals how phenotypic memory produces temporal variation in critical thermal minima and maxima and predicts that the thermal niche is constricted by long-term exposure to warm temperatures (e.g., during summer months), but that high frequency temperature fluctuations can expand a population’s thermal niche. This work provides a mechanistic framework for considering the ecological implications of phenotypic memory.
Recent studies suggest large language models (LLMs) can generate human-like responses, aligning with human behavior in economic experiments, surveys, and political discourse. This has led many to propose that LLMs can be used as surrogates or simulations for humans in social science research. However, LLMs differ fundamentally from humans, relying on probabilistic patterns, absent the embodied experiences or survival objectives that shape human cognition. We assess the reasoning depth of LLMs using the 11-20 money request game. Nearly all advanced approaches fail to replicate human behavior distributions across many models. The causes of failure are diverse and unpredictable, relating to input language, roles, safeguarding, and more. These results warrant caution in using LLMs as surrogates or for simulating human behavior in research.
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A cure for chronic hepatitis B requires eliminating or permanently silencing covalently closed circular DNA (cccDNA). A pivotal target of this approach is the hepatitis B virus (HBV) X protein (HBx), which is a key factor that promotes transcription from cccDNA. However, the HBx structure remains unsolved. Here, we present the cryoelectron microscopy structure of HBx in complex with DDB1, which is an essential complex for cccDNA transcription. In this structure, hydrophobic interactions within HBx were identified, and mutational analysis highlighted their importance in the HBV life cycle. Our biochemical analysis revealed that the HBx–DDB1 complex directly interacts simultaneously with NSE3, which is a component of the SMC5/6 complex, and Spindlin1. Additionally, HBx–DDB1 complex dynamics were explored via high-speed atomic force microscopy. These findings provide comprehensive insights into the structure and function of HBx in HBV replication.
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Antlers, a male deer secondary sex characteristic, are unique mammalian appendages that fully regenerate annually, under androgen regulation. Stem cells located in the antlerogenic periosteum (AP), a tissue overlaying the frontal crest of both male and female deer, play a crucial role in antlerogenesis. Nonetheless, the underlying molecular mechanisms as to how antlerogenesis is regulated by androgens remain largely unexplored. Here, we show that androgens regulate antler growth via macrophages. Bulk RNA sequencing revealed a significant enrichment of immune-related factors in the androgen-activated antlerogenic periosteum (AAP), and single-cell RNA sequencing identified a cluster of AAP cells overexpressing macrophage chemokine CCL2. Additionally, the presence of a substantial number of monocytes/macrophages was detected in the skin overlying the AAP. Histological examination confirmed macrophage accumulation in the AAP. Removal of macrophages with clodronate effectively inhibited antler generation in male sika deer as well as in nude mice engrafted with the AP. Furthermore, testosterone up-regulated CCL2 expression in the AP cells (APCs), thus enhancing their chemotactic effect on recruitment of macrophages. Remarkably, female sika deer developed antlers following local injection of CCL2, autologous macrophages, or even immune response inducer lipopolysaccharide (LPS). Therefore, macrophages play an essential role in deer antler generation.
Hydrogen embrittlement (HE) remains a critical scientific challenge in building reliable infrastructure for a carbon-free hydrogen economy. Predictive models for hydrogen-induced material failure are still lacking, largely due to an incomplete understanding of hydrogen’s effects on deformation behavior, especially in multiphase alloys with complex compositions and microstructures. Here, we demonstrate a synergistic hydrogen embrittlement (SHE) phenomenon in high-strength martensitic steels, where hydrogen interacts with carbon in solution to activate hydrogen-enhanced localized plasticity (HELP). Microcantilever bending tests revealed greater hydrogen susceptibility with higher carbon content, evidenced by a significant reduction in work-hardening capacity, promoting slip localization and reduced ductility. First-principles calculations and theoretical modeling revealed that carbon intensifies hydrogen–dislocation interactions and amplifies hydrogen redistribution around screw dislocations, inhibiting cross-slip. This work integrates experimental and modeling approaches to elucidate the synergistic interactions between hydrogen and solute elements, providing critical insights for designing high-strength, hydrogen-tolerant structural materials.
Plague continues to pose a public health problem in multiple regions of the world, including Madagascar, where it is characterized by a pronounced seasonal pattern. The drivers of plague seasonality remain poorly understood. Using a deterministic compartmental model, calibrated to rat and flea capture data, serological data collected in active rural foci, and human plague surveillance data, we analyzed the effects of seasonal rat and flea population dynamics on plague transmission. The models that incorporated seasonal fluctuations in rat and flea populations provided better predictive performances than those that did not. We found that a simpler mass-action model also performed well. Driven by these seasonal changes, the effective reproduction number (Re) between rats peaks at 1.45 [95% credible interval (CI): 1.41, 1.48] in October and falls to 0.6 (95% CI: 0.57, 0.63) in March. We estimated that 0.5% (95% CI: 0.2%, 0.9%) of rats are infected annually, indicating that plague is not the main driver of rat population changes. Using our model, we evaluated intervention strategies and found that targeting both rats and their fleas at the start of the epidemic season (July–September) was the most effective approach for reducing human plague cases. Such an approach contrasts with the reactive strategy currently employed in Madagascar. Our findings highlight the role of flea and rat populations in plague seasonality and identify strategies that could be deployed in Madagascar to better control plague epidemics.
Cancer therapy is limited by resistance to standard-of-care chemotherapeutic and/or by treatment-associated toxicity. Identifying molecular mechanisms that modulate cellular toxicity is crucial for enhancing treatment efficacy. We characterize CDADC1, a vertebrate-specific orphan enzyme, as an unprecedented eukaryotic dCTP deaminase. CDADC1 catalyzes the conversion of dCTP into dUTP. While bacteria use this activity to sustain proliferation, CDADC1 evolved independently and is not required for mammalian cell proliferation, as demonstrated in cell lines and by the normal growth and standard lifespan of Cdadc1-deficient mice. However, we uncover a role of CDADC1 in metabolizing nucleotide analogs gemcitabine and decitabine. Gain- and loss-of-function assays in cancer cell lines, along with ectopic mouse models of pancreatic cancer, show that CDADC1 reduces these drugs’ efficacy. By the same token,Cdadc1−/−mice are hypersensitive to gemcitabine. Mechanistically, CDADC1 deaminates the active triphosphate form of gemcitabine and decitabine, rendering them susceptible to inactivation by deoxyuridine triphosphatase. In contrast, the dCMP deaminase DCTD contributes to cell proliferation and promotes gemcitabine and decitabine toxicity. Thus, CDADC1 underpins a previously unrecognized mechanism of intrinsic chemoresistance in cancer cells and has a nonredundant role in protecting from gemcitabine toxicity. CDADC1 reveals a clinically relevant metabolic pathway that might be exploited to enhance the efficacy of deoxycytidine analogs but calls for assessing CDADC1 status to avoid lethal toxicities.
Grain growth in polycrystals is traditionally considered a capillarity-driven process, where grain boundaries (GBs) migrate toward their centers of curvature (i.e., mean curvature flow) with a velocity proportional to the local curvature (including extensions to account for anisotropic GB energy and mobility). Experimental and simulation evidence shows that this simplistic view is untrue. We demonstrate that the failure of the classical mean curvature flow description of grain growth mainly originates from the shear deformation naturally coupled with GB motion (i.e., shear coupling). Our findings are built on large-scale microstructure evolution simulations incorporating the fundamental (crystallography-respecting) microscopic mechanism of GB migration. The nature of the deviations from curvature flow revealed in our simulations is consistent with observations in recent experimental studies on different materials. This work also demonstrates how to incorporate the mechanical effects that are essential to the accurate prediction of microstructure evolution.
The α-hemolysin (HlyA) of uropathogenicEscherichia coli(UPEC) is a pore-forming toxin (PFT) that is thought to function by disrupting the host cell plasma membrane. Although CD18 (LFA-1) has been implicated as a receptor on myeloid cells, the mechanisms underlying HlyA cytotoxicity to epithelial cells are poorly defined. Here, we show that HlyA secretion by UPEC markedly intensifies renal tubular epithelial injury in a murine model of ascending pyelonephritis. A CRISPR-Cas9 loss-of-function screen in renal collecting duct cells revealed an unexpected requirement for clathrin-mediated endocytosis in HlyA-induced cytotoxicity. Following internalization, HlyA triggered lysosomal permeabilization, resulting in protease leakage, cytoplasmic acidification, and mitochondrial impairment, culminating in rapid epithelial cell death—a pathway distinct from canonical membrane-disrupting mechanisms of other PFTs. Moreover, we identify the low-density lipoprotein receptor (LDLR) as a critical epithelial receptor for HlyA; genetic ablation or competitive inhibition of the HlyA–LDLR interaction fully abrogated cytotoxicity. Our findings detail a paradigm for HlyA function in which epithelial toxicity relies on LDLR-mediated endocytic uptake rather than plasma membrane poration. These mechanistic insights illuminate potential therapeutic strategies to attenuate HlyA-mediated tissue damage during UPEC infections.
Isoprene is the most abundant nonmethane biogenic hydrocarbon emitted by some plants, mostly trees. It plays critical roles in atmospheric chemistry by contributing to ozone and aerosol formation. Isoprene also benefits plants, particularly under stress, through its signaling roles. Legume crops like soybean were thought to have evolutionarily lost isoprene synthase (ISPS) and are typically considered nonemitters. Here, we report that damage to soybean leaves by wounding or burning triggered a burst of isoprene emission from the undamaged part of the leaves. In silico analysis identified intactISPSgenes in the soybean genome, with features similar to known ISPSs. Protein made from these gene sequences catalyzed isoprene production in the presence of dimethylallyl diphosphate. Isoprene emission in soybeans was linked to reduced photosynthesis rates and stomatal conductance. Metabolomic analysis showed that leaf damage caused a surge in glyceraldehyde 3-phosphate and pyruvate levels, leading to an increase of most of the methylerythritol 4-phosphate pathway metabolites.
Biological microswimmers exhibit intricate taxis behaviors in response to environmental stimuli and swim in complex trajectories to navigate their environment. How microswimmers respond to stimulus instantaneously, and how adaptation to stimulus influences their long-term behavioral changes, remains largely unclear. Here, we report an oscillatory phototaxis observed inChlamydomonas reinhardtiiat intermediate light intensities, where cells swim back-and-forth under a constant, unidirectional light stimulus due to alternation between positive and negative phototaxis. The phototaxis switching can be captured by the change in phase relationship between eyespot and helical swimming. Oscillatory phototaxis of individual cells leads to a global pattern of millimeter-scale propagating density bands that persists for∼30 min. High-speed imaging and long-time tracking experiments at single-cell level verify a unified phototaxis mechanism that couples light detection, light adaptation, flagella responses, and behavioral switching. By experimentally tracking steady swimming and transient turning states, we verify that phototaxis transition is achieved via the modulation of flagella waveforms and flagella phase difference, which can be captured by a hydrodynamic model accounting for photoresponses. Adaptation acts effectively as an oscillator damper to mediate multipurpose tasking across multiple system levels (subcellular flagella beats, oscillatory phototaxis, colonial pattern formation) and timescales (from milliseconds to over 30 min). This adaptive phototaxis mechanism provides a comprehensive understanding of how microswimmers achieve complex behavioral changes across multiple temporal scales with a single sensor–actuator circuit featuring relatively simple adaptive feedback responses.
PKD2 is a member of the polycystin subfamily of transient receptor potential (TRP) ion channel subunits which traffic and function in primary cilia organelle membranes. Millions of individuals carry pathogenic genetic variants in PKD2 that cause a life-threatening condition called autosomal dominant polycystic kidney disease (ADPKD). Although ADPKD is a common monogenetic disorder, there is no drug cure or available therapeutics which address the underlying channel dysregulation. Furthermore, the structural and mechanistic impacts of most disease-causing variants are uncharacterized. Using direct cilia electrophysiology, cryogenic electron microscopy (cryo-EM), and superresolution imaging, we have found mechanistic differences in channel dysregulation caused by three germline missense variants located in PKD2’s pore helix 1. Variant C632R reduces protein thermal stability, resulting in impaired channel assembly and abolishes primary cilia trafficking. In contrast, variants F629S and R638C retain native cilia trafficking but exhibit gating defects. Cryo-EM structures (2.7 to 2.8 Å resolution) indicate loss of critical pore helix interactions which precipitate allosteric collapse of the channels inner gate. Results demonstrate how ADPKD-causing mutations cause mechanistically divergent and ranging impacts on PKD2 function, despite their shared structural proximity. These unexpected findings highlight the need for structural and biophysical characterization of polycystin variants, which will guide rational drug development of ADPKD therapeutics.
Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated viaOvgp1-driven Cre recombinase effecting CRISPR/Cas9-mediated deletion ofTrp53, Rb1, andNf1tumor suppressors in mouse oviductal epithelium (m-sgPRNmodel). Cyclin-dependent kinase 12 (CDK12) inactivation—frequently observed in human HGSC—is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation ofCdk12(m-sgPRN;Cdk12KO) recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated)Trp53/Nf1/Rb1triple knockout model with concurrentCdk12ablation (PRN;Cdk12KOmice), we observed T cell–rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts ofCDK12-inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/Cas9 synthetic lethality screen inPRN;Cdk12KO-derived cell lines identified CDK13—an essential paralog of CDK12—as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from bothm-sgPRN;Cdk12KOandPRN;Cdk12KOmodels. Our results defineCDK12as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach inCDK12-inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.
Mass-independent isotope fractionation (MIF) enables powerful geochemical tracers for various geological and planetary problems, yet the mechanisms driving MIF for tin (Sn) remain ambiguous. Here, we demonstrate that distinct Sn isotope fractionation signatures were produced during photolysis of organic Sn species (i.e., methyltin) under laboratory UV irradiation and natural sunlight. UV irradiation of methyltin induced pronounced Sn-MIF in all odd Sn isotopes (Δ115Sn up to 21.82‰, Δ117Sn up to 23.16‰, Δ119Sn up to 24.01‰), with their ratios (Δ117Sn/Δ115Sn = 1.069; Δ119Sn/Δ115Sn = 1.099; Δ119Sn/Δ117Sn = 1.028) strongly correlating with nuclear magnetic moments. This unambiguously identifies the magnetic isotope effect (MIE) as the driving mechanism, ruling out other causes such as the nuclear volume effect (NVE). Methyl radicals (•CH3) were detectable during the methyltin photolysis experiments, and the magnitude of MIF for Sn was suppressed by the presence of electron spin trapping agent (DMPO) for radicals, supporting that the pronounced Sn-MIF originated from radical-mediated singlet-triplet state transitions of Sn species. Furthermore, the magnitude of Sn-MIF depended nonmonotonically on external magnetic fields (peak suppression at 100 to 180 G), implying competition between hyperfine coupling and Zeeman interactions. Notably, Sn-MIF was absent during photolysis of methyltin by natural sunlight despite significant mass-dependent Sn isotope fractionation (e.g., >3‰ in δ122/116Sn), attributed to atmospheric ozone shielding of short-wavelength UV (<290 nm) required for radical generation. Our results register Sn-MIF as a sensitive tracer of UV-driven photochemistry in low-oxygen environments, underlining the potential of Sn isotopes in studies of early Earth’s atmosphere and planetary environments.
Evolution of complexity in human languages has been vigorously debated, including the proposal that complexity can build in small, isolated populations but is often lost in situations of language contact. If it is generally true that small, isolated languages can build morphological complexity over time, but complexity tends to be lost in situations of language contact, then we should find that forms of language complexity that have evolved multiple times will tend to be associated with population size, isolation, and language age. We test this hypothesis by focusing on one particular form of morphological complexity, polysynthesis, where words built from many parts embody complex phrases. By assembling a global database of polysynthetic languages and conducting phylospatial analyses, we show that languages with highly complex word morphology are more likely to have small population sizes, less likely to occur with many other languages in direct contact, and have a greater tendency to be on long phylogenetically isolated lineages. These findings are consistent with the hypothesis that languages that evolve in isolation for long periods may be more likely to accrue morphological complexity. Polysynthetic languages also tend to have higher levels of endangerment. Our results provide phylogenetically informed evidence that one particular form of complex language morphology is more likely to occur in small, isolated languages and is prone to loss in contact.
Cushing’s syndrome (CS) is an abnormal condition characterized by elevated cortisol levels, often resulting from genetic alterations in thePRKACAgene, which encodes the catalytic subunit of cAMP-dependent protein kinase A (PKA-C). The most common CS mutation, L205R, lies at the P + 1 loop. Understanding how this mutation alters the internal allosteric network within PKA-C and changes nucleotide and substrate cooperativity is a major goal. Using molecular dynamics (MD) simulations and protein residue networks based on local spatial pattern (LSP) method, we compare crystal structures of wild-type PKA-C and L205R. Our findings indicate that L205R not only locally disrupts the P + 1 hydrophobic pocket, leading to the displacement of the P + 1-residue and altered substrate specificity, but also has long-range effects in the linker connecting the A helix to β strand 1. The MD simulations and LSP analyses also reveal critical changes at the phosphoryl transfer site. Some of these changes are captured in the L205R crystal structure while others are not. With this strategy, we also show how the dynamics of local and distal allosteric networks are differentially influenced by backbone and side-chain dynamics.
To decide how to move around the world, we must determine which locomotive actions (e.g., walking, swimming, or climbing) are afforded by the immediate visual environment. The neural basis of our ability to recognize locomotive affordances is unknown. Here, we compare human behavioral annotations, functional MRI (fMRI) measurements, and deep neural network (DNN) activations to both indoor and outdoor real-world images to demonstrate that the human visual cortex represents locomotive action affordances in complex visual scenes. Hierarchical clustering of behavioral annotations of six possible locomotive actions show that humans group environments into distinct affordance clusters using at least three separate dimensions. Representational similarity analysis of multivoxel fMRI responses in the scene-selective visual cortex shows that perceived locomotive affordances are represented independently from other scene properties such as objects, surface materials, scene category, or global properties and independent of the task performed in the scanner. Visual feature activations from DNNs trained on object or scene classification as well as a range of other visual understanding tasks correlate comparatively lower with behavioral and neural representations of locomotive affordances than with object representations. Training DNNs directly on affordance labels or using affordance-centered language embeddings increases alignment with human behavior, but none of the tested models fully captures locomotive action affordance perception. These results uncover a type of representation in the human brain that reflects locomotive action affordances.
Polygenic risk scores (PRS) are essential tools for estimating individual susceptibility to complex diseases by aggregating the effects of many genetic variants. With the advent of whole-genome sequencing (WGS), rare and de novo variants can now be detected at scale, presenting new opportunities to enhance PRS performance. Additionally, regulatory mechanisms that govern gene expression play a critical role in disease manifestation, suggesting further potential for improvement. However, most existing PRS methods are not well-equipped to incorporate nonlinear variant effects, rare variant contributions, or regulatory context. To address these limitations, we developed Epi-PRS, a novel framework that leverages large language models (LLMs) to impute cell-type-specific epigenomic signals from personal diploid genotypes. These imputed signals act as informative intermediates between genotype and phenotype, allowing for more accurate modeling of variant impact. Our simulation studies demonstrate that Epi-PRS improves predictive accuracy by incorporating nonlinear relationships, rare variant effects, and regulatory information across large genomic regions. When applied to real data from the UK Biobank, Epi-PRS significantly outperforms existing PRS approaches in predicting risk for both breast cancer and type 2 diabetes. These results underscore the advantages of integrating WGS data, epigenomic context, and advanced LLMs framework to enhance both the predictive power and interpretability of PRS. Overall, Epi-PRS represents a promising step toward more precise and biologically informed disease risk prediction, with broad implications for advancing personalized medicine and understanding complex genetic architectures.
The relationship between genotype and phenotype remains an outstanding question for organism-level traits because these traits are generallycomplex. The challenge arises from complex traits being determined by a combination of multiple genes (or loci), which leads to an explosion of possible genotype–phenotype mappings. The primary techniques to resolve these mappings are genome/transcriptome-wide association studies, which are limited by their lack of causal inference and statistical power. Here, we develop an approach that combines transcriptional data endowed with causal information and a generative machine learning model designed to strengthen statistical power. Our implementation of the approach—dubbed transcriptome-wide conditional variational autoencoder (TWAVE)—includes a variational autoencoder trained on human transcriptional data, which is incorporated into an optimization framework. Given a trait phenotype, TWAVE generates expression profiles, which we dimensionally reduce by identifying independently varying generalized pathways (eigengenes). We then conduct constrained optimization to find causal gene sets that are the gene perturbations whose measured transcriptomic responses best explain trait phenotype differences. By considering several complex traits, we show that the approach identifies causal genes that cannot be detected by the primary existing techniques. Moreover, the approach identifies complex diseases caused by distinct sets of genes, meaning that the disease is polygenicandexhibits distinct subtypes driven by different genotype–phenotype mappings. We suggest that the approach will enable the design of tailored experiments to identify multigenic targets to address complex diseases.
Characterizing the feedback linking human behavior and the transmission of infectious diseases (i.e., behavioral changes) remains a significant challenge in computational and mathematical epidemiology. Existing behavioral epidemic models often lack real-world data calibration and cross-model performance evaluation in both retrospective analysis and forecasting. In this study, we systematically compare the performance of three mechanistic behavioral epidemic models across nine geographies and two modeling tasks during the first wave of COVID-19, using various metrics. The first model, a Data-Driven Behavioral Feedback Model, incorporates behavioral changes by leveraging mobility data to capture variations in contact patterns. The second and third models are Analytical Behavioral Feedback Models, which simulate the feedback loop either through the explicit representation of different behavioral compartments within the population or by utilizing an effective nonlinear force of infection. Our results do not identify a single best model overall, as performance varies based on factors such as data availability, data quality, and the choice of performance metrics. While the Data-Driven Behavioral Feedback Model incorporates substantial real-time behavioral information, the Analytical Compartmental Behavioral Feedback Model often demonstrates superior or equivalent performance in both retrospective fitting and out-of-sample forecasts. Overall, our work offers guidance for future approaches and methodologies to better integrate behavioral changes into the modeling and projection of epidemic dynamics.
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Clostridium thermocellum, a cellulolytic thermophilic anaerobe, is considered by many to be a prime candidate for the realization of consolidated bioprocessing (CBP) and is known as an industry standard for biofuel production.C. thermocellumis among the best biomass degraders identified to date in nature and produces ethanol as one of its main products. Many studies have helped increase ethanol titers in this microbe; however, ethanol production usingC. thermocellumis still not economically viable. Therefore, a better understanding of its ethanol synthesis pathway is required. The main pathway for ethanol production inC. thermocelluminvolves the bifunctional aldehyde-alcohol dehydrogenase (AdhE). To better understand the function of theC. thermocellumAdhE, we used cryo-electron microscopy (cryo-EM) to obtain a 3.28 Å structure of the AdhE complex. This high-resolution structure, in combination with molecular dynamics simulations, provides insight into the substrate channeling of the toxic intermediate acetaldehyde, indicates the potential role ofC. thermocellumAdhE to regulate activity and cofactor pools, and establishes a basis for future engineering studies. The containment strategy found in this enzyme offers a template that could be replicated in other systems where toxic intermediates need to be sequestered to increase the production of valuable biochemicals.
Neurons in the brain are known to encode diverse information through their spiking activity, primarily reflecting external stimuli and internal states. However, whether individual neurons also embed information about their own anatomical location within their spike patterns remains largely unexplored. Here, we show that machine learning models can predict a neuron’s anatomical location across multiple brain regions and structures based solely on its spiking activity. Analyzing high-density recordings from thousands of neurons in awake, behaving mice, we demonstrate that anatomical location can be reliably decoded from neuronal activity across various stimulus conditions, including drifting gratings, naturalistic movies, and spontaneous activity. Crucially, anatomical signatures generalize across animals and even across different research laboratories, suggesting a fundamental principle of neural organization. Examination of trained classifiers reveals that anatomical information is enriched in specific interspike intervals as well as responses to stimuli. Within the visual isocortex, anatomical embedding is robust at the level of layers and primary versus secondary but does not robustly separate individual secondary structures. In contrast, structures within the hippocampus and thalamus are robustly separable based on their spike patterns. Our findings reveal a generalizable dimension of the neural code, where anatomical information is multiplexed with the encoding of external stimuli and internal states. This discovery provides new insights into the relationship between brain structure and function, with broad implications for neurodevelopment, multimodal integration, and the interpretation of large-scale neuronal recordings. Computational approximations of anatomy have the potential to support in vivo electrode localization.
Clostridium thermocellum, a cellulolytic thermophilic anaerobe, is considered by many to be a prime candidate for the realization of consolidated bioprocessing (CBP) and is known as an industry standard for biofuel production.C. thermocellumis among the best biomass degraders identified to date in nature and produces ethanol as one of its main products. Many studies have helped increase ethanol titers in this microbe; however, ethanol production usingC. thermocellumis still not economically viable. Therefore, a better understanding of its ethanol synthesis pathway is required. The main pathway for ethanol production inC. thermocelluminvolves the bifunctional aldehyde-alcohol dehydrogenase (AdhE). To better understand the function of theC. thermocellumAdhE, we used cryo-electron microscopy (cryo-EM) to obtain a 3.28 Å structure of the AdhE complex. This high-resolution structure, in combination with molecular dynamics simulations, provides insight into the substrate channeling of the toxic intermediate acetaldehyde, indicates the potential role ofC. thermocellumAdhE to regulate activity and cofactor pools, and establishes a basis for future engineering studies. The containment strategy found in this enzyme offers a template that could be replicated in other systems where toxic intermediates need to be sequestered to increase the production of valuable biochemicals.
Neurons in the brain are known to encode diverse information through their spiking activity, primarily reflecting external stimuli and internal states. However, whether individual neurons also embed information about their own anatomical location within their spike patterns remains largely unexplored. Here, we show that machine learning models can predict a neuron’s anatomical location across multiple brain regions and structures based solely on its spiking activity. Analyzing high-density recordings from thousands of neurons in awake, behaving mice, we demonstrate that anatomical location can be reliably decoded from neuronal activity across various stimulus conditions, including drifting gratings, naturalistic movies, and spontaneous activity. Crucially, anatomical signatures generalize across animals and even across different research laboratories, suggesting a fundamental principle of neural organization. Examination of trained classifiers reveals that anatomical information is enriched in specific interspike intervals as well as responses to stimuli. Within the visual isocortex, anatomical embedding is robust at the level of layers and primary versus secondary but does not robustly separate individual secondary structures. In contrast, structures within the hippocampus and thalamus are robustly separable based on their spike patterns. Our findings reveal a generalizable dimension of the neural code, where anatomical information is multiplexed with the encoding of external stimuli and internal states. This discovery provides new insights into the relationship between brain structure and function, with broad implications for neurodevelopment, multimodal integration, and the interpretation of large-scale neuronal recordings. Computational approximations of anatomy have the potential to support in vivo electrode localization.
Liquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions, including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives the formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around p130Cas-coated beads allowed their isolation, which were enriched in a subset of focal adhesion proteins, mRNAs, and RNA binding proteins, including those implicated in inhibiting mRNA translation. Plating cells on very high concentrations of fibronectin to induce large focal adhesions inhibited message translation which required p130Cas and correlated with droplet formation. Photo-induction of p130Cas condensates using the Cry2 system also reduced translation. These results identify a novel regulatory mechanism in which high adhesion limits message translation via induction of p130Cas-dependent cytoplasmic LLPS. This mechanism may contribute to the quiescent state of very strongly adhesive myofibroblasts and senescent cells.
Background:An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.Methods:In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.Results:From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor's immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.Conclusions:These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.Funding:This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).Clinical trial number:ChiCTR2200066117.
Background:An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.Methods:In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.Results:From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor's immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.Conclusions:These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.Funding:This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).Clinical trial number:ChiCTR2200066117.
Liquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions, including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives the formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around p130Cas-coated beads allowed their isolation, which were enriched in a subset of focal adhesion proteins, mRNAs, and RNA binding proteins, including those implicated in inhibiting mRNA translation. Plating cells on very high concentrations of fibronectin to induce large focal adhesions inhibited message translation which required p130Cas and correlated with droplet formation. Photo-induction of p130Cas condensates using the Cry2 system also reduced translation. These results identify a novel regulatory mechanism in which high adhesion limits message translation via induction of p130Cas-dependent cytoplasmic LLPS. This mechanism may contribute to the quiescent state of very strongly adhesive myofibroblasts and senescent cells.
In electroreceptive jawed fishes and amphibians, individual lateral line placodes form lines of neuromasts on the head containing mechanosensory hair cells, flanked by fields of ampullary organs containing electroreceptors - modified hair cells that respond to weak electric fields. Extensively shared gene expression between neuromasts and ampullary organs suggests that conserved molecular mechanisms are involved in their development, but a few transcription factor genes are restricted either to the developing electrosensory or mechanosensory lateral line. Here, we used CRISPR/Cas9-mediated mutagenesis in G0-injected sterlet embryos (Acipenser ruthenus, a sturgeon) to test the function of three such genes. We found that the 'hair cell' transcription factor geneAtoh1is required for both hair cell and electroreceptor differentiation in sterlet, and forPou4f3andGfi1expression in both neuromasts and ampullary organs. These data support the conservation of developmental mechanisms between hair cells and electroreceptors. Targeting ampullary organ-restrictedNeurod4did not yield any phenotype, potentially owing to redundancy with otherNeurodgenes that we found to be expressed in sterlet ampullary organs. After targeting mechanosensory-restrictedFoxg1, ampullary organs formed within neuromast lines, suggesting that Foxg1 normally represses their development, whether directly or indirectly. We speculate that electrosensory organs may be the 'default' developmental fate of lateral line primordia in electroreceptive vertebrates.
Patients with cerebellar damage experience various motor impairments, but the specific sequence of primary and compensatory processes that contribute to these deficits remains unclear. To clarify this, we reversibly blocked cerebellar outflow in monkeys engaged in planar reaching tasks. This intervention led to a spatially selective reduction in hand velocity, primarily due to decreased muscle torque, especially in movements requiring high inter-joint torque coupling. When examining repeated reaches to the same target, we found that the reduced velocity resulted from both an immediate deficit and a gradually developing compensatory slowing to reduce passive inter-joint interactions. However, the slowed hand velocity did not account for the fragmented and variable movement trajectories observed during the cerebellar block. Our findings indicate that cerebellar impairment results in motor deficits due to both inadequate muscle torque and an altered motor control strategy for managing impaired limb dynamics. Additionally, impaired motor control elevates noise, which cannot be entirely mitigated through compensatory strategies.
It is widely accepted that more time and information yield better decisions. However, some decisions manage to be extremely fast and yet accurate. The trick of such highspeed decisions appears to be the use of simplifying heuristics that works well for the most common condition but lacks flexibility otherwise. Here, we describe an unexpected level of flexibility in a complex highspeed decision that is made faster than an Olympic sprinter can respond to the start gun. In this decision, archerfish observe the initial speed, direction, and height of falling prey and then use these initial values to turn right towards where ballistically falling prey would later land. To analyze the limits in flexibility of this highspeed decision, we developed and critically tested a system that allowed us to replace the usual ballistic relation between initial prey motion and the expected landing point with another deterministic rule. We discovered that, surprisingly, adult fish could reprogram their highspeed decision to the new rule. Moreover, after reprogramming their decision fish were immediately able to generalize their decision to novel untrained settings, showing a remarkable degree of abstraction in how the decision circuit represented the novel rule. The decision circuit is even capable of simultaneously using two distinct sets of rules, one for each of two visually distinct objects. The flexibility and level of cognition are unexpected for a decision that lacks a speed-accuracy tradeoff and is made in less than 100 ms. Our findings demonstrate the enormous potential highspeed decision making can have and strongly suggest that we presently underappreciate this form of decision making.
Insect wings, a key innovation that contributed to the explosive diversification of insects, are recognized for their remarkable variation and many splendid adaptations. Classical morphological work subdivides insect wings into several distinct domains along the anteroposterior (AP) axis, each of which can evolve relatively independently to produce the myriad forms we see in nature. Important insights into AP subdivision of insect wings come from work inDrosophila melanogaster; however, they do not fully explain the diversity of AP domains observed across broad-winged insects. Here, we show that the transcription factormirroracts as a selector gene to differentiate a far posterior domain in the butterfly wing, classically defined as the vannus, and has effects on wing shape, scale morphology, and color pattern. Our results support models of how selector genes may facilitate evolutionarily individuation of distinct AP domains in insect wings outside ofDrosophilaand suggest that theD. melanogasterwing blade has been reduced to represent only a portion of the archetypal insect wing.
Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which depends on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies, or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3’s crucial role in NNV entry and its potential as an antiviral target.
It is widely accepted that more time and information yield better decisions. However, some decisions manage to be extremely fast and yet accurate. The trick of such highspeed decisions appears to be the use of simplifying heuristics that works well for the most common condition but lacks flexibility otherwise. Here, we describe an unexpected level of flexibility in a complex highspeed decision that is made faster than an Olympic sprinter can respond to the start gun. In this decision, archerfish observe the initial speed, direction, and height of falling prey and then use these initial values to turn right towards where ballistically falling prey would later land. To analyze the limits in flexibility of this highspeed decision, we developed and critically tested a system that allowed us to replace the usual ballistic relation between initial prey motion and the expected landing point with another deterministic rule. We discovered that, surprisingly, adult fish could reprogram their highspeed decision to the new rule. Moreover, after reprogramming their decision fish were immediately able to generalize their decision to novel untrained settings, showing a remarkable degree of abstraction in how the decision circuit represented the novel rule. The decision circuit is even capable of simultaneously using two distinct sets of rules, one for each of two visually distinct objects. The flexibility and level of cognition are unexpected for a decision that lacks a speed-accuracy tradeoff and is made in less than 100 ms. Our findings demonstrate the enormous potential highspeed decision making can have and strongly suggest that we presently underappreciate this form of decision making.
Tissue-resident memory T cells (TRM) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection are defined at minimum by three quantities: the rate at which new TRMare generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quantifying these processes individually is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4+TRMin the skin and gut lamina propria (LP) of healthy adult mice. We show that CD69+CD4+TRMin skin reside for ∼24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks, and approximately 2% of cells are replaced daily from precursors. CD69+CD4+TRMin LP have shorter residencies (∼14 days) and are maintained largely by immigration (4–6% per day). We also find evidence that the continuous replacement of CD69+CD4+TRMat both sites derives from circulating effector-memory CD4+T cells, in skin possibly via a local CD9−intermediate. Our approach maps the ontogeny of CD4+TRMin skin and LP and exposes their dynamic and distinct behaviours, with continuous seeding and erosion potentially impacting the duration of immunity at these sites.
SalmonellaDublin is a host-adapted, invasive nontyphoidalSalmonella(iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1303 genomes, coupled with in vitro assays, we examined the evolutionary, resistance, and virulence characteristics ofS. Dublin. Our analysis revealed strong geographical associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci, includingSalmonellapathogenicity island (SPI)-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies forS.Dublin infections. Collectively, this study represents the most comprehensive investigation ofS. Dublin to date and, importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinctS.Dublin lineages highlight the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.
Patients with cerebellar damage experience various motor impairments, but the specific sequence of primary and compensatory processes that contribute to these deficits remains unclear. To clarify this, we reversibly blocked cerebellar outflow in monkeys engaged in planar reaching tasks. This intervention led to a spatially selective reduction in hand velocity, primarily due to decreased muscle torque, especially in movements requiring high inter-joint torque coupling. When examining repeated reaches to the same target, we found that the reduced velocity resulted from both an immediate deficit and a gradually developing compensatory slowing to reduce passive inter-joint interactions. However, the slowed hand velocity did not account for the fragmented and variable movement trajectories observed during the cerebellar block. Our findings indicate that cerebellar impairment results in motor deficits due to both inadequate muscle torque and an altered motor control strategy for managing impaired limb dynamics. Additionally, impaired motor control elevates noise, which cannot be entirely mitigated through compensatory strategies.
Tissue-resident memory T cells (TRM) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection are defined at minimum by three quantities: the rate at which new TRMare generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quantifying these processes individually is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4+TRMin the skin and gut lamina propria (LP) of healthy adult mice. We show that CD69+CD4+TRMin skin reside for ∼24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks, and approximately 2% of cells are replaced daily from precursors. CD69+CD4+TRMin LP have shorter residencies (∼14 days) and are maintained largely by immigration (4–6% per day). We also find evidence that the continuous replacement of CD69+CD4+TRMat both sites derives from circulating effector-memory CD4+T cells, in skin possibly via a local CD9−intermediate. Our approach maps the ontogeny of CD4+TRMin skin and LP and exposes their dynamic and distinct behaviours, with continuous seeding and erosion potentially impacting the duration of immunity at these sites.
Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which depends on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies, or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3’s crucial role in NNV entry and its potential as an antiviral target.
Insect wings, a key innovation that contributed to the explosive diversification of insects, are recognized for their remarkable variation and many splendid adaptations. Classical morphological work subdivides insect wings into several distinct domains along the anteroposterior (AP) axis, each of which can evolve relatively independently to produce the myriad forms we see in nature. Important insights into AP subdivision of insect wings come from work inDrosophila melanogaster; however, they do not fully explain the diversity of AP domains observed across broad-winged insects. Here, we show that the transcription factormirroracts as a selector gene to differentiate a far posterior domain in the butterfly wing, classically defined as the vannus, and has effects on wing shape, scale morphology, and color pattern. Our results support models of how selector genes may facilitate evolutionarily individuation of distinct AP domains in insect wings outside ofDrosophilaand suggest that theD. melanogasterwing blade has been reduced to represent only a portion of the archetypal insect wing.
SalmonellaDublin is a host-adapted, invasive nontyphoidalSalmonella(iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1303 genomes, coupled with in vitro assays, we examined the evolutionary, resistance, and virulence characteristics ofS. Dublin. Our analysis revealed strong geographical associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci, includingSalmonellapathogenicity island (SPI)-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies forS.Dublin infections. Collectively, this study represents the most comprehensive investigation ofS. Dublin to date and, importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinctS.Dublin lineages highlight the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.
A growing body of research suggests that dopamine is involved in working memory updating and that the striatum takes up a critical role in the subprocess of working memory gating . In this study, we investigated subcortical – in particular, possible dopaminergic – involvement in working memory updating subprocesses using the reference-back task and ultrahigh field 7 Tesla functional magnetic resonance imaging (fMRI). Using a scanning protocol optimized for BOLD sensitivity in the subcortex, we found no evidence of subcortical activation during working memory gate opening, predominantly activations in frontoparietal network regions, which challenges the idea of a striatal gating mechanism. However, during gate closing, subcortical activation was observed. Furthermore, a ready-to-update mode demonstrated large-spread subcortical activation, including basal ganglia nuclei, suggesting that the basal ganglia are engaged in general updating processes rather than specifically controlling the working memory gate. Moreover, substituting new information into working memory elicited activation in dopamine-producing midbrain regions along with the striatum, thalamus, and prefrontal cortex, indicating engagement of the basal ganglia-thalamo-cortical loop possibly driven by (potential) dopaminergic activity. These findings expand our understanding of subcortical regions involved in working memory updating, shifting the focus from gate opening to substitution as a midbrain-driven updating process.
A growing body of research suggests that dopamine is involved in working memory updating and that the striatum takes up a critical role in the subprocess of working memory gating . In this study, we investigated subcortical – in particular, possible dopaminergic – involvement in working memory updating subprocesses using the reference-back task and ultrahigh field 7 Tesla functional magnetic resonance imaging (fMRI). Using a scanning protocol optimized for BOLD sensitivity in the subcortex, we found no evidence of subcortical activation during working memory gate opening, predominantly activations in frontoparietal network regions, which challenges the idea of a striatal gating mechanism. However, during gate closing, subcortical activation was observed. Furthermore, a ready-to-update mode demonstrated large-spread subcortical activation, including basal ganglia nuclei, suggesting that the basal ganglia are engaged in general updating processes rather than specifically controlling the working memory gate. Moreover, substituting new information into working memory elicited activation in dopamine-producing midbrain regions along with the striatum, thalamus, and prefrontal cortex, indicating engagement of the basal ganglia-thalamo-cortical loop possibly driven by (potential) dopaminergic activity. These findings expand our understanding of subcortical regions involved in working memory updating, shifting the focus from gate opening to substitution as a midbrain-driven updating process.
The risk for developing primary open-angle glaucoma (POAG) correlates with the magnitude of ocular hypertension (OHT) and the concentration of transforming growth factor-β2 (TGFβ2) in the aqueous humor. Effective treatment of POAG requires a detailed understanding of the interaction between pressure sensing mechanisms in the trabecular meshwork (TM) and biochemical risk factors. Here, we employed molecular, optical, electrophysiological, and tonometric strategies to establish the role of TGFβ2 in transcription and functional expression of mechanosensitive channel isoforms alongside studies of TM contractility in biomimetic hydrogels and intraocular pressure (IOP) regulation in a mouse model of TGFβ2-induced OHT. TGFβ2 upregulated expression ofTrpv4andPiezo1transcripts and time-dependently augmented functional TRPV4 activation. TRPV4 agonists induced contractility of TM-seeded hydrogels, whereas pharmacological inhibition suppressed TGFβ2-induced hypercontractility and abrogated OHT in eyes overexpressing TGFβ2.Trpv4-deficient mice resisted TGFβ2-driven increases in IOP, but nocturnal OHT was not additive to TGFβ-evoked OHT. Our study establishes the fundamental role of TGFβ as a modulator of mechanosensing in nonexcitable cells, identifies the TRPV4 channel as the final common mechanism for TM contractility and circadian and pathological OHT, and offers insights for future treatments that can lower IOP in the sizeable cohort of hypertensive glaucoma patients that resist current treatments.
Recent studies have provided evidence for the concurrent encoding of sensory percepts and visual working memory (VWM) contents across visual areas; however, it has remained unclear how these two types of representations are concurrently present. Here, we reanalyzed an open-access fMRI dataset where participants memorized a sensory stimulus while simultaneously being presented with sensory distractors. First, we found that the VWM code in several visual regions did not fully generalize between different time points, suggesting a dynamic code. A more detailed analysis revealed that this was due to shifts in coding spaces across time. Second, we collapsed neural signals across time to assess the degree of interference between VWM contents and sensory distractors, specifically by testing the alignment of their encoding spaces. We find that VWM and feature-matching sensory distractors are encoded in coding spaces that do not fully overlap, but the separation decreases when distractors negatively impact behavioral performance in recalling the target. Together, these results indicate a role of dynamic coding and temporally stable coding spaces in helping multiplex perception and VWM within visual areas.
Group identification may influence collective behaviors and result in variations in collective performance. However, the evidence for this hypothesis and the neural mechanisms involved remain elusive. To this end, we conducted a study using both single-brain activation and multi-brain synchronization analyses to investigate how group identification influences collective problem-solving in a murder mystery case. Our results showed that groups with high levels of identification performed better individually compared to those with low identification, as supported by single-brain activation in the dorsolateral prefrontal cortex (DLPFC). Furthermore, high-identification groups also showed enhanced collective performance, supported by within-group neural synchronization in the orbitofrontal cortex (OFC). The DLPFC–OFC connectivity played a crucial role in linking individual and collective performance. Overall, our study provides a two-in-one neural model to explain how group identification affects collective decision-making processes, offering valuable insights into the dynamics of group interactions.
Understanding the complex three-dimensional structure of cells is crucial across many disciplines in biology and especially in neuroscience. Here, we introduce a set of models including a 3D transformer (SwinUNetR) and a novel 3D self-supervised learning method (WNet3D) designed to address the inherent complexity of generating 3D ground truth data and quantifying nuclei in 3D volumes. We developed a Python package called CellSeg3D that provides access to these models in Jupyter Notebooks and in a napari GUI plugin. Recognizing the scarcity of high-quality 3D ground truth data, we created a fully human-annotated mesoSPIM dataset to advance evaluation and benchmarking in the field. To assess model performance, we benchmarked our approach across four diverse datasets: the newly developed mesoSPIM dataset, a 3D platynereis-ISH-Nuclei confocal dataset, a separate 3D Platynereis-Nuclei light-sheet dataset, and a challenging and densely packed Mouse-Skull-Nuclei confocal dataset. We demonstrate that our self-supervised model, WNet3D – trained without any ground truth labels – achieves performance on par with state-of-the-art supervised methods, paving the way for broader applications in label-scarce biological contexts.
Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore,Il1r1-/-LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32°C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.
Group identification may influence collective behaviors and result in variations in collective performance. However, the evidence for this hypothesis and the neural mechanisms involved remain elusive. To this end, we conducted a study using both single-brain activation and multi-brain synchronization analyses to investigate how group identification influences collective problem-solving in a murder mystery case. Our results showed that groups with high levels of identification performed better individually compared to those with low identification, as supported by single-brain activation in the dorsolateral prefrontal cortex (DLPFC). Furthermore, high-identification groups also showed enhanced collective performance, supported by within-group neural synchronization in the orbitofrontal cortex (OFC). The DLPFC–OFC connectivity played a crucial role in linking individual and collective performance. Overall, our study provides a two-in-one neural model to explain how group identification affects collective decision-making processes, offering valuable insights into the dynamics of group interactions.
The attentional blink reflects a ubiquitous bottleneck with selecting and processing the second of two targets that occur in close temporal proximity. An extensive literature has examined the attention blink as a unitary phenomenon. As a result, which specific component of attention – perceptual sensitivity, choice bias, or both – is compromised during the attentional blink, and their respective neural bases, remains unknown. Here, we address this question with a multialternative task and novel signal detection model, which decouples sensitivity from bias effects. We find that the attentional blink impairs specifically one component of attention – sensitivity – while leaving the other component – bias – unaffected. Distinct neural markers of the attentional blink were mapped onto distinct subcomponents of the sensitivity deficits. Parieto-occipital N2p and P3 potential amplitudes characterized target detection deficits, whereas long-range high-beta band (20–30 Hz) coherence between frontoparietal electrodes signaled target discrimination deficits. We synthesized these results with representational geometry analysis. The analysis revealed that detection and discrimination deficits were encoded along separable neural dimensions, whose configural distances robustly correlated with the neural markers of each. Overall, these findings provide detailed insights into the subcomponents of the attentional blink and reveal dissociable neural bases underlying its detection and discrimination bottlenecks.
Understanding the complex three-dimensional structure of cells is crucial across many disciplines in biology and especially in neuroscience. Here, we introduce a set of models including a 3D transformer (SwinUNetR) and a novel 3D self-supervised learning method (WNet3D) designed to address the inherent complexity of generating 3D ground truth data and quantifying nuclei in 3D volumes. We developed a Python package called CellSeg3D that provides access to these models in Jupyter Notebooks and in a napari GUI plugin. Recognizing the scarcity of high-quality 3D ground truth data, we created a fully human-annotated mesoSPIM dataset to advance evaluation and benchmarking in the field. To assess model performance, we benchmarked our approach across four diverse datasets: the newly developed mesoSPIM dataset, a 3D platynereis-ISH-Nuclei confocal dataset, a separate 3D Platynereis-Nuclei light-sheet dataset, and a challenging and densely packed Mouse-Skull-Nuclei confocal dataset. We demonstrate that our self-supervised model, WNet3D – trained without any ground truth labels – achieves performance on par with state-of-the-art supervised methods, paving the way for broader applications in label-scarce biological contexts.
We explored neural mechanisms underlying sighing in mice. Photostimulation of parafacial (pF) neuromedin B (NMB) or gastrin-releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.
We explored neural mechanisms underlying sighing in mice. Photostimulation of parafacial (pF) neuromedin B (NMB) or gastrin-releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.
Chromosome segregation is essential for cellular proliferation. Unlike eukaryotes, bacteria lack cytoskeleton-based machinery to segregate their chromosomal DNA (nucleoid). The bacterial ParABS system segregates the duplicated chromosomal regions near the origin of replication. However, this function does not explain how bacterial cells partition the rest (bulk) of the chromosomal material. Furthermore, some bacteria, includingEscherichia coli, lack a ParABS system. Yet,E. colifaithfully segregates nucleoids across various growth rates. Here, we provide theoretical and experimental evidence that polysome production during chromosomal gene expression helps compact, split, segregate, and position nucleoids inE. colithrough nonequilibrium dynamics that depend on polysome synthesis, degradation (through mRNA decay), and exclusion from the DNA meshwork. These dynamics inherently couple chromosome segregation to biomass growth across nutritional conditions. Halting chromosomal gene expression and thus polysome production immediately stops sister nucleoid migration, while ensuing polysome depletion gradually reverses nucleoid segregation. Redirecting gene expression away from the chromosome and toward plasmids causes ectopic polysome accumulations that are sufficient to drive aberrant nucleoid dynamics. Cell width enlargement experiments suggest that limiting the exchange of polysomes across DNA-free regions ensures nucleoid segregation along the cell length. Our findings suggest a self-organizing mechanism for coupling nucleoid compaction and segregation to cell growth without the apparent requirement of regulatory molecules.
Chromosome segregation is essential for cellular proliferation. Unlike eukaryotes, bacteria lack cytoskeleton-based machinery to segregate their chromosomal DNA (nucleoid). The bacterial ParABS system segregates the duplicated chromosomal regions near the origin of replication. However, this function does not explain how bacterial cells partition the rest (bulk) of the chromosomal material. Furthermore, some bacteria, includingEscherichia coli, lack a ParABS system. Yet,E. colifaithfully segregates nucleoids across various growth rates. Here, we provide theoretical and experimental evidence that polysome production during chromosomal gene expression helps compact, split, segregate, and position nucleoids inE. colithrough nonequilibrium dynamics that depend on polysome synthesis, degradation (through mRNA decay), and exclusion from the DNA meshwork. These dynamics inherently couple chromosome segregation to biomass growth across nutritional conditions. Halting chromosomal gene expression and thus polysome production immediately stops sister nucleoid migration, while ensuing polysome depletion gradually reverses nucleoid segregation. Redirecting gene expression away from the chromosome and toward plasmids causes ectopic polysome accumulations that are sufficient to drive aberrant nucleoid dynamics. Cell width enlargement experiments suggest that limiting the exchange of polysomes across DNA-free regions ensures nucleoid segregation along the cell length. Our findings suggest a self-organizing mechanism for coupling nucleoid compaction and segregation to cell growth without the apparent requirement of regulatory molecules.
The risk for developing primary open-angle glaucoma (POAG) correlates with the magnitude of ocular hypertension (OHT) and the concentration of transforming growth factor-β2 (TGFβ2) in the aqueous humor. Effective treatment of POAG requires a detailed understanding of the interaction between pressure sensing mechanisms in the trabecular meshwork (TM) and biochemical risk factors. Here, we employed molecular, optical, electrophysiological, and tonometric strategies to establish the role of TGFβ2 in transcription and functional expression of mechanosensitive channel isoforms alongside studies of TM contractility in biomimetic hydrogels and intraocular pressure (IOP) regulation in a mouse model of TGFβ2-induced OHT. TGFβ2 upregulated expression ofTrpv4andPiezo1transcripts and time-dependently augmented functional TRPV4 activation. TRPV4 agonists induced contractility of TM-seeded hydrogels, whereas pharmacological inhibition suppressed TGFβ2-induced hypercontractility and abrogated OHT in eyes overexpressing TGFβ2.Trpv4-deficient mice resisted TGFβ2-driven increases in IOP, but nocturnal OHT was not additive to TGFβ-evoked OHT. Our study establishes the fundamental role of TGFβ as a modulator of mechanosensing in nonexcitable cells, identifies the TRPV4 channel as the final common mechanism for TM contractility and circadian and pathological OHT, and offers insights for future treatments that can lower IOP in the sizeable cohort of hypertensive glaucoma patients that resist current treatments.
In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism underlying the ULK complex assembly have yet to be fully clarified. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 engages the bases of the two UBL domains in the FIP200 dimer via two phenylalanines and also binds the tandem microtubule-interacting and transport domain of ULK1, thereby yielding the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13–FIP200 triadic interaction is crucial for autophagosome formation and provides a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.
In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism underlying the ULK complex assembly have yet to be fully clarified. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 engages the bases of the two UBL domains in the FIP200 dimer via two phenylalanines and also binds the tandem microtubule-interacting and transport domain of ULK1, thereby yielding the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13–FIP200 triadic interaction is crucial for autophagosome formation and provides a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.
Striatal cholinergic interneurons (SCINs) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors (D2Rs), though the underlying membrane currents remain unknown. Moreover, the role of D5 receptors (D5Rs) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCINs, followed by a pause mediated by the activation of a Kv1-dependent delayed rectifier current. Endogenous dopamine promotes this pause through D2R stimulation, while pharmacological stimulation of D5Rs suppresses it. Remarkably, this pause is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In contrast, the D2-type receptor agonists quinpirole and sumanirole failed to reinstate a pause in dyskinetic mice. In conclusion, stimulation of thalamic inputs induces excitation followed by a pause in SCINs, which is lost in parkinsonian mice that have been rendered dyskinetic. This pause is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinson’s disease.
Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore,Il1r1-/-LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32°C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.
Recent studies have provided evidence for the concurrent encoding of sensory percepts and visual working memory (VWM) contents across visual areas; however, it has remained unclear how these two types of representations are concurrently present. Here, we reanalyzed an open-access fMRI dataset where participants memorized a sensory stimulus while simultaneously being presented with sensory distractors. First, we found that the VWM code in several visual regions did not fully generalize between different time points, suggesting a dynamic code. A more detailed analysis revealed that this was due to shifts in coding spaces across time. Second, we collapsed neural signals across time to assess the degree of interference between VWM contents and sensory distractors, specifically by testing the alignment of their encoding spaces. We find that VWM and feature-matching sensory distractors are encoded in coding spaces that do not fully overlap, but the separation decreases when distractors negatively impact behavioral performance in recalling the target. Together, these results indicate a role of dynamic coding and temporally stable coding spaces in helping multiplex perception and VWM within visual areas.
The attentional blink reflects a ubiquitous bottleneck with selecting and processing the second of two targets that occur in close temporal proximity. An extensive literature has examined the attention blink as a unitary phenomenon. As a result, which specific component of attention – perceptual sensitivity, choice bias, or both – is compromised during the attentional blink, and their respective neural bases, remains unknown. Here, we address this question with a multialternative task and novel signal detection model, which decouples sensitivity from bias effects. We find that the attentional blink impairs specifically one component of attention – sensitivity – while leaving the other component – bias – unaffected. Distinct neural markers of the attentional blink were mapped onto distinct subcomponents of the sensitivity deficits. Parieto-occipital N2p and P3 potential amplitudes characterized target detection deficits, whereas long-range high-beta band (20–30 Hz) coherence between frontoparietal electrodes signaled target discrimination deficits. We synthesized these results with representational geometry analysis. The analysis revealed that detection and discrimination deficits were encoded along separable neural dimensions, whose configural distances robustly correlated with the neural markers of each. Overall, these findings provide detailed insights into the subcomponents of the attentional blink and reveal dissociable neural bases underlying its detection and discrimination bottlenecks.
Striatal cholinergic interneurons (SCINs) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors (D2Rs), though the underlying membrane currents remain unknown. Moreover, the role of D5 receptors (D5Rs) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCINs, followed by a pause mediated by the activation of a Kv1-dependent delayed rectifier current. Endogenous dopamine promotes this pause through D2R stimulation, while pharmacological stimulation of D5Rs suppresses it. Remarkably, this pause is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In contrast, the D2-type receptor agonists quinpirole and sumanirole failed to reinstate a pause in dyskinetic mice. In conclusion, stimulation of thalamic inputs induces excitation followed by a pause in SCINs, which is lost in parkinsonian mice that have been rendered dyskinetic. This pause is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinson’s disease.
Serial dependence describes the phenomenon that current object representations are attracted to previously encoded and reported representations. While attractive biases have been observed reliably in behavior, a direct neural correlate has not been established. Previous studies have either shown a reactivation of past information without observing a neural signal related to the bias of the current information, or a repulsive distortion of current neural representations contrasting the behavioral bias. The present study recorded neural signals with magnetoencephalography (MEG) during a working memory task to identify neural correlates of serial dependence. Participants encoded and memorized two sequentially presented motion directions per trial, one of which was later retro-cued for report. Multivariate analyses provided reliable reconstructions of both motion directions. Importantly, the reconstructed directions in the current trial were attractively shifted toward the target direction of the previous trial. This neural bias mirrored the behavioral attractive bias, thus reflecting a direct neural signature of serial dependence. The use of a retro-cue task in combination with MEG allowed us to determine that this neural bias emerged at later, post-encoding time points. This timing suggests that serial dependence in working memory affects memorized information during read-out and reactivation processes that happen after the initial encoding.
Sensorimotor computations for learning and behavior rely on precise patterns of synaptic connectivity. Yet, we typically lack the synaptic wiring diagrams for long-range connections between sensory and motor circuits in the brain. Here, we provide the synaptic wiring diagram for sensorimotor circuits involved in learning and production of male zebra finch song, a natural and ethologically relevant behavior. We examined the functional synaptic connectivity from the 4 main sensory afferent pathways onto the three known classes of projection neurons of the song premotor cortical region HVC. Recordings from hundreds of identified projection neurons reveal rules for monosynaptic connectivity and the existence of polysynaptic ensembles of excitatory and inhibitory neuronal populations in HVC. Circuit tracing further identifies novel connections between HVC’s presynaptic partners. Our results indicate a modular organization of ensemble-like networks for integrating long-range input with local circuits, providing important context for information flow and computations for learned vocal behavior.
Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell–cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
Serial dependence describes the phenomenon that current object representations are attracted to previously encoded and reported representations. While attractive biases have been observed reliably in behavior, a direct neural correlate has not been established. Previous studies have either shown a reactivation of past information without observing a neural signal related to the bias of the current information, or a repulsive distortion of current neural representations contrasting the behavioral bias. The present study recorded neural signals with magnetoencephalography (MEG) during a working memory task to identify neural correlates of serial dependence. Participants encoded and memorized two sequentially presented motion directions per trial, one of which was later retro-cued for report. Multivariate analyses provided reliable reconstructions of both motion directions. Importantly, the reconstructed directions in the current trial were attractively shifted toward the target direction of the previous trial. This neural bias mirrored the behavioral attractive bias, thus reflecting a direct neural signature of serial dependence. The use of a retro-cue task in combination with MEG allowed us to determine that this neural bias emerged at later, post-encoding time points. This timing suggests that serial dependence in working memory affects memorized information during read-out and reactivation processes that happen after the initial encoding.
Sensorimotor computations for learning and behavior rely on precise patterns of synaptic connectivity. Yet, we typically lack the synaptic wiring diagrams for long-range connections between sensory and motor circuits in the brain. Here, we provide the synaptic wiring diagram for sensorimotor circuits involved in learning and production of male zebra finch song, a natural and ethologically relevant behavior. We examined the functional synaptic connectivity from the 4 main sensory afferent pathways onto the three known classes of projection neurons of the song premotor cortical region HVC. Recordings from hundreds of identified projection neurons reveal rules for monosynaptic connectivity and the existence of polysynaptic ensembles of excitatory and inhibitory neuronal populations in HVC. Circuit tracing further identifies novel connections between HVC’s presynaptic partners. Our results indicate a modular organization of ensemble-like networks for integrating long-range input with local circuits, providing important context for information flow and computations for learned vocal behavior.
Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell–cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
Cognitive control tasks require using one class of information while ignoring competing classes of information. The central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cognitive control, as inferred, typically from the task design. In prior work, we used an active place avoidance task where a rat or mouse on a rotating arena is required to avoid the stationary task-relevant locations of a mild shock and ignore the rotating task-irrelevant locations of those shocks. The task is impaired by hippocampal manipulations, and the discharge of hippocampal place cell populations judiciously alternates between representing stationary locations near the shock zone and rotating locations far from the shock zone, demonstrating cognitive control concurrently in behavior and the hippocampal representation of spatial information. Here, we test whether rat mPFC lesion impairs the active place avoidance task to evaluate two competing hypotheses, a ‘central-computation’ hypothesis that the mPFC is essential for the computations required for cognitive control and an alternative ‘local-computation’ hypothesis that other brain areas can perform the computations required for cognitive control, independent of mPFC. Ibotenic acid lesion of the mPFC was effective, damaging the cingulate, prelimbic, and infralimbic cortices. The lesion also altered the normal coordination of metabolic activity across remaining structures. The lesion did not impair learning to avoid the initial location of shock or long-term place avoidance memory, but impaired avoidance after the shock was relocated. The lesion also did not impair the alternation between task-relevant and task-irrelevant hippocampal representations of place information. These findings support the local-computation hypothesis that computations required for cognitive control can occur locally in brain networks independently of the mPFC.
Understanding neural activity organization is vital for deciphering brain function. By recording whole-brain calcium activity in larval zebrafish during hunting and spontaneous behaviors, we find that the shape of the neural activity space, described by the neural covariance spectrum, is scale-invariant: a smaller,randomly sampledcell assembly resembles the entire brain. This phenomenon can be explained by Euclidean Random Matrix theory, where neurons are reorganized from anatomical to functional positions based on their correlations. Three factors contribute to the observed scale invariance: slow neural correlation decay, higher functional space dimension, and neural activity heterogeneity. In addition to matching data from zebrafish and mice, our theory and analysis demonstrate how the geometry of neural activity space evolves with population sizes and sampling methods, thus revealing an organizing principle of brain-wide activity.
Cognitive control tasks require using one class of information while ignoring competing classes of information. The central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cognitive control, as inferred, typically from the task design. In prior work, we used an active place avoidance task where a rat or mouse on a rotating arena is required to avoid the stationary task-relevant locations of a mild shock and ignore the rotating task-irrelevant locations of those shocks. The task is impaired by hippocampal manipulations, and the discharge of hippocampal place cell populations judiciously alternates between representing stationary locations near the shock zone and rotating locations far from the shock zone, demonstrating cognitive control concurrently in behavior and the hippocampal representation of spatial information. Here, we test whether rat mPFC lesion impairs the active place avoidance task to evaluate two competing hypotheses, a ‘central-computation’ hypothesis that the mPFC is essential for the computations required for cognitive control and an alternative ‘local-computation’ hypothesis that other brain areas can perform the computations required for cognitive control, independent of mPFC. Ibotenic acid lesion of the mPFC was effective, damaging the cingulate, prelimbic, and infralimbic cortices. The lesion also altered the normal coordination of metabolic activity across remaining structures. The lesion did not impair learning to avoid the initial location of shock or long-term place avoidance memory, but impaired avoidance after the shock was relocated. The lesion also did not impair the alternation between task-relevant and task-irrelevant hippocampal representations of place information. These findings support the local-computation hypothesis that computations required for cognitive control can occur locally in brain networks independently of the mPFC.
Phosphoprotein phosphatase 1 (PP1) relies on association with PP1-interacting proteins (PIPs) to generate substrate-specific PIP/PP1 holoenzymes, but the lack of well-defined substrates has hindered elucidation of the mechanisms involved. We previously demonstrated that the Phactr1 PIP confers sequence specificity on the Phactr1/PP1 holoenzyme by remodelling the PP1 hydrophobic substrate groove. Phactr1 defines a group of ‘RVxF-ΦΦ-R-W’ PIPs that all interact with PP1 in a similar fashion. Here, we use a PP1-PIP fusion approach to address sequence specificity and identify substrates of the RVxF-ΦΦ-R-W family PIPs. We show that the four Phactr proteins confer identical sequence specificities on their holoenzymes. We identify the 4E-BP and p70 S6K translational regulators as substrates for the Neurabin/Spinophilin PIPs, implicated in neuronal plasticity, pointing to a role for their holoenzymes in mTORC1-dependent translational control. Biochemical and structural experiments show that in contrast to the Phactrs, substrate recruitment and catalytic efficiency of the PP1-Neurabin and PP1-Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining their RVxF-ΦΦ-R-W motifs, rather than by recognition of the remodelled PP1 hydrophobic groove. Thus, even PIPs that interact with PP1 in a similar manner use different mechanisms to ensure substrate selectivity.
Phosphoprotein phosphatase 1 (PP1) relies on association with PP1-interacting proteins (PIPs) to generate substrate-specific PIP/PP1 holoenzymes, but the lack of well-defined substrates has hindered elucidation of the mechanisms involved. We previously demonstrated that the Phactr1 PIP confers sequence specificity on the Phactr1/PP1 holoenzyme by remodelling the PP1 hydrophobic substrate groove. Phactr1 defines a group of ‘RVxF-ΦΦ-R-W’ PIPs that all interact with PP1 in a similar fashion. Here, we use a PP1-PIP fusion approach to address sequence specificity and identify substrates of the RVxF-ΦΦ-R-W family PIPs. We show that the four Phactr proteins confer identical sequence specificities on their holoenzymes. We identify the 4E-BP and p70 S6K translational regulators as substrates for the Neurabin/Spinophilin PIPs, implicated in neuronal plasticity, pointing to a role for their holoenzymes in mTORC1-dependent translational control. Biochemical and structural experiments show that in contrast to the Phactrs, substrate recruitment and catalytic efficiency of the PP1-Neurabin and PP1-Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining their RVxF-ΦΦ-R-W motifs, rather than by recognition of the remodelled PP1 hydrophobic groove. Thus, even PIPs that interact with PP1 in a similar manner use different mechanisms to ensure substrate selectivity.
Understanding neural activity organization is vital for deciphering brain function. By recording whole-brain calcium activity in larval zebrafish during hunting and spontaneous behaviors, we find that the shape of the neural activity space, described by the neural covariance spectrum, is scale-invariant: a smaller,randomly sampledcell assembly resembles the entire brain. This phenomenon can be explained by Euclidean Random Matrix theory, where neurons are reorganized from anatomical to functional positions based on their correlations. Three factors contribute to the observed scale invariance: slow neural correlation decay, higher functional space dimension, and neural activity heterogeneity. In addition to matching data from zebrafish and mice, our theory and analysis demonstrate how the geometry of neural activity space evolves with population sizes and sampling methods, thus revealing an organizing principle of brain-wide activity.
Streptococcus suis(S. suis) is an important zoonotic pathogen causing substantial economic losses in the swine industry.S. suisserotype 2 (SS2) is often isolated from the diseased.S. suisexpresses capsular polysaccharide (CPS), a virulence factor crucial for their survival in the blood. However, the role of CPS in the pathogenesis ofS. suisis incomplete. Here, we showed that thin CPS or no CPS was associated with efficient binding of an SS2 strain, 05ZYH33, to respiratory epithelial cells, while thick CPS increased resistance of 05ZYH33 to blood clearance. In a mouse infection model, 05ZYH33 was detected in the nasal-associated lymphoid tissue (NALT) and cerebrospinal fluid (CSF) as early as 30 min after intranasal inoculation without bacteremia. Histological analysis revealed that 05ZYH33 in the nasal cavity invaded the olfactory epithelium, resulting in early brain inflammation. Transmission electron microscopy showed that 05ZYH33 isolated from NALT and CSF at early infection time had a thin layer of CPS, and those detected in the blood 5 hr post-inoculation showed a much thicker CPS. In addition, adoptive transfer of anti-CPS restricted 05ZYH33 in the blood but not in NALT or CSF. However, an antiserum directed to multiple non-CPS virulence factors (anti-V5) efficiently inhibited 05ZYH33 in NALT, CSF, and blood. Thus, 05ZYH33 colonizes NALT more efficiently without CPS and subsequently invades the meninges through the olfactory nerve system. These findings provide valuable information for the treatment ofS. suisinfection and the development of vaccines across serotypes ofS. suisby targeting CPS-independent immunity.
Streptococcus suis(S. suis) is an important zoonotic pathogen causing substantial economic losses in the swine industry.S. suisserotype 2 (SS2) is often isolated from the diseased.S. suisexpresses capsular polysaccharide (CPS), a virulence factor crucial for their survival in the blood. However, the role of CPS in the pathogenesis ofS. suisis incomplete. Here, we showed that thin CPS or no CPS was associated with efficient binding of an SS2 strain, 05ZYH33, to respiratory epithelial cells, while thick CPS increased resistance of 05ZYH33 to blood clearance. In a mouse infection model, 05ZYH33 was detected in the nasal-associated lymphoid tissue (NALT) and cerebrospinal fluid (CSF) as early as 30 min after intranasal inoculation without bacteremia. Histological analysis revealed that 05ZYH33 in the nasal cavity invaded the olfactory epithelium, resulting in early brain inflammation. Transmission electron microscopy showed that 05ZYH33 isolated from NALT and CSF at early infection time had a thin layer of CPS, and those detected in the blood 5 hr post-inoculation showed a much thicker CPS. In addition, adoptive transfer of anti-CPS restricted 05ZYH33 in the blood but not in NALT or CSF. However, an antiserum directed to multiple non-CPS virulence factors (anti-V5) efficiently inhibited 05ZYH33 in NALT, CSF, and blood. Thus, 05ZYH33 colonizes NALT more efficiently without CPS and subsequently invades the meninges through the olfactory nerve system. These findings provide valuable information for the treatment ofS. suisinfection and the development of vaccines across serotypes ofS. suisby targeting CPS-independent immunity.
Human Immunodeficiency Virus type 1 (HIV-1) RNA genome organization remains a critical knowledge gap in understanding its replication cycle. To address this, we developed HiCapR, a psoralen crosslinking-based RNA proximity ligation method coupled with post-library hybridization, enabling high-resolution mapping of RNA-RNA interactions across the HIV-1 genome. This approach confirmed canonical structural motifs, including stem-loop architectures in the 5’-untranslated region (5’-UTR) and Rev Response Element (RRE), as well as dimerization sites within the 5’-UTR critical for viral packaging. Notably, HiCapR identified novel homodimerization events distributed along the genome, suggesting an expanded regulatory role of RNA multimerization in splicing regulation and selective encapsidation. Intriguingly, while infected cells exhibited extensive long-range RNA interactions—particularly within the 5’-UTR—virion-packaged genomes displayed a marked reduction in such interactions, indicative of a structural transition from a loosely organized state to a condensed conformation. This spatial reorganization coincided with the preservation of stable genomic domains essential for dimerization, which persisted throughout virion assembly. These domains, enriched at homodimer interfaces, likely serve as structural scaffolds ensuring fidelity during genome packaging. This work establishes HiCapR as a robust tool for probing RNA interactomes and provides mechanistic insights into how HIV-1 exploits RNA topological heterogeneity to regulate its life cycle. The identification of conserved structural domains and transient interaction networks opens avenues for targeting RNA conformation in antiviral strategies.
Perceptual updating has been hypothesised to rely on a network reset modulated by bursts of ascending neuromodulatory neurotransmitters, such as noradrenaline, abruptly altering the brain’s susceptibility to changing sensory activity. To test this hypothesis at a large-scale, we analysed an ambiguous figures task using pupillometry and functional magnetic resonance imaging (fMRI). Behaviourally, qualitative shifts in the perceptual interpretation of an ambiguous image were associated with peaks in pupil diameter, an indirect readout of phasic bursts in neuromodulatory tone. We further hypothesised that stimulus ambiguity drives neuromodulatory tone, leading to heightened neural gain, hastening perceptual switches. To explore this hypothesis computationally, we trained a recurrent neural network (RNN) on an analogous perceptual categorisation task, allowing gain to change dynamically with classification uncertainty. As predicted, higher gain accelerated perceptual switching by transiently destabilising the network’s dynamical regime in periods of maximal uncertainty. We leveraged a low-dimensional readout of the RNN dynamics to develop two novel macroscale predictions: perceptual switches should occur with peaks in low-dimensional brain state velocity and with a flattened egocentric energy landscape. Using fMRI, we confirmed these predictions, highlighting the role of the neuromodulatory system in the large-scale network reconfigurations mediating adaptive perceptual updates.
Human Immunodeficiency Virus type 1 (HIV-1) RNA genome organization remains a critical knowledge gap in understanding its replication cycle. To address this, we developed HiCapR, a psoralen crosslinking-based RNA proximity ligation method coupled with post-library hybridization, enabling high-resolution mapping of RNA-RNA interactions across the HIV-1 genome. This approach confirmed canonical structural motifs, including stem-loop architectures in the 5’-untranslated region (5’-UTR) and Rev Response Element (RRE), as well as dimerization sites within the 5’-UTR critical for viral packaging. Notably, HiCapR identified novel homodimerization events distributed along the genome, suggesting an expanded regulatory role of RNA multimerization in splicing regulation and selective encapsidation. Intriguingly, while infected cells exhibited extensive long-range RNA interactions—particularly within the 5’-UTR—virion-packaged genomes displayed a marked reduction in such interactions, indicative of a structural transition from a loosely organized state to a condensed conformation. This spatial reorganization coincided with the preservation of stable genomic domains essential for dimerization, which persisted throughout virion assembly. These domains, enriched at homodimer interfaces, likely serve as structural scaffolds ensuring fidelity during genome packaging. This work establishes HiCapR as a robust tool for probing RNA interactomes and provides mechanistic insights into how HIV-1 exploits RNA topological heterogeneity to regulate its life cycle. The identification of conserved structural domains and transient interaction networks opens avenues for targeting RNA conformation in antiviral strategies.
Perceptual updating has been hypothesised to rely on a network reset modulated by bursts of ascending neuromodulatory neurotransmitters, such as noradrenaline, abruptly altering the brain’s susceptibility to changing sensory activity. To test this hypothesis at a large-scale, we analysed an ambiguous figures task using pupillometry and functional magnetic resonance imaging (fMRI). Behaviourally, qualitative shifts in the perceptual interpretation of an ambiguous image were associated with peaks in pupil diameter, an indirect readout of phasic bursts in neuromodulatory tone. We further hypothesised that stimulus ambiguity drives neuromodulatory tone, leading to heightened neural gain, hastening perceptual switches. To explore this hypothesis computationally, we trained a recurrent neural network (RNN) on an analogous perceptual categorisation task, allowing gain to change dynamically with classification uncertainty. As predicted, higher gain accelerated perceptual switching by transiently destabilising the network’s dynamical regime in periods of maximal uncertainty. We leveraged a low-dimensional readout of the RNN dynamics to develop two novel macroscale predictions: perceptual switches should occur with peaks in low-dimensional brain state velocity and with a flattened egocentric energy landscape. Using fMRI, we confirmed these predictions, highlighting the role of the neuromodulatory system in the large-scale network reconfigurations mediating adaptive perceptual updates.
Babesiosis is a disease brought on by intraerythrocytic parasites of the genusBabesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs againstBabesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyPlasmodiumandToxoplasma. This study evaluated the growth-inhibiting properties of CIP againstBabesiaspp. and investigated the mechanism of CIP onB. gibsoni. The half inhibitory concentration (IC50) values of CIP against the in vitro growth ofB. bovisandB. gibsoniwere 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofB. microtiandB. rodhainiin vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4L921Vand BgATP4L921I, respectively, compared to that of BgATP4WT. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4L921Vand BgATP4L921Icompared to BgATP4WT. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC50values. Combining CIP with TQ effectively eliminatedB. microtiinfection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.
Salmonellais a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections.Salmonellamust utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellularSalmonellagrowth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical forSalmonellareplication inside macrophages. The concentration of β-alanine is decreased inSalmonella-infected macrophages, while the addition of exogenous β-alanine enhancesSalmonellareplication in macrophages, suggesting thatSalmonellacan uptake host-derived β-alanine for intracellular growth. Moreover, the expression ofpanD,the rate-limiting gene required for β-alanine synthesis inSalmonella,is upregulated whenSalmonellaenters macrophages. Mutation ofpanDimpairedSalmonellareplication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellularSalmonellagrowth and systemic infection. Additionally, we revealed that β-alanine influencesSalmonellaintracellular replication and in vivo virulence partially by increasing expression of the zinc transporter genesznuABC, which in turn facilitates the uptake of the essential micronutrient zinc bySalmonella. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence ofSalmonella, andpanDis a promising target for controlling systemicSalmonellainfection.
Salmonellais a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections.Salmonellamust utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellularSalmonellagrowth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical forSalmonellareplication inside macrophages. The concentration of β-alanine is decreased inSalmonella-infected macrophages, while the addition of exogenous β-alanine enhancesSalmonellareplication in macrophages, suggesting thatSalmonellacan uptake host-derived β-alanine for intracellular growth. Moreover, the expression ofpanD,the rate-limiting gene required for β-alanine synthesis inSalmonella,is upregulated whenSalmonellaenters macrophages. Mutation ofpanDimpairedSalmonellareplication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellularSalmonellagrowth and systemic infection. Additionally, we revealed that β-alanine influencesSalmonellaintracellular replication and in vivo virulence partially by increasing expression of the zinc transporter genesznuABC, which in turn facilitates the uptake of the essential micronutrient zinc bySalmonella. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence ofSalmonella, andpanDis a promising target for controlling systemicSalmonellainfection.
Babesiosis is a disease brought on by intraerythrocytic parasites of the genusBabesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs againstBabesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyPlasmodiumandToxoplasma. This study evaluated the growth-inhibiting properties of CIP againstBabesiaspp. and investigated the mechanism of CIP onB. gibsoni. The half inhibitory concentration (IC50) values of CIP against the in vitro growth ofB. bovisandB. gibsoniwere 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofB. microtiandB. rodhainiin vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4L921Vand BgATP4L921I, respectively, compared to that of BgATP4WT. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4L921Vand BgATP4L921Icompared to BgATP4WT. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC50values. Combining CIP with TQ effectively eliminatedB. microtiinfection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.
Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher- and lower-level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA receptors and recurrent processing in humans has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively improved decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings suggest that NMDA inhibition through memantine enhances recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.
Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher- and lower-level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA receptors and recurrent processing in humans has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively improved decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings suggest that NMDA inhibition through memantine enhances recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.
In mammals, olfactory sensory neurons (OSNs) are born throughout life, ostensibly solely to replace neurons lostviaturnover or injury. This assumption follows from the hypothesis that olfactory neurogenesis is stochastic with respect to neuron subtype, as defined by the single odorant receptor that each neural precursor stochastically chooses out of hundreds of possibilities. This assumption is challenged, however, by recent findings that the birthrates of a fraction of OSN subtypes are selectively reduced by olfactory deprivation. These findings raise questions about how, and why, olfactory stimuli are required to accelerate the neurogenesis rates of some subtypes, including whether the stimuli are specific (e.g. discrete odorants) or generic (e.g. broadly activating odors or mechanical stimuli). Based on previous findings that the exposure of mice to sex-specific odors can increase the representations of subtypes responsive to those odors, we hypothesized that the neurogenic stimuli comprise discrete odorants that selectively stimulate OSNs of the same subtypes whose birthrates are accelerated. In support of this, we have found, using scRNA-seq and subtype-specific OSN birthdating, that exposure to male and exogenous musk odors can accelerate the birthrates of subtypes responsive to those odors. These findings reveal that certain odor experiences can selectively ‘amplify’ specific OSN subtypes and suggest that persistent OSN neurogenesis serves, in part, an adaptive function.
Radiotherapy resistance in nasopharyngeal carcinoma (NPC) is a major cause of recurrence and metastasis. Identifying radiotherapy-related biomarkers is crucial for improving patient survival outcomes. This study developed the nasopharyngeal carcinoma radiotherapy sensitivity score (NPC-RSS) to predict radiotherapy response. By evaluating 113 machine learning algorithm combinations, the glmBoost+NaiveBayes model was selected to construct the NPC-RSS based on 18 key genes, which demonstrated good predictive performance in both public and in-house datasets. The study found that NPC-RSS is closely associated with immune features, including chemokine factors and their receptor families and the major histocompatibility complex (MHC). Gene functional analysis revealed that NPC-RSS influences key signaling pathways such as Wnt/β-catenin, JAK-STAT, NF-κB, and T cell receptors. Cell line validation confirmed that SMARCA2 and CD9 gene expression is consistent with NPC-RSS. Single-cell analysis revealed that the radiotherapy-sensitive group exhibited richer immune infiltration and activation states. NPC-RSS can serve as a predictive tool for radiotherapy sensitivity in NPC, offering new insights for precise screening of patients who may benefit from radiotherapy.
Larvae of the ascidianCionainitiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowingCionato maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator ofCionametamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation.
In the past, immune memory was considered an exclusive feature of the adaptive immune system. However, accumulating evidence suggests that the innate immune system, the most primitive and fundamental component of immunity, can mount more robust responses to non-specific stimuli following prior exposure to different types of initial stimuli, a phenomenon known as trained immunity. Trained immunity has been extensively studied in diverse disease contexts, including infectious diseases, autoimmune disorders, and chronic inflammatory conditions. Notably, significant advancements have been made in recent years in understanding the roles and therapeutic potential of trained immunity in oncology. This review aims to explore the multifaceted roles of trained immunity across different cancer types, providing a comprehensive summary of the pertinent stimuli and associated molecular mechanisms. Additionally, we evaluate the clinical applications of various trained immunity stimuli in cancer therapy and offer perspectives on future directions for integrating trained immunity into cancer treatment strategies.
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Radiotherapy resistance in nasopharyngeal carcinoma (NPC) is a major cause of recurrence and metastasis. Identifying radiotherapy-related biomarkers is crucial for improving patient survival outcomes. This study developed the nasopharyngeal carcinoma radiotherapy sensitivity score (NPC-RSS) to predict radiotherapy response. By evaluating 113 machine learning algorithm combinations, the glmBoost+NaiveBayes model was selected to construct the NPC-RSS based on 18 key genes, which demonstrated good predictive performance in both public and in-house datasets. The study found that NPC-RSS is closely associated with immune features, including chemokine factors and their receptor families and the major histocompatibility complex (MHC). Gene functional analysis revealed that NPC-RSS influences key signaling pathways such as Wnt/β-catenin, JAK-STAT, NF-κB, and T cell receptors. Cell line validation confirmed that SMARCA2 and CD9 gene expression is consistent with NPC-RSS. Single-cell analysis revealed that the radiotherapy-sensitive group exhibited richer immune infiltration and activation states. NPC-RSS can serve as a predictive tool for radiotherapy sensitivity in NPC, offering new insights for precise screening of patients who may benefit from radiotherapy.
In mammals, olfactory sensory neurons (OSNs) are born throughout life, ostensibly solely to replace neurons lostviaturnover or injury. This assumption follows from the hypothesis that olfactory neurogenesis is stochastic with respect to neuron subtype, as defined by the single odorant receptor that each neural precursor stochastically chooses out of hundreds of possibilities. This assumption is challenged, however, by recent findings that the birthrates of a fraction of OSN subtypes are selectively reduced by olfactory deprivation. These findings raise questions about how, and why, olfactory stimuli are required to accelerate the neurogenesis rates of some subtypes, including whether the stimuli are specific (e.g. discrete odorants) or generic (e.g. broadly activating odors or mechanical stimuli). Based on previous findings that the exposure of mice to sex-specific odors can increase the representations of subtypes responsive to those odors, we hypothesized that the neurogenic stimuli comprise discrete odorants that selectively stimulate OSNs of the same subtypes whose birthrates are accelerated. In support of this, we have found, using scRNA-seq and subtype-specific OSN birthdating, that exposure to male and exogenous musk odors can accelerate the birthrates of subtypes responsive to those odors. These findings reveal that certain odor experiences can selectively ‘amplify’ specific OSN subtypes and suggest that persistent OSN neurogenesis serves, in part, an adaptive function.
Larvae of the ascidianCionainitiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowingCionato maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator ofCionametamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation.
Experiments with tools designed to detect DNA damage reveal unique and conserved features of telomeres in cancer cells.
Heterotopic ossification (HO) occurs following mechanical trauma and burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidylinositol 3-kinase alpha (PI3Kα) may be a useful therapy for patients undergoing HO. In this study, using the already marketed BYL719/Alpelisib/Piqray drug, we have further confirmed these results, detailed the underlying mechanisms of action, and optimized the timing of the administration of BYL719. We found that BYL719 effectively prevents HO even when administered up to 3–7 days after injury. We demonstrate in cell cultures and in a mouse model of HO that the major actions of BYL719 are on-target effects through the inhibition of PI3Kα, without directly affecting ACVR1 or FOP-inducing ACVR1R206Hkinase activities. In vivo, we found that a lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification but also reduces the inflammatory response. BYL719 inhibits the migration, proliferation, and expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specificPhosphatase and tensin homologconditional knockout (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway inPten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-outCtnnb1, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.
Contextual fear conditioning (CFC) is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. Few paradigms examine contextual fear in head-fixed mice, and none use freezing—the most common measure of fear in freely moving animals—as the behavioral readout. To address this gap, we developed a CFC paradigm for head-fixed mice using virtual reality (VR). We designed an apparatus to deliver tail shocks while mice navigated a VR environment. We tested three versions of this paradigm and, in all of them, observed increased freezing, particularly on the first trial, in the shock-paired VR compared to a neutral one. These results demonstrate that head-fixed mice can be fear-conditioned in VR and exhibit context-specific freezing behavior. Additionally, using two-photon calcium imaging, we tracked large populations of hippocampal CA1 neurons before, during, and following CFC. As in freely moving mice, CA1 place cells remapped and developed narrower fields following fear conditioning. Thus, our approach enables new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories.
Most of the human gastric cancer (GC) worldwide are ascribed toHelicobacter pyloriinfections, which have a detrimental effect on the immunotherapy’s efficacy. Comprehensively dissecting the key cell players and molecular pathways associated with cancer immunotherapies is critical for developing novel therapeutic strategies againstH. pyloriinfection-associated human GC. We performed a comprehensive single-cell transcriptome analysis of nine GC patients with currentH. pyloriinfection (HpGC), three GC patients with previousH. pyloriinfection (ex-HpGC), six GC patients withoutH. pyloriinfection (non-HpGC), and six healthy controls (HC). We also investigated key cell players and molecular pathways associated with GC immunotherapy outcomes. We revealed the molecular heterogeneity of different cell components in GC, including epithelium, immune cells, and cancer-associated fibroblasts (CAFs) at the single-cell level. The malignant epithelium of HpGC exhibited high expression level of inflammatory and epithelial–mesenchymal transition signature, HpGC and ex-HpGC were enriched with VEGFA+ angiogenic tumor-associated macrophages (Angio-TAM) and IL11+ inflammatory CAF (iCAF), characterized by high expression levels of NECTIN2 and VEGFA/B. Additionally, we found significant correlations between the abundance of iCAF with Angio-TAM and TIGIT+ suppressive T cells, and iCAF interacted with Angio-TAM through the VEGF and ANGPTL angiogenic pathways. We also developed an immune signature and angiogenic signature and demonstrated that the iCAF abundance and angiogenic signature could predict poor immunotherapy outcomes in GC. We revealed the transcriptome characteristics and heterogeneity of various cellular constituents of HpGC patients and demonstrated that a synergistic combination of immunotherapy and anti-angiogenic targeted therapy may be an effective therapeutic modality for HpGC patients.
The nervous system undergoes functional modification independent of cell turnover. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins ofDrosophilaexecutioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near the plasma membrane. We demonstrated thatFas3Goverexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically,Fas3Goverexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly restricted caspase activation, defined by caspase-proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase-proximal proteins.
The nervous system undergoes functional modification independent of cell turnover. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins ofDrosophilaexecutioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near the plasma membrane. We demonstrated thatFas3Goverexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically,Fas3Goverexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly restricted caspase activation, defined by caspase-proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase-proximal proteins.
Contextual fear conditioning (CFC) is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. Few paradigms examine contextual fear in head-fixed mice, and none use freezing—the most common measure of fear in freely moving animals—as the behavioral readout. To address this gap, we developed a CFC paradigm for head-fixed mice using virtual reality (VR). We designed an apparatus to deliver tail shocks while mice navigated a VR environment. We tested three versions of this paradigm and, in all of them, observed increased freezing, particularly on the first trial, in the shock-paired VR compared to a neutral one. These results demonstrate that head-fixed mice can be fear-conditioned in VR and exhibit context-specific freezing behavior. Additionally, using two-photon calcium imaging, we tracked large populations of hippocampal CA1 neurons before, during, and following CFC. As in freely moving mice, CA1 place cells remapped and developed narrower fields following fear conditioning. Thus, our approach enables new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories.
Most of the human gastric cancer (GC) worldwide are ascribed toHelicobacter pyloriinfections, which have a detrimental effect on the immunotherapy’s efficacy. Comprehensively dissecting the key cell players and molecular pathways associated with cancer immunotherapies is critical for developing novel therapeutic strategies againstH. pyloriinfection-associated human GC. We performed a comprehensive single-cell transcriptome analysis of nine GC patients with currentH. pyloriinfection (HpGC), three GC patients with previousH. pyloriinfection (ex-HpGC), six GC patients withoutH. pyloriinfection (non-HpGC), and six healthy controls (HC). We also investigated key cell players and molecular pathways associated with GC immunotherapy outcomes. We revealed the molecular heterogeneity of different cell components in GC, including epithelium, immune cells, and cancer-associated fibroblasts (CAFs) at the single-cell level. The malignant epithelium of HpGC exhibited high expression level of inflammatory and epithelial–mesenchymal transition signature, HpGC and ex-HpGC were enriched with VEGFA+ angiogenic tumor-associated macrophages (Angio-TAM) and IL11+ inflammatory CAF (iCAF), characterized by high expression levels of NECTIN2 and VEGFA/B. Additionally, we found significant correlations between the abundance of iCAF with Angio-TAM and TIGIT+ suppressive T cells, and iCAF interacted with Angio-TAM through the VEGF and ANGPTL angiogenic pathways. We also developed an immune signature and angiogenic signature and demonstrated that the iCAF abundance and angiogenic signature could predict poor immunotherapy outcomes in GC. We revealed the transcriptome characteristics and heterogeneity of various cellular constituents of HpGC patients and demonstrated that a synergistic combination of immunotherapy and anti-angiogenic targeted therapy may be an effective therapeutic modality for HpGC patients.
Heterotopic ossification (HO) occurs following mechanical trauma and burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidylinositol 3-kinase alpha (PI3Kα) may be a useful therapy for patients undergoing HO. In this study, using the already marketed BYL719/Alpelisib/Piqray drug, we have further confirmed these results, detailed the underlying mechanisms of action, and optimized the timing of the administration of BYL719. We found that BYL719 effectively prevents HO even when administered up to 3–7 days after injury. We demonstrate in cell cultures and in a mouse model of HO that the major actions of BYL719 are on-target effects through the inhibition of PI3Kα, without directly affecting ACVR1 or FOP-inducing ACVR1R206Hkinase activities. In vivo, we found that a lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification but also reduces the inflammatory response. BYL719 inhibits the migration, proliferation, and expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specificPhosphatase and tensin homologconditional knockout (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway inPten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-outCtnnb1, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.
Dopaminergic neurons (DANs) play key roles in processing rewards and punishments across species. They evaluate sensory input, store memories, and update them based on relevance. To understand how individual DANs contribute to these functions, we studiedDrosophilalarvae, which have only about 120 DANs. Only eight of these project to the mushroom body (MB), a center for olfactory learning. These eight are divided into the pPAM and DL1 clusters, with four DANs each. We confirmed that pPAM neurons in the MB medial lobe encode sugar rewards. In the DL1 cluster, four neurons—DAN-c1, DAN-d1, DAN-f1, and DAN-g1—each target different MB regions. Notably, optogenetic activation of DAN-f1 and DAN-g1 can substitute for punishment. Additional methods (inhibition, calcium imaging, connectomics) show each DL1 DAN encodes a unique aspect of punishment, with DAN-g1 being pivotal for salt-based signals. Our findings reveal a clear division of labor among larval DL1 DANs for encoding punishment. The striking resemblance in the organizing principle of larval DANs with that of its adult counterpart and the mammalian basal ganglion suggests that there may be a limited number of efficient neural circuit solutions available to address more complex cognitive challenges in nature.
Dopaminergic neurons (DANs) play key roles in processing rewards and punishments across species. They evaluate sensory input, store memories, and update them based on relevance. To understand how individual DANs contribute to these functions, we studiedDrosophilalarvae, which have only about 120 DANs. Only eight of these project to the mushroom body (MB), a center for olfactory learning. These eight are divided into the pPAM and DL1 clusters, with four DANs each. We confirmed that pPAM neurons in the MB medial lobe encode sugar rewards. In the DL1 cluster, four neurons—DAN-c1, DAN-d1, DAN-f1, and DAN-g1—each target different MB regions. Notably, optogenetic activation of DAN-f1 and DAN-g1 can substitute for punishment. Additional methods (inhibition, calcium imaging, connectomics) show each DL1 DAN encodes a unique aspect of punishment, with DAN-g1 being pivotal for salt-based signals. Our findings reveal a clear division of labor among larval DL1 DANs for encoding punishment. The striking resemblance in the organizing principle of larval DANs with that of its adult counterpart and the mammalian basal ganglion suggests that there may be a limited number of efficient neural circuit solutions available to address more complex cognitive challenges in nature.
The brain is thought to construct an optimal internal model representing the probabilistic structure of the environment accurately. Evidence suggests that spontaneous brain activity gives such a model by cycling through activity patterns evoked by previous sensory experiences with the experienced probabilities. The brain’s spontaneous activity emerges from internally driven neural population dynamics. However, how cortical neural networks encode internal models into spontaneous activity is poorly understood. Recent computational and experimental studies suggest that a cortical neuron can implement complex computations, including predictive responses, through soma–dendrite interactions. Here, we show that a recurrent network of spiking neurons subject to the same predictive learning principle provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. In this network, the learning rules minimize probability mismatches between stimulus-evoked and internally driven activities in all excitatory and inhibitory neurons. This learning paradigm generates stimulus-specific cell assemblies that internally remember their activation probabilities using within-assembly recurrent connections. Our model contrasts previous models that encode the statistical structure of sensory experiences into Markovian transition patterns among cell assemblies. We demonstrate that the spontaneous activity of our model well replicates the behavioral biases of monkeys performing perceptual decision making. Our results suggest that interactions between intracellular processes and recurrent network dynamics are more crucial for learning cognitive behaviors than previously thought.
Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening.
Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus respond to multiple metabolic signals and distribute neuroendocrine information to other brain regions such as the paraventricular hypothalamic nucleus (PVH), which plays a central role in metabolic homeostasis. Neural projections from AgRP neurons to the PVH form during the postnatal lactational period in mice and these projections are reduced in offspring of dams that consumed a high-fat diet (HFD) during lactation (MHFD-L). Here, we used immunohistochemistry to visualize microglial morphology in MHFD-L offspring and identified changes that were regionally localized to the PVH and appeared temporally restricted to the period when AgRP neurons innervate this region. In addition, axon labeling experiments revealed that microglia engulf AgRP terminals in the PVH, and that the density of AgRP innervation to the PVH in MHFD-L offspring may be dependent on microglia, because microglial depletion blocked the decrease in PVH AgRP innervation observed in MHFD-L offspring, as well as prevented the increased body weight exhibited at weaning. Together, these findings suggest that microglia are activated by exposure to MHFD-L and interact directly with AgRP axons during postnatal development to permanently alter innervation of the PVH, with implications for developmental programming of metabolic phenotype.
Sensory perception is the ability through which an organism is able to process sensory stimuli from the environment. This stimulus is transmitted from the peripheral sensory organs to the central nervous system, where it is interpreted.Drosophila melanogasterlarvae possess peripheral sense organs on their head, thoracic, and abdominal segments. These are specialized to receive diverse environmental information, such as olfactory, gustatory, temperature, or mechanosensory signals. In this work, we complete the description of the morphology of external larval sensilla and provide a comprehensive map of the ultrastructure of the different types of sensilla that comprise them. This was achieved by 3D electron microscopic analysis of partial and whole body volumes, which contain high-resolution and complete three-dimensional data of the anatomy of the sensilla and adjacent ganglia. Our analysis revealed three main types of sensilla on thoracic and abdominal segments: the papilla sensillum, the hair sensillum, and the knob sensillum. They occur solitary or organized in compound sensilla such as the thoracic keilin’s organ or the terminal sensory cones. We present a spatial map defining these sensilla by their position on thoracic and abdominal segments. Furthermore, we identify and name the sensilla at the larval head and the last fused abdominal segments. We show that mechanosensation dominates in the larval peripheral nervous system, as most sensilla have corresponding structural properties. The result of this work, the construction of a complete structural and neuronal map of the external larval sensilla, provides the basis for following molecular and functional studies to understand which sensory strategies theDrosophilalarva employs to orient itself in its natural environment.
Sensory perception is the ability through which an organism is able to process sensory stimuli from the environment. This stimulus is transmitted from the peripheral sensory organs to the central nervous system, where it is interpreted.Drosophila melanogasterlarvae possess peripheral sense organs on their head, thoracic, and abdominal segments. These are specialized to receive diverse environmental information, such as olfactory, gustatory, temperature, or mechanosensory signals. In this work, we complete the description of the morphology of external larval sensilla and provide a comprehensive map of the ultrastructure of the different types of sensilla that comprise them. This was achieved by 3D electron microscopic analysis of partial and whole body volumes, which contain high-resolution and complete three-dimensional data of the anatomy of the sensilla and adjacent ganglia. Our analysis revealed three main types of sensilla on thoracic and abdominal segments: the papilla sensillum, the hair sensillum, and the knob sensillum. They occur solitary or organized in compound sensilla such as the thoracic keilin’s organ or the terminal sensory cones. We present a spatial map defining these sensilla by their position on thoracic and abdominal segments. Furthermore, we identify and name the sensilla at the larval head and the last fused abdominal segments. We show that mechanosensation dominates in the larval peripheral nervous system, as most sensilla have corresponding structural properties. The result of this work, the construction of a complete structural and neuronal map of the external larval sensilla, provides the basis for following molecular and functional studies to understand which sensory strategies theDrosophilalarva employs to orient itself in its natural environment.
Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.
Motivational deficits are common in several brain disorders, and motivational syndromes like apathy and anhedonia predict worse outcomes. Disrupted effort-based decision-making may represent a neurobiological underpinning of motivational deficits, shared across neuropsychiatric disorders. We measured effort-based decision-making in 994 participants using a gamified online task, combined with computational modelling, and validated offline for test–retest reliability. In two pre-registered studies, we first replicated studies linking impaired effort-based decision-making to neuropsychiatric syndromes, taking both a transdiagnostic and a diagnostic-criteria approach. Next, testing participants withearlyandlatecircadian rhythms in the morning and evening, we find circadian rhythm interacts with time-of-testing to produce parallel effects on effort-based decision-making. Circadian rhythm may be an important variable in computational psychiatry, decreasing reliability or distorting results when left unaccounted for. Disentangling effects of neuropsychiatric syndromes and circadian rhythm on effort-based decision-making will be essential to understand motivational pathologies and to develop tailored clinical interventions.
Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.
Describing morphogenesis generally consists in aggregating the multiple high-resolution spatiotemporal processes involved into reproducible low-dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks as they can be time consuming, hence unfit for scale, and often lack standardization and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardized framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.
Schuster et al.demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (Schuster et al., 2021). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in 1 out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions.
Schuster et al.demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (Schuster et al., 2021). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in 1 out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions.
The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
The brain is thought to construct an optimal internal model representing the probabilistic structure of the environment accurately. Evidence suggests that spontaneous brain activity gives such a model by cycling through activity patterns evoked by previous sensory experiences with the experienced probabilities. The brain’s spontaneous activity emerges from internally driven neural population dynamics. However, how cortical neural networks encode internal models into spontaneous activity is poorly understood. Recent computational and experimental studies suggest that a cortical neuron can implement complex computations, including predictive responses, through soma–dendrite interactions. Here, we show that a recurrent network of spiking neurons subject to the same predictive learning principle provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. In this network, the learning rules minimize probability mismatches between stimulus-evoked and internally driven activities in all excitatory and inhibitory neurons. This learning paradigm generates stimulus-specific cell assemblies that internally remember their activation probabilities using within-assembly recurrent connections. Our model contrasts previous models that encode the statistical structure of sensory experiences into Markovian transition patterns among cell assemblies. We demonstrate that the spontaneous activity of our model well replicates the behavioral biases of monkeys performing perceptual decision making. Our results suggest that interactions between intracellular processes and recurrent network dynamics are more crucial for learning cognitive behaviors than previously thought.
Describing morphogenesis generally consists in aggregating the multiple high-resolution spatiotemporal processes involved into reproducible low-dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks as they can be time consuming, hence unfit for scale, and often lack standardization and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardized framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.
Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are trained and tested on cross-sectional data from primarily Caucasian, adult participants. It is thus unclear how well these models generalize to non-Caucasian participants, especially children. Here, we tested a previously published deep learning model on Singaporean elderly participants (55−88 years old) and children (4−11 years old). We found that the model directly generalized to the elderly participants, but model finetuning was necessary for children. After finetuning, we found that the rate of change in brain age gap was associated with future executive function performance in both elderly participants and children. We further found that lateral ventricles and frontal areas contributed to brain age prediction in elderly participants, while white matter and posterior brain regions were more important in predicting brain age of children. Taken together, our results suggest that there is potential for generalizing brain age models to diverse populations. Moreover, the longitudinal change in brain age gap reflects developing and aging processes in the brain, relating to future cognitive function.
Motivational deficits are common in several brain disorders, and motivational syndromes like apathy and anhedonia predict worse outcomes. Disrupted effort-based decision-making may represent a neurobiological underpinning of motivational deficits, shared across neuropsychiatric disorders. We measured effort-based decision-making in 994 participants using a gamified online task, combined with computational modelling, and validated offline for test–retest reliability. In two pre-registered studies, we first replicated studies linking impaired effort-based decision-making to neuropsychiatric syndromes, taking both a transdiagnostic and a diagnostic-criteria approach. Next, testing participants withearlyandlatecircadian rhythms in the morning and evening, we find circadian rhythm interacts with time-of-testing to produce parallel effects on effort-based decision-making. Circadian rhythm may be an important variable in computational psychiatry, decreasing reliability or distorting results when left unaccounted for. Disentangling effects of neuropsychiatric syndromes and circadian rhythm on effort-based decision-making will be essential to understand motivational pathologies and to develop tailored clinical interventions.
Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus respond to multiple metabolic signals and distribute neuroendocrine information to other brain regions such as the paraventricular hypothalamic nucleus (PVH), which plays a central role in metabolic homeostasis. Neural projections from AgRP neurons to the PVH form during the postnatal lactational period in mice and these projections are reduced in offspring of dams that consumed a high-fat diet (HFD) during lactation (MHFD-L). Here, we used immunohistochemistry to visualize microglial morphology in MHFD-L offspring and identified changes that were regionally localized to the PVH and appeared temporally restricted to the period when AgRP neurons innervate this region. In addition, axon labeling experiments revealed that microglia engulf AgRP terminals in the PVH, and that the density of AgRP innervation to the PVH in MHFD-L offspring may be dependent on microglia, because microglial depletion blocked the decrease in PVH AgRP innervation observed in MHFD-L offspring, as well as prevented the increased body weight exhibited at weaning. Together, these findings suggest that microglia are activated by exposure to MHFD-L and interact directly with AgRP axons during postnatal development to permanently alter innervation of the PVH, with implications for developmental programming of metabolic phenotype.
Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening.
Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are trained and tested on cross-sectional data from primarily Caucasian, adult participants. It is thus unclear how well these models generalize to non-Caucasian participants, especially children. Here, we tested a previously published deep learning model on Singaporean elderly participants (55−88 years old) and children (4−11 years old). We found that the model directly generalized to the elderly participants, but model finetuning was necessary for children. After finetuning, we found that the rate of change in brain age gap was associated with future executive function performance in both elderly participants and children. We further found that lateral ventricles and frontal areas contributed to brain age prediction in elderly participants, while white matter and posterior brain regions were more important in predicting brain age of children. Taken together, our results suggest that there is potential for generalizing brain age models to diverse populations. Moreover, the longitudinal change in brain age gap reflects developing and aging processes in the brain, relating to future cognitive function.
Touch-sensitive neurons in the fingertips take previous physical contacts into account when relaying tactile information to the brain.
Human skin and its underlying tissues constitute a viscoelastic medium, implying that any deformation depends not only on the currently applied force, but also on the recent loading history. The extent to which this physical memory influences the signaling of first-order tactile neurons during natural hand use is not well understood. Here, we examined the effect of past loading on the responses of fast-adapting (FA-1) and slowly-adapting (SA-1 and SA-2) first-order tactile neurons innervating the human fingertip to loadings applied in different directions representative of object manipulation tasks. We found that variation in the preceding loading affected neurons’ overall signaling of force direction. Some neurons kept signaling the current direction, while others signaled both the current and preceding direction, or even primarily the preceding direction. In addition, ongoing impulse activity in SA-2 neurons between loadings signaled information related to the fingertip’s viscoelastic deformation state. We conclude that tactile neurons at the population level signal continuous information about the fingertip’s viscoelastic deformation state, which is shaped by both its recent history and current loading. Such information might be sufficient for the brain to correctly interpret current force loading and help in computing accurate motor commands for interactions with objects in manipulation and haptic tasks.
Complex brain function comprises a multitude of neural operations in parallel and often at different speeds. Each of these operations is carried out across a network of distributed brain regions. How multiple distributed processes are facilitated in parallel is largely unknown. We postulate that such processing relies on a multiplex of dynamic network patterns emerging in parallel but from different functional connectivity (FC) timescales. Given the dominance of inherently slow fMRI in network science, it is unknown whether the brain leverages such multi-timescale network dynamics. We studied FC dynamics concurrently across a breadth of timescales (from infraslow to γ-range) in rare, simultaneously recorded intracranial EEG and fMRI in humans, and source-localized scalp EEG-fMRI data in humans. We examined spatial and temporal convergence of connectome trajectories across timescales. ‘Spatial convergence’ refers to spatially similar EEG and fMRI connectome patterns, while ‘temporal convergence’ signifies the more specific case of spatial convergence at corresponding timepoints in EEG and fMRI. We observed spatial convergence but temporal divergence across FC timescales; connectome states (recurrent FC patterns) with partial spatial similarity were found in fMRI and all EEG frequency bands, but these occurred asynchronously across FC timescales. Our findings suggest that hemodynamic and frequency-specific electrophysiological signals, while involving similar large-scale networks, represent functionally distinct connectome trajectories that operate at different FC speeds and in parallel. This multiplex is poised to enable concurrent connectivity across multiple sets of brain regions independently.
Breast carcinoma amplified sequence 2 (BCAS2), a core component of the hPrP19 complex, plays crucial roles in various physiological and pathological processes. However, whether BCAS2 has functions other than being a key RNA-splicing regulator within the nucleus remains unknown. Here, we show that BCAS2 is essential for primitive hematopoiesis in zebrafish and mouse embryos. The activation of Wnt/β-catenin signaling, which is required for hematopoietic progenitor differentiation, is significantly decreased upon depletion ofbcas2in zebrafish embryos and mouse embryonic fibroblasts. Interestingly, BCAS2 deficiency has no obvious impact on the splicing efficiency of β-catenin pre-mRNA, while significantly attenuating β-catenin nuclear accumulation. Moreover, we find that BCAS2 directly binds to β-catenin via its coiled-coil domains, thereby sequestering β-catenin within the nucleus. Thus, our results uncover a previously unknown function of BCAS2 in promoting Wnt signaling by enhancing β-catenin nuclear retention during primitive hematopoiesis.
Human skin and its underlying tissues constitute a viscoelastic medium, implying that any deformation depends not only on the currently applied force, but also on the recent loading history. The extent to which this physical memory influences the signaling of first-order tactile neurons during natural hand use is not well understood. Here, we examined the effect of past loading on the responses of fast-adapting (FA-1) and slowly-adapting (SA-1 and SA-2) first-order tactile neurons innervating the human fingertip to loadings applied in different directions representative of object manipulation tasks. We found that variation in the preceding loading affected neurons’ overall signaling of force direction. Some neurons kept signaling the current direction, while others signaled both the current and preceding direction, or even primarily the preceding direction. In addition, ongoing impulse activity in SA-2 neurons between loadings signaled information related to the fingertip’s viscoelastic deformation state. We conclude that tactile neurons at the population level signal continuous information about the fingertip’s viscoelastic deformation state, which is shaped by both its recent history and current loading. Such information might be sufficient for the brain to correctly interpret current force loading and help in computing accurate motor commands for interactions with objects in manipulation and haptic tasks.
Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across the occipital cortex and are usually largest when the cortex is inactive. However, recent studies measuring visual receptive fields have reported that local alpha power increases when cortex is excited by visual stimulation. This contrasts with the expectation that alpha oscillations are associated with cortical inactivity. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We hypothesized that stimulus-driven local increases in alpha power result from a mixture of two effects: a reduction in alpha oscillatory power and a simultaneous increase in broadband power. To test this, we implemented a model to separate these components. The two components were then independently fit by population receptive field (pRF) models. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power but are several times larger and exhibit the opposite effect: alpha oscillatory power decreases in response to stimuli within the receptive field, reinforcing the link between alpha oscillations and cortical inactivity, whereas broadband power increases. The results demonstrate that alpha suppression in the human visual cortex can be precisely tuned, but that to measure these effects, it is essential to separate the oscillatory signal from broadband power changes. Finally, we show how the large size and the negative valence of alpha pRFs can explain key features of exogenous visual attention.
Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across the occipital cortex and are usually largest when the cortex is inactive. However, recent studies measuring visual receptive fields have reported that local alpha power increases when cortex is excited by visual stimulation. This contrasts with the expectation that alpha oscillations are associated with cortical inactivity. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We hypothesized that stimulus-driven local increases in alpha power result from a mixture of two effects: a reduction in alpha oscillatory power and a simultaneous increase in broadband power. To test this, we implemented a model to separate these components. The two components were then independently fit by population receptive field (pRF) models. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power but are several times larger and exhibit the opposite effect: alpha oscillatory power decreases in response to stimuli within the receptive field, reinforcing the link between alpha oscillations and cortical inactivity, whereas broadband power increases. The results demonstrate that alpha suppression in the human visual cortex can be precisely tuned, but that to measure these effects, it is essential to separate the oscillatory signal from broadband power changes. Finally, we show how the large size and the negative valence of alpha pRFs can explain key features of exogenous visual attention.
Metazoans detect and differentiate between innocuous (non-painful) and/or noxious (harmful) environmental cues using primary sensory neurons, which serve as the first node in a neural network that computes stimulus-specific behaviors to either navigate away from injury-causing conditions or to perform protective behaviors that mitigate extensive injury. The ability of an animal to detect and respond to various sensory stimuli depends upon molecular diversity in the primary sensors and the underlying neural circuitry responsible for the relevant behavioral action selection. Recent studies inDrosophilalarvae have revealed that somatosensory class III multidendritic (CIII md) neurons function as multimodal sensors regulating distinct behavioral responses to innocuous mechanical and nociceptive thermal stimuli. Recent advances in circuit bases of behavior have identified and functionally validatedDrosophilalarval somatosensory circuitry involved in innocuous (mechanical) and noxious (heat and mechanical) cues. However, central processing of cold nociceptive cues remained unexplored. We implicate multisensory integrators (Basins), premotor (Down-and-Back), and projection (A09e and TePns) neurons as neural substrates required for cold-evoked behavioral and calcium responses. Neural silencing of cell types downstream of CIII md neurons led to significant reductions in cold-evoked behaviors, and neural co-activation of CIII md neurons plus additional cell types facilitated larval contraction (CT) responses. Further, we demonstrate that optogenetic activation of CIII md neurons evokes calcium increases in these neurons. Finally, we characterize the premotor to motor neuron network underlying cold-evoked CT and delineate the muscular basis of CT response. Collectively, we demonstrate howDrosophilalarvae process cold stimuli through functionally diverse somatosensory circuitry responsible for generating stimulus-specific behaviors.
Single-cell RNA-sequencing (scRNA-seq) coupled with robust computational analysis facilitates the characterization of phenotypic heterogeneity within tumors. Current scRNA-seq analysis pipelines are capable of identifying a myriad of malignant and non-malignant cell subtypes from single-cell profiling of tumors. However, given the extent of intra-tumoral heterogeneity, it is challenging to assess the risk associated with individual cell subpopulations, primarily due to the complexity of the cancer phenotype space and the lack of clinical annotations associated with tumor scRNA-seq studies. To this end, we introduce SCellBOW, a scRNA-seq analysis framework inspired by document embedding techniques from the domain of Natural Language Processing (NLP). SCellBOW is a novel computational approach that facilitates effective identification and high-quality visualization of single-cell subpopulations. We compared SCellBOW with existing best practice methods for its ability to precisely represent phenotypically divergent cell types across multiple scRNA-seq datasets, including our in-house generated human splenocyte and matched peripheral blood mononuclear cell (PBMC) dataset. For tumor cells, SCellBOW estimates the relative risk associated with each cluster and stratifies them based on their aggressiveness. This is achieved by simulating how the presence or absence of a specific cell subpopulation influences disease prognosis. Using SCellBOW, we identified a hitherto unknown and pervasive AR−/NElow(androgen-receptor-negative, neuroendocrine-low) malignant subpopulation in metastatic prostate cancer with conspicuously high aggressiveness. Overall, the risk-stratification capabilities of SCellBOW hold promise for formulating tailored therapeutic interventions by identifying clinically relevant tumor subpopulations and their impact on prognosis.
Complex brain function comprises a multitude of neural operations in parallel and often at different speeds. Each of these operations is carried out across a network of distributed brain regions. How multiple distributed processes are facilitated in parallel is largely unknown. We postulate that such processing relies on a multiplex of dynamic network patterns emerging in parallel but from different functional connectivity (FC) timescales. Given the dominance of inherently slow fMRI in network science, it is unknown whether the brain leverages such multi-timescale network dynamics. We studied FC dynamics concurrently across a breadth of timescales (from infraslow to γ-range) in rare, simultaneously recorded intracranial EEG and fMRI in humans, and source-localized scalp EEG-fMRI data in humans. We examined spatial and temporal convergence of connectome trajectories across timescales. ‘Spatial convergence’ refers to spatially similar EEG and fMRI connectome patterns, while ‘temporal convergence’ signifies the more specific case of spatial convergence at corresponding timepoints in EEG and fMRI. We observed spatial convergence but temporal divergence across FC timescales; connectome states (recurrent FC patterns) with partial spatial similarity were found in fMRI and all EEG frequency bands, but these occurred asynchronously across FC timescales. Our findings suggest that hemodynamic and frequency-specific electrophysiological signals, while involving similar large-scale networks, represent functionally distinct connectome trajectories that operate at different FC speeds and in parallel. This multiplex is poised to enable concurrent connectivity across multiple sets of brain regions independently.
Single-cell RNA-sequencing (scRNA-seq) coupled with robust computational analysis facilitates the characterization of phenotypic heterogeneity within tumors. Current scRNA-seq analysis pipelines are capable of identifying a myriad of malignant and non-malignant cell subtypes from single-cell profiling of tumors. However, given the extent of intra-tumoral heterogeneity, it is challenging to assess the risk associated with individual cell subpopulations, primarily due to the complexity of the cancer phenotype space and the lack of clinical annotations associated with tumor scRNA-seq studies. To this end, we introduce SCellBOW, a scRNA-seq analysis framework inspired by document embedding techniques from the domain of Natural Language Processing (NLP). SCellBOW is a novel computational approach that facilitates effective identification and high-quality visualization of single-cell subpopulations. We compared SCellBOW with existing best practice methods for its ability to precisely represent phenotypically divergent cell types across multiple scRNA-seq datasets, including our in-house generated human splenocyte and matched peripheral blood mononuclear cell (PBMC) dataset. For tumor cells, SCellBOW estimates the relative risk associated with each cluster and stratifies them based on their aggressiveness. This is achieved by simulating how the presence or absence of a specific cell subpopulation influences disease prognosis. Using SCellBOW, we identified a hitherto unknown and pervasive AR−/NElow(androgen-receptor-negative, neuroendocrine-low) malignant subpopulation in metastatic prostate cancer with conspicuously high aggressiveness. Overall, the risk-stratification capabilities of SCellBOW hold promise for formulating tailored therapeutic interventions by identifying clinically relevant tumor subpopulations and their impact on prognosis.
Metazoans detect and differentiate between innocuous (non-painful) and/or noxious (harmful) environmental cues using primary sensory neurons, which serve as the first node in a neural network that computes stimulus-specific behaviors to either navigate away from injury-causing conditions or to perform protective behaviors that mitigate extensive injury. The ability of an animal to detect and respond to various sensory stimuli depends upon molecular diversity in the primary sensors and the underlying neural circuitry responsible for the relevant behavioral action selection. Recent studies inDrosophilalarvae have revealed that somatosensory class III multidendritic (CIII md) neurons function as multimodal sensors regulating distinct behavioral responses to innocuous mechanical and nociceptive thermal stimuli. Recent advances in circuit bases of behavior have identified and functionally validatedDrosophilalarval somatosensory circuitry involved in innocuous (mechanical) and noxious (heat and mechanical) cues. However, central processing of cold nociceptive cues remained unexplored. We implicate multisensory integrators (Basins), premotor (Down-and-Back), and projection (A09e and TePns) neurons as neural substrates required for cold-evoked behavioral and calcium responses. Neural silencing of cell types downstream of CIII md neurons led to significant reductions in cold-evoked behaviors, and neural co-activation of CIII md neurons plus additional cell types facilitated larval contraction (CT) responses. Further, we demonstrate that optogenetic activation of CIII md neurons evokes calcium increases in these neurons. Finally, we characterize the premotor to motor neuron network underlying cold-evoked CT and delineate the muscular basis of CT response. Collectively, we demonstrate howDrosophilalarvae process cold stimuli through functionally diverse somatosensory circuitry responsible for generating stimulus-specific behaviors.
Breast carcinoma amplified sequence 2 (BCAS2), a core component of the hPrP19 complex, plays crucial roles in various physiological and pathological processes. However, whether BCAS2 has functions other than being a key RNA-splicing regulator within the nucleus remains unknown. Here, we show that BCAS2 is essential for primitive hematopoiesis in zebrafish and mouse embryos. The activation of Wnt/β-catenin signaling, which is required for hematopoietic progenitor differentiation, is significantly decreased upon depletion ofbcas2in zebrafish embryos and mouse embryonic fibroblasts. Interestingly, BCAS2 deficiency has no obvious impact on the splicing efficiency of β-catenin pre-mRNA, while significantly attenuating β-catenin nuclear accumulation. Moreover, we find that BCAS2 directly binds to β-catenin via its coiled-coil domains, thereby sequestering β-catenin within the nucleus. Thus, our results uncover a previously unknown function of BCAS2 in promoting Wnt signaling by enhancing β-catenin nuclear retention during primitive hematopoiesis.
Zebrafish is an important organism for genetic studies, but its early germ cell types and the mechanism of sex differentiation have not been fully characterized. Here, we profiled single-cell transcriptomes and charted a developmental trajectory going from germline stem cells, through early, committed, and late progenitors, to pre-meiotic and meiotic cells. We showed that transcription factor Foxl2l expressed in the progenitor directed progenitor differentiation toward oocytes. CRISPR-Cas9-mediated mutation offoxl2lproduced 100% male fish with normal fertility. Another single-cell profiling offoxl2l-/-germ cells revealed the arrest of germ cell development at the stage of progenitor commitment. Concomitantly,nanos2transcript (germline stem cell marker) was elevated together with an increase ofnanos2+germ cells infoxl2lmutants, indicating the acquisition of a novel stem cell state. Thus, we have identified developmental stages of germ cells in juvenile zebrafish and demonstrated that zebrafish Foxl2l drives progenitor germ cells toward feminization and prevents them from expressingnanos2.
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Background:Trials of incretins are making it increasingly clear that body mass index (BMI) is linked to several diseases throughout life, but trials cannot easily provide a comprehensive assessment of the role of BMI in health-related attributes for men and women. To systematically investigate the role of BMI, we conducted a sex-specific Mendelian randomization-phenome-wide association study.Methods:We comprehensively examined the associations of genetically predicted BMI in women (n: 194,174) and men (n: 167,020) using health-related attributes from the UK Biobank with inverse variance weighting and sensitivity analysis.Results:BMI impacted 232 of 776 traits considered in women and 203 of 680 traits in men, after adjusting for false discovery; differences by sex were found for 105 traits, and 46 traits remained after adjusting for false discovery. BMI was more strongly positively associated with myocardial infarction, major coronary heart disease events, ischemic heart disease, and heart attack in men than women. BMI was more strongly positively associated with apolipoprotein B (ApoB) and diastolic blood pressure in women than men.Conclusions:Our study revealed that BMI might affect a wide range of health-related attributes and also highlights notable sex differences in its impact, including opposite associations for certain attributes, such as ApoB; and stronger effects in men, such as for cardiovascular diseases. Our findings underscore the need for nuanced, sex-specific policy related to BMI to address inequities in health.Funding:None.
Kinesin motor proteins facilitate microtubule-based transport by converting chemical energy into mechanical forces, but this activity is autoinhibited until cargo is loaded. Regulatory mechanisms underlying this autoinhibitory conformation are not well understood. Here, we show that a NEver in mitosis Kinase NEKL-3 directly phosphorylates a flexible elbow region between two coiled-coil domains connecting the motor head and tail of an intraflagellar transport kinesin, OSM-3. The phosphor-dead (PD) mutation, but not phosphor-mimic (PM) mutation, induces constitutive motility of OSM-3 in vitro. Using knock-in animals, we discovered that both PD and PM mutations shorten theC. eleganssensory cilia. The constitutively active OSM-3PD fails to enter cilia and abnormally accumulates in neurites, mimicking another hyperactive mutation, OSM-3G444E. Conversely, OSM-3PM enters cilia but moves at a reduced speed, indicating an inhibitory role of elbow phosphorylation in kinesin motility. These findings highlight the crucial role of elbow phosphorylation in regulating kinesin autoinhibition.
Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea that seriously threatens public health. The disruption of normal gut microbiota by the use of broad-spectrum antimicrobial agents enablesC. difficileto proliferate in the colon. The emergence and prevalence of hypervirulentC. difficilestrains result in increased morbidity, mortality, and high recurrence rates of CDI, thus creating a pressing need for novel therapeutics. The multi-domain toxins TcdA and TcdB are the primary determinants of CDI pathogenesis, rendering them ideal drug targets in the anti-virulence paradigm. In this study, we identified caffeic acid and its derivatives from natural compounds library as active inhibitors of TcdB via a cell-based high-throughput phenotypic screening. Further mechanistic investigations revealed that caffeic acid phenethyl ester (CAPE) could directly bind to TcdB, thus suppressing InsP6-induced autoproteolysis and inhibiting glucosyltransferase activity. CAPE treatment remarkably reduces the pathology of CDI in a murine infection model in terms of alleviated diarrhea symptoms, decreased bacterial colonization, and relieved histopathological lesions. Moreover, CAPE treatment ofC. difficile-challenged mice induces a remarkable increase in the diversity and composition of the gut microbiota and alterations of gut metabolites (e.g., adenosine, D-proline, and melatonin), which might partially contribute to the therapeutic outcomes of CAPE against CDI. Our results reveal the potential of CAPE as a therapeutic for the management of CDI, or CAPE might serve as a lead compound for the development of antivirulence drugs targeting TcdB.
Background:Trials of incretins are making it increasingly clear that body mass index (BMI) is linked to several diseases throughout life, but trials cannot easily provide a comprehensive assessment of the role of BMI in health-related attributes for men and women. To systematically investigate the role of BMI, we conducted a sex-specific Mendelian randomization-phenome-wide association study.Methods:We comprehensively examined the associations of genetically predicted BMI in women (n: 194,174) and men (n: 167,020) using health-related attributes from the UK Biobank with inverse variance weighting and sensitivity analysis.Results:BMI impacted 232 of 776 traits considered in women and 203 of 680 traits in men, after adjusting for false discovery; differences by sex were found for 105 traits, and 46 traits remained after adjusting for false discovery. BMI was more strongly positively associated with myocardial infarction, major coronary heart disease events, ischemic heart disease, and heart attack in men than women. BMI was more strongly positively associated with apolipoprotein B (ApoB) and diastolic blood pressure in women than men.Conclusions:Our study revealed that BMI might affect a wide range of health-related attributes and also highlights notable sex differences in its impact, including opposite associations for certain attributes, such as ApoB; and stronger effects in men, such as for cardiovascular diseases. Our findings underscore the need for nuanced, sex-specific policy related to BMI to address inequities in health.Funding:None.
Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individual’s age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength, and stimulus-reaction time. The model predicted a person’s age with best accuracy when it heavily weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated ‘biological’ age and chronological age (∆Age) appear to reflect an individual’s relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate ∆Age. Remarkably, the effect of each year of physiological ∆Age on Gompertz mortality risk was equivalent to that of one chronological year. A genome-wide association study (GWAS) of ∆Age and analysis of environmental factors associated with ∆Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a person’s biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.
The brain learns an internal model of the environment through sensory experiences, which is essential for high-level cognitive processes. Recent studies show that spontaneous activity reflects such a learned internal model. Although computational studies have proposed that Hebbian plasticity can learn the switching dynamics of replayed activities, it is still challenging to learn dynamic spontaneous activity that obeys the statistical properties of sensory experience. Here, we propose a pair of biologically plausible plasticity rules for excitatory and inhibitory synapses in a recurrent spiking neural network model to embed stochastic dynamics in spontaneous activity. The proposed synaptic plasticity rule for excitatory synapses seeks to minimize the discrepancy between stimulus-evoked and internally predicted activity, while inhibitory plasticity maintains the excitatory-inhibitory balance. We show that the spontaneous reactivation of cell assemblies follows the transition statistics of the model’s evoked dynamics. We also demonstrate that simulations of our model can replicate recent experimental results of spontaneous activity in songbirds, suggesting that the proposed plasticity rule might underlie the mechanism by which animals learn internal models of the environment.
Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individual’s age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength, and stimulus-reaction time. The model predicted a person’s age with best accuracy when it heavily weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated ‘biological’ age and chronological age (∆Age) appear to reflect an individual’s relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate ∆Age. Remarkably, the effect of each year of physiological ∆Age on Gompertz mortality risk was equivalent to that of one chronological year. A genome-wide association study (GWAS) of ∆Age and analysis of environmental factors associated with ∆Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a person’s biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.
Kinesin motor proteins facilitate microtubule-based transport by converting chemical energy into mechanical forces, but this activity is autoinhibited until cargo is loaded. Regulatory mechanisms underlying this autoinhibitory conformation are not well understood. Here, we show that a NEver in mitosis Kinase NEKL-3 directly phosphorylates a flexible elbow region between two coiled-coil domains connecting the motor head and tail of an intraflagellar transport kinesin, OSM-3. The phosphor-dead (PD) mutation, but not phosphor-mimic (PM) mutation, induces constitutive motility of OSM-3 in vitro. Using knock-in animals, we discovered that both PD and PM mutations shorten theC. eleganssensory cilia. The constitutively active OSM-3PD fails to enter cilia and abnormally accumulates in neurites, mimicking another hyperactive mutation, OSM-3G444E. Conversely, OSM-3PM enters cilia but moves at a reduced speed, indicating an inhibitory role of elbow phosphorylation in kinesin motility. These findings highlight the crucial role of elbow phosphorylation in regulating kinesin autoinhibition.
Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis.RUNX2has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis and apoptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferation in vitro and tumorigenesis in vivo in oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis and apoptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can upregulate RUNX2 isoform II to inhibit ferroptosis and apoptosis and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway.
Mapping the vascular organization of the brain is of great importance across various domains of basic neuroimaging research, diagnostic radiology, and neurology. However, the intricate task of precisely mapping vasculature across brain regions and cortical layers presents formidable challenges, resulting in a limited understanding of neurometabolic factors influencing the brain’s microvasculature. Addressing this gap, our study investigates whole-brain vascular volume using ferumoxytol-weighted laminar-resolution multi-echo gradient-echo imaging in macaque monkeys. We validate the results with published data for vascular densities and compare them with cytoarchitecture, neuron and synaptic densities. The ferumoxytol-induced change in transverse relaxation rate (ΔR2*), an indirect proxy measure of cerebral blood volume (CBV), was mapped onto 12 equivolumetric laminar cortical surfaces. Our findings reveal that CBV varies threefold across the brain, with the highest vascular volume observed in the inferior colliculus and lowest in the corpus callosum. In the cerebral cortex, CBV is notably high in early primary sensory areas and low in association areas responsible for higher cognitive functions. Classification of CBV into distinct groups unveils extensive replication of translaminar vascular network motifs, suggesting distinct computational energy supply requirements in areas with varying cytoarchitecture types. Regionally, baseline R2* and CBV exhibit positive correlations with neuron density and negative correlations with receptor densities. Adjusting image resolution based on the critical sampling frequency of penetrating cortical vessels allows us to delineate approximately 30% of the arterial–venous vessels. Collectively, these results mark significant methodological and conceptual advancements, contributing to the refinement of cerebrovascular MRI. Furthermore, our study establishes a linkage between neurometabolic factors and the vascular network architecture in the primate brain.
The brain learns an internal model of the environment through sensory experiences, which is essential for high-level cognitive processes. Recent studies show that spontaneous activity reflects such a learned internal model. Although computational studies have proposed that Hebbian plasticity can learn the switching dynamics of replayed activities, it is still challenging to learn dynamic spontaneous activity that obeys the statistical properties of sensory experience. Here, we propose a pair of biologically plausible plasticity rules for excitatory and inhibitory synapses in a recurrent spiking neural network model to embed stochastic dynamics in spontaneous activity. The proposed synaptic plasticity rule for excitatory synapses seeks to minimize the discrepancy between stimulus-evoked and internally predicted activity, while inhibitory plasticity maintains the excitatory-inhibitory balance. We show that the spontaneous reactivation of cell assemblies follows the transition statistics of the model’s evoked dynamics. We also demonstrate that simulations of our model can replicate recent experimental results of spontaneous activity in songbirds, suggesting that the proposed plasticity rule might underlie the mechanism by which animals learn internal models of the environment.
Mapping the vascular organization of the brain is of great importance across various domains of basic neuroimaging research, diagnostic radiology, and neurology. However, the intricate task of precisely mapping vasculature across brain regions and cortical layers presents formidable challenges, resulting in a limited understanding of neurometabolic factors influencing the brain’s microvasculature. Addressing this gap, our study investigates whole-brain vascular volume using ferumoxytol-weighted laminar-resolution multi-echo gradient-echo imaging in macaque monkeys. We validate the results with published data for vascular densities and compare them with cytoarchitecture, neuron and synaptic densities. The ferumoxytol-induced change in transverse relaxation rate (ΔR2*), an indirect proxy measure of cerebral blood volume (CBV), was mapped onto 12 equivolumetric laminar cortical surfaces. Our findings reveal that CBV varies threefold across the brain, with the highest vascular volume observed in the inferior colliculus and lowest in the corpus callosum. In the cerebral cortex, CBV is notably high in early primary sensory areas and low in association areas responsible for higher cognitive functions. Classification of CBV into distinct groups unveils extensive replication of translaminar vascular network motifs, suggesting distinct computational energy supply requirements in areas with varying cytoarchitecture types. Regionally, baseline R2* and CBV exhibit positive correlations with neuron density and negative correlations with receptor densities. Adjusting image resolution based on the critical sampling frequency of penetrating cortical vessels allows us to delineate approximately 30% of the arterial–venous vessels. Collectively, these results mark significant methodological and conceptual advancements, contributing to the refinement of cerebrovascular MRI. Furthermore, our study establishes a linkage between neurometabolic factors and the vascular network architecture in the primate brain.
Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis.RUNX2has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis and apoptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferation in vitro and tumorigenesis in vivo in oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis and apoptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can upregulate RUNX2 isoform II to inhibit ferroptosis and apoptosis and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway.
Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea that seriously threatens public health. The disruption of normal gut microbiota by the use of broad-spectrum antimicrobial agents enablesC. difficileto proliferate in the colon. The emergence and prevalence of hypervirulentC. difficilestrains result in increased morbidity, mortality, and high recurrence rates of CDI, thus creating a pressing need for novel therapeutics. The multi-domain toxins TcdA and TcdB are the primary determinants of CDI pathogenesis, rendering them ideal drug targets in the anti-virulence paradigm. In this study, we identified caffeic acid and its derivatives from natural compounds library as active inhibitors of TcdB via a cell-based high-throughput phenotypic screening. Further mechanistic investigations revealed that caffeic acid phenethyl ester (CAPE) could directly bind to TcdB, thus suppressing InsP6-induced autoproteolysis and inhibiting glucosyltransferase activity. CAPE treatment remarkably reduces the pathology of CDI in a murine infection model in terms of alleviated diarrhea symptoms, decreased bacterial colonization, and relieved histopathological lesions. Moreover, CAPE treatment ofC. difficile-challenged mice induces a remarkable increase in the diversity and composition of the gut microbiota and alterations of gut metabolites (e.g., adenosine, D-proline, and melatonin), which might partially contribute to the therapeutic outcomes of CAPE against CDI. Our results reveal the potential of CAPE as a therapeutic for the management of CDI, or CAPE might serve as a lead compound for the development of antivirulence drugs targeting TcdB.
Understanding developmental changes in neuronal lineages is crucial to elucidate how they assemble into functional neural networks. Studies investigating nervous system development in model systems have only focused on select regions of the CNS due to the limited availability of genetic drivers that target specific neuronal lineages throughout development and adult life. This has hindered our understanding of how distinct neuronal lineages interconnect to form neuronal circuits during development. Here, we present a split-GAL4 library composed of genetic driver lines, which we generated via editing the genomic locus of lineage-specific transcription factors and demonstrate that we can use this library to specifically target most individual neuronal hemilineages in theDrosophilaventral nerve cord (VNC) throughout development and into adulthood. Using these genetic driver lines, we found striking morphological changes in neuronal processes within a lineage during metamorphosis. We also demonstrated how neurochemical features of neuronal classes can be quickly assessed. Lastly, we documented behaviors elicited in response to optogenetic activation of individual neuronal lineages and generated a comprehensive lineage-behavior map of the entire fly VNC. Looking forward, this lineage-specific split-GAL4 driver library will provide the genetic tools needed to address the questions emerging from the analysis of the recent VNC connectome and transcriptome datasets.
Dynamic CpG methylation ‘barcodes’ were read from 15,000–21,000 single cells from three human male brains. To overcome sparse sequencing coverage, the barcode had ~31,000 rapidly fluctuating X-chromosome CpG sites (fCpGs), with at least 500 covered sites per cell and at least 30 common sites between cell pairs (average of ~48). Barcodes appear to start methylated and record mitotic ages because excitatory neurons and glial cells that emerge later in development were less methylated. Barcodes are different between most cells, with average pairwise differences (PWDs) of ~0.5 between cells. About 10 cell pairs per million were more closely related with PWDs <0.05. Barcodes appear to record ancestry and reconstruct trees where more related cells had similar phenotypes, albeit some pairs had phenotypic differences. Inhibitory neurons showed more evidence of tangential migration than excitatory neurons, with related cells in different cortical regions. fCpG barcodes become polymorphic during development and can distinguish between thousands of human cells.
Understanding developmental changes in neuronal lineages is crucial to elucidate how they assemble into functional neural networks. Studies investigating nervous system development in model systems have only focused on select regions of the CNS due to the limited availability of genetic drivers that target specific neuronal lineages throughout development and adult life. This has hindered our understanding of how distinct neuronal lineages interconnect to form neuronal circuits during development. Here, we present a split-GAL4 library composed of genetic driver lines, which we generated via editing the genomic locus of lineage-specific transcription factors and demonstrate that we can use this library to specifically target most individual neuronal hemilineages in theDrosophilaventral nerve cord (VNC) throughout development and into adulthood. Using these genetic driver lines, we found striking morphological changes in neuronal processes within a lineage during metamorphosis. We also demonstrated how neurochemical features of neuronal classes can be quickly assessed. Lastly, we documented behaviors elicited in response to optogenetic activation of individual neuronal lineages and generated a comprehensive lineage-behavior map of the entire fly VNC. Looking forward, this lineage-specific split-GAL4 driver library will provide the genetic tools needed to address the questions emerging from the analysis of the recent VNC connectome and transcriptome datasets.
During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner. Weak synapses are preferentially removed, but the mechanism linking neuronal activity to synapse removal is unclear. Here, we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 deficiency results in defects in synapse elimination driven by both spontaneous and experience-dependent neural activity. Notably, caspase-3 deficiency blocks activity-dependent synapse elimination, as evidenced by reduced engulfment of inactive synapses by microglia. Furthermore, in a mouse model of Alzheimer’s disease, caspase-3 deficiency protects against synapse loss induced by amyloid-β deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.
The myometrium plays a critical role during pregnancy as it is responsible for both the structural integrity of the uterus and force generation at term. Emerging studies in mice indicate a dynamic change of the myometrial epigenome and transcriptome during pregnancy to ready the contractile machinery for parturition. However, the regulatory systems underlying myometrial gene expression patterns throughout gestation remain largely unknown. Here, we investigated human term pregnant nonlabor myometrial biopsies for transcriptome, enhancer histone mark cistrome, and chromatin conformation pattern mapping. More than thirty thousand putative enhancers with H3K27ac and H3K4me1 double positive marks were identified in the myometrium. Enriched transcription factor binding motifs include known myometrial regulators AP-1, STAT, NFkB, and PGR among others. Putative myometrial super enhancers are mostly colocalized with progesterone receptor-occupying sites and preferentially associated with highly expressing genes, suggesting a conserved role of PGR in regulating the myometrial transcriptome between species. In human myometrial specimens, inferred PGR activities are positively correlated with phospholipase C like 2 (PLCL2) mRNA levels, supporting that PGR may act through this genomic region to promotePLCL2expression. PGR overexpression facilitatedPLCL2gene expression in myometrial cells. Using CRISPR activation, we assessed the functionality of a PGR putative enhancer 35 kilobases upstream of the contractile-restrictive genePLCL2. In summary, the results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women’s health research.
During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner. Weak synapses are preferentially removed, but the mechanism linking neuronal activity to synapse removal is unclear. Here, we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 deficiency results in defects in synapse elimination driven by both spontaneous and experience-dependent neural activity. Notably, caspase-3 deficiency blocks activity-dependent synapse elimination, as evidenced by reduced engulfment of inactive synapses by microglia. Furthermore, in a mouse model of Alzheimer’s disease, caspase-3 deficiency protects against synapse loss induced by amyloid-β deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.
Dynamic CpG methylation ‘barcodes’ were read from 15,000–21,000 single cells from three human male brains. To overcome sparse sequencing coverage, the barcode had ~31,000 rapidly fluctuating X-chromosome CpG sites (fCpGs), with at least 500 covered sites per cell and at least 30 common sites between cell pairs (average of ~48). Barcodes appear to start methylated and record mitotic ages because excitatory neurons and glial cells that emerge later in development were less methylated. Barcodes are different between most cells, with average pairwise differences (PWDs) of ~0.5 between cells. About 10 cell pairs per million were more closely related with PWDs <0.05. Barcodes appear to record ancestry and reconstruct trees where more related cells had similar phenotypes, albeit some pairs had phenotypic differences. Inhibitory neurons showed more evidence of tangential migration than excitatory neurons, with related cells in different cortical regions. fCpG barcodes become polymorphic during development and can distinguish between thousands of human cells.
The myometrium plays a critical role during pregnancy as it is responsible for both the structural integrity of the uterus and force generation at term. Emerging studies in mice indicate a dynamic change of the myometrial epigenome and transcriptome during pregnancy to ready the contractile machinery for parturition. However, the regulatory systems underlying myometrial gene expression patterns throughout gestation remain largely unknown. Here, we investigated human term pregnant nonlabor myometrial biopsies for transcriptome, enhancer histone mark cistrome, and chromatin conformation pattern mapping. More than thirty thousand putative enhancers with H3K27ac and H3K4me1 double positive marks were identified in the myometrium. Enriched transcription factor binding motifs include known myometrial regulators AP-1, STAT, NFkB, and PGR among others. Putative myometrial super enhancers are mostly colocalized with progesterone receptor-occupying sites and preferentially associated with highly expressing genes, suggesting a conserved role of PGR in regulating the myometrial transcriptome between species. In human myometrial specimens, inferred PGR activities are positively correlated with phospholipase C like 2 (PLCL2) mRNA levels, supporting that PGR may act through this genomic region to promotePLCL2expression. PGR overexpression facilitatedPLCL2gene expression in myometrial cells. Using CRISPR activation, we assessed the functionality of a PGR putative enhancer 35 kilobases upstream of the contractile-restrictive genePLCL2. In summary, the results of this study serve as a resource to study gene regulatory mechanisms in the human myometrium at the term pregnancy stage for further advancing women’s health research.
Experiments in mice reveal how three rare mutations in a gene calledTRIOcan lead to different neurodevelopmental outcomes.
Background:This study investigated the presence of the healthy vaccinee effect—the imbalance in health status between vaccinated and unvaccinated individuals—in two rigorously conducted COVID-19 vaccine effectiveness studies involving primary series and booster vaccinations. It also examined the temporal patterns and variability of this effect across different subpopulations by analyzing the association between COVID-19 vaccination and non-COVID-19 mortality in Qatar.Methods:Two matched, retrospective cohort studies assessed the incidence of non-COVID-19 death in national cohorts of individuals with a primary series vaccination versus no vaccination (two-dose analysis), and individuals with three-dose (booster) vaccination versus primary series vaccination (three-dose analysis), from January 5, 2021, to April 9, 2024.Results:The adjusted hazard ratio (aHR) for non-COVID-19 death was 0.76 (95% CI: 0.64–0.90) in the two-dose analysis and 0.85 (95% CI: 0.67–1.07) in the three-dose analysis. In the first 6 months of follow-up in the two-dose analysis, the aHR was 0.35 (95% CI: 0.27–0.46); however, the combined analysis of all subsequent periods showed an aHR of 1.52 (95% CI: 1.19–1.94). In the first 6 months of follow-up in the three-dose analysis, the aHR was 0.31 (95% CI: 0.20–0.50); however, the combined analysis of all subsequent periods showed an aHR of 1.37 (95% CI: 1.02–1.85). The overall effectiveness of the primary series and third-dose vaccinations against severe, critical, or fatal COVID-19 was 95.9% (95% CI: 94.0–97.1) and 34.1% (95% CI: –46.4–76.7), respectively. Subgroup analyses showed that the healthy vaccinee effect is pronounced among those aged 50 years and older and among those more clinically vulnerable to severe COVID-19.Conclusions:A pronounced healthy vaccinee effect was observed during the first 6 months following vaccination, despite meticulous cohort matching. This effect may have stemmed from a lower likelihood of vaccination among seriously ill, end-of-life individuals, and less mobile elderly populations.Funding:Biomedical Research Program and the Biostatistics, Epidemiology, and Biomathematics Research Core, and Junior Faculty Transition to Independence Program, all at Weill Cornell Medicine-Qatar, Qatar University, Ministry of Public Health, Hamad Medical Corporation, Sidra Medicine, Qatar Genome Programme, Qatar University Biomedical Research Center, and L’Oréal-UNESCO For Women In Science Middle East Regional Young Talents Program.
Xist,a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However,Xist’s ability to diffuse under select circumstances has also been documented, leading us to suspect thatXistRNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate thatXistRNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status.Xistbinds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for humanXISTRNA. We find thatXistbinding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi,Xistbinding does not lead to full silencing and also does not spread beyond the target gene. Over-expressingXistin transgenic ES cells similarly leads to autosomal gene suppression, while deletingXist’s Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with theXistinhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal thatXisttargets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by a small molecule inhibitor.
Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis.Drosophilatracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the fibroblast growth factor mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here, we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.
Xist,a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However,Xist’s ability to diffuse under select circumstances has also been documented, leading us to suspect thatXistRNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate thatXistRNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status.Xistbinds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for humanXISTRNA. We find thatXistbinding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi,Xistbinding does not lead to full silencing and also does not spread beyond the target gene. Over-expressingXistin transgenic ES cells similarly leads to autosomal gene suppression, while deletingXist’s Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with theXistinhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal thatXisttargets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by a small molecule inhibitor.
Genetic variants inTRIOare associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD), and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ),and+/M2145T(bipolar disorder, BPD) – impacts mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that model clinical phenotypes in humans.Triovariants differentially impact head and brain size, with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but+/K1431Mmice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in+/K1431Mvariant cortex. Our work reveals that discrete NDD-associatedTriovariants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.
Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis.Drosophilatracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the fibroblast growth factor mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here, we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.
Genetic variants inTRIOare associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD), and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ),and+/M2145T(bipolar disorder, BPD) – impacts mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that model clinical phenotypes in humans.Triovariants differentially impact head and brain size, with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but+/K1431Mmice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in+/K1431Mvariant cortex. Our work reveals that discrete NDD-associatedTriovariants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.
The zona pellucida (ZP) is vital for species-specific fertilization as this barrier mediates sperm-oocyte binding. Here, we determined whether sperm from distant mammalian orders (Carnivora, Primates, and Rodentia) could penetrate bovine oocytes by examining the role of bovine oviductal fluid and species-specific oviductal glycoprotein (OVGP1 or oviductin) from bovine, murine, or human sources in modulating the species-specificity of bovine and murine oocytes. Sperm from all the species were found to penetrate intact bovine ovarian oocytes to form hybrid embryos. However, contact with oviductal fluid or bovine, murine, or human OVGP1, conferred the ZP species-specificity, allowing only the penetration of the corresponding sperm regardless of the ZP’s origin. Glycolytic and microstructural analyses revealed that OVGP1 covers the pores present in the ZP and that OVGP1 glycosylation determines sperm specificity. This suggests specific fertilization capacity is acquired in the oviduct through the ZP’s incorporation of specific oviductin.
The zona pellucida (ZP) is vital for species-specific fertilization as this barrier mediates sperm-oocyte binding. Here, we determined whether sperm from distant mammalian orders (Carnivora, Primates, and Rodentia) could penetrate bovine oocytes by examining the role of bovine oviductal fluid and species-specific oviductal glycoprotein (OVGP1 or oviductin) from bovine, murine, or human sources in modulating the species-specificity of bovine and murine oocytes. Sperm from all the species were found to penetrate intact bovine ovarian oocytes to form hybrid embryos. However, contact with oviductal fluid or bovine, murine, or human OVGP1, conferred the ZP species-specificity, allowing only the penetration of the corresponding sperm regardless of the ZP’s origin. Glycolytic and microstructural analyses revealed that OVGP1 covers the pores present in the ZP and that OVGP1 glycosylation determines sperm specificity. This suggests specific fertilization capacity is acquired in the oviduct through the ZP’s incorporation of specific oviductin.
The General Stress Response promotes survival of bacteria in adverse conditions, but how sensor proteins transduce species-specific signals to initiate the response is not known. The serine/threonine phosphatase RsbU initiates the General Stress Response inBacillus subtilisupon binding a partner protein (RsbT) that is released from sequestration by environmental stresses. We report that RsbT activates RsbU by inducing otherwise flexible linkers of RsbU to form a short coiled-coil that dimerizes and activates the phosphatase domains. Importantly, we present evidence that related coiled-coil linkers and phosphatase dimers transduce signals from diverse sensor domains to control the General Stress Response and other signaling across bacterial phyla. This coiled-coil linker transduction mechanism additionally suggests a resolution to the mystery of how shared sensory domains control serine/threonine phosphatases, diguanylate cyclases and histidine kinases. We propose that this provides bacteria with a modularly exchangeable toolkit for the evolution of diverse signaling pathways.
Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.
Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.
Protein abundance tends to be more evolutionarily conserved than mRNA levels both within and between species, yet the mechanisms underlying this phenomenon remain largely unknown. Upstream open reading frames (uORFs) are widespreadcis-regulatory elements in eukaryotic genomes that regulate translation, but it remains unclear whether and how uORFs contribute to stabilizing protein levels. In this study, we performed ribosome translation simulations on mRNA to quantitatively assess the extent to which uORF translation influences the translational variability of downstream coding sequences (CDSs) across varying contexts. Our simulations revealed that uORF translation dampens CDS translational variability, with buffering capacity increasing in proportion to uORF translation efficiency, length, and number. We then compared the translatomes at different developmental stages of twoDrosophilaspecies, demonstrating that uORFs buffer mRNA translation fluctuations during both evolution and development. Experimentally, deleting a uORF in thebicoid(bcd) gene—a prominent example of translational buffering—resulted in extensive changes in gene expression and phenotypes inDrosophila melanogaster. Additionally, we observed uORF-mediated buffering between primates and within human populations. Together, our results reveal a novel regulatory mechanism by which uORFs stabilize gene translation during development and across evolutionary time.
The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, the involvements of DA release, real-time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.
Protein abundance tends to be more evolutionarily conserved than mRNA levels both within and between species, yet the mechanisms underlying this phenomenon remain largely unknown. Upstream open reading frames (uORFs) are widespreadcis-regulatory elements in eukaryotic genomes that regulate translation, but it remains unclear whether and how uORFs contribute to stabilizing protein levels. In this study, we performed ribosome translation simulations on mRNA to quantitatively assess the extent to which uORF translation influences the translational variability of downstream coding sequences (CDSs) across varying contexts. Our simulations revealed that uORF translation dampens CDS translational variability, with buffering capacity increasing in proportion to uORF translation efficiency, length, and number. We then compared the translatomes at different developmental stages of twoDrosophilaspecies, demonstrating that uORFs buffer mRNA translation fluctuations during both evolution and development. Experimentally, deleting a uORF in thebicoid(bcd) gene—a prominent example of translational buffering—resulted in extensive changes in gene expression and phenotypes inDrosophila melanogaster. Additionally, we observed uORF-mediated buffering between primates and within human populations. Together, our results reveal a novel regulatory mechanism by which uORFs stabilize gene translation during development and across evolutionary time.
The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, the involvements of DA release, real-time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.
The General Stress Response promotes survival of bacteria in adverse conditions, but how sensor proteins transduce species-specific signals to initiate the response is not known. The serine/threonine phosphatase RsbU initiates the General Stress Response inBacillus subtilisupon binding a partner protein (RsbT) that is released from sequestration by environmental stresses. We report that RsbT activates RsbU by inducing otherwise flexible linkers of RsbU to form a short coiled-coil that dimerizes and activates the phosphatase domains. Importantly, we present evidence that related coiled-coil linkers and phosphatase dimers transduce signals from diverse sensor domains to control the General Stress Response and other signaling across bacterial phyla. This coiled-coil linker transduction mechanism additionally suggests a resolution to the mystery of how shared sensory domains control serine/threonine phosphatases, diguanylate cyclases and histidine kinases. We propose that this provides bacteria with a modularly exchangeable toolkit for the evolution of diverse signaling pathways.
We present a method for spatially resolving the electric field potential throughout the entire volume of the human brain from electroencephalography (EEG) data. The method isnota variation of the well-known ‘source reconstruction’ methods, but rather a direct solution to the EEG inverse problem based on our recently developed model for brain waves that demonstrates the inadequacy of the standard ‘quasi-static approximation’ that has fostered the belief that such a reconstruction is not physically possible. The method retains the high temporal/frequency resolution of EEG, yet has spatial resolution comparable to (or better than) functional MRI (fMRI), without its significant inherent limitations. The method is validated using simultaneous EEG/fMRI data in healthy subjects, intracranial EEG data in epilepsy patients, comparison with numerical simulations, and a direct comparison with standard state-of-the-art EEG analysis in a well-established attention paradigm. The method is then demonstrated on a very large cohort of subjects performing a standard gambling task designed to activate the brain’s ‘reward circuit’. The technique uses the output from standard extant EEG systems and thus has potential for immediate benefit to a broad range of important basic scientific and clinical questions concerning brain electrical activity. By offering an inexpensive and portable alternative to fMRI, it provides a realistic methodology to efficiently promote the democratization of medicine.
The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson’s disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable. We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. At the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients displaying brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition. In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Furthermore, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence.
Attention mechanisms guide visuomotor behavior by weighing physical salience and internal goals to prioritize stimuli as choices for action. Although less well studied, selection history, which reflects multiple facets of experience with recent events, is increasingly recognized as a distinct source of attentional bias. To examine how selection history impacts saccadic choices, we trained two macaque monkeys to perform an urgent version of an oddball search task in which a red target appeared among three green distracters or vice versa. By imposing urgency, performance could be tracked continuously as it transitioned from uninformed guesses to informed choices as a function of processing time. This, in turn, permitted assessment of attentional control as manifest in motor biases, processing speed, and asymptotic accuracy. Here, we found that the probability of making a correct choice was strongly modulated by the histories of preceding target locations and target colors. Crucially, although both effects were gated by success (or reward), their dynamics were clearly distinct: whereas location history promoted a motor bias, color history modulated perceptual sensitivity, and these influences acted independently. Thus, combined selection histories can give rise to enormous swings in visuomotor performance even in simple tasks with highly discriminable stimuli.
Attention mechanisms guide visuomotor behavior by weighing physical salience and internal goals to prioritize stimuli as choices for action. Although less well studied, selection history, which reflects multiple facets of experience with recent events, is increasingly recognized as a distinct source of attentional bias. To examine how selection history impacts saccadic choices, we trained two macaque monkeys to perform an urgent version of an oddball search task in which a red target appeared among three green distracters or vice versa. By imposing urgency, performance could be tracked continuously as it transitioned from uninformed guesses to informed choices as a function of processing time. This, in turn, permitted assessment of attentional control as manifest in motor biases, processing speed, and asymptotic accuracy. Here, we found that the probability of making a correct choice was strongly modulated by the histories of preceding target locations and target colors. Crucially, although both effects were gated by success (or reward), their dynamics were clearly distinct: whereas location history promoted a motor bias, color history modulated perceptual sensitivity, and these influences acted independently. Thus, combined selection histories can give rise to enormous swings in visuomotor performance even in simple tasks with highly discriminable stimuli.
Although hierarchy is commonly invoked in descriptions of motor cortical function, its presence and manifestation in firing patterns remain poorly resolved. Here, we use optogenetic inactivation to demonstrate that short-latency influence between forelimb premotor and primary motor cortices is asymmetric during reaching in mice, demonstrating a partial hierarchy between the endogenous activity in each region. Multi-region recordings revealed that some activity is captured by similar but delayed patterns where either region’s activity leads, with premotor activity leading more. Yet firing in each region is dominated by patterns shared between regions and is equally predictive of firing in the other region at the single-neuron level. In dual-region network models fit to data, regions differed in their dependence on across-region input, rather than the amount of such input they received. Our results indicate that motor cortical hierarchy, while present, may not be exposed when inferring interactions between populations from firing patterns alone.
The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson’s disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable. We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. At the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients displaying brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition. In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Furthermore, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence.
Oxidative phosphorylation has emerged as a critical therapeutic vulnerability ofM. tuberculosis(Mtb). However, it is unknown how intracellular bacterial pathogens such asMtbmaintain respiration during infection despite the chemical effectors of host immunity.Mtbsynthesizes diisonitrile lipopeptides that tightly chelate copper, but the role of these chalkophores in host-pathogen interactions is also unknown. We demonstrate thatM. tuberculosischalkophores maintain the function of the heme-copperbcc:aa3respiratory supercomplex under copper limitation. Chalkophore deficiency impairsMtbsurvival, respiration to oxygen, and ATP production under copper deprivation in culture, effects that are exacerbated by loss of the heme-dependent Cytochrome BD respiratory oxidase. Our genetic analyses indicate that the maintenance of respiration is the major cellular target of chalkophore-mediated copper acquisition.M. tuberculosislacking chalkophore biosynthesis is attenuated in mice, a phenotype that is also severely exacerbated by loss of the CytBD respiratory oxidase. We find that the host immune pressure that attenuates chalkophore-deficientMtbis independent of adaptive immunity and neutrophils. These data demonstrate that chalkophores counter host-inflicted copper deprivation and highlight a multilayered system by whichM. tuberculosismaintains respiration during infection.
Understanding the variability of the environment is essential to function in everyday life. The brain must hence take uncertainty into account when updating its internal model of the world. The basis for updating the model are prediction errors that arise from a difference between the current model and new sensory experiences. Although prediction error neurons have been identified in layer 2/3 of diverse brain areas, how uncertainty modulates these errors and hence learning is, however, unclear. Here, we use a normative approach to derive how uncertainty should modulate prediction errors and postulate that layer 2/3 neurons represent uncertainty-modulated prediction errors (UPE). We further hypothesise that the layer 2/3 circuit calculates the UPE through the subtractive and divisive inhibition by different inhibitory cell types. By implementing the calculation of UPEs in a microcircuit model, we show that different cell types can compute the means and variances of the stimulus distribution. With local activity-dependent plasticity rules, these computations can be learned context-dependently, and allow the prediction of upcoming stimuli and their distribution. Finally, the mechanism enables an organism to optimise its learning strategy via adaptive learning rates.
A classic problem in metabolism is that fast-proliferating cells use seemingly wasteful fermentation for energy biogenesis in the presence of sufficient oxygen. This counterintuitive phenomenon, known as overflow metabolism or the Warburg effect, is universal across various organisms. Despite extensive research, its origin and function remain unclear. Here, we show that overflow metabolism can be understood through growth optimization combined with cell heterogeneity. A model of optimal protein allocation, coupled with heterogeneity in enzyme catalytic rates among cells, quantitatively explains why and how cells choose between respiration and fermentation under different nutrient conditions. Our model quantitatively illustrates the growth rate dependence of fermentation flux and enzyme allocation under various perturbations and is fully validated by experimental results inEscherichia coli. Our work provides a quantitative explanation for the Crabtree effect in yeast and the Warburg effect in cancer cells and can be broadly used to address heterogeneity-related challenges in metabolism.
A classic problem in metabolism is that fast-proliferating cells use seemingly wasteful fermentation for energy biogenesis in the presence of sufficient oxygen. This counterintuitive phenomenon, known as overflow metabolism or the Warburg effect, is universal across various organisms. Despite extensive research, its origin and function remain unclear. Here, we show that overflow metabolism can be understood through growth optimization combined with cell heterogeneity. A model of optimal protein allocation, coupled with heterogeneity in enzyme catalytic rates among cells, quantitatively explains why and how cells choose between respiration and fermentation under different nutrient conditions. Our model quantitatively illustrates the growth rate dependence of fermentation flux and enzyme allocation under various perturbations and is fully validated by experimental results inEscherichia coli. Our work provides a quantitative explanation for the Crabtree effect in yeast and the Warburg effect in cancer cells and can be broadly used to address heterogeneity-related challenges in metabolism.
We present a method for spatially resolving the electric field potential throughout the entire volume of the human brain from electroencephalography (EEG) data. The method isnota variation of the well-known ‘source reconstruction’ methods, but rather a direct solution to the EEG inverse problem based on our recently developed model for brain waves that demonstrates the inadequacy of the standard ‘quasi-static approximation’ that has fostered the belief that such a reconstruction is not physically possible. The method retains the high temporal/frequency resolution of EEG, yet has spatial resolution comparable to (or better than) functional MRI (fMRI), without its significant inherent limitations. The method is validated using simultaneous EEG/fMRI data in healthy subjects, intracranial EEG data in epilepsy patients, comparison with numerical simulations, and a direct comparison with standard state-of-the-art EEG analysis in a well-established attention paradigm. The method is then demonstrated on a very large cohort of subjects performing a standard gambling task designed to activate the brain’s ‘reward circuit’. The technique uses the output from standard extant EEG systems and thus has potential for immediate benefit to a broad range of important basic scientific and clinical questions concerning brain electrical activity. By offering an inexpensive and portable alternative to fMRI, it provides a realistic methodology to efficiently promote the democratization of medicine.
Although hierarchy is commonly invoked in descriptions of motor cortical function, its presence and manifestation in firing patterns remain poorly resolved. Here, we use optogenetic inactivation to demonstrate that short-latency influence between forelimb premotor and primary motor cortices is asymmetric during reaching in mice, demonstrating a partial hierarchy between the endogenous activity in each region. Multi-region recordings revealed that some activity is captured by similar but delayed patterns where either region’s activity leads, with premotor activity leading more. Yet firing in each region is dominated by patterns shared between regions and is equally predictive of firing in the other region at the single-neuron level. In dual-region network models fit to data, regions differed in their dependence on across-region input, rather than the amount of such input they received. Our results indicate that motor cortical hierarchy, while present, may not be exposed when inferring interactions between populations from firing patterns alone.
Understanding the variability of the environment is essential to function in everyday life. The brain must hence take uncertainty into account when updating its internal model of the world. The basis for updating the model are prediction errors that arise from a difference between the current model and new sensory experiences. Although prediction error neurons have been identified in layer 2/3 of diverse brain areas, how uncertainty modulates these errors and hence learning is, however, unclear. Here, we use a normative approach to derive how uncertainty should modulate prediction errors and postulate that layer 2/3 neurons represent uncertainty-modulated prediction errors (UPE). We further hypothesise that the layer 2/3 circuit calculates the UPE through the subtractive and divisive inhibition by different inhibitory cell types. By implementing the calculation of UPEs in a microcircuit model, we show that different cell types can compute the means and variances of the stimulus distribution. With local activity-dependent plasticity rules, these computations can be learned context-dependently, and allow the prediction of upcoming stimuli and their distribution. Finally, the mechanism enables an organism to optimise its learning strategy via adaptive learning rates.
The successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit–host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than 400 topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.
The successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit–host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than 400 topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.
Oxidative phosphorylation has emerged as a critical therapeutic vulnerability ofM. tuberculosis(Mtb). However, it is unknown how intracellular bacterial pathogens such asMtbmaintain respiration during infection despite the chemical effectors of host immunity.Mtbsynthesizes diisonitrile lipopeptides that tightly chelate copper, but the role of these chalkophores in host-pathogen interactions is also unknown. We demonstrate thatM. tuberculosischalkophores maintain the function of the heme-copperbcc:aa3respiratory supercomplex under copper limitation. Chalkophore deficiency impairsMtbsurvival, respiration to oxygen, and ATP production under copper deprivation in culture, effects that are exacerbated by loss of the heme-dependent Cytochrome BD respiratory oxidase. Our genetic analyses indicate that the maintenance of respiration is the major cellular target of chalkophore-mediated copper acquisition.M. tuberculosislacking chalkophore biosynthesis is attenuated in mice, a phenotype that is also severely exacerbated by loss of the CytBD respiratory oxidase. We find that the host immune pressure that attenuates chalkophore-deficientMtbis independent of adaptive immunity and neutrophils. These data demonstrate that chalkophores counter host-inflicted copper deprivation and highlight a multilayered system by whichM. tuberculosismaintains respiration during infection.
Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.
Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.
The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimer’s disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty-related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics, and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.
The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimer’s disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty-related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics, and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.
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Targeted monotherapies for cancer often fail due to inherent or acquired drug resistance. By aiming at multiple targets simultaneously, drug combinations can produce synergistic interactions that increase drug effectiveness and reduce resistance. Computational models based on the integration of omics data have been used to identify synergistic combinations, but predicting drug synergy remains a challenge. Here, we introduce Drug synergy Interaction Prediction (DIPx), an algorithm for personalized prediction of drug synergy based on biologically motivated tumor- and drug-specific pathway activation scores (PASs). We trained and validated DIPx in the AstraZeneca-Sanger (AZS) DREAM Challenge human cell-line dataset using two separate test sets: Test Set 1 comprised the combinations already present in the training set, while Test Set 2 contained combinations absent from the training set, thus indicating the model’s ability to handle novel combinations. The Spearman’s correlation coefficients between predicted and observed drug synergy were 0.50 (95% CI: 0.47–0.53) in Test Set 1 and 0.26 (95% CI: 0.22–0.30) in Test Set 2, compared to 0.38 (95% CI: 0.34–0.42) and 0.18 (95% CI: 0.16–0.20), respectively, for the best performing method in the Challenge. We show evidence that higher synergy is associated with higher functional interaction between the drug targets, and this functional interaction information is captured by PAS. We illustrate the use of PAS to provide a potential biological explanation in terms of activated pathways that mediate the synergistic effects of combined drugs. In summary, DIPx can be a useful tool for personalized prediction of drug synergy and exploration of activated pathways related to the effects of combined drugs.
Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 × 10-6, OR = 0.437, SE = 0.182) in theHLA-DPB1gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.
Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 × 10-6, OR = 0.437, SE = 0.182) in theHLA-DPB1gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.
The interferon-induced GTPase GVIN1 prevents bacteria from spreading among cells by coating them and rendering them immobile.
Targeted monotherapies for cancer often fail due to inherent or acquired drug resistance. By aiming at multiple targets simultaneously, drug combinations can produce synergistic interactions that increase drug effectiveness and reduce resistance. Computational models based on the integration of omics data have been used to identify synergistic combinations, but predicting drug synergy remains a challenge. Here, we introduce Drug synergy Interaction Prediction (DIPx), an algorithm for personalized prediction of drug synergy based on biologically motivated tumor- and drug-specific pathway activation scores (PASs). We trained and validated DIPx in the AstraZeneca-Sanger (AZS) DREAM Challenge human cell-line dataset using two separate test sets: Test Set 1 comprised the combinations already present in the training set, while Test Set 2 contained combinations absent from the training set, thus indicating the model’s ability to handle novel combinations. The Spearman’s correlation coefficients between predicted and observed drug synergy were 0.50 (95% CI: 0.47–0.53) in Test Set 1 and 0.26 (95% CI: 0.22–0.30) in Test Set 2, compared to 0.38 (95% CI: 0.34–0.42) and 0.18 (95% CI: 0.16–0.20), respectively, for the best performing method in the Challenge. We show evidence that higher synergy is associated with higher functional interaction between the drug targets, and this functional interaction information is captured by PAS. We illustrate the use of PAS to provide a potential biological explanation in terms of activated pathways that mediate the synergistic effects of combined drugs. In summary, DIPx can be a useful tool for personalized prediction of drug synergy and exploration of activated pathways related to the effects of combined drugs.
The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, andTET2knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of theFBP1promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, andTET2knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of theFBP1promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
A fundamental challenge in neuroscience is understanding neural functioning and plasticity of the brain. The anterior temporal lobe (ATL) is a hub for semantic memory, which generates coherent conceptual representations. GABAergic inhibition plays a crucial role in shaping human cognition and plasticity, but it is unclear how this inhibition relates to human semantic memory and its plasticity. Here, we employed a combination of continuous theta burst stimulation (cTBS), MR spectroscopy and fMRI to investigate the role of GABA in semantic memory and its neuroplasticity. We found that inhibitory cTBS increased GABA concentrations in the ATL and reduced blood-oxygen level-dependent (BOLD) activation during semantic tasks. Crucially, changes in GABA were tightly linked to changes in regional activity, suggesting that GABA mediates cTBS-induced plasticity. Individuals with better semantic performance exhibited selective activity in the ATL, attributable to higher GABA levels, which can sharpen distributed semantic representations. Our results revealed a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic performance, thus offering an explanation for the individual differences in semantic memory function and neuromodulation outcomes. These findings offer a neurochemical explanation for individual variability in neuromodulation and provide insights for developing targeted interventions for semantic impairments.
A fundamental challenge in neuroscience is understanding neural functioning and plasticity of the brain. The anterior temporal lobe (ATL) is a hub for semantic memory, which generates coherent conceptual representations. GABAergic inhibition plays a crucial role in shaping human cognition and plasticity, but it is unclear how this inhibition relates to human semantic memory and its plasticity. Here, we employed a combination of continuous theta burst stimulation (cTBS), MR spectroscopy and fMRI to investigate the role of GABA in semantic memory and its neuroplasticity. We found that inhibitory cTBS increased GABA concentrations in the ATL and reduced blood-oxygen level-dependent (BOLD) activation during semantic tasks. Crucially, changes in GABA were tightly linked to changes in regional activity, suggesting that GABA mediates cTBS-induced plasticity. Individuals with better semantic performance exhibited selective activity in the ATL, attributable to higher GABA levels, which can sharpen distributed semantic representations. Our results revealed a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic performance, thus offering an explanation for the individual differences in semantic memory function and neuromodulation outcomes. These findings offer a neurochemical explanation for individual variability in neuromodulation and provide insights for developing targeted interventions for semantic impairments.
Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.
Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar (Melopsittacus undulatus) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.
Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: (1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs. non-specific mid-cervical expression), and (2) can this method produce a sustained increase in inspiratory tidal volume? Wild-type (C57Bl/6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild-type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive neuronal DREADD expression in the C4 ventral horns, targeting phrenic motoneurons. Diaphragm electromyograms (EMG) were recorded in isoflurane-anesthetized spontaneously breathing mice at 4–9 weeks post-AAV delivery. The DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in ChAT-Cre rats were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume during spontaneous breathing, assessed using whole-body plethysmography without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in tidal volume. Subsequently, phrenic nerve recordings performed under urethane anesthesia confirmed that J60 evoked a >200% increase in inspiratory output. We conclude that targeting mid-cervical spinal DREADD expression to the phrenic motoneuron pool enables ligand-induced, sustained increases in phrenic motor output and tidal volume. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.
Daptomycin is a potent lipopeptide antibiotic used in the treatment of life-threatening Gram-positive infections, but the molecular mechanism of its interaction with bacterial membrane remains unclear. Here, we show that this interaction is divided into two stages, of which the first is a fast and reversible binding of the drug to phospholipid membrane in milliseconds, and the second is a slow and irreversible insertion into membrane in minutes, only in the presence of the bacteria-specific lipid phosphatidylglycerol, to a saturating point where the ratio of the drug to phosphatidylglycerol is 1:2. Fluorescence-based titration showed that the antibiotic simultaneously binds two molecules of phosphatidylglycerol with a nanomolar binding affinity in the presence of calcium ion. The resulting stable complex is easily formed in a test tube and readily isolated from the membrane of drug-treated bacterial cells, strongly supporting a unique drug uptake mechanism in which daptomycin forms a stable multicomponent complex with calcium and phosphatidylglycerol. Revelation of this novel uptake mechanism provides fresh insights into the mode of action of daptomycin and paves the way to new strategies to attenuate resistance to the drug.
Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar (Melopsittacus undulatus) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.
Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.
The imprinted geneZDBF2is regulated through a unique mechanism involving a transient paternal transcript in early embryos, rather than persistent gametic DNA methylation. In humans and mice, this transcript—CMKLR2-AS(also known asGPR1-AS) or the long isoform ofZdbf2(Liz/Zdbf2linc/Platr12)—arises from the unmethylated paternal allele and initiates secondary epigenetic marks that maintainZDBF2expression. Here, we investigate the evolutionary origin of this mechanism, and show that the first exon of humanGPR1-ASoverlaps with a MER21C long terminal repeat (LTR), a retrotransposon subfamily specific to Boreoeutherian mammals. Comparative analyses revealed that this MER21C insertion occurred in the common ancestor of Euarchontoglires, including primates, rodents, and rabbits. Although not annotated, the first exon of mouseLizdisplays conserved features with the MER21C-overlapping exon in humans. In rabbit and nonhuman primate placentas,GPR1-ASorthologs with LTR-embedded first exons were also identified. In contrast, in non-Euarchontoglire mammals such as cow and tammar wallaby,ZDBF2is biallelically expressed, suggesting absence of imprinting. These findings suggest thatZDBF2imprinting emerged in Euarchontoglires via MER21C insertion. Together with our prior work on LTR-driven imprinting in oocytes, our findings demonstrate that post-fertilization activation of retrotransposons can also drive lineage-specific acquisition of imprinting.
Nervous necrosis virus typically enters host cells via endocytosis, but it can also enter via a process called macropinocytosis.
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AbstractThe development of novel anti-seizure drugs targeting novel mechanisms is crucial, especially for patients with intractable epilepsy. Previous studies using focal onset seizure rodent models have demonstrated that Icilin and WS-3, agonists of the transient receptor potential melastatin 8 (TRPM8) channel, suppress drug-induce epileptiform discharges (EDs) and seizures (ESs). In contrast, TRPM8 deficiency exacerbates EDs and ESs. This study investigated the mechanism underlying the anti-seizure effects of the TRPM8 agonist, WS-3, using a focal onset seizure mouse model. Mice were injected with WS-3 either before or after administering the seizure inducer, penicillin G potassium. EDs, ESs, and glutamate levels were subsequently evaluated. In wild-type (WT) mice, WS-3 injected after the seizure inducer reduced glutamate levels and ED power by 44% and 60%, respectively, with a positive correlation between WS-3 efficacy and these parameters. WS-3 injection before seizure induction suppressed the increase in glutamate levels and the development of ED and ES, with positive correlations observed among the three parameters. Conversely, TRPM8-knockout mice showed no anti-seizure effects from WS-3. TRPM8 deficiency led to a further increase in the glutamate levels, ED power, and ES severity after the seizure inducer injection. Additionally, TRPM8-deficient mice experienced EDs with fewer glutamate exposures and shortened latency to ED development following seizure induction. These findings suggest that TRPM8 agonists suppress the development of EDs and ESs by reduction of extracellular glutamate levels, indicating that TRPM8 channels may represent a promising treatment option for epilepsy.
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AbstractWe developed an approach to disrupt cocaine-seeking behaviors using mediated devaluation. Male rats underwent cocaine self-administration training in which active lever responses led to cocaine infusions and the presentation of a tone-light conditioned stimulus (CS). Subsequently, during mediated devaluation rats received non-contingent presentations of the cocaine-associated CS in a second distinct context, which led to the cue-evoked retrieval of associated memories. This was immediately followed by an intraperitoneal injection of lithium chloride (LiCl) and served to pair the memory of cocaine reward with gastric malaise. Consequently, this led to a substantial reduction in cocaine-seeking behavior during extinction training, relative to rats that received CS-saline or LiCl alone during mediated devaluation. Cue- and cocaine-evoked reinstatement testing indicated that the manipulations did not devalue the CS or the reinforcing properties of cocaine. A separate cohort of rats received a dual-viral chemogenetic strategy that permitted circuit-specific inactivation of midbrain ventral tegmental area (VTA) cells projecting to the nucleus accumbens (NAc). Inactivation of VTA→NAc circuitry during mediated devaluation prevented the subsequent reduction of cocaine-seeking behavior during extinction training. Overall, these findings suggest that intact mesolimbic signaling is required to enable disruptions in cocaine-seeking behavior following mediated devaluation.
AbstractThe role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [11C]CURB λk3, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [11C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [11C]CURB λk3were observed between MDD participants and controls (F1,27= 0.32;p= 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [11C]CURB λk3binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F1,11= 6.75;p= 0.02). Depressive severity and anxiety did not have a significant relationship to [11C]CURB λk3binding. The relationship of greater fronto-limbic [11C]CURB λk3to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.
AbstractPain syndromes include physical, sensory, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. Experimental induction of long-term inflammatory pain in rodents by hindpaw injection of complete Freund’s adjuvant (CFA) produces anhedonia and dysregulated naturalistic behaviors, similar to the effects of unregulated stress. We examined whether these similarities extend to changes in sleep and rhythms, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG in mice. Comparisons were made between groups that received injections at the onset of the light or dark phase. We found that CFA-induced inflammatory pain alters sleep architecture in both sexes; most notably, it increased sleep duration in the dark phase—when mice are normally more likely to be awake—while also increasing sleep bout length and reducing wake bout length. In contrast, during the light phase, it decreased sleep bout length, indicating fragmentation. Similarly, CFA-induced increases in REM and SWS duration and bouts were largest during the dark phase. Dark-phase effects were remarkably consistent regardless of whether the mice had been injected at darkness onset or 12 h earlier, whereas light-phase effects were more dependent on time since injection. Injections also produced non-specific alterations in circadian rhythmicity. Our findings indicate that inflammatory pain prominently increases sleep during normally active phases as well as transitions between sleep and wakefulness throughout the day. These effects align with clinical observations and establish a basis for mechanistic studies and use of these procedures to better predict outcomes in humans.
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AbstractAbnormal motivation for natural rewards is a hallmark of various psychiatric disorders, including behavioral addiction. The mesolimbic dopamine pathway has been identified as a critical modulator of motivated behavior primarily based on studies using food-reinforced operant tasks. However, the focus on food rewards in previous studies limits the generalizability of these findings to other natural rewards implicated in behavioral addiction. In this study, we investigated the reinforcing and high motivational properties of wheel running in rodents by developing a wheel running-reinforced operant conditioning procedure. This procedure allowed for the independent quantification of appetitive and consummatory behaviors as operant responses and running duration, respectively, facilitating an in-depth exploration of the role of dopamine signaling in the medial nucleus accumbens (mNAc) in wheel running motivation. The results indicated that the systemic inhibition of dopamine D1and D2receptors suppressed appetitive behavior, whereas inhibition of D1receptors reduced consummatory behavior. Similarly, inhibition of mNAc neural activity and blockade of D1and D2receptors within this region diminished appetitive behavior, with D1receptor inhibition uniquely impairing consummatory behavior. Fiber photometry recordings demonstrated that decreases in mNAc neural activity and increases in dopamine levels preceded appetitive behavior. Additionally, mNAc neural activity and dopamine levels were elevated following cues signaling the availability of wheel running. Furthermore, systemic D1receptor inhibition attenuated the reduction in mNAc neural activity observed during appetitive behavior. These findings suggest that increased dopamine release and the subsequent D1receptor-mediated suppression of mNAc neural activity underlie the motivated behavior for wheel running.
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AbstractNovel treatment evaluation for youth with alcohol use disorder (AUD) is needed. Cannabidiol (CBD), a constituent of theCannabis sativaplant, may be a promising candidate pharmacotherapy due to its potential therapeutic properties and preclinical research suggesting it decreases alcohol use. Due to limited data in humans, rigorous screening of the acute neural, psychophysiological, and alcohol-related effects of CBD is indicated to assess its viability as a potential treatment for youth AUD. Using a within-subjects, randomized, double-blind, placebo-controlled design, we tested acute multi-modal effects of CBD (600 mg) in non-treatment seeking youth with AUD (N= 36; ages 17–22; 69% female). Outcomes included (1) glutamate+glutamine (Glx) and GABA levels in the anterior cingulate cortex measured with proton magnetic resonance spectroscopy; (2) whole-brain and a priori region-of-interest neural alcohol cue-reactivity measured with functional MRI; (3) psychophysiological response to alcohol olfactory cues measured by self-reported acute alcohol craving, heart rate variability, and skin conductance; and (4) alcohol use. No CBD-associated adverse events were observed. There were no effects of acute CBD administration, compared to placebo, on any outcomes of interest. This is the first adequately powered medication screening study for the use of CBD in youth with AUD. We did not detect significant effects of CBD on neurometabolic, neurobehavioral, psychophysiological, or alcohol use outcomes in this sample. Future studies may benefit from chronic administration to better understand substance-related effects.Clinicaltrials.gov NCT05317546https://clinicaltrials.gov/study/NCT05317546
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AbstractWe have previously shown that neuropeptide Y (NPY) reduces social fear in an animal model that closely mimics the key behavioral symptoms of social anxiety disorder (SAD). Since NPY cannot yet be routinely administered to patients, we investigated the effects of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor approved for the treatment of type 2 diabetes mellitus, on social fear and comorbid depression in mice. In addition to its well-known effects on glucose metabolism, sitagliptin also prevents the degradation of NPY, thereby increasing its concentration in the blood and the brain. We show that sitagliptin administration via drinking water (50 and 100 mg/kg/day, for 4 weeks) not only reduced social fear but also prevented the onset of comorbid depressive-like behavior in outbred CD1 mice. A similar phenotype was observed in homozygous DPP4-deficient mice, emphasizing the role of DPP4 in regulating these behaviors. However, in NPY-deficient mice, sitagliptin showed reduced efficacy, suggesting that NPY plays an important role in mediating the effects of sitagliptin on social fear and comorbid depression. These findings have important clinical implications, indicating that early intervention with sitagliptin could be an effective strategy for treating SAD, alleviating both core symptoms and reducing the risk of developing comorbid mood disorders that often complicate treatment outcomes.
AbstractStress and traumatic experiences have significant and lasting effects on sensory systems. We recently identified unique expression of proteins associated with epidermal skin cells (keratinocytes) and mechanosensory Merkel cells (MC) in circulating extracellular vesicles from adult women who had experienced sexual trauma specifically during adolescence, biologically linking trauma exposure with a specific neuron-like skin cell. Here, we aimed to develop and validate a preclinical mouse model utilizing chemogenetic (DREADD Gq) activation of a population of MC. Using a reporter line, we confirmed the expected pattern of the Krt14 Cre in specific MC skin areas and that these tissues expressed relevant MC marker genes similarly between male and female mice. Chemogenetic stimulation of MC produced robust neuronal activation of the insular cortex (IC), a brain region relevant to somatosensory and valence integration. To determine if the mice could detect MC activation, home cage behaviors following CNO treatment significantly increased nest grooming time. Conditioned place preference further revealed an avoidance response following MC stimulation; an effect that was stronger in female mice. Finally, to connect back to our trauma question, we examined MC activation in fear conditioning and identified deficits in fear extinction. Overall, these studies validate utilization of this preclinical model in further investigating the mechanosensory system and its potential involvement in PTSD symptoms and therapeutic interventions. Ongoing studies will focus on critical developmental periods relevant to both MC development and sex differences associated with trauma vulnerability and potential sensory based therapeutic options for PTSD-related symptoms.
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AbstractCues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or ‘neuronal ensembles’ in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify ‘anti-craving’ relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of ‘originally’, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost – resulting in their persistent activation and non-cue selective activation or ‘excitatory overdrive’. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting ‘inhibitory underdrive’. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory ‘overdrive’ and inhibitory ‘underdrive’ likely underlies EE’s anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.
AbstractAntidepressant-induced apathy syndrome is reported in a high number of patients. It is characterised by loss of motivation for daily activities and emotional blunting. It has a negative impact on quality of life and treatment outcome, yet the changes in underlying neurobiology driving this syndrome remain unclear. To begin to address this, a comprehensive understanding of how different classes of antidepressant treatment impact on behaviours relevant to apathy is critical. Rodent motivation for reward is commonly assessed using effort-based operant conditioning paradigms such as the Effort for Reward task. However, motivation to perform spontaneous/innate behaviours may provide additional insight into changes in behaviour reflective of daily activities. We tested the acute and chronic effects of antidepressants on the Effort for Reward task, and the spontaneous/innate Effort-Based Forage task. Acute treatment revealed important divergence in drug effect between tasks, where selective serotonin reuptake inhibitor (SSRI)/serotonin and noradrenaline reuptake inhibitor (SNRI) treatment impaired foraging behaviour in the Effort Based Forage task, but enhanced high-effort, high-value reward responding in the Effort for Reward task. Treatment with a noradrenaline reuptake inhibitor (NRI) or multimodal agent impaired foraging behaviour but did not affect high reward responding in the Effort for Reward task. Conversely, chronic treatment with an SSRI but not SNRI enhanced motivated foraging behaviour but led to a general impairment in Effort for Reward task output. Together, these data demonstrate that SSRI treatment induces opposing effects on conditioned versus innate motivation which may have significant translational relevance when interpreting drug effect. Further, these behavioural effects differ depending on whether antidepressants are acutely or chronically administered.
Attention samples visual space sequentially to enhance behaviorally relevant sensory representations. While traditionally conceptualized as a static continuous spotlight, contemporary models of attention highlight its discrete nature. But which neural mechanisms govern the temporally precise allocation of attention? Periodic brain activity as exemplified by neuronal oscillations as well as aperiodic temporal structure in the form of intrinsic neural timescales have been proposed to orchestrate the attentional sampling process in space and time. However, both mechanisms have been largely studied in isolation. To date, it remains unclear whether periodic and aperiodic temporal structure reflect distinct neural mechanisms. Here, we combined computational simulations with a multimodal approach encompassing five experiments, and three different variants of classic spatial attention paradigms, to differentiate aperiodic from oscillatory-based sampling. Converging evidence across behavior as well as scalp and intracranial electroencephalography (EEG) revealed that periodic and aperiodic temporal regularities can theoretically and experimentally be distinguished. Our results extend the rhythmic sampling framework of attention by demonstrating that aperiodic neural timescales predict behavior in a spatially-, context-, and demand-dependent manner. Aperiodic timescales increased from sensory to association cortex, decreased during sensory processing or action execution, and were prolonged with increasing behavioral demands. These results reveal that multiple, concurrent temporal regularities govern attentional sampling.
Humans sometimes have an insight that leads to a sudden and drastic performance improvement on the task they are working on. The precise origins of such insights are unknown. Some evidence has shown that sleep facilitates insights, while other work has not found such a relationship. One recent suggestion that could explain this mixed evidence is that different sleep stages have differential effects on insight. In addition, computational work has suggested that neural variability and regularisation play a role in increasing the likelihood of insight. To investigate the link between insight and different sleep stages as well as regularisation, we conducted a preregistered study in which N=90 participants performed a perceptual insight task before and after a 20 minute daytime nap. Sleep EEG data showed that N2 sleep, but not N1 sleep, increases the likelihood of insight after a nap, suggesting a specific role of deeper sleep. Exploratory analyses of EEG power spectra showed that spectral slopes could predict insight beyond sleep stages, which is broadly in line with theoretical suggestions of a link between insight and regularisation. In combination, our findings point towards a role of N2 sleep and aperiodic, but not oscillatory, neural activity for insight.
[Fe-S] clusters are ancient and ubiquitous protein co-factors, which contributed to the emergence of life in an anoxic planet. We have recently identified two minimal [Fe-S] biogenesis systems, MIS and SMS, inferred to be ancestral systems dating back to the Last Universal Common Ancestor and which gave rise to the well-studied modern Iron-Sulfur Cluster (ISC), Nitrogen Fixation (NIF), and Sulfur Mobilization (SUF) machineries. The present study focuses on the ancestor SMS from the hyperthermophilic archaeonMethanocaldococcus jannaschii. Biochemical and structural studies showed that SMS is made of a SmsC2B2heterotetratmer wherein the SmsC subunit hosts both ATP and [Fe-S] cluster binding sites. Binding of ATP and assembly of [Fe-S] were found to be mutually exclusive allowing for a regulatory coupling between binding of both substrates. Mutagenesis and in vitro transfer experiments revealed the key role of SmsC-contained Cys residues in cluster assembly. Strikingly, the SMS system rescued a non-viableEscherichia colistrain lacking endogenous ISC and SUF systems grown under anoxic conditions, in the presence of Na2S, indicating that sulfide is a source of sulfur for SMS. In addition, we predict that most archaea SmsC proteins hold a similar C-terminal [Fe-S] cluster assembly site. Taking into account those unique structural and functional features, we propose a mechanistic model describing how SmsC2B2assembles and distributes [4Fe-4S] clusters. Altogether this study established SMS as a newbona fide[Fe-S] biogenesis system that operated in anaerobic prokaryotes prior to evolve to SUF after the Great Oxydation Event.
Innovations often shape the trajectory of macroevolution, yet their effects are usually considered independently, thus ignoring the functional and evolutionary interactions between them. Two innovations that have underpinned the ecological and evolutionary success of ray-finned fishes (Actinopterygii) are large teeth and highly protrusible jaws, which independently expanded the diversity of prey capture strategies. Here, we explore the functional relationship between these innovations across actinopterygians using high-speed videography and phylogenetic comparative methods. We find that these two innovations are functionally and evolutionarily incompatible because there is an overarching tradeoff between jaw protrusion and tooth size. Having large teeth decreases the kinematic diversity of prey capture by restricting species to overtake prey predominantly by swimming, while highly protrusible jaws are only found in species with small teeth. The space within tooth-bearing bones may impose this constraint, by limiting the maximum tooth size of species with gracile jaws adapted for high mobility and jaw protrusion. Nevertheless, some species break this constraint on tooth size through novel adaptations that accommodate exceptionally large teeth, unlocking new feeding modes which may have expanded the nature of aquatic feeding and influenced the ecosystems themselves. Although both high jaw protrusion and large teeth separately expanded prey capture strategies in fishes, they are generally not found in combination and are evolutionarily incompatible.
Viruses encounter a range of selective pressures, but inefficiencies during replication can be masked. To uncover factors that limit viral replication, we used forward genetics to enrich for a murine norovirus (MNV) mutant with faster replication. We sequentially harvested the earliest progeny in cultured cells and identified a single amino acid change in the viral NS3 protein, K40R, that was sufficient to enhance replication speed. We found that the NS3-K40R virus induced earlier cell death and viral egress compared with wild-type virus. Mechanistically, NS3-K40R protein disrupted membranes more efficiently than wild-type NS3 protein, potentially contributing to increased mitochondrial dysfunction and cell death. Immunodeficient mice infected with NS3-K40R virus had increased titers, suggesting that increasing egress did not reduce fitness in vivo. Overall, by using a forward genetic approach, we identified a previously unknown inefficiency in norovirus egress and provide new insights into selective pressures that influence viral replication and evolution.
The ‘sprawling-parasagittal’ postural transition is a key part of mammalian evolution, associated with sweeping reorganization of the postcranial skeleton in mammals compared to their forebears, the non-mammalian synapsids. However, disputes over forelimb function in fossil synapsids render the precise nature of the ‘sprawling-parasagittal’ transition controversial. We shed new light on the origins of mammalian posture, using evolutionary adaptive landscapes to integrate 3D humerus shape and functional performance data across a taxonomically comprehensive sample of fossil synapsids and extant comparators. We find that the earliest pelycosaur-grade synapsids had a unique mode of sprawling, intermediate between extant reptiles and monotremes. Subsequent evolution of synapsid humerus form and functional traits showed little evidence of a direct progression from sprawling pelycosaurs to parasagittal mammals. Instead, posture was evolutionarily labile, and the ecological diversification of successive synapsid radiations was accompanied by variation in humerus morphofunctional traits. Further, synapsids frequently evolve toward parasagittal postures, diverging from the reconstructed optimal evolutionary path; the optimal path only aligns with becoming increasingly mammalian in derived cynodonts. We find the earliest support for habitual parasagittal postures in stem therians, implying that synapsids evolved and radiated with distinct forelimb trait combinations for most of their recorded history.
Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate uniquein vitromodels to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.
Ovulation is a spatiotemporally coordinated process that involves several tightly controlled events, including oocyte meiotic maturation, cumulus expansion, follicle wall rupture and repair, and ovarian stroma remodeling. To date, no studies have detailed the precise window of ovulation at single-cell resolution. Here, we performed parallel single-cell RNA-seq and spatial transcriptomics on paired mouse ovaries across an ovulation time course to map the spatiotemporal profile of ovarian cell types. We show that major ovarian cell types exhibit time-dependent transcriptional states enriched for distinct functions and have specific localization profiles within the ovary. We also identified gene markers for ovulation-dependent cell states and validated these using orthogonal methods. Finally, we performed cell–cell interaction analyses to identify ligand-receptor pairs that may drive ovulation, revealing previously unappreciated interactions. Taken together, our data provides a rich and comprehensive resource of murine ovulation that can be mined for discovery by the scientific community.
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The ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and non-infectious granulomas and the foreign body response, but are also observed in the aging ovary. The function and consequence of ovarian MNGCs remain unknown as their biological activity is highly context-dependent, and their large size has limited their isolation and analysis through technologies such as single-cell RNA sequencing. In this study, we define ovarian MNGCs through a deep analysis of their presence across age and species using advanced imaging technologies as well as their unique transcriptome using laser capture microdissection. MNGCs form complex interconnected networks that increase with age in both mouse and nonhuman primate ovaries. MNGCs are characterized by highGpnmbexpression, a putative marker of ovarian and non-ovarian MNGCs. Pathway analysis highlighted functions in apoptotic cell clearance, lipid metabolism, proteolysis, immune processes, and increased oxidative phosphorylation and antioxidant activity. Thus, MNGCs have signatures related to degradative processes, immune function, and high metabolic activity. These processes were enriched in MNGCs compared to primary ovarian macrophages, suggesting discrete functionality. MNGCs express CD4 and colocalize with T-cells, which were enriched in regions of MNGCs, indicative of a close interaction between these immune cell types. These findings implicate MNGCs in modulation of the ovarian immune landscape during aging given their high penetrance and unique molecular signature that supports degradative and immune functions.
Intelligent behavior involves mentally arranging learned information in novel ways and is particularly well developed in humans. While nonhuman primates (NHP) will learn to arrange new items in serial order and re-arrange neighboring items within that order, it has remained contentious whether they are capable to re-assign items more flexibly to non-adjacent serial positions. Such mental re-indexing is facilitated by inferring the sequential structure of experiences as opposed to learning serial chains of item-item associations. Here, we tested the ability for flexible mental re-indexing in rhesus macaques. Subjects learned to choose five objects in a predetermined sequential order. A change of the background context indicated when the object order changed, probing the subjects to mentally re-arrange objects to non-adjacent positions of the learned serial structure. Subjects successfully used the context cue to pro-actively re-index items to new, non-adjacent positions. Mental re-indexing was more likely when the initial order had been learned at a higher level, improved with more experience of the re-indexing rule and correlated with working memory performance in a delayed match-to-sample task. These findings suggest that NHPs inferred the sequential structure of experiences beyond a chaining of item-item associations and mentally re-arrange items within that structure. The pattern of results indicates that NHPs form non-spatial cognitive maps of their experiences, which is a hallmark for flexible mental operations in many serially ordered behaviors including communication, counting or foraging.
Across saccades, neurons in retinotopically organized visual representations experience drastically different images, but visual percepts remain stable. Here we investigated whether such stability can be mediated, in part, via prediction-error signaling by neurons processing post-saccadic visual images. We specifically recorded from foveal superior colliculus (SC) neurons when a visual image only overlapped with their response fields (RF’s) after foveating saccades but not pre-saccadically. When we rapidly changed the target features intra-saccadically, the foveal neurons’ post-saccadic visual reafferent responses were elevated, even though the neurons did not directly sample the pre-saccadic extrafoveal target features. This effect did not occur in the absence of saccades, and it also scaled with the extent of the introduced intra-saccadic image feature discrepancies. These results suggest that foveal SC neurons may signal a trans-saccadic prediction error when the foveated image stimulating them is inconsistent with that expected from pre-saccadic extrafoveal representations, a potential perceptual stability mechanism.
Glycoprotein 2 (GP2) and Uromodulin (UMOD) are considered as paralogs that share high sequence similarity and have similar antibacterial functions. UMOD are abundant as filaments in the urinary tract, and a high-mannose N-glycosylation site located on the N-terminal region protruding from UMOD filament core (referred to as branch) acts as an adhesion antagonist against pathogenic bacterial infections. The antibacterial function of UMOD can be eliminated by proteases, as the UMOD branch is susceptible to proteolytic activity. GP2 is expressed in the pancreas and secreted into the digestive tract. Whether GP2 executes its function in filament form and how it remains functional in the protease-enriched digestive tract is unclear. In this study, we extract GP2 filaments from surgically excised human pancreas and determined their cryo-EM structure. Our structure analysis unveiled that GP2 forms filaments with its ZP modules, composing the ZPN and ZPC domains along with a linker that connects these two domains. The N-terminal region (branch) of GP2 does not constitute the filament core and appears flexible in the cryo-EM structure. Our biochemical experiments suggested that although the GP2 branch is also protease-susceptible, additional high-mannose N-glycans were identified on the protease-resistant GP2 filament core. Consequently, the branch-free GP2 filaments retain their binding ability to the bacterial adhesin FimH, ensuring GP2’s antibacterial function unaffected in the proteolytic environment. Our study provides the first experimental evidence of GP2 filament formation and reveals the molecular mechanisms underlying GP2’s adaptation to a different environment compared to UMOD.
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T stem cell-like memory cells (TSCMcells) are considered to be essential for the maintenance of immune memory. The TSCMpopulation has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human TSCMpopulation consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-termin vivolabelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profilesex vivo, different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi TSCMincreases with age. Most importantly, CD95hi and CD95int TSCMcells also have very different dynamicsin vivowith CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int TSCM. While both TSCMsubpopulations exhibit considerable multipotency, no single population of TSCMcells has both the properties of self-renewal and clonal longevity. Instead, the “stemness” of the TSCMpopulation is generated by the complementary dynamic properties of the two subpopulations: CD95int TSCMwhich have the property of clonal longevity and CD95hi TSCMwhich have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.
Predictive coding posits the brain predicts incoming sensory information and signals a positive prediction error when the actual input exceeds what was predicted, and a negative prediction error when it falls short of the prediction. It is theorized that specific neurons encode the negative prediction error, distinct from those for the positive prediction error, and are linked to responses to omitted expected inputs. However, what information is actually encoded by omission responses remains unclear. This information is essential to confirm their role as negative prediction errors. Here, we record single-unit activity in the rat auditory cortex during an omission paradigm where tone probabilities are manipulated to vary the prediction content. We identify neurons that robustly respond to omissions, with responses that increase with evidence accumulation and directly correlate with tone predictability—key characteristics suggesting their role as negative prediction-error neurons. Interestingly, these neurons showed selective omission responses but broad tone responses, revealing an asymmetry in error signaling. To capture this asymmetry, we propose a circuit model composed of laterally interconnected prediction-error neurons that qualitatively reproduce the observed asymmetry. Furthermore, we demonstrate that these lateral connections enhance the precision and efficiency of prediction encoding across receptive fields, and that their validity is supported by the free energy principle.
The evolution of sexual secondary characteristics necessitates regulatory factors that confer sexual identity to differentiating tissues and cells. InColias eurythemebutterflies, males exhibit two specialized wing scale types—ultraviolet-iridescent (UVI) and spatulate scales—which are absent in females and likely integral to male courtship behavior. This study investigates the regulatory mechanisms and single-nucleus transcriptomics underlying these two sexually dimorphic cell types during wing development. We show thatDoublesex(Dsx) expression is itself dimorphic and required to repress the UVI cell state in females, while unexpectedly, UVI activation in males is independent fromDsx. In the melanic marginal band,Dsxis required in each sex to enforce the presence of spatulate scales in males, and their absence in females. Single-nucleus RNAseq reveals that UVI and spatulate scale cell precursors each show distinctive gene expression profiles at 40% of pupal development, with marker genes that include regulators of transcription, cell signaling, cytoskeletal patterning, and chitin secretion. Both male-specific cell types share a low expression of theBric-a-brac(Bab) transcription factor, a key repressor of the UVI fate. Bab ChIP-seq profiling suggests that Bab binds thecis-regulatory regions of gene markers associated to UVI fate, including potential effector genes involved in the regulation of cytoskeletal processes and chitin secretion, and loci showing signatures of recent selective sweeps in a UVI-polymorphic population. These findings open new avenues for exploring wing patterning and scale development, shedding light on the mechanisms driving the specification of sex-specific cell states and the differentiation of specialized cell ultrastructures.
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Successful initiation of animal development requires activation of the egg immediately prior to fusion of gamete pronuclei. In all taxa, this is initiated by waves of calcium transients which transverse across the egg. Calcium waves also occur at cleavage furrows during later blastula cytokinesis. Calcium is released from the endoplasmic reticulum through activation of inositol-1,4,5-trisphosphate (IP3) receptors. Only a subset of the mechanisms employed to generate IP3during vertebrate egg activation are defined, with strong evidence that other critical mechanisms exist. Serine proteases have been long implicated in egg activation and fertilization. Here, we report that treatment of zebrafish eggs with serine protease inhibitors leads to defective calcium wave propagation and failed egg activation. We further show that mutation of zebrafish Protease-activated receptor 2a (Par2a) also results in severe disruption of egg activation, leading to failed chorion elevation and ooplasmic segregation. Milderpar2amutants progress further, but then show abnormal blastomere cleavage. We observed thatpar2amutants show decreased amplitude and duration of calcium transients. Restoring Ca++or direct injection of IP3ligand rescues egg activation aborted by either serine protease inhibitor treatment or by mutation of Par2a. We thus show that serine protease activity is a critical regulator of IP3and subsequent calcium wave amplification during zebrafish egg activation, and link this to intracellular calcium release via the protease receptor, Par2a. This constitutes a novel signaling pathway critical for successful fertilization.
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The dynamic fluctuations in the amplitude of sound, known as sound envelopes, are ubiquitous in natural sounds and convey information critical for the recognition of speech, and of sounds generally. We are perceptually most sensitive to slow modulations which are most common. However, previous studies of envelope coding in the brainstem found an under-representation of these slow, low-frequency, modulations. Specifically, the synchronization of spike times to the envelope was enhanced in some neuron types, forming channels specialized for envelope processing but tuned to a restricted range of fast, high-frequency, envelopes (200–500 Hz). Here, we show using a historical dataset from cats that previous analyses, which made strong assumptions about the neural code, underestimated the encoding of low-frequency envelopes. While some neurons encode envelope better than others, most encode a wide range of envelope frequencies, and represent slower envelope fluctuations most accurately in their precise patterns of spike times. Identification of envelope frequency from spike-timing was linked to reliability, and to the way that dynamics of spiking interacted with the time-varying envelope. In some of the best-performing neurons, temporally complex “mode-locked” spike patterns served to enhance envelope coding. A second long-standing contradiction was that neural envelope coding is degraded at high sound levels, whilst the perception of envelope is robust at a wide range of sound levels. We find that spike-time encoding of envelope shape becomes level-robust for small populations of neurons. These findings argue against feature-specific coding of envelopes in the brainstem, and for a distributed population spike-time code for which synchrony to the envelope is an incomplete description. This code is accurate for slow fluctuations and robust across sound level. Thus, precise spike-timing information in the brainstem is after-all aligned with the needs of communication and the perception of environmental sounds.
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Understanding synaptic dynamics during the sleep–wake cycle in the cortex is crucial yet remains controversial. The synaptic homeostasis hypothesis (SHY) suggests synaptic depression during non-rapid eye movement (NREM) sleep, while other studies report synaptic potentiation or synaptic changes during NREM sleep depending on activities in wakefulness. To find boundary conditions between these contradictory observations, we focused on learning rules and firing patterns that contribute to the synaptic dynamics. Using computational models considering mammalian cortical neurons, we found that under Hebbian and spike-timing dependent plasticity (STDP), wake-like firing patterns decrease synaptic weights, while sleep-like patterns strengthen synaptic weights. We refer to this tendency as Wake Inhibition and Sleep Excitation (WISE). Conversely, under Anti-Hebbian and Anti-STDP, synaptic depression during NREM sleep was observed, aligning with the conventional synaptic homeostasis hypothesis. Moreover, synaptic changes depended on firing rate differences between NREM sleep and wakefulness. We provide a unified framework that could explain synaptic homeodynamics under the sleep–wake cycle.
Bacteria produce a plethora of natural products that are in clinical, agricultural and biotechnological use. Genome mining has uncovered millions of biosynthetic gene clusters (BGCs) that encode their biosynthesis, the vast majority of them lacking a clear product or function. Thus, a major challenge is to predict the bioactivities of the molecules these BGCs specify, and how to elicit their expression. Here, we present an innovative strategy whereby we harness the power of regulatory networks combined with global gene expression patterns to predict BGC functions. Bioinformatic analysis of all genes predicted to be controlled by the iron master regulator DmdR1 combined with co-expression data, led to identification of the novel operondesJGHthat plays a key role in the biosynthesis of the iron overload drug desferrioxamine (DFO) B inStreptomyces coelicolor. Deletion of eitherdesGordesHstrongly reduces the biosynthesis of DFO B, while that of DFO E is enhanced. DesJGH most likely act by changing the balance between the DFO precursors. Our work shows the power of harnessing regulation-based genome mining to functionally prioritize BGCs, accelerating the discovery of novel bioactive molecules.
Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is epistatic over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, supported by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells.
Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, most of these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased toward the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published functional screens and proteomics data to reveal (i) common pathways that were identified in all OMICs datasets—including regulation of Wnt signaling and gap junctions, (ii) pathways uniquely identified in this screen—including NADH oxidation, or (iii) pathways supported by this screen and proteomics data but not published functional screens—including arachionate production and MAPK signaling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 32 proteins that were determined to impact viral replication and 27 impacting late stages of infection, respectively. Additionally, a subset of proteins was tested across other coronaviruses revealing a subset of proviral factors that were conserved across pandemic SARS-CoV-2, epidemic SARS-CoV-1 and MERS-CoV, and the seasonal coronavirus OC43-CoV. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus–host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.
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Migraine aura – manifesting as transient, neurological disturbances – presents a complex and unresolved relationship with migraine headache. Cortical spreading depolarization (SD), recognized as the mechanism underlying aura symptoms, has been shown to trigger head pain through activation of trigeminal nociceptors in animal models. However, recent clinical data challenge the notion that aura causes migraine headache in patients. In this Essay, we critically examine the pathophysiology of migraine aura and migraine headache, exploring evidence from clinical observations, (genetic) mouse models, and pharmacological studies. We also discuss the role of SD, the trigeminovascular system, and the impact of pharmacological agents that both trigger and treat migraine attacks. Our essay highlights the complexities and conflicting data surrounding the interplay between aura and headache, emphasizing the need for further research to unravel this mystery and improve therapeutic strategies for individuals with migraine.
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Presynaptic scaffold proteins, including liprin-α, RIM, and ELKS, are pivotal to the assembly of the active zone and regulating the coupling of calcium signals and neurotransmitter release, yet the underlying mechanism remains poorly understood. Here, we determined the crystal structure of the liprin-α2/RIM1 complex, revealing a multifaceted intermolecular interaction that drives the liprin-α/RIM assembly. Neurodevelopmental disease-associated mutations block the formation of the complex. Disrupting this interaction in cultured human neurons impairs synaptic transmission and reduces the readily releasable pool of synaptic vesicles. Super-resolution imaging analysis supports a role for liprin-α in recruiting RIM1 to the active zone, presumably by promoting the liquid–liquid phase separation (LLPS) of RIM1. Strikingly, the liprin-α/RIM interaction modulates the competitive distribution of ELKS1 and voltage-gated Ca2+channels (VGCCs) in RIM1 condensates. Disrupting the liprin-α/RIM interaction significantly decreased VGCC accumulation in the condensed phase and rendered release more sensitive to the slow calcium buffer EGTA, suggesting an increased physical distance between VGCC and vesicular calcium sensors. Together, our findings provide a plausible mechanism of the liprin-α/RIM complex in regulating the coupling of calcium channels and primed synaptic vesicles via LLPS for efficient synaptic transmission and uncover the pathological implication of liprin-α mutations in neurodevelopmental disorders.
Genes do not act in isolation, and the effects of a specific variant at one locus can often be greatly modified by polymorphic variants at other loci. A good example isFLOWERING LOCUS C(FLC), which has been inferred to explain much of the flowering time variation inArabidopsis thaliana. We use a set of 62flcspecies-wide mutants to document pleiotropic, genotype-dependent effects forFLCon flowering as well as several other traits. Time to flowering was greatly reduced in all mutants, with the remaining variation explained mainly by allelic variation at theFLCtargetFT. Analysis ofFTsequence variation suggested that extremely early combinations ofFLCandFTalleles should exist in the wild, which we confirmed by targeted collections. Our study provides a proof of concept on how pan-genetic analysis of hub genes can reveal the true extent of genetic networks in a species.
tRNA halves are among the most abundant short non-coding RNAs in the cellular transcriptome. Here we report that in androgen receptor-positive LNCaP prostate cancer cells, the hormone-dependent 5′-tRNALysCUUhalf promoted cell proliferation by facilitating cell cycle progression. Global mRNA profiling upon the 5′-tRNALysCUUhalf depletion revealed that the mRNA of p21, a negative regulator of the cell cycle, is post-transcriptionally destabilized via a 5′-tRNALysCUUhalf-driven mechanism. YBX1, identified as a protein interacting with 5′-tRNALysCUUhalf in the cytosol, was shown to stabilize p21 mRNA. Specific sequences resembling the 5′-tRNALysCUUhalf, located in the 3′-UTR of p21 mRNA and termed LL588, were identified as the binding site for YBX1 and are required for p21 mRNA stability. In vitro binding assays demonstrated that the 5′-tRNALysCUUhalf is capable of displacing YBX1 from LL588. Collectively, our findings suggest that the 5′-tRNALysCUUhalf directly binds to and displaces YBX1 from p21 mRNA, leading to the destabilization of p21 mRNA and the promotion of cell cycle progression in hormone-dependent cancers. Our study illuminates the role of tRNA halves in regulating mRNA stability and suggests that this may be part of broader regulatory networks affecting mRNA levels, orchestrated by various tRNA halves and their interacting proteins.
Neural tracking (entrainment) of auditory rhythms enhances perception. We previously demonstrated that transcranial alternating current stimulation (tACS) can enhance or suppress entrainment to rhythmic auditory stimuli, depending on the timing between the electrical and auditory signals, although tACS effects are primarily modulatory. This study further investigated entrainment to tACS and auditory rhythms when the electrical and auditory signals were presented together (Experiment 1,N= 34) or independently (Experiment 2,N= 24; Experiment 3,N= 12). We hypothesized that tACS effects would be more pronounced when the auditory rhythm was made less perceptually salient to reduce the competition with the electrical rhythm. Participants detected silent gaps in modulated or unmodulated noise stimuli. In Experiment 1, auditory stimuli predominated in entraining behavior. While behavioral entrainment to sound rhythms was affected by the modulation depth of the auditory stimulus, entrainment to tACS was not. In Experiment 2, with no rhythmic information from the sound, 17 of 24 participants showed significant behavioral entrainment to tACS, although the most effective tACS frequency varied across participants. An oscillator model with a free parameter for the individual resonance frequency produced profiles similar to those we observed behaviorally. In Experiment 3, both neural and behavioral entrainment to rhythmic sounds were affected by the auditory stimulus frequency, but again the most effective entraining frequency varied across participants. Our findings suggest that tACS effects depend on the individual’s preferred frequency when there is no competition with sensory stimuli, emphasizing the importance of targeting individual frequencies in tACS experiments. When both sensory and electrical stimuli are rhythmic and compete, sensory stimuli prevail, indicating the superiority of sensory stimulation in modulating behavior.
Generalization from past experience is an important feature of intelligent systems. When faced with a new task, one efficient computational approach is to evaluate solutions to earlier tasks as candidates for reuse. Consistent with this idea, we found that human participants (n= 38) learned optimal solutions to a set of training tasks and generalized them to novel test tasks in a reward-selective manner. This behavior was consistent with a computational process based on the successor representation known as successor features and generalized policy improvement (SF&GPI). Neither model-free perseveration or model-based control using a complete model of the environment could explain choice behavior. Decoding from functional magnetic resonance imaging data revealed that solutions from the SF&GPI algorithm were activated on test tasks in visual and prefrontal cortex. This activation had a functional connection to behavior in that stronger activation of SF&GPI solutions in visual areas was associated with increased behavioral reuse. These findings point to a possible neural implementation of an adaptive algorithm for generalization across tasks.
Body ownership disorders can be triggered by disease or body damage. Methods to probe limb embodiment are required to address those disorders. This includes the development of neuroprostheses that better integrate into the body scheme of the user. To this end, the “rubber hand illusion” protocol is a key behavioral method to probe the powerful embodiment that can be triggered by congruent somatosensory and visual inputs from the limb. So far, the neurophysiology of limb embodiment remains poorly known, in part because translating the rubber hand illusion to animal models such as the mouse remains challenging. Yet, mapping out the brain circuits of embodiment thanks to the use of genetic and optogenetic research tools would allow to propose novel embodiment restoration strategies. Here, we show that the rubber hand illusion described in humans can be translated to the mouse forelimb model using an automated, videography-based procedure. We exposed head-fixed mice to a visible, static 3D-printed replica of the right forelimb, while their own forelimb was hidden from their sight. We synchronously brushed their hidden forelimb and the replica. Following these visuo-tactile associations, the replica was visually threatened, and we probed the reaction of the mice using automated tracking of pupils and facial expression. The mice focused significantly more of their gaze toward the threatened forelimb replica after receiving synchronous tactile and visual information compared to asynchronous. More generally, across test and control conditions, the mouse pupillary response was consistent with the human overt response to the rubber hand illusion. Thus, our results show that mice exhibit quantifiable behavioral markers of the embodiment of an artificial forelimb.
Indisulam, a sulfonamide-based compound, is employed as a second-line therapy for NSCLC due to its anti-tumor activity. However, its clinical efficacy is hindered by acquired resistance, the molecular basis of which remains poorly understood. Here, we demonstrate that hypermethylation of RNA-binding protein 39 (RBM39), a specific target of Indisulam, is closely associated with Indisulam resistance. PRMT6 methylates RBM39 at R92. This methylation inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 protein levels, promotes alternative splicing and expression of proto-oncogenes, and ultimately leads to malignant proliferation and metastasis of NSCLC cells and tumor growth in xenograft mouse models. Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC.
Inhaled anesthetics were first introduced into clinical use in the 1840s. Molecular and transgenic animal studies indicate that inhaled anesthetics act through several ion channels, including γ-aminobutyric acid type A receptors (GABAARs) and two-pore domain K+(K2P) channels, but other targets may mediate anesthetic effects. Mutations in the type 1 ryanodine receptor (RyR1), which is a calcium release channel on the endoplasmic reticulum membrane, are relevant to malignant hyperthermia, a condition that can be induced by inhaled anesthetics. However, it was previously uncertain whether inhaled anesthetics directly interact with RyR1. In our study, we demonstrated that isoflurane and other inhaled anesthetics activate wild-type RyR1. By employing systematic mutagenesis, we discovered that altering just one amino acid residue negates the response to isoflurane, thus helping us to pinpoint the potential binding site. Knock-in mice engineered to express a mutant form of RyR1 that is insensitive to isoflurane exhibited resistance to the loss of righting reflex (LORR) when exposed to isoflurane anesthesia. This observation suggests a connection between RyR1 activation and the anesthetic effects in vivo. Moreover, it was shown that RyR1 is involved in the neuronal response to isoflurane. Additionally, administering new RyR1 agonists, which share the same binding site as isoflurane, resulted in a sedation-like state in mice. We propose that isoflurane directly activates RyR1, and this activation is pertinent to its anesthetic/sedative effects.
A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, the sound of an approaching vehicle signals when it is safe to cross the street; distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in predictive licking for reward. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impaired animals’ ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.
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AbstractA variety of biomarkers other than degree of neurovascular compression have been used to estimate the likelihood of long-term pain-freedom after microvascular decompression (MVD). In this study, we report the prognostic implications of microstructural changes found in patients with idiopathic trigeminal neuralgia (iTN) with an arterial contactwithoutmorphological changes. Patients 18 years or older who underwent MVD as their initial surgical procedure for iTN witharterial contact without morphological changesbetween March 2013 and December 2021 were analyzed. Mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy (MD, RD, AD, and FA) were extracted from the cisternal segment of the trigeminal nerve immediately adjacent to the root entry point. Metrics were compared between symptomatic and asymptomatic trigeminal nerves. Metrics from the symptomatic trigeminal nerve were compared between responders and nonresponders to MVD. To avoid false discovery of a significantP-value, we used the Bonferroni correction method. A statistical significance criterion of q < 0.05 was used. When comparing the symptomatic trigeminal nerve with the asymptomatic trigeminal nerve, the MD was significantly increased on the symptomatic side (q = 0.00047), the RD was significantly increased on the symptomatic side (q = 0.0000066), and the FA was significantly decreased on the symptomatic side (q = 0.0000054). Fractional anisotropy was significantly decreased in nonresponders (q = 0.0056). Fractional anisotropy has potential to preoperatively identify patients with iTN with arterial contact without morphological changes that will respond to MVD. This study identifies a subset of patients with iTN who are not truly “idiopathic.”
AbstractAs individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by “inflammaging,” a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link between inflammaging and age-related development of pain is crucial for identifying novel therapeutic targets. We hypothesized that the circulatory milieu plays a role in regulating pain and that inflammaging contributes to changes in pain behavior with age. To test these hypotheses, we monitored nociception and postsurgical pain in male and female mice aged 3 and 24 months and analyzed their serum proteome, including cytokine/chemokine profiles. Our results demonstrated that compared with young mice, aging mice were hyposensitive to mechanical stimulation, yet their pain response to incision was aggravated and prolonged. Serum proteomic analysis revealed sex-specific inflammaging patterns. To explore the link between inflammaging and age-related alteration in pain behavior, we applied a rejuvenation strategy by transferring serum from 3-month-old mice to 19- to 21-month-old mice. Young serum normalized mechanical sensitivity in aged mice, alleviated postsurgical mechanical pain, and promoted recovery. Alongside the improvements in pain behavior phenotype, young serum recalibrated the aging serum profile. It reduced age-associated increases of cytokine/chemokine levels in male mice and rescued age-related, female-selective downregulation of inflammatory pathways such as liver X receptor/retinoid X receptor activation, D24-dehydrocholesterol reductase, and complement signaling. Our findings suggest that the circulatory environment, notably inflammaging, plays a significant role in altered pain behavior of aging mice. The sex-specific signature of age-dependent systemic inflammation highlights the importance of investigating inflammaging through the lens of sexual dimorphism.
AbstractResearch on social disparities in pain and pain treatment has grown substantially in recent decades, as reflected in a growing number of review articles on these topics. This scoping review of reviews provides a macrolevel overview of scholarship in this area by examining what specific topics and findings have been presented in published reviews. We searched CINAHL, Cochrane Database of Systematic Reviews, Embase, PsycINFO, PubMed, and Web of Science for English-language, peer-reviewed review articles, qualitative or quantitative, that aimed to characterize or explain pain-related differences or inequities across social groups. Of 4432 unique records screened, 397 articles, published over a 56-year period, were included. For each, we documented (1) axes of social difference studied (eg, sex/gender, race/ethnicity), (2) pain-related outcomes (eg, chronic pain prevalence), (3) broad findings, (4) types of mechanisms proposed, and (5) policy or practice recommendations. Findings reveal a sharp increase in the number of published review articles on pain-related disparities since approximately the year 2000. The most commonly studied social dimension was sex/gender, followed by race/ethnicity and age. Studies examining disparities by socioeconomic status, geography, or other categories were rarer. While most findings showed disadvantaged social groups to have worse pain outcomes, there were intriguing exceptions. Biological, psychological, and sociocultural mechanisms were considered much more frequently than sociostructural (macrolevel) ones. Policy/practice recommendations were typically individual-level behavioral suggestions for providers or patients. We identify high-priority areas for future research, including greater attention to lower-income countries, chronic pain prevention, and macrolevel drivers of pain disparities.
AbstractThe inclusion of diverse populations in pain research is crucial to obtaining a complete understanding of how the biopsychosocial experience of pain is seen through the lens of different populations. Traditionally, individuals who identify as Black/African American or Hispanic/Latino have not participated in early phase clinical trials, and as a result, their unique perspectives of the management of pain have not been included in study results. In this qualitative research study, we sought to uncover barriers that prevent diverse populations from participating in pain treatment clinical trials. Partnering with a community organization, we used a semistructured interview to conduct nine focus groups among underrepresented populations to obtain these perspectives. A total of 54 patients with ages ranging from 23 to 77 years old were recruited for this study. Of the patients recruited for the study, 74% identified as non-Hispanic Black, and 24% identified as Hispanic/Latino. Results were recorded, transcribed, and analyzed for thematic saturation using inductive qualitative content analysis. Results uncovered an array of different perspectives including the recognition of historical wrongs that lead to mistrust of the research and healthcare systems. However, other perspectives include recognition that the location of study sites, time required for participation, and overall accessibility of the study play a significant role in an individual's willingness to participate.
AbstractThis cross-sectional retrospective study evaluated the diagnostic accuracy of cold detection thresholds (CDT) and warm detection thresholds (WDT), measured by quantitative sensory testing, for detecting small fiber impairment in polyneuropathy and diagnosing small fiber neuropathy (SFN). A total of 384 individuals with distally distributed sensory disturbances were included. Using ACTTION criteria, 138 patients with polyneuropathy were identified. Among them, 36 were diagnosed with SFN, 91 with mixed fiber polyneuropathy, and 11 with pure large fiber polyneuropathy. First, we assessed CDT and WDT accuracy, both individually and combined (ie, an abnormal value in either CDT or WDT), in detecting small fiber impairment in polyneuropathy. Next, we calculated CDT and WDT diagnostic accuracy for SFN, both alone and combined, and evaluated their accuracy when integrated with small fiber–related clinical abnormalities. Isolated abnormalities in CDT or WDT showed relatively low diagnostic accuracy. However, combined abnormalities achieved a sensitivity of 69% and specificity of 70% for detecting small fiber impairment in distal symmetric polyneuropathy. For SFN diagnosis, combining CDT and WDT yielded 78% sensitivity, 70% specificity, and a 94% negative predictive value. These metrics improved to 78% sensitivity and 100% specificity when CDT or WDT were integrated with small-fiber-related clinical abnormalities. Although individual CDT and WDT assessments offer limited diagnostic accuracy, their combination provides a practical, noninvasive approach for screening small fiber impairment in distal symmetric polyneuropathy and diagnosing SFN. This strategy may reduce the need for more invasive and less cost-effective procedures, like skin biopsy.
AbstractOffset analgesia reflects time-dependent, central nervous system pain inhibition and refers to a dramatic drop in pain intensity after an offset of noxious stimulus intensity. Neuropathic and nociplastic pain conditions with strong central nervous system pathophysiologic mechanisms show deficits in offset analgesia. Whether offset analgesia is altered in more peripherally driven chronic nociceptive pain was unknown. Therefore, the primary goal of the current study was to determine whether chronic nociceptive pain is associated with changes in offset analgesia. We measured offset analgesia and sensory function using quantitative sensory tests, patient-reported pain and function, and walking and stair climbing performance using standardized tasks in knee osteoarthritis patients with equivalent joint degeneration but Moderate-to-Severe (n = 36) or Mild pain intensity (n = 36) and Pain-free controls without knee osteoarthritis (n = 30) matching for age, gender, and body mass index. Offset analgesia was significantly reduced in knee osteoarthritis groups compared with the Pain-free controls, with deficits occurring at both the nonpainful forearm and painful knee and in both genders. Greater deficits in offset analgesia were associated with more impairment in walking and stair climbing. Onset hyperalgesia, a novel measure of time-dependent pain facilitation, was reduced in women with Mild knee pain but not in men. These results suggest that deficits in temporal pain inhibition and gender-specific changes in temporal pain facilitation may contribute to pain and functional impairment in knee osteoarthritis, supporting further study of central pain modulation as a clinically relevant mechanism of chronic nociceptive pain.
AbstractTraumatic stress exposures (TSEs) are common in life. Although most individuals recover after a TSE, a substantial subset develop adverse post-traumatic neuropsychiatric sequelae such as chronic post-traumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the Advancing Understanding of RecOvery afteR traumA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding, combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In Advancing Understanding of RecOvery afteR traumA study participants (n = 2480), using multinomial logistic regression modeling of 4 identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (odds ratio [OR] = 1.047,P< 0.001), the moderate pain class (OR = 1.031,P< 0.001), and the moderate recovery pain class (OR = 1.018,P= 0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison with SPS alone, neonatal limited bedding combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197) = 3.22,P< 0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP.
AbstractPain is multidimensional, including sensory-discriminative, affective-motivational, and cognitive-evaluative components. Although the concept of pain is learned through life, it is not known when and how the brain networks that are required to encode these different dimensions of pain develop. Using the 2 largest available databases of brain magnetic resonance images—the developing Human Connectome Project and the Human Connectome Project—we have mapped the development of the pain connectome—the neural network required for pain perception—in infants from 26 to 42 weeks of postmenstrual age (PMA, n = 372), compared with adults (n = 98). Partial correlation analysis of resting BOLD signal between pairwise combinations of 12 pain-related brain regions showed that overall functional connectivity is significantly weaker before 32 weeks PMA compared with adults. However, over the following weeks, significantly different developmental trajectories emerge across pain connectome subnetworks. The first subnetwork to reach adult levels in strength and proportion of connections is the sensory-discriminative subnetwork (34-36 weeks PMA), followed by the affective-motivational subnetwork (36-38 weeks PMA), while the cognitive-evaluative subnetwork has still not reached adult levels at term. This study reveals a previously unknown pattern of early development of the infrastructure necessary to encode different components of pain experience. Newborn neural pathways required for mature pain processing in the brain are incomplete in newborns compared with adults, particularly regarding the emotional and evaluative aspects of pain. The rapid age-related changes suggest that pain processing, and consequently pain experience, changes rapidly over this developmental period and unlikely to be the same as in adults, even at term.
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AbstractChronic musculoskeletal pain (CMP) is the most prevalent form of chronic pain. A subgroup of patients with CMP shows altered pain processing, including impaired endogenous pain modulation, as evaluated by experimental pain measures. One hypothesis is that genetic and/or epigenetic variants may contribute to individual differences in outcomes of dynamic experimental pain assessment. Therefore, a systematic review was performed to comprehensively summarize the current evidence regarding genetic and epigenetic influences on dynamic experimental pain measures in adults with and without CMP. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four electronic databases were searched to identify relevant studies. Risk of bias and quality of evidence were assessed using the Newcastle Ottawa Scale and the Grading of Recommendations, Assessment, Development, and Evaluation approach, respectively. A total of 24 articles were included, accounting for 34 different regions of interest. Low-quality evidence indicated no association between the rs4680 single-nucleotide polymorphism (SNP) of theCOMTgene or the serotonin-transporter-linked polymorphic region SNP of theSLC6Agene and conditioned pain modulation in healthy volunteers or in patients with CMP. In addition, low-quality evidence was found for the lack of an association between the rs1799971 SNP of theOPRM1gene and conditioned pain modulation in healthy volunteers. Other genetic and epigenetic variants provided limited or conflicting evidence. For now, it seems that dynamic experimental pain measurements are robust to genetic and epigenetic variations. However, more reproducible research is warranted to better understand whether or not and how genetic and epigenetic variations influence (altered) pain processing, which is crucial for advancing both preventive and therapeutic strategies in CMP populations.
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AbstractCoronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global health crisis, with many patients experiencing not only acute neurological and sensory symptoms but also persistent sensory abnormalities, commonly referred to as long COVID sequelae. The mechanisms underlying somatosensory abnormalities induced by SARS-CoV-2 remain largely unclear. In this study, we investigate the role of the SARS-CoV-2 nucleocapsid (N) protein in pain regulation. Our data show that SARS-CoV-2 N protein exacerbates pathological pain in mouse models of bone cancer, chemotherapy, neuropathic, and inflammatory, and promotes the chronification of acute inflammatory pain. We also identify a potential interaction between the N protein and Nav1.7 in dorsal root ganglion neurons from mice, monkeys, and humans. Furthermore, the N protein significantly increases Nav1.7 currents in dorsal root ganglion neurons from both mice and monkeys by delaying Nav1.7 inactivation without altering its expression or membrane trafficking. This modulation of Nav1.7 function by the N protein not only intensifies pain hypersensitivity but also prolongs the duration of pain, potentially facilitating the transition from acute to chronic pain. Our findings underscore the importance of vigilant management of SARS-CoV-2 infection in patients with pathological pain and suggest potential therapeutic targets for mitigating COVID-19–related pain.
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AbstractMaintaining a dynamic balance among various life-history traits is crucial for survival in a warming world, yet the underlying mechanisms remain enigmatic. In this study, we employed the western clawed frog (Xenopus tropicalis) as a model and conducted a long-tern experiment from zygotes to adult stage. We find that even within the previously considered normal temperature range, a 5 °C increase in ambient temperature can establish a new metabolic state, resulting in elevated oxidative stress and a shift in energy allocation towards immune defense at the expense of sexual development. This conceptual framework of temperature-dependent trade-off strategy suggests that, while some studies observed that warm temperature reduces the risk of infection, it is important to note that this change may present challenges in the form of accelerated aging and reduced fertility, especially in ectotherms. These results not only indicate a far more complex adaptive response to future climate change than previously anticipated, but also provide a concise method for constructing animal models to explore diseases related to homeostatic disorders.
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AbstractCross-ecosystem subsidies influence the structure and dynamics of recipient ecosystems and can be sensitive to disturbance. Primary production exported from marine to shoreline ecosystems is among the largest known cross-ecosystem subsidies. However, the spatial scales at which this important connection is manifested are largely unquantified. We used local and regional observations of nearshore kelp canopy biomass and beach kelp wrack inputs to evaluate the scales at which connectivity between kelp forests and beaches is maximized. Regardless of the spatial and temporal scales considered, connectivity was highly local (<10 km) and strongest in winter. Kelp canopy biomass was the primary driver of wrack subsidies, but recipient ecosystem attributes, particularly beach width and orientation, were also important. These drivers of connectivity highlight that disturbance to either ecosystem will have large implications for beach ecosystem productivity. Spatial connectivity can regulate recovery from disturbances such that ecosystem connections must be considered in conservation efforts.
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AbstractCRISPR-Cas diagnostics are revolutionizing point-of-care molecular testing due to the programmability, simplicity, and sensitivity of Cas systems withtrans-cleavage activity. CRISPR-Cas12 assays are promising for detecting single nucleotide polymorphisms (SNPs). However, reports vary widely describing Cas12 SNP sensitivity, and an underlying mechanism is lacking. We systematically varied crRNA length and valency to investigate the role of crRNA architectures on Cas12 biosensing in the context of speed-of-detection, sensitivity, and selectivity. Our results demonstrate that crRNAs complementary to 20 base pairs of the target DNA is optimal for rapid and sensitive detection, while a complementary length of 15 base pairs is ideal for robust SNP detection. Additionally, we uncovered a unique periodicity in SNP sensitivity based on nucleotide position and developed a structural model explaining what drives Cas12 SNP sensitivity. Lastly, we showed that bivalent CRISPR-Cas sensors have synergistic and enhanced activity that is distance dependent.
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AbstractThree dimensional immunohistochemistry (3D-IHC), immunolabeling of 3D tissues, reveals the spatial organization of molecular and cellular assemblies in the context of the tissue architecture. Deep and rapid penetration of antibodies into 3D tissues and highly sensitive detection are critical for high-throughput imaging analysis of immunolabeled 3D tissues. Here, we report a nanobody (nAb)-based 3D-IHC, POD-nAb/FT-GO 3D-IHC, for high-speed and high-sensitive detection of targets within 3D tissues. Peroxidase-fused nAbs (POD-nAbs) enhanced immunolabeling depth and allowed for highly sensitive detection by combined with a fluorescent tyramide signal amplification system, Fluorochromized Tyramide-Glucose Oxidase (FT-GO). Multiplex labeling was implemented to the 3D-IHC by quenching POD with sodium azide. Using the 3D-IHC technique, we successfully visualized somata and processes of neuronal and glial cells in millimeter-thick mouse brain tissues within three days. Given its high-speed and high-sensitive detection, our 3D-IHC protocol, POD-nAb/FT-GO 3D-IHC, would provide a useful platform for histochemical analysis in 3D tissues.
AbstractQuenchbodies, antibodies labelled with fluorophores that increase in intensity upon antigen binding, offer great promise for biosensor development. Nanobody-based quenchbodies are particularly attractive due to their small size, ease of expression, high stability, rapid evolvability, and amenability to protein engineering. However, existing designs for protein detection show limited dynamic range, with fluorescence increases of only 1.1–1.4 fold. Here we identify the tryptophan residues in the nanobody complementarity-determining regions (CDRs) that are critical to quenchbody performance. Using a combination of rational design and molecular dynamics simulations, we developed an optimised nanobody scaffold with tryptophans introduced at key positions. We used this scaffold in an in vitro directed-evolution screen against human inflammatory cytokine interleukin-6 (IL-6). This yielded quenchbodies with 1.5–2.4-fold fluorescence increases, enabling IL-6 detection down to 1–2 nM. Our scaffold provides a valuable platform for developing biosensors for diverse protein targets, with applications in research, diagnostics, and environmental monitoring.
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AbstractBrassicales plants defend themselves with glucosinolates that, upon herbivory, are hydrolyzed into toxic isothiocyanates (ITCs) and other derivatives. The side chain diversity of glucosinolates results in a range of structurally distinct products, but how this chemical variation affects herbivores and their detoxification responses remains incompletely understood. Here, we show the effects of ITC hydrolysis products with various side chains onSpodoptera littoralislarvae and their detoxification system. ITCs inhibit larval growth to varying degrees, depending on the chemical nature of their side chain. The larvae metabolize ITCs by conjugating them to glutathione in the mercapturic acid pathway and to lysine forming an amine conjugate. Over half of the 34S. littoralisglutathione-S-transferases (GSTs), tested as His-tagged derivatives, actively conjugate ITCs, with most catalyzing reactions with multiple substrates. Larval performance on various ITC-containing diets correlates positively with GST activity, highlighting this detoxification system’s role in supporting growth on glucosinolate-containing plants. The propensity of multiple GSTs to react with an individual ITC and the wide expression of GST-encoding genes across larval organs likely promote the ability of this generalist herbivore to thrive on glucosinolate-defended Brassicales plants. These findings provide insight into herbivore adaptation and may inform future research on plant–insect interactions.
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AbstractVDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid–protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
AbstractOptic flow, the retinal pattern of motion experienced during self-motion, contains information about one’s direction of heading. The global pattern due to self-motion is locally confounded when moving objects are present, and the flow is the sum of components due to the different causal sources. Nonetheless, humans can accurately retrieve information from such flow, including the direction of heading and the scene-relative motion of an object. Flow parsing is a process speculated to allow the brain’s sensitivity to optic flow to separate the causal sources of retinal motion in information due to self-motion and information due to object motion. In a computational model that retrieves object and self-motion information from optic flow, we implemented flow parsing based on heading likelihood maps, whose distributions indicate the consistency of parts of the flow with self-motion. This allows for concurrent estimation of heading, detecting and localizing a moving object, and estimating its scene-relative motion. We developed a paradigm that allows the model to perform all these estimations while systematically varying the object’s contribution to the flow field. Simulations of that paradigm show that the model replicates many aspects of human performance, including the dependence of heading estimation on object speed and direction.
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AbstractThree-dimensional multiplexed fluorescence imaging is an indispensable technique in neuroscience. For two-dimensional multiplexed imaging, cyclic immunofluorescence, which involves repeating staining, imaging, and signal removal over multiple cycles, has been widely used. However, the application of cyclic immunofluorescence to three dimensions poses challenges, as a single staining process can take more than 12 hours for thick specimens, and repeating this process for multiple cycles can be prohibitively long. Here, we propose SEPARATE (Spatial Expression PAttern-guided paiRing And unmixing of proTEins), a method that reduces the number of cycles by half by imaging two proteins using a single fluorophore. This is achieved by labeling two proteins with the same fluorophores and unmixing their signals based on their three-dimensional spatial expression patterns, using a neural network. We employ a feature extraction network to quantify the spatial distinction between proteins, with these quantified values, termed feature-based distances, used to identify protein pairs. We then validate the feature extraction network with ten proteins, showing a high correlation between spatial pattern distinction and signal unmixing performance. We finally demonstrate the volumetric multiplexed imaging of six proteins using three fluorophores, pairing them based on feature-based distances and unmixing their signals through protein separation networks.
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AbstractLittle is known about host-gut microbiome interactions within natural populations at the intestinal mucosa, the primary interface. We investigate associations between the intestinal microbiome and mucosal immune measures while controlling for host, social and ecological factors in 199 samples of 158 wild spotted hyenas (Crocuta crocuta) in the Serengeti National Park, Tanzania. We profile the microbiome composition using a multi-amplicon approach and measure faecal immunoglobulin A and mucin. Probabilistic models indicate that both immune measures predicted microbiome similarity among individuals in an age-dependent manner. These associations are the strongest within bacteria, intermediate within parasites, and weakest within fungi communities. Machine learning models accurately predicted both immune measures and identify the taxa driving these associations: symbiotic bacteria reported in humans and laboratory mice, unclassified bacteria, parasitic hookworms and fungi. These findings improve our understanding of the gut microbiome, its drivers, and interactions in wild populations under natural selection.
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AbstractIgGs have become successful drug scaffolds by combining specific target binding with the ability to induce cellular cytotoxicity. Furthermore, IgGs possess unusually long half-lives in the blood (2-3 weeks). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with the FcRn-receptor whereby IgGs are recycled. No high-resolution structure of FcRn in complex with a full-length IgG is available, and the interaction was long thought to be mediated solely via the IgG-Fc. However, some IgGs with identical Fc-parts, but different Fab-domains, exhibit different half-lives, suggesting involvement of the Fab-domains in FcRn binding. Here, we employ structural mass spectrometry (HDX-MS and XL-MS) to explore the interaction of full-length IgGs with FcRn. HDX-MS and XL-MS experiments confirm an interaction between FcRn and the Fc-region of IgGs, through three cross-links between FcRn and the IgG-Fc-domain and a reduction in HDX in both the receptor and the Fc-region upon complex formation. However, FcRn-induced changes in HDX are also observed in the Fab-domains, supported by cross-links between the Fab-domains and the α3-domain of FcRn. Our results thus provide direct evidence for an IgG Fab-FcRn interaction. We envision that these results could advance the engineering of IgG-antibodies with tailored pharmacokinetics and enhanced efficacy.
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AbstractDue to the low disease prevalence, transcriptomic studies of neurodevelopmental disorders (NDDs) often face limited statistical power, constraining the depth of insights they can provide. To tackle this limitation, we integrated 151 human RNA sequencing datasets from 115 independent studies, and characterized the common and distinct molecular pathways of NDDs and their neurological phenotypes. In addition to revealing an aberrant expression profile of imprinted genes, our analysis identified transcriptomic changes in inflammatory, translational, mitochondrial, and synaptic processes across the different NDDs. We further highlight disorder-associated alterations, including upregulation ofITGB4across Rett syndrome datasets. Moreover, gene expression changes inLHX1/5-mediated cerebellar Purkinje cell layer formation were found to be specific to seizure-associated NDDs. We combined the datasets into a publicly accessible NDD transcriptomic atlas:https://SyNUM.shinyapps.io/NDD-transcriptomic-atlas/. Together, our findings provide fundamental insights into the molecular pathophysiology of NDDs and highlight genes and pathways with aberrant transcriptomic profiles. This knowledge can guide future therapeutic development and precision medicine approaches.
AbstractCocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven in part by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations─or ensembles─across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse.
AbstractMatrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, and integrate multi-omics with imaging and biochemical assays to investigate the molecular mechanisms. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimulus. We also identify activation of p-JUN in response to the stiff matrix and promoting phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness may be responsible for various fibrotic diseases and provide insight into intervening approaches.
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AbstractDevelopmental processes underlying the characteristic segmented body plans in arthropods vary widely. WhileDrosophilais well-studied, few other arthropod species offer platforms for comparable genomics at single-cell resolution. Here, we present high-quality quantitative data from single-nucleus RNA sequencing of spiderParasteatoda tepidariorumembryos at late stage 5 and stage 7, a critical period of emergence of segmental units along the anterior–posterior (AP) axis. Clustering analysis of the stage-7 dataset reconstructs an axial alignment of ectoderm cells, reflecting the differing cell states along the segmenting AP axis. This enables us to obtain genome-wide quantitative gene expression profiles along the reconstructed axis, which were used for unbiased and thorough molecular investigation of pattern elements employing statistical methods. Comprehensive gene-to-gene correlation analyses suggest distinct gene-regulatory interactions in different regions along the reconstructed axis. This study lays the foundation for exploring the origins of developmental diversity in the arthropod body plan.
AbstractHeterogeneity among somatosensory neurons is necessary for internal and external sensation. Precise patterns of gene transcription orchestrated through enhancer activation maintain heterogeneity. Thus, high-resolution cell type classification, chromatin accessibility and its relation to enhancer activation can explain the governing principles for sensory neuron heterogeneity. Here, we present an integrated atlas from published high-quality scRNA-seq datasets and resequencing the dorsal root ganglion, including over 44,000 neurons. MERSCOPE spatial transcriptomics confirms cell types in situ, including previously unrecognized neuronal types, and a spatial zonation of both neurons and non-neuronal cells. We present a cell type specific open chromatin atlas revealing enhancer driven regulons and gene-regulatory networks organized into co-regulated gene-programs that together define sensory neuron diversity. Cell type complexity is shown to be generated by layered co-regulated transcriptional modules representing shared functions across different scales of the neuronal type hierarchy with cell type specific contribution as the exception.
AbstractVisual attention paradigms have revealed that neural excitability in higher-order visual areas is modulated according to a priority map guiding attention towards task-relevant locations. Neural activity in early visual regions, however, has been argued to be modulated based on bottom-up salience. Here, we combined Magnetoencephalography (MEG) and Rapid Invisible Frequency Tagging (RIFT) in a classic visual search paradigm to study feature-guidance in early human visual cortex. Our results demonstrate evidence for both target boosting and distractor suppression when the participants were informed about the task-relevant and -irrelevant colour (guided search) compared to when they were not (unguided search). These results conceptually replicated using both a magnitude-squared coherence approach and a General Linear Model based on a single-trial measure of the RIFT response. The present findings reveal that feature-guidance in visual search affects neuronal excitability as early as primary visual cortex, possibly contributing to a priority-map-based mechanism.
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AbstractA diverse subset of cyanobacteria can transiently modify their photosynthetic machinery during far-red light photoacclimation to drive photosynthesis with less energetic photons (700 nm–800 nm). To achieve this, all the main light-driven components of the photosynthetic apparatus, including their allophycocyanin antenna, are replaced with red-shifted paralogues. Recent studies based on the structure of an incomplete complex provided some insights into the tuning of the far-red phycobiliproteins. Here, we solved the structure of the intact bicylindrical allophycocyanin complex from the cyanobacteriumChroococcidiopsis thermalisPCC 7203 at a resolution of 2.51 Å determined by Cryo-electron microscopy single particle analysis. A comparison between conserved structural features in far-red and white light allophycocyanin cores provides insight on the evolutionary adaptations needed to optimize excitation energy transfer in the far-red light adapted photosynthetic apparatus. The reduction in antenna size in far-red photosynthesis suggests a need to optimize membrane packing to increase the number of photosystems and tune the ratio between chlorophyllfmolecules and bilin pigments, while the wider spread in the absorption range of the bilins suggests faster and more efficient excitation energy transfer to far-red Photosystem II by limiting backflow of excitation from the reaction centres to the far-red bilin pigments.
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AbstractKlebsiella pneumoniaeis the leading cause of neonatal sepsis, strongly associated to antimicrobial resistance, with no vaccine available. K-antigens (KAg) have been identified as potential targets, but their diversity makes vaccine development challenging. Alternatively, the use of subcapsular O-antigens (OAg) raises questions about antibodies accessibility. We characterized clinical isolates from the BARNARDS study, designed to identify the burden of neonatal sepsis in low-middle income countries. Genomic prediction was verified through structural analysis of polysaccharides. Antibodies generated against common KAg and OAg bound all homologous organisms, regardless of specific polysaccharide structural features. Interestingly, anti-KAg antibodies exhibited bactericidal activity against a comparable number of isolates as anti-OAg antibodies. There was no association between polysaccharide characteristics andK. pneumoniaesusceptibility to killing. Antibody cross-reactivity among different KAg was observed, together with extensive cross-reactivity among OAg antibodies. This study aids in defining an optimal vaccine composition to prevent neonatal sepsis caused byK. pneumoniae.
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AbstractWorking memory allows temporary storage and manipulation of information during cognitive tasks. While the primate lateral prefrontal cortex (PFC) is involved in working memory, little is known about neuronal activity during memory updating. We trained macaque monkeys on an oculomotor n-back task, requiring them to remember locations of sequentially presented visual stimuli and generate a saccade to the location of the most recent or previous stimulus based on task rules. Many PFC neurons showed transient activity when a memory of a particular stimulus location was no longer needed, whereas others showed sustained activity for remembered locations. Decoding analysis successfully predicted future target selection based on the task rule from neuronal activity, indicating that these neuronal populations contain sufficient information to guide behavior. Furthermore, electrical stimulation at recording sites erased specific spatial memories, demonstrating a causal role of prefrontal neurons in maintaining and updating short-term memory.
AbstracttRNA undergoes various post-transcriptional modifications in the anticodon loop. FTSJ1, a protein conserved among most eukaryotes, mediates 2’-O-methylations at position 32 (Nm32) or position 34 (Nm34), complexed with THADA or WDR6, respectively. These methylations are crucial for accurate translation and cellular growth. FTSJ1 mutations are associated with non-syndromic X-linked intellectual disability. Although the structure of the FTSJ1-WDR6 complex in yeast has been solved, the structural details of the FTSJ1-THADA complex formation and substrate recognition remain unclear. Herein, using cryo-electron microscopy, we solve the high-resolution structure of FTSJ1-THADA with or without a tRNA substrate. FTSJ1 binds to THADA via its C-terminal region, with a unique interaction mode distinct from the FTSJ1-WDR6 complex. The tRNA substrate is anchored inside THADA, and key THADA residues for THADA-tRNA interaction are identified via structural and biochemical analyses. These findings demonstrate how FTSJ1 and THADA form a complex to mediate Nm32 modification in various tRNAs.
AbstractAI image processing techniques hold promise for clinical applications by enabling analysis of complex status information from cells. Importantly, real-time brightfield imaging has advantages of informativeness, non-destructive nature, and low cost over fluorescence imaging. Currently, human liver organoids (HLOs) offer an alternative to animal models due to their excellent physiological recapitulation including basic functions and drug metabolism. Here we show a drug-induced liver injury (DILI) level prediction model using HLO brightfield images (DILITracer) considering that DILI is the major causes of drug withdrawals. Specifically, we utilize BEiT-V2 model, pretrained on 700,000 cell images, to enhance 3D feature extraction. A total of 30 compounds from FDA DILIrank are selected (classified into Most-, Less-, and No-DILI) to activate HLOs and corresponding brightfield images are collected at different time series and z-axis. Our computer vision model based on image-spatial-temporal coding layer excavates fully spatiotemporal information of continuously captured images, links HLO morphology with DILI severity, and final output DILI level of compounds. DILITracer achieves an overall accuracy of 82.34%. To our knowledge, this is the first model to output ternary classification of hepatotoxicity. Overall, DILITracer, using clinical data as an endpoint categorization label, offers a rapid and effective approach for screening hepatotoxic compounds.
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AbstractBrain activity emerges in a dynamic landscape of regional increases and decreases that span the cortex. Increases in activity during a cognitive task are often assumed to reflect the processing of task-relevant information, while reductions can be interpreted as suppression of irrelevant activity to facilitate task goals. Here, we explore the relationship between task-induced increases and decreases in activity from a geometric perspective. Using a technique known as kriging, developed in earth sciences, we examined whether the spatial organisation of brain regions showing positive activity could be predicted based on the spatial layout of regions showing activity decreases (and vice versa). Consistent with this hypothesis we established the spatial distribution of regions showing reductions in activity could predict (i) regions showing task-relevant increases in activity in both groups of humans and single individuals; (ii) patterns of neural activity captured by calcium imaging in mice; and, (iii) showed a high degree of generalisability across task contexts. Our analysis, therefore, establishes that antagonistic relationships between brain regions are topographically determined, a spatial analog for the well documented anti-correlation between brain systems over time.
AbstractMRG15, a chromatin remodeling protein, plays a pivotal role in cellular senescence and proliferation. However, the precise roles and mechanisms of MRG15 in aging regulation remain unclear. Our research elucidates the distinct functions of MRG15’s splice variants in aging. We find that MRG15L, contrary to the previously assumed MRG15S, accumulates with advancing age. Using histone peptide binding assays and protein interaction analysis, we demonstrate that MRG15L exhibits reduced affinity for histone H4 acetylation sites, thereby weakening CDK1 regulation, leading to G2/M phase arrest and promoting cellular senescence. During postnatal cardiac development, MRG15L expression increases and is linked to reduced regenerative capacity. Moreover, targeted knockout of MRG15L in mice enhances cardiac repair and regeneration following myocardial ischemia-reperfusion injury. These findings highlight MRG15L as a promising therapeutic target for age-related diseases, revealing its critical role in modulating aging pathways through alternative splicing.
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AbstractEpigenetic mapping studies across individuals have identified many positions of epigenetic variation across the human genome. However the relationships between these positions, and in particular global patterns that recur in many regions of the genome, remains understudied. In this study, we use a stacked chromatin state model to systematically learn global patterns of epigenetic variation across individuals and annotate the human genome based on them. We apply this framework to histone modification data across individuals in lymphoblastoid cell lines and across autism spectrum disorder cases and controls in prefrontal cortex tissue. We find that global patterns are correlated across multiple histone modifications and with gene expression. We use the global patterns as a framework to predict trans-regulators and study a complex disorder. The frameworks for identifying and analyzing global patterns of epigenetic variation are general and we expect will be useful in other systems.
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AbstractAlthough long considered safe, recent data have shown that emulsifiers such as polysorbates promoted intestinal inflammation and were associated with increased risks of developing chronic pathologies. We evaluated the potential of plant-based emulsifiers (pea protein isolate, PPI, and corn arabinoxylans, CAX) as alternatives to Polysorbate 80 (Tween 80, T80). Combining PPI and CAX led to a similar vitamin D3bioavailability to T80 in vitro and in vivo in mice. We then exposed female and male mice to dietary doses of emulsifiers in oil-in-water emulsions (180 mg/kg/day for T80, 5 days/week) for 11 weeks. Conversely to previous studies conducted with higher doses of emulsifiers, T80, PPI, and PPI + CAX groups were similar to the control group (oil alone) in terms of physiological characteristics and inflammation biomarkers. However, LPS-specific serum IgG levels were reduced in the PPI (−31.05%, p = 0.0006) and PPI + CAX (−34.66%, p = 0.0001) groups compared to the T80 group at the end of the intervention. Exposure to T80, but not to PPI or PPI + CAX, reduced the distance between bacteria and the jejunal epithelium (−60.67%, p = 0.0779) and significantly increased Firmicutes_D phylla in male mice. Overall, we showed that a combination of pea protein and arabinoxylans appears as a sustainable alternative to polysorbates for vitamin D3delivery.
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AbstractImmature great apes learn how to build their nests over multiple years, yet how they do so has remained largely unclear. We investigated the detailed role of social learning in the acquisition of nest-building skills in wild Sumatran orangutans (Pongo abelii) using data on nest-building, nest practice, and nest peering behaviour from 44 individuals, collected over 17 years. We found that nest peering (but not being close to a nesting individual without peering) is associated with a significant increase in nest practice and is primarily directed at multi-step nest elements. Dependent immatures mostly peer at their mothers and use nest tree species in common with her, independent immatures peer at a larger range of individuals and use nest tree species in common with them. Our results suggest that orangutans acquire their nest-building skills through observational social learning, selective attention to “know-how” and the transmission of “know-what” information.
AbstractPredicting prokaryotic phenotypes—observable traits that govern functionality, adaptability, and interactions—holds significant potential for fields such as biotechnology, environmental sciences, and evolutionary biology. In this study, we leverage machine learning to explore the relationship between prokaryotic genotypes and phenotypes. Utilizing the highly standardized datasets in the BacDivedatabase, we model eight physiological properties based on protein family inventories, evaluate model performance using multiple metrics, and examine the biological implications of our predictions. The high confidence values achieved underscore the importance of data quality and quantity for reliably inferring bacterial phenotypes. Our approach generates 50,396 completely new datapoints for 15,938 strains, now openly available in the BacDivedatabase, thereby enriching existing phenotypic resources and enabling further research. The open-source software we provide can be readily applied to other datasets, such as those from metagenomic studies, and to various applications, including assessing the potential of soil bacteria for bioremediation.
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AbstractIncreasing evidence suggests vaginal dysbiosis is associated with persistent high-risk human papillomavirus (hrHPV) infection and cervical intraepithelial neoplasia (CIN) development. In this pilot longitudinal study, we investigate the potential of vaginal microbiome biomarkers to predict CIN3 development in hrHPV-positive (hrHPV+) women of reproductive age and assess loop electrosurgical excision procedure (LEEP) outcomes.Fifty-nine non-menopausal women 20–53 years old, with normal cytology, were selected from the ARTISTIC trial and followed up twice over six years. Vaginal microbiome was analysed by 16S rRNA sequencing. HrHPV+ women with CIN3 showed a significant overrepresentation ofSneathia amnii,Megasphaera genomosp., Peptostreptococcus anaerobius and Achromobacter spanius(p< 0.05). Successfully LEEP-treated hrHPV-negative women exhibited increasedLactobacillusspecies, especiallyLactobacillus gasseri. Additionally,Lactobacillus helveticus,suntoryeusandvaginalisshowed a potential protective role against CIN3 development.These unique microbial biomarkers associated with CIN3 development and recovery following LEEP treatment bring new insights into the vaginal microbiome’s role on disease progression.
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AbstractMemory consolidation is highly influenced by ongoing experiences. Here, we explore the temporal rules that determine whether events are cooperatively associated or competitively separated. We show that neutral events are associated with fearful events if they occur within less than 30 min. In some individuals, memory association can lead to a competitive suppression of the fearful response by the neutral event. Activation of the thalamic MGm inputs to the lateral amygdala, results in an increase in memory association, whereas manipulation of the cortical inputs have no effect. Introducing a third event leads to competition depending on the temporal relationship between the initial association and the competitive event. Our results show a critical temporal rule of memory association, modulated by thalamic activity that shapes fear memory consolidation.
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AbstractConvulsive seizure behaviors are a hallmark feature of epilepsy, but automated detection of these events in freely moving animals is difficult. Here, we employed a high-resolution multi-camera array microscope with high-speed video acquisition and custom supervised machine learning (ML) for automated detection of larval zebrafish between 3- and 7-days post-fertilization (dpf). We assessed data from over 2700 zebrafish either exposed to a chemoconvulsant (pentylenetetrazole, PTZ) or genetic zebrafish lines representing Developmental Epileptic Encephalopathy (DEE) syndromes. Using eight-point skeletal body pose estimation for tracking individual larvae arrayed in a 96-well format, we report reliable, quantitative and age-dependent changes in maximum swim speed, as well as eye-, head- and tail- angle kinematics. Finally, we employed an ML-based algorithm to automatically identify normal and abnormal behaviors in an unbiased manner. Our results offer a robust framework for automated detection of zebrafish seizure-associated behaviors.
AbstractGreen macroalgae within the order Bryopsidales lack the fundamental photoprotective mechanisms of green algae, the xanthophyll cycle and energy-dependent dissipation of excess light. Here, by measuring chlorophyll fluorescence at 77 K after specific light treatments, we show that Bryopsidales algae also lack state transitions, another ubiquitous photoprotection mechanism present in other green algae. Certain Sacoglossa sea slugs can feed on Ulvophyceae algae, including some Bryopsidales, and steal chloroplasts – kleptoplasts – that remain functional inside the animal cells for months without the support of the algal nucleus. Our data reveal that the state transition capacity is not retained in the kleptoplasts of the sea slugs, and we provide evidence that the loss is caused by structural changes during their incorporation by the animals. Enforced chloroplast sphericity was observed in all studied kleptoplastic associations, and we propose that it is a fundamental property supporting long-term retention of kleptoplasts in photosynthetic sea slugs.
AbstractColorectal cancers (CRCs) present across a range of differentiation grades, which impact patient outcome and management; however, the molecular features and drivers of differentiation status are not fully understood. To address this, 84 commonly used human CRC cell lines were grown as xenografts in mice, revealing models of low-grade (LG) and high-grade (HG) CRC. Transcriptional profiling revealed coordinate downregulation of multiple transcription factors involved in intestinal development and differentiation, markers of colonic lineage-specific differentiation, and effectors of normal functions of the colonic epithelium in HG tumours. Mechanistically, multiple genes suppressed in HG tumours harboured promoter methylation, indicative of stable epigenetic silencing. Furthermore, markers of LGR5+ colon stem cells were suppressed in HG tumours, while markers of cell proliferation, fetal-like intestinal stem cells, and non-canonical cell types including mesenchymal cells were increased. These changes manifested in HG cell line displaying increased proliferation, migration and metastatic capacity. Importantly, CRC cell line-derived transcriptional profiles of differentiation grade were reflected in LG and HG patient-derived tumour organoids and primary CRCs, revealing cell lines accurately model differentiation grade. The models and tumour differentiation-related properties identified herein may inform new approaches for tailored CRC treatments based on tumour grade.
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AbstractKcnq channels are low-threshold voltage-dependent K+channels that generate M-currents, which regulate the peri-threshold membrane potential. Kcnq channels reportedly participate in band-pass frequency responses (i.e., resonance), but it remains largely unclear how they contribute to generating resonance. We examined resonance in HEK293 cells expressingmouse Kcnq2andKcnq3(Kcnq2/3) using whole-cell recording.Kcnq2/3-expressing cells generated resonance-like frequency-dependent responses. Kcnh7 channels displayed a rapid opposing conductance change followed by slow activation in response to a depolarizing voltage step, properties thought to be necessary for inductor-like activity. However, Kcnq2/3 channels exhibited only slow activation. The lack of an opposing conductance change was caused by the absence of rapid Kcnq2/3 channel inactivation. These data suggest that core ion channel characteristics that cause resonance-like frequency responses are not uniform among ion channels. The opposing conductance change is not necessary for resonance-like frequency responses but is crucial for fine frequency tuning and oscillation.
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AbstractIn almost all respiratory organisms, organic substrates are degraded via catabolic processes to the central metabolite acetyl-CoA which is then oxidized to CO2for energy metabolism or used as a building block for anabolism. Most microorganisms have either the closed tricarboxylic acid cycle or the complete Wood-Ljungdahl-pathway for acetyl-CoA oxidation, but the sulfate-reducing, naphthalene-degrading culture N47 possesses both completely. Combining13C- labeled substrates and mass-specific GC-MS analysis of amino acids and fatty acids with enzyme activity assays suggests that N47 has a chemoorganoautotrophic metabolism degrading complex organic substrates such as naphthalene. Surprisingly, however, the biomass is mainly produced from acetyl-CoA generated de novo via CO2-fixation. This metabolism probably requires both a complete Wood-Ljungdahl pathway for acetyl-CoA oxidation and a reverse tricarboxylic acid cycle for CO2fixation. Based on genome analysis, this chemoorganoautotrophic metabolism seems to also occur in other sulfate-reducers and anaerobic ammonium-oxidizers.
AbstractPeach (Prunus persica), a model species in the Rosaceae family and a globally significant temperate fruit, requires advanced genotyping tools to accelerate genomics-assisted breeding. To address this need, we developed the PeachSNP170K array and genotyped 489 peach accessions, generating a high-resolution SNP-based kinship framework that surpasses the limitations of traditional pedigree analysis. This approach enabled the identification of genomic regions underlying key phenotypic variations. Genome-wide association studies (GWAS) uncovered 1202 SNPs linked to sugar and acid content, as well as flowering time, including identified loci associated with citrate content and flowering time. Notably, we identifiedPpNHX1(sodium/proton antiporter 1) within a citrate-associated locus, which influences citrate accumulation in peach fruit. Additionally, haplotype analysis revealed a highly selected haplotype, Hap3, within a major flowering-time locus, contributing to low-latitude adaptation. These findings establish the PeachSNP170K array as a powerful tool for high-throughput genomic analysis, providing valuable resources for peach research and breeding.
AbstractThe nature and distribution of the synaptic changes that underlie memory are not well understood. Here we examine the synaptic plasticity behind context fear conditioning in male and female mice and find that new learning produces synaptic potentiation specifically onto engram neurons in the basolateral amygdala. This potentiation lasts at least 7 days, is reversed by extinction, and its disruption impairs memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles, or biochemical induction of synaptic potentiation in US-responsive neurons alone, is sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons underlies memory formation and is necessary and sufficient to establish context fear associations.
AbstractWe investigated Transglutaminase 2 (TGM2) in high fat diet (HFD) obese mice, finding upregulated TGM2+ adipose tissue macrophages (ATMs) in HFD epididymal white adipose tissue (eWAT) compared to chow diet (CD) eWAT. UsingTgm2CRISPR silencing, we examined TGM2 modulation of inflammation in vitro within bone marrow-derived macrophages (BMMs), as well as in co-cultured eWAT stromal vascular fraction (SVF) cells. Tgm2 silencing in BMMs led to increased pro-inflammation, compared to control. In contrast, in vitro exposure of eWAT SVF to recombinant TGM2 increased anti-inflammatory IL-10 secretion. However, IL-10 was not induced by recombinant TGM2 in CD activated CD4 + T cells, or in HFD-derived SVF CD4 + T cells. In vivoTgm2silencing in CD11b+ cells in HFD mice resulted in pro-inflammation in eWAT and serum, and increased adiposity and insulin resistance, suggesting that TGM2 + ATMs possess an anti-inflammatory role in obesity that is insufficient to reverse obesity-induced inflammation.
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AbstractMonoallelic gene expression is a pivotal phenomenon in developmental biology, notably through the influence of imprinted genes. Our model predicts that monoallelic expression generates expression variability, which we assess by measuring genetic noise and entropy within Shannon’s information theory framework. Analyzing single-cell allele-specific expression across human and mouse datasets, we consistently observe increased expression variability due to monoallelic expression, affecting both imprinted and co-expressed non-imprinted genes. Moreover, we find decreasing variability in developing neurons and increasing variability in glial cells. The discovery of distinct noise patterns in over 80% of analyzed genes between glial and neuronal populations highlights the importance of differential noise in neurodevelopmental processes. Given the critical role of imprinted genes in biological processes such as growth and brain development, disruptions in their expression might contribute to various disorders. Understanding the stochastic nature of monoallelic expression and its genome-wide impact offers new insights into the mechanisms underlying these pathologies.
AbstractLysine propionylation modification (Kpr) plays an important role in the pathogenesis of several cardiovascular diseases, but the role of Kpr in postoperative atrial fibrillation (POAF) is unclear. Here, we established an atlas of proteomics and propionylation proteomics in the atrial appendage tissues from 28 CABG patients, exploring the role of Kpr proteins in the occurrence of POAF. The Kpr of ALDH6A1 was most significantly increased on Lys113 (2.25 folds). The activity of ALDH6A1 increased due to higher binding energy of propionylated ALDH6A1 and NAD+, causing an increase in NADH levels in cells and triggering abnormal energy metabolism. Furthermore, the increase in NADH levels triggered the accumulation of reactive oxygen species, which may cause oxidative stress, resulting in the development of AF. This study reveals the important role of ALDH6A1-NADH pathway in POAF, and provides new insights for exploring the pathogenesis of POAF in CABG.
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AbstractIntelligence is a broad mental capability influencing human performance across tasks. Individual differences in intelligence have been linked to characteristics of structural and functional brain networks. Here, we consider their alignment, the structural-functional brain network coupling (SC-FC coupling) during resting state and during active cognition, to predict general intelligence. Using diffusion-weighted and functional magnetic resonance imaging data from 764 participants of the Human Connectome Project (replication:N1= 126,N2= 180), we model SC-FC coupling with similarity and communication measures that capture functional interactions unfolding on top of structural brain networks. By accounting for variations in brain region-specific neural signaling strategies, we show that individual differences in SC-FC coupling patterns predict individual intelligence scores. Most robust predictions result from cognitively demanding tasks and task combinations. Our study suggests the existence of an intrinsic SC-FC coupling organization enabling fine-drawn intelligence-relevant adaptations that support efficient information processing by facilitating brain region-specific adjustment to external task demands.
AbstractMarine mammals host a diverse array of parasites engaged in a continuous evolutionary arms race. However, our understanding of the biology of parasitic insects associated with marine mammals, particularly their adaptations to challenging marine environments, remains limited. The seal louse,Echinophthirius horridus, which infests true seals, is one of thirteen insect species capable of enduring prolonged dives in open seas. This ectoparasite has evolved several adaptations to withstand extreme conditions, such as low oxygen levels (hypoxia), temperature fluctuations, hydrostatic pressure, and strong drag forces during dives. To prevent drowning during their host’s 20–35 min dives, seal lice have developed specialized respiratory mechanisms that allow them to survive in oxygen-poor waters and at depths up to 600 m. Advanced imaging techniques, including CLSM, SEM, synchrotronX-ray microtomography, and histological sectioning and 3D-reconstruction, have revealed a specialized spiracle closing apparatus for storing oxygen in their tracheal system. Furthermore, our buoyancy experiments showed that the lice consume oxygen under water and, with morphological data, provide what is to our knowledge the first direct evidence against plastron presence. These findings enhance our understanding of the physical adaptations of lice and their survival in extreme ecological conditions, contributing to broader ecological and evolutionary theories.
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AbstractOptical pooled screening is an important tool to study dynamic phenotypes for libraries of genetically engineered cells. However, the desired engineering often requires that the barcodes used for in situ genotyping are expressed from the chromosome. This has not previously been achieved in bacteria. Here we describe a method for in situ genotyping of libraries with genomic barcodes inEscherichia coli. The method is applied to measure the intracellular maturation time of 84 red fluorescent proteins.
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AbstractDecreased renal uric acid excretion is a major contributor to hyperuricemia (HUA), but its underlying mechanism remains unclear. Here, we identify cathepsin B (CTSB) as a key regulator of urate handling in HUA. Urinary CTSB levels were elevated in HUA patients, and renal CTSB expression was increased in HUA mice. In CTSBtecKOmice, the expression of reabsorptive urate transporters URAT1 and GLUT9 was decreased, while the secretory transporter ABCG2 was upregulated, leading to enhanced renal uric acid excretion and reduced serum uric acid (SUA). CTSB deficiency also reduced serum IL-1β, IL-6, and TNF-α levels. In vitro and transcriptomic analyses revealed that CTSB inhibition suppressed glycolysis—marked by reduced HK2 and PKM2 expression—downregulated URAT1 and GLUT9, and upregulated ABCG2. Conversely, CTSB overexpression enhanced glycolysis and reversed these effects. These findings suggest that CTSB promotes urate retention via glycolysis and may serve as a novel target for HUA treatment.
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ABSTRACTTrifluoperazine (TFP), a known inhibitor of Ca2+‐bound calmodulin (Ca2+/CaM), has been reported to elevate cytosolic Ca2+levels by disinhibiting inositol 1,4,5‐triphosphate receptor 2 (IP3R2), thereby suppressing glioblastoma invasion and inducing apoptosis. Interestingly, TFP induces a sustained Ca2+plateau, sensitive to extracellular Ca2+, suggesting involvement of Ca2+entry such as store‐operated calcium entry (SOCE). However, the underlying molecular mechanism remains elusive. Here, we report that TFP induces sustained Ca2+signals by blocking the Ca2+/CaM‐dependent desensitization of SOCE channels in cortical astrocyte cultures. TFP induces a prolonged Ca2+response, with distinct kinetics compared to other Ca2+modulators such as TFLLR‐NH2(a Gαq‐coupled GPCR agonist) and thapsigargin (a sacro/endoplasmic reticulum Ca2+‐ATPase inhibitor). Under extracellular Ca2+‐free conditions, Ca2+levels increase without reaching a plateau, suggesting that the sustained Ca2+signal relies on Ca2+influx. Pharmacological analysis shows that sustained Ca2+signals by TFP are CaM‐dependent. Gene silencing targeting STIM1 and Orai1–3 confirmed their essential roles in the sustained response. We find that TFP effectively “locks open” SOCE channels by inhibiting their desensitization, maintaining SOCE activity. This effect is also observed in ex vivo hippocampal dentate gyrus astrocytes. Structural modeling supports a mechanism in which TFP disrupts the interaction between Ca2+/CaM and the SOAR domain of STIM1. Together, these findings indicate that TFP elevates cytosolic Ca2+levels by maintaining SOCE activation, offering novel insights into the molecular actions of this drug. TFP can be a pharmacological tool for SOCE research as it locks SOCE channels open.
ABSTRACTOligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS) are capable of proliferating, migrating, and differentiating into oligodendrocytes. OPCs are crucial for the myelination of axons during development and remyelination after injury in adulthood. OPCs also play important roles in promoting angiogenesis, neurotrophy, and immunomodulation, which makes them a relevant element of regenerative approaches for many CNS diseases, especially demyelinating ones. OPC migration is important during neurodevelopment and regeneration, and as such is regulated by a multitude of intracellular and extracellular factors. Identifying these factors will facilitate the optimized regulation of OPC migration and thus enhance therapeutic effects. This field is a current research hotspot, and new findings are constantly emerging. Here, we comprehensively review research progress on the regulatory factors that control OPC migration.
ABSTRACTSpinal cord injury (SCI) results in significant disruption of nerve fibers responsible for transmitting signals between the brain and body, often leading to partial or complete motor, sensory, and autonomic dysfunction below the injury site. Astrocytes are an important component in scar formation, crucial for suppression of injury propagation, effective wound healing, and the regulation of neuronal plasticity. Here, we identify the role of the actin‐binding protein Drebrin (DBN) in reactive astrogliosis following SCI. SCI induces the upregulation of DBN in astrocytes, which controls immediate injury containment but also the long‐term preservation of tissue integrity and healing in the spinal cord. DBN knockout results in enlarged spinal cord lesions, increased immune cell infiltration, and neurodegeneration. Mechanistically, DBN loss disrupts the polarization of scar border‐forming astrocytes, leading to impaired encapsulation of the injury. In summary, DBN serves as a pivotal regulator of SCI outcome by modulating astrocytic polarity, which is essential for establishing a protective barrier confining the lesion site.
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Azurin is a copper-containing redox protein naturally produced by Pseudomonas aeruginosa, which has shown promising activity against human cancer cells by inducing apoptosis. The present study describes the design of a recombinant vector, pT7-MAT-Tag-2-Azu, for azurin production in E. coli cells. The cytotoxic effects of purified azurin were tested on three breast cancer cell lines (MCF-7, MDA-MB-231, and HCC38) and a normal breast epithelial cell line (MCF10A) using the MTT assay. The results showed cytotoxicity against cancer cell lines with minimal effects on normal cells. Further analysis showed that azurin induced apoptosis through mitochondrial pathways, as evidenced by increased expression of apoptosis-related genes (Bax, TP53, Apaf-1, caspase-3, -8, -9) and their corresponding proteins, elevated levels of reactive oxygen species (ROS), and DNA damage, mitochondrial membrane potential (MMP), or brine shrimp lethality assay. Furthermore, in silico molecular docking, simulations predicted a stable, electrostatically driven interaction between azurin and the p53 protein, providing a structural basis for its mechanism of action. These findings suggest that recombinant azurin may serve as a potential therapeutic agent for breast cancer after further multifaceted research.
Triple-negative breast cancer (TNBC) poses significant challenges due to its high aggressiveness, poor prognosis, and the lack of effective targeted therapies. Paclitaxel (PTX) is a chemotherapeutic agent commonly used in the treatment of TNBC; however, its efficacy is often compromised by drug resistance mediated by autophagy. This study investigated the synergistic effects of the autophagy inhibitor 3-methyladenine (3-MA) and PTX in a TNBC nude mouse model. Monitoring tumor volume and employing HE staining, immunofluorescence, and transmission electron microscopy revealed that PTX monotherapy induced tumor autophagy, characterized by the accumulation of LC3B/VPS34 proteins and an increase in autophagosomes. However, the co-administration of 3-MA reversed this process, significantly decreasing the tumor growth rate. Immunofluorescence and qPCR demonstrated that the combination group had fewer Ki-67-positive cells and more Caspase-3-positive cells, along with upregulated expression of autophagy-related genes and Caspase-family apoptosis genes. Consequently, this study suggests that inhibiting autophagy with 3-MA disrupts the autophagy-mediated protective mechanism of tumor cells, promoting the activation of apoptotic signals and enhancing the antitumor activity of PTX. These findings may offer new molecular mechanistic insights and potential therapeutic strategies for overcoming PTX resistance in TNBC.
Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N5,N3-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC50 to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors.
Placenta accreta spectrum (PAS) and placenta previa (PP) are severe obstetric disorders associated with high maternal and perinatal morbidity. Early diagnosis of both conditions remains challenging, particularly in cases with subtle imaging findings. This study was aimed to evaluate the diagnostic value of first-trimester maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (β-hCG) in predicting PAS and PP. In this retrospective case–control study, a total of 100 pregnant women were included: 36 with PAS, 32 with PP, and 32 healthy controls. Serum levels were measured at 11–136 weeks of gestation. Both biomarkers were significantly altered in pathological groups compared to controls: PAPP-A was lower in PP (3.04 [1.42–4.52] IU/L) and PAS (3.63 [2.51–5.39] IU/L) vs. controls (5.34 [3.72–8.41] IU/L; p < 0.001), while β-hCG was higher in PP (45.4 [40.1–54.9] IU/L) and PAS (51.4 [32.3–74.8] IU/L) vs. controls (33.5 [22.7–54.1] IU/L; p = 0.044 and p < 0.001, respectively). ROC analysis demonstrated that combined biomarker modeling improved diagnostic accuracy over single-marker use, with AUCs reaching 0.85 (sensitivity 85.2%, specificity 72%) for PAS and 0.88 (sensitivity 100%, specificity 72%) for PP. These findings support the integration of biochemical screening into first-trimester risk assessment protocols. Incorporating maternal serum biomarkers may enhance early identification of high-risk pregnancies, allow timely referral to specialized care, and reduce adverse outcomes. Further prospective studies are warranted to validate the utility of this dual-marker approach across diverse populations and clinical settings.
The Dof (DNA-binding with one finger) domain protein family is a plant-specific zinc finger transcription factor family that plays a role in various biological processes in plants. However, research on Dof transcription factors in soybean (Glycine max) remains limited. In this study, we identified 79 putative soybean Dof genes, which are distributed across the entire genome. A comparative phylogenetic analysis of the Dof gene family in soybean, Arabidopsis, rice, maize, and Medicago revealed five major groups. The synteny relationship analysis showed a large number of gene duplication events in soybean. Twelve cis-acting elements were detected in the promoter region of the Dof gene, including five hormone response elements and several environmental response elements. Expression pattern analysis indicated that most Gmdof genes exhibited specific expression patterns. Nine genes in group V, which exhibited higher expression in the root, were identified as significantly responsive to salt stress through qRT-PCR. The possible biological functions of several Gmdof genes were discussed, including Gmdof11.2, Gmdof2.1, and Gmdof16.2. In summary, this study integrated phylogenetic analysis with genome-wide expression profiling to provide valuable information for understanding the functional characteristics of Dof genes in soybean.
Monomeric C-reactive protein (mCRP), derived from the dissociation of the native pentameric CRP (pCRP), has been implicated in the pathophysiology of various neurological conditions, particularly intracerebral hemorrhage (ICH) and neurodegenerative diseases. mCRP accumulates in the brain after hemorrhagic stroke, contributing to the formation of the metabolic penumbra and promoting inflammation. Recent studies have linked mCRP to the activation of microglia, endothelial cells, and complement pathways, which collectively intensify neuroinflammation and disrupt tissue repair mechanisms. Additionally, mCRP is associated with cognitive decline, particularly in ICH survivors, by promoting microvascular damage, neurodegeneration, and vascular instability. The presence of mCRP in distant regions of the brain, including the hypothalamus, suggests its potential role in spreading inflammation and exacerbating long-term neurological damage. This review synthesizes findings on the pathogenic role of mCRP in stroke and neurodegeneration, proposing that mCRP could serve as both a biomarker and a therapeutic target for improving outcomes in stroke patients. Emerging immunopharmacological strategies are being actively pursued to mitigate the pathogenic activity of mCRP, a potent pro-inflammatory effector implicated in a variety of immune-mediated and neuroinflammatory conditions. These approaches encompass the inhibition of native pentameric CRP dissociation into its monomeric isoform, the disruption of mCRP’s high-affinity interactions with lipid rafts and cell surface receptors involved in innate immune activation, and the enhancement of its clearance through mechanisms such as solubilization, opsonin-mediated tagging, and phagocytic engagement. Targeting these immunoregulatory pathways offers a compelling therapeutic framework for attenuating mCRP-driven inflammatory cascades in both systemic and CNS-specific pathologies.
Estrogens are potent hormones involved in numerous physiological and pathological processes. Their typically low concentrations in biological samples necessitate highly sensitive analytical methods for accurate quantification. This study presents a high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method for quantifying estradiol and its metabolites in blood serum and saliva. Analytes were extracted using solid-phase microextraction with a divinylbenzene sorbent and methanol as the desorption agent. FLD was performed after the derivatization of the analytes with dansyl chloride. Separation was achieved on a Poroshell 120 EC-C18 column (2.1 × 100 mm, 2.7 µm) at 50 °C using water with 0.1% formic acid and methanol as the mobile phase at 0.5 mL/min. A gradient elution increased the methanol concentration from 76% to 100% over 0–8 min, then it returned to 76% at 8.1 min and was held until 11 min had passed. Detection was at λEX 350 nm and λEM 530 nm. Good linearity was observed for estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol (10–300 ng/mL; R2 = 0.9893–0.9995). The LOQ for all analytes was 10 ng/mL. Solid-phase microextraction (SPME) offered advantages over liquid–liquid extraction. The method is suitable for quantifying estrogens in the 10 ng/mL–1 µg/mL range.
Colorectal cancer (CRC) remains one of the most prevalent malignancies of the gastrointestinal tract worldwide, with chronic inflammation recognized as a key factor in its progression. Among pro-inflammatory cytokines, interleukin 8 (IL-8) plays a pivotal role in promoting angiogenesis, tumor cell migration, and metastasis. Elevated IL-8 expression is frequently associated with advanced CRC stages. This study investigated the effects of betulin and its semi-synthetic derivatives, EB5 and ECH147, on IL-8 expression in CRC cell lines characterized by differing malignancy grades. IL-8 transcript and protein levels were quantified using real-time RT-qPCR and a proximity ligation assay, respectively, following compound exposure at 2, 8, and 24 h. Basal IL-8 levels were significantly higher in low-grade CRC cell lines. Among the compounds tested, ECH147 exerted the most pronounced, time-dependent inhibitory effect on CXCL8 expression. Furthermore, molecular docking analyses revealed that ECH147 exhibits stronger binding affinity toward the IL-8 protein compared to conventional chemotherapeutics. These findings suggest that the modification of the betulin structure via the incorporation of a propynoyl moiety enhances both its molecular interaction with CXCL8 and its anti-inflammatory potential. ECH147 and EB5 thus emerge as promising candidates for further development as immunomodulatory agents targeting the IL-8-associated pathway in CRC.
Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurosteroids, including allopregnanolone (ALLO), play critical roles in modulating neuronal activity in the brain. Levels of these compounds dynamically fluctuate in response to physiological and environmental conditions, particularly stress, suggesting complex regulatory interactions. This study aimed to explore the effects of acute stress and ALLO (individually and combined) on hippocampal expression of BDNF, its TrkB receptor, and other neurotrophins in sheep, a translational large animal model. Adult, luteal-phase sheep (n = 24), implanted with a guide cannula into the third brain ventricle, were divided into four experimental groups: (i) 3 days of Ringer–Locke solution (RL) infusion as the control; (ii) 3 days of RL infusion with 4 h acute stress on day three; (iii) 3 days of ALLO infusion (4 × 15 µg/60 µL/30 min) with 4 h acute stress on day three; and (iv) 3 days of ALLO infusion alone (n = 6 per group). Both acute stress and ALLO alone significantly reduced BDNF concentration and BDNF transcript abundance in the hippocampal CA1 and CA3 fields compared to the control group. The combined application of both stress and ALLO resulted in decreased levels of these parameters, except for BDNF concentration in the CA3 region. Additionally, TrkB mRNA expression in both hippocampal fields was significantly reduced in all treatment groups. Changes in mRNA levels for other neurotrophins, including nerve growth factor (NGF) and neurotrophin 3 (NT3) and 4 (NT4), varied under experimental conditions. While an inhibitory effect was predominant, NGF expression in the CA1 region remained unaffected by stress or ALLO. Interestingly, stress alone induced a significant increase in NT4 mRNA expression in the CA3 field compared to the control. In conclusion, the study demonstrated that a 4 h acute stress exposure inhibited the synthesis of BDNF, TrkB, and several other neurotrophins in the sheep hippocampus. Furthermore, ALLO, whose increased levels are highly correlated with the initial stress response, may serve as a mediator of this stress effect, temporarily preventing over-stimulation of hippocampal BDNF release and signaling.
Poplar leaves (Populi folium) are a herbal remedy traditionally used for the treatment of rheumatic diseases and prostate inflammation. The aim of our study was a comprehensive identification of secondary metabolites occurring in the leaves of Populus alba, Populus × candicans, and Populus nigra, in order to search for a source of raw plant material rich in active compounds. Total salicylate (TSC), flavonoid (TFC), and phenolic compound (TPC) contents were determined, and the antioxidant potential was assessed using DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2′-azino-bis(3-ethylbenzothiazoline- 6-sulfonic acid) diammonium salt), and FRAP (ferric reducing antioxidant power) assays as well as 2D-TLC (two-dimensional thin layer chromatography) bioautography using DPPH, riboflavin-light-NBT (nitro blue tetrazolium chloride), and xanthine oxidase inhibition tests. Secondary metabolites present in the analyzed poplar leaves were identified under the developed HPLC-DAD-ESI/MS (high performance liquid chromatography with photodiode array detection and electrospray ionization mass spectrometric detection analysis conditions and using the 2D-TLC method. Among the 80 identified compounds, 13 were shown for the first time in the genus Populus. The most diverse and similar set of flavonoids characterized the leaves of P. × candicans and P. nigra, while numerous salicylic compounds were present in the leaves of P. alba and P. × candicans. All analyzed leaves are a rich source of phenolic compounds. The highest flavonoid content was found in the leaves of P. × candicans and P. nigra, while the leaves of P. alba were characterized by the highest content of salicylates. All examined poplar leaves demonstrated antioxidant potential in all the assays used, which decreased in the following order: P. nigra, P. × candicans, P. alba.
Abnormal expressions and genetic mutations of EGFR are broadly involved in the progression of many human solid tumors, which has led to the development of small molecule inhibitors (TKIs). However, patients’ tumors usually develop resistance to targeted therapeutic TKIs after a period of treatment, mostly due to secondary mutations in EGFR. To date, three major and prevalent point mutations in EGFR, including L858R, T790M, and C797S, impact the use of TKIs in non-small cell lung cancer patients. Although at least four generations of TKIs have been designed and developed by targeting these mutations, how each mono, dual, or triple variant responds to clinical TKIs remains largely undeciphered. To fill this gap, we constructed a series of EGFR mutants and assessed their responses to clinical TKIs in vitro. The first-generation TKI, erlotinib, completely blocked the autophosphorylation of WT, L858R, C797S, and C797S/L858R, but only partially, if at all, in EGFR containing the T790M mutation alone or in combination. The third generation, osimertinib, completely abolished the autophosphorylation of WT, T790M, L858R, and T790M/L858R. It also significantly inhibited C797S and C790S/L858R, but had no effect on T790M/C797S or T790M/C797S/L858R. EAI045, as the fourth-generation TKI, almost completely inhibited WT and all mutants in complete growth media, but EGF-mediated phosphorylation of WT, C797S, and C797S/L858R were only partially inhibited in quiescence media, while the other mutants were fully inhibited. Furthermore, the abolishment of the enhanced tolerance to Dox in cells transiently expressing T790M/L858R and T790M/C797S/L858R by EAI045 suggests that their enhanced autophosphorylation is involved in their resistant ability. These findings provide some insights into how patients carrying typical mutations should be correctly and efficiently treated and why patients present side effects (because of non-specific inhibitory effects on cells without EGFR mutations).
Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes.
Melanoma is the most aggressive form of skin cancer, and despite significant therapeutic advances over the past decade, a substantial number of patients still progress to a fatal outcome. The initiation and progression of melanoma are strongly influenced by interactions between melanoma cells and other components of the tumor microenvironment (TME). In this review, we focus on the interplay between fibroblasts resident in the tumor microenvironment and tumor cells. In particular, we examine the molecular mechanisms through which melanoma cells induce the transformation of resident fibroblasts into their active form, known as cancer-associated fibroblasts (CAFs). We also explore the role of CAFs in shaping the melanoma microenvironment (MME) and in organizing the pre-metastatic niche, a specialized microenvironment that forms in distant organs or tissues to support the survival and expansion of metastatic melanoma cells. Finally, we discuss emerging therapeutic strategies aimed at disrupting the interactions between CAFs, melanoma cells, and other components of the tumor microenvironment to improve treatment outcomes.
Dengue virus (DENV) remains a critical global health challenge, with no approved antiviral treatments currently available. The growing prevalence of DENV infections highlights the urgent need for effective therapeutics. Antiviral peptides (AVPs) have gained significant attention due to their potential to inhibit viral replication. However, traditional drug discovery methods are often time-consuming and resource-intensive. Advances in artificial intelligence, particularly deep generative models (DGMs), offer a promising approach to accelerating AVP discovery. This report provides a comprehensive assessment of the role of DGMs in identifying novel AVPs for DENV. It presents an extensive survey of existing antimicrobial and AVP datasets, peptide sequence feature representations, and the integration of DGMs into computational peptide design. Additionally, in vitro and in silico screening data from previous studies highlight the therapeutic potential of AVPs against DENV. Variational autoencoders and generative adversarial networks have been extensively documented in the literature for their applications in AVP generation. These models have demonstrated a remarkable capacity to generate diverse and structurally viable compounds, significantly expanding the repertoire of potential antiviral candidates. Additionally, this report assesses both the strengths and limitations of DGMs, providing valuable insights for guiding future research directions. As a data-driven and scalable framework, DGMs offer a promising avenue for the rational design of potent AVPs targeting DENV and other emerging viral pathogens, contributing to the advancement of next-generation therapeutic strategies.
The tumor suppressor p16INK4a, encoded by CDKN2A, is frequently inactivated in cancer through genetic or epigenetic mechanisms. While promoter hypermethylation is the most common epigenetic cause, aberrant methylation of CDKN2A exon 2 has also been associated with various tumor types. However, analyzing DNA methylation of exon 2 is challenging due to its high sequence similarity with CDKN2B. We developed a pyrosequencing assay to analyze CpGs in CDKN2A exon 2, which was previously found to be hypermethylated in breast cancer. Our novel primer set enabled co-amplification of the homologous regions in CDKN2A, including CpGs 1–24, and CDKN2B CpGs 1–23. By quantifying the proportion of CDKN2A, we could accurately determine methylation levels for CpGs in CDKN2A exon 2. This method was applied to patient-derived glioma cells and commercial breast cancer cell lines. To reveal the role of exon 2 methylation in gene regulation, we additionally examined CDKN2AINK4a promoter methylation and expression at both mRNA and protein levels in breast cancer cell lines. We observed a range of (epi)genetic alterations, including homozygous deletions, transcript-specific expression, and exon 2 skipping. Our findings indicate that both promoter and exon 2 methylation contribute to regulation of CDKN2A expression. This novel method provides a valuable tool for future studies seeking a deeper understanding of CDKN2A regulation in cancer.
Spatial transcriptomics is an emerging technology that maps gene expression within tissue architecture. Its expanding use in medicine and veterinary science supports research, precision diagnostics, biomarker discovery, and development of targeted treatment strategies. While spatial transcriptomics applications in human health are well-documented with significant publication diversity and volume, published applications in veterinary medicine remain limited. A comprehensive search of PubMed was conducted, focusing on studies published from 2016 to early 2025 that employed spatial transcriptomics in the context of disease research, diagnosis, or treatment in human or animal health. The review followed the Arksey and O’Malley framework and adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. A total of 1398 studies met the inclusion criteria. The studies highlighted emerging trends of comparative research with animal model use for human health research. Commonly used spatial transcriptomics platforms included 10× Visium, Slide-seq, Nanostring (GeoMx, CosMX), and multiplexed error-robust fluorescence in situ hybridization (MERFISH). Key gaps in publications include limited veterinary representation, interspecies comparisons, standardized methods, public data use, and therapeutic studies, alongside biases in disease, species, organ, and geography. This review presents the current landscape of spatial transcriptomics publications for human and animal research and medicine, providing comprehensive data and highlighting underrepresented research areas and gaps for future consideration.
Skin aging is a multi-factorial process characterized by the progressive deterioration of biomechanical properties and cellular functionality. One such factor is the formation of advanced glycation end products (AGEs), which are known to have detrimental effects on the skin, including stiffening of the extracellular matrix (ECM) and reduction of cellular proliferation. AGEs accumulate because of sugar metabolism dysfunction; however, the direct impact of elevated sugar levels on cellular physiology requires further investigation. Here, we elucidated the effects of elevated fructose levels on skin cell function using in vitro models and hypothesized that high fructose levels adversely impact cell function. By fluorescence microscopy, we observed that high fructose induced different cellularity, cell morphology, and stress fiber appearance than the controls. Skin cells exposed to high fructose levels showed impaired growth and delayed closure in an artificial wound model. Mechanistically, high fructose conditions induce inflammatory cytokines and activate the NFκB pathway. Furthermore, we observed for the first time an increase in the senescence markers p16, p21, and p53 in response to high fructose levels. Taken together, we show that high fructose levels affect many critical skin functions that contribute to the aging process and recapitulate several aspects of aging related to AGEs.
Glioblastoma is the most prevalent and aggressive form of brain malignancy. Actual treatments face several challenges due to its high aggressiveness and poor prognosis. The chemotherapeutic agent temozolomide (TMZ) has limited therapeutic efficacy, and mutations in the tumour protein p53 gene (TP53) have been associated with treatment resistance. Thus, this study aimed to explore an innovative therapeutic strategy to enhance treatment efficacy of GBM. Previously, our team had developed a WRAP5 cell-penetrating peptide (CPP) functionalized with a transferrin receptor ligand (Tf) for the targeted delivery of TMZ and a p53-encoding plasmid to glioma cells. Our research had elucidated the circadian oscillations of the clock genes in the U87 glioma cells by employing two different computational models and observed that T16 and T8 time points revealed the highest circadian activity for Bmal1 and Per2 genes, respectively. Similar analysis was conducted for the transferrin receptor, which revealed that T7 and T8 were the key time points for its expression. A confocal microscopy study indicated the highest intracellular uptake of complexes and p53 mRNA expression at T8, the time point with the highest Per2 and transferrin receptor expression. Following mRNA analysis, the evaluation of p53 levels confirmed transcriptional changes at the protein level, and that T16 appears to be a favourable time point for enhancing therapeutic efficacy in U87 glioblastoma cells. These findings suggested that synchronizing the complexes’ administration with the biological clock of GBM cells may significantly improve glioblastoma therapeutics.
Type II testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men and are classified into seminomas and non-seminomatous subtypes. Seminomas are known for their highly pro-inflammatory tumor microenvironment (TME) with abundant immune cell infiltration. While previous work has demonstrated that the seminoma-derived cell line TCam-2 induces immune cell activation in co-culture and undergoes phenotypic changes itself, the underlying mechanisms remained unclear. To explore the role of direct cell–cell interaction and the effects mediated by soluble mediators such as cytokines, we conducted co-culture experiments of TCam-2 cells with purified human T cells or monocytes, including Transwell assays and treatments with IL-6, TNFα, or their respective blocking antibodies Tocilizumab and Adalimumab. In this way, we found that immune cell activation, indicated by enhanced secretion of pro-inflammatory cytokines and an upregulation of activation markers, strongly depended on direct physical contact between both cell types. Nonetheless, we also unveiled the role of soluble mediators in both immune cell activation and promoting a shift in TCam-2 cells from a seminoma-like phenotype to a more dedifferentiated phenotype, suggesting that cytokines critically shape the TME. These observations highlight the complexity of tumor–immune interactions in the seminoma microenvironment, offering new insight into immune-driven dynamics in TGCTs.
Currently, there is no standard treatment for renal cell carcinoma (RCC) that is free of side effects and resistance. Additionally, limited information exists on how curcumin affects the gene expression profiles of patients with translocation renal cell carcinoma (tRCC) and papillary renal cell carcinoma (pRCC). The pathways responsible for metastasis in tRCC are still not well understood, and there is no established treatment or reliable biomarker to predict outcomes for metastatic tRCC. Primary clinical data from patients were retrieved from the TCGA database and analyzed using cBioPortal, stitch, string, R and Python. Various analyses were performed, including differential gene expression, protein-protein interaction (PPI) network analysis, drug-targeted gene analysis, gene ontology (GO), enrichment analyses, and systematic searches to assess the impact of curcumin on the transcriptomic profiles of tRCC, pRCC, and clear cell renal cell carcinoma (ccRCC). No significant impact of sensitive genes on survival in KIRC and KIRP was found, though a trend suggested they may delay disease progression. The combination of curcumin with sunitinib showed promise in overcoming drug resistance in ccRCC by inducing ferroptosis, reducing iron, and increasing ADAMTS18 expression. This study, leveraging data from the TCGA database and other databases explored the impact of curcumin on transcriptomic profiles in tRCC, pRCC, and clear cell RCC (ccRCC). Gene analysis revealed immune and metabolic differences, with KIRC showing a stronger immune response. This study is the first to propose that future research into the miR-148/ADAMTS18 genes and the ferroptosis pathway in tRCC and pRCC could lead to the development of new therapies and the identification of novel therapeutic targets, potentially overcoming drug resistance and metastasis.
Age-related macular degeneration (AMD) is a progressive retinal disorder and a leading cause of irreversible blindness among elderly individuals, impacting millions of people globally. This review synthesizes the current understanding of the cellular and molecular signaling mechanisms driving AMD, with a focus on the distinct pathophysiological features of dry and wet AMD subtypes. Key mechanisms include oxidative stress, inflammation, lipid metabolism dysregulation, and immune dysregulation, all of which converge on the retinal pigment epithelium (RPE) as a central player in disease initiation and progression. In dry AMD, oxidative damage, mitochondrial dysfunction, and lipofuscin accumulation impair RPE function, contributing to drusen formation and geographic atrophy. In wet AMD, vascular endothelial growth factor-mediated angiogenesis, coupled with inflammation and endothelial metabolic reprogramming, drives choroidal neovascularization. This article integrates findings from multiomics approaches and highlights the potential of artificial intelligence in elucidating AMD pathogenesis and advancing personalized therapies. Future research directions emphasize targeting these molecular pathways to develop innovative treatments, offering hope for improved management of this debilitating condition.
Thermokinetic characterization of amorphous carbamazepine was performed utilizing non-isothermal differential scanning calorimetry (DSC) and thermogravimetry (TGA). Structural relaxation of the amorphous matrix was described in terms of the Tool–Narayanaswamy–Moynihan model with the following parameters: Δh* ≈ 200–300 kJ·mol−1, β = 0.57, x = 0.44. The crystallization of the amorphous phase was modeled using complex Šesták–Berggren kinetics, which incorporates temperature-dependent activation energy and degree of autocatalysis. The activation energy of the crystal growth was determined to be >320 kJ·mol−1 at the glass transition temperature (Tg). Owing to such a high value, the amorphous carbamazepine is stable at Tg, allowing for extensive processing of the amorphous phase (e.g., self-healing of the quench-induced mechanical defects or internal stress). A discussion was conducted regarding the converse relation between the activation energies of relaxation and crystal growth, which is possibly responsible for the absence of sub-Tg crystal growth modes. The high-temperature thermal decomposition of carbamazepine proceeds via multistep kinetics, identically in both an inert and an oxidizing atmosphere. A complex reaction mechanism, consisting of a series of consecutive and competing reactions, was proposed to explain the second decomposition step, which exhibited a temporary mass increase. Whereas a negligible degree of carbamazepine degradation was predicted for the temperature characteristic of the pharmaceutical hot-melt extrusion (~150 °C), the degradation risk during the pharmaceutical 3D printing was calculated to be considerably higher (1–2% mass loss at temperatures 190–200 °C).
Plant-derived polyphenols have become a subject of scientific interest in recent decades due to their widespread occurrence in dietary sources and multi-faceted biological activity, with many of these compounds being recognized as antioxidants and anti-inflammatory agents. Several of these chemicals have, moreover, attracted further interest as their anti-tumoral capabilities were discovered, promising potential implementation in the treatment of proliferative diseases, including various cancers. Malignancies of the central nervous system, the most prevalent of which are glioblastomas, are noted for their aggressiveness, dismal prognosis and low survival rates. This review focuses on two polyphenols with the most expansive body of research on this topic, namely resveratrol and curcumin. It covers recent developments in the research, including in vitro findings, animal model studies and clinical trials on these compounds’ effects on the growth and progression of glial tumors of the central nervous system. Its aim is to present the latest findings on the subject of the mechanisms of action of these phytochemicals and their synergistic activity with conventional therapies, as well as strategies to improve their efficacy for future therapeutic applications.
Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell dyscrasia. According to revised diagnostic criteria, pPCL is defined by the presence of ≥5% circulating plasma cells (CPCs) in the peripheral blood of patients with newly diagnosed multiple myeloma (NDMM). pPCL is characterized by a distinct cytogenetic profile, including frequent t(11;14), MAF/MAB translocations, 1q gain, and del(17p). While t(11;14) is generally associated with a favorable prognosis, the coexistence of multiple high-risk cytogenetic abnormalities is linked to poorer outcomes. Tandem autologous hematopoietic stem cell transplantation and novel anti-myeloma agents have improved survival in some patients; however, overall prognosis remains poor, particularly in those ineligible for transplantation. Venetoclax and emerging immunotherapies, such as CAR-T cells and bispecific antibodies, show promise and merit clinical trials focused on pPCL-enriched cohorts. Additionally, recent findings associating even minimal CPCs with adverse outcomes in NDMM support broader inclusion criteria in future trials. A deeper understanding of pPCL’s molecular pathology is critical for the development of effective targeted therapies. This article reviews recent advances in the molecular understanding of and treatment strategies for pPCL.
In recent years, as gene therapy technology has rapidly developed, there has been growing concern that it could be misused by athletes as a means of doping. However, current testing methods for gene doping have a range of limitations and require further improvement. Furthermore, significant progress has been made in the fields of blood storage, next-generation sequencing (NGS), and LabDroid (experimental robots). Against this background, this study was implemented to develop a test method for gene doping using dried blood spot (DBS), NGS, and the LabDroid ”Maholo”. As a first step, recombinant adeno-associated virus containing the human erythropoietin gene (hEPO) was injected into mice to establish a gene doping model. Subsequently, DBS was created using whole blood. Maholo was used to extract DNA from the DBS and to create DNA libraries for NGS. NGS in combination with bioinformatic analysis clearly identified DNA fragments that provided definitive evidence of gene doping in the mouse model, which were absent in the control mouse. To the best of our knowledge, this is the first attempt to use a biological model of hEPO gene doping in conjunction with Maholo, NGS, and DBS. This method should facilitate the further development of gene doping tests.
Ulva prolifera (Chlorophyta), a pivotal species in green tide generation, is particularly vulnerable to abiotic stressors, including variations in temperature and light intensity, requiring specific regulatory frameworks for survival. Epigenetic modification is recognized as a molecular mechanism contributing to the flexible adaptability to environmental alterations. In this study, using DNA methylation pattern analysis, we investigated abiotic stress responsive methylation events, as well as gene and pathway expression patterns, in green macroalgae U. prolifera cultured under elevated temperature–light stress (30 °C and 300 µmol photons m−2 s−1) and identified a negative correlation between CG methylation and gene expression patterns which indicated that abiotic stress caused CG demethylation and afterwards provoked the transcription response. CHG and CHH methylation exhibited an increased mutability and were preeminently found in transposable elements and intergenic regions, possibly contributing to genetic stability by restricting transposon activity. Furthermore, a rapid regeneration through spore ejection and the formation of new thalli was observed, which emphasized its tenacity capacity for stress memory. Our study also revealed an upregulation of genes associated with the glycolysis pathway and highlighted the critical roles of hexokinase, 6-phosphofructokinase-1, and fructose-6-phosphate in triggering glycolysis as a significant stress-adaptive pathway. Overall, these findings suggested that DNA methylation functions as a potential regulatory mechanism, maintaining environmental adaptability, genomic integrity, and underpinning regenerative capacity in U. prolifera. The findings elucidated the molecular resilience of U. prolifera, highlighting its feasibility for sustainable development and biotechnological applications.
Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that are multifactorial in nature. The pathophysiology involves interactions between the host immune system and environmental factors, including the gut microbiota, in genetically predisposed individuals. Advances in understanding these interactions have led to the development of novel therapeutic targets, ranging from anti-TNFα to more recent anti-interleukin 23 treatments. However, some patients still experience resistance to these therapies. Monogenic intestinal diseases (MIDs), which present with more severe symptoms than IBD and typically begin early in life, result from significant disruptions of intestinal homeostasis. MIDs are driven by mutations in a single gene, offering a unique opportunity to explore the mechanisms underlying intestinal homeostasis in health. In this review, we provide a comprehensive overview of the mechanisms of intestinal homeostasis by examining the cellular and molecular features of IBD and MID pathophysiologies.
Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC50 values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells.
The rising prevalence of antibiotic-resistant bacteria demands exploration of alternative antimicrobials. Antimicrobial peptides (AMPs) are a promising group of compounds naturally produced by microorganisms and could serve as potent agents against resistant pathogens. In this study, we evaluated the antimicrobial potential of the cell-free supernatant obtained from Pedobacter silvilitoris—a bacterium originally isolated from decomposing wood—and performed comprehensive genomic screening to uncover novel AMP-encoding genes. The supernatant showed strong inhibitory effects against a diverse selection of pathogens. Scanning electron microscopy (SEM) revealed extensive membrane damage, including pore formation in target bacterial cells, suggesting AMP-mediated activity. A genomic analysis identified 11 candidate AMP genes, named PS_AMP1 to PS_AMP11, based on the significant sequence similarity with known AMPs. Transcriptomic profiling further indicated that several candidates are expressed differentially between the logarithmic and stationary growth phases. Functional assays via gene cloning and peptide synthesis confirmed antimicrobial activity against both Gram-stain-negative and Gram-stain-positive bacteria, with PS_AMP11 emerging as the most effective candidate. Our findings demonstrate that AMPs derived from P. silvilitoris hold substantial promise as alternative antimicrobial agents. Nonetheless, additional structural optimizations may be necessary to fine-tune specificity and to reduce potential host toxicity before clinical deployment.
To advance our understanding of multiple sclerosis (MS), accurate identification of protein expression profiles as biomarkers for MS in cerebrospinal fluid (CSF) is critical. However, proteomic studies investigating MS have yielded inconsistent findings due to variability in sample sizes, diagnostic criteria, and data processing methods. We aimed to tackle these challenges by performing a thorough meta-analysis of proteomics datasets sourced from multiple independent studies. We conducted a thorough database search to gather all relevant studies using appropriate keywords. We screened articles using defined inclusion and exclusion criteria, and finally, six studies were included. We retrieved and combined data from five CSF datasets for discovery and two additional datasets for validation in 368 MS patients and controls. After data preprocessing, we calculated Z-scores for all datasets and for the integrated dataset. We used logistic regression models using training and validation datasets. We identified 11 differentially expressed proteins in the integrated dataset, revealing significant alterations in key pathways involved in immune response, neuroinflammation, and synaptic function. Notably, IGKC exhibited strong diagnostic potential, with an AUROC of 0.81. These findings highlight the value of re-analysing publicly available proteomics data to develop robust biomarker panels for MS diagnosis.
Alkaline phosphatase (ALP) deficiency has been linked to reduced physical performance, as seen in hypophosphatasia (HPP). However, its potential role in muscle function has not been fully explored. This was a cross-sectional study in 34 HPP adults and 34 matched healthy controls. Muscle strength was assessed using handgrip strength (HGS), considering values below the 10th percentile of the Spanish population as low strength. Muscle mass was evaluated using dual-energy X-ray absorptiometry and morphometric ultrasound. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and total hip. The prevalence of low muscle strength was significantly higher in the HPP group compared to controls (30% vs. 6%; p = 0.009), with decreased HGS in the HPP group (p = 0.039). Positive associations were observed between ALP and femoral neck BMD, leg circumference, and fat-free mass and an inverse association with tricipital skinfold. Subjects with serum ALP activity below the sex-adjusted median had a significantly higher risk of low muscle strength independently of HPP diagnosis. ALP remained independently associated with HGS (p = 0.005), and a predictive model using ALP values showed strong capability to predict low-muscle-strength risk. Based on these results, we conclude circulating ALP levels are independently associated with muscle strength and may represent a useful biomarker for the early detection of muscle dysfunction. Future longitudinal or interventional studies are needed to assess whether ALP plays a causal role in muscle strength.
Preeclampsia, one of the leading causes of maternal and fetal morbidity and mortality, affects approximately 3–5% of pregnancies worldwide. However, its etiology remains poorly understood. The aim of this study was to identify molecular markers of preeclampsia. Protein concentrations in blood and urine were determined using the Bio-Plex Kidney Toxicity 1 assay Bio-Rad, Hercules, CA, USA followed by magnetic separation and flow cytometry. This study included 51 patients with preeclampsia and 25 healthy pregnant women. The results revealed that five out of the six serum biomarkers of kidney injury were elevated in the preeclampsia group compared to the control group (calbindin 1, clusterin, glutathione transferase pi (GSTP1), monocyte chemotactic protein 1 (MCP-1), and kidney injury molecule type 1 (KIM-1)). Additionally, the serum concentrations of calbindin 1, clusterin, GSTP1, and KIM-1 were significantly higher in both early-onset and late-onset preeclampsia compared to the control group. The analysis of urinary proteins showed that only the KIM-1 concentration was elevated in late-onset preeclampsia compared to the control group. These findings suggest that the calbindin 1, clusterin, GSTP1, KIM-1, and MCP-1 concentrations in maternal plasma could serve as potential biomarkers for monitoring kidney injury in preeclamptic women. This study provides a foundation for future research to explore novel biomarkers of preeclampsia and renal injury in pregnant women.
Delta-9-tetrahydrocannabinol (THC) is a psychoactive element of Cannabis sativa and affects the human cannabinoid system through its receptors, CB1R and CB2R. CB1R was found in several brain areas, including the hippocampal formation (HF), and it is responsible for most THC side effects. We investigated THC’s effects in the HF of female Wistar rats to assess changes in its neurotransmission. Female Wister rats (n = 20) were gonadectomized under anesthesia at 8 weeks old. Afterwards, they received estradiol benzoate (EB) and/or THC. Immunohistochemistry was performed to assess the expression of the cholinergic receptor alpha 7 subunit (CHRNA7), the vesicular acetylcholine transporter (VAChT), the vesicular glutamate transporter (VGLUT), the gamma-aminobutyric acid type A receptor (GABRA), the CB1 receptor, and estradiol receptor alpha (EBα). In the HF, the expression of CHRNA7 was increased by EB and by THC in the Oil groups but decreased by THC in the EB groups. The same is true for VGLUT expression in the DG and hilum and for GABRA expression in the hilum. The expression of VAChT and CB1 is reduced by EB, while the concomitant administration of THC increases it. GAD expression is reduced by EB administration in CA1, CA3, and DG. Our results may help with decision-making regarding the prescription of low doses of THC as a therapeutical approach.
The development of orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a promising therapeutic avenue for the treatment of type 2 diabetes mellitus (T2DM) and obesity. An extensive in silico approach combining structure-based drug design and ligand-based strategies together with pharmacokinetic properties and drug-likeness predictions is implemented to identify novel non-peptidic GLP-1RAs from the COCONUT and Marine Natural Products (CMNPD) libraries. More than 700,000 compounds were screened by shape-based similarity filtering in combination with precision docking against the orthosteric site of the GLP-1 receptor (PDB ID: 6X1A). The docked candidates were further assessed with the molecular mechanics MM-GBSA tool to check the binding affinities; the final list of candidates was validated by running a 500 ns long MD simulation. Twenty final hits were identified, ten from each database. The hits contained compounds with reported antidiabetic effects but with no evidence of GLP-1 agonist activity, including hits 1, 6, 7, and 10. These findings proposed a novel mechanism for these hits through GLP-1 activity and positioned the other hits as potential promising scaffolds. Among the studied compounds—especially hits 1, 5, and 9—possessed strong and stable interactions with critical amino acid residues such as TRP-203, PHE-381, and GLN-221 at the active site of the 6X1A-substrate along with favorable pharmacokinetic profiles. Moreover, the RMSF and RMSD plots further suggested the possibility of stable interactions. Specifically, hit 9 possessed the best docking score with a ΔG_bind value of −102.78 kcal/mol, surpassing even the control compound in binding affinity. The ADMET profiling also showed desirable drug-likeness and pharmacokinetic characteristics for hit 9. The pipeline of computational integration underscores the potential of non-peptidic alternatives in natural product libraries to pursue GLP-1-mediated metabolic therapy into advanced preclinical validation.
Hypertensive disorders of pregnancy are associated with a higher risk of later cardiovascular disease, but the mechanistic links are unknown. We recruited two groups of women, one during pregnancy and another at least two years after delivery, including both cases (with a hypertensive disorder of pregnancy) and controls (with a normotensive pregnancy). We measured metabolites using liquid chromatography–mass spectroscopy and applied machine learning to identify metabolomic signatures at three time points: antepartum, postpartum, and mid-life. The mean ages of the pregnancy cohort (58 cases, 46 controls) and the mid-life group (71 cases, 74 controls) were 33.8 and 40.8 years, respectively. The levels of 157 metabolites differed significantly between the cases and the controls antepartum, including 19 acylcarnitines, 12 gonadal steroids, 11 glycerophospholipids, nine fatty acids, six vitamin D metabolites, and four corticosteroids. The machine learning model developed using all antepartum metabolite levels discriminated well between the cases and the controls antepartum (c-index = 0.96), postpartum (c-index = 0.63), and in mid-life (c-index = 0.60). Levels of 10,20-dihydroxyeicosanoic acid best distinguished the cases from the controls both antepartum and postpartum. These data suggest that the pattern of differences in metabolites found antepartum continues to distinguish women who had a hypertensive disorder of pregnancy from women with a normotensive pregnancy for years after delivery.
The diversity of structural types of carrageenans (CRGs)—sulfated polysaccharides of red algae—determines their different biological activities. The different types of CRGs (kappa, lambda, kappa/beta-CRGs) were isolated from the red algae of the Pacific coast. Molecular docking was performed to determine potential interactions of CRGs with the receptor-binding domain (RBD) of SARS-CoV-2 and its cellular receptor—angiotensin—converting enzyme type 2 (ACE2). CRGs interacted with ACE2 and RBD via hydrogen bonding and ionic interactions. The strongest binding affinity of CRGs and ACE2 was observed for kappa-CRG. Molecular docking was confirmed by results studying the effects of CRGs against SARS-CoV-2 in vitro. The ability of CRGs, as well as the complex CRG with sea urchin echinochrome (Ech), to inhibit SARS-CoV-2 replication in Vero E6 cells was studied using cytopathic effect (CPE) inhibition and RT-PCR assays. The simultaneous treatment of cells with CRGs and the virus revealed that kappa-CRG exhibited the most significant antiviral effect among all the polysaccharides, with a selective index (SI) of 33. The kappa-CRG/Ech complex exhibited the highest virucidal effect on SARS-CoV-2 particles with an SI above 70 (more than two times higher than that of CRG and Ech) and reduced viral RNA levels by 45% (IC = 45%). Our results illustrate that CRGs and kappa-CRG/Ech complex can act as protective agents against SARS-CoV-2.
Pre-metastatic niche (PMN) formation is a critical step in metastatic progression. However, the biological effects of subtherapeutic doses of ionizing radiation (SDIRs) following radiotherapy on this process remain unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIRs (3 × 0.3 Gy) on lung PMN development and metastasis upon SDIR exposure on days 8–10 post-tumor injection, followed by mastectomy and analyzed on day 24. SDIRs significantly increased the total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, the SDIR acted as an early catalyst for niche priming, upregulating Bv8 expression, enhancing neutrophil recruitment, and increasing MMP9, S100A8, and Il6 production in the PMN by day 11. Moreover, SDIR drives metastasis through distinct mechanisms. Proteomic analysis revealed SDIR-driven metabolic reprogramming, with a shift away from fatty acid metabolism toward glycolysis and lipid accumulation within the PMN. This shift contributes to extracellular matrix (ECM) remodeling, immune modulation, and the upregulation of adhesion-related pathways, shaping a microenvironment that accelerates metastatic outgrowth. By reprogramming the pre-metastatic lung, the SDIR highlights the need to integrate organ-specific radiation exposure into metastasis models. Metabolic and immune-stromal pathways emerge as potential therapeutic targets, underscoring the importance of refining radiotherapy strategies to mitigate unintended pro-metastatic effects.
Atopic dermatitis (AD) is a chronic inflammatory skin disease marked by impaired barrier function and immune dysregulation. This study explores transcriptomic differences between lesional (IL) and perilesional (PL) skin in patients with AD, focusing on barrier-related and vitamin D-associated pathways. RNA sequencing was performed on matched IL and PL biopsies from 21 adults with moderate-to-severe AD. Differential gene expression, pathway enrichment, and correlation analysis with clinical variables were assessed. A total of 8817 genes were differentially expressed in IL versus PL skin (padj < 0.05). Among genes with the highest level of dysregulation, strong upregulation was observed for inflammatory mediators (IL-19, IL-8, CXCL6), and epidermal remodeling and barrier-disrupting genes (MMP1, GJB2). The vitamin D pathway genes CYP27B1 and CYP24A1 were also significantly upregulated. In contrast, key barrier-related genes such as FLG2 and CGNL1 were markedly downregulated. While some patterns in gene expression showed subgroup-specific trends, no independent clinical predictors emerged in multivariate models. Reactome pathway analysis revealed the enrichment of pathways involved in keratinization, cornified envelope formation, IL-4/IL-13 signaling, chemokine activity, and antimicrobial responses, highlighting coordinated structural and immunologic dysregulation in lesional skin. Lesional skin in AD displays a distinct transcriptomic profile marked by barrier impairment, heightened inflammatory signaling, and activation of vitamin D-related pathways. These findings provide the first RNA-seq-based comparison of IL and adjacent PL skin in AD. We identify subclinical activation in PL skin and vitamin D pathway upregulation with disrupted gene coordination in lesions. These findings enhance our understanding of the molecular mechanisms underlying inflammation in AD.
Narenga porphyrocoma (Hance) Bor is a close relative of sugarcane, with traits such as drought resistance, robustness, early maturity, and disease resistance. In this study, we report the first genome assembly of N. porphyrocoma (Hance) Bor GXN1, a diploid species with a chromosomal count of 2n = 30. We assembled the genome into 15 pseudochromosomes with an N50 of 128.80 Mp, achieving a high level of completeness (99.0%) using benchmarking universal single-copy orthologs (BUSCO) assessment. The genome was approximately 1.8 Gb. Our analysis identified a substantial proportion of repetitive sequences, primarily long terminal repeats (LTRs), contributing to 69.12% of the genome. In total, 70,680 protein-coding genes were predicted and annotated, focusing on genes related to drought resistance. Transcriptome analysis under drought stress revealed the key gene families involved in plant physiological rhythms and hormone signal transduction, including aquaporins, late embryogenesis abundant proteins, and heat shock proteins. This research reveals the genome of the diploid wild sugarcane relative N. porphyrocoma (Hance) Bor, encouraging future studies on gene function, genome evolution, and genetic improvement of sugarcane.
Immuno-oncology has rapidly evolved into a cornerstone of modern cancer therapy, offering promising avenues for durable responses and personalized treatment strategies. This narrative review provides a thorough overview of the mechanisms underlying tumor–immune system interactions and the therapeutic innovations emerging from this knowledge. Central to this discussion is the tumor microenvironment (TME), a complex ecosystem of immune and stromal cells that supports tumor growth and shapes therapeutic outcomes. Key cellular and molecular factors within the TME are examined, along with diverse immune escape strategies. We further analyze the landscape of immunotherapeutic approaches, including immune checkpoint inhibitors, cancer vaccines, adoptive cell therapies such as CAR-T cells, and cytokine-based interventions. This review also addresses the increasing importance of predictive biomarkers in immuno-oncology, particularly in patient stratification, monitoring resistance, and managing immunotherapy-related toxicity. Finally, we explore the emerging role of the microbiome as a modulator of immunotherapy efficacy, shedding light on host–microbe–immune interactions that may influence clinical outcomes. By integrating current biological insights with therapeutic innovation, this review outlines the challenges and opportunities ahead in immuno-oncology and emphasizes the need for translational research and cross-disciplinary collaboration to optimize cancer immunotherapy in the era of precision medicine.
Arbuscular mycorrhizae fungi (AMF) plays an important role in plants’ response to environmental stress, and the main environmental stress encountered in grape production is high temperature stress. This study aims to inoculate Funneliformis mosseae (A type of AMF) on grapes and investigate their tolerance to high temperature stress after inoculation. The results showed that AMF could infect grape roots, and the mycorrhizal infection rate was 20.78%. After inoculation with AMF, the growth of grape plants was significantly better than that in the non-inoculation group. Compared with the uninoculated group, the net photosynthetic rate, transpiration rate and stomatal conductance were higher in the AMF group, and the intercellular CO2 concentration was lower. After high temperature treatment, there was no significant difference in the content of hydrogen peroxide (H2O2) in grape leaves between the two experimental groups at each time, and the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and other enzymes showed great differences, especially after high temperature treatment for 6 h. The activities of SOD, POD and CAT in AMF group were significantly higher than those in uninoculated group. The content of malondialdehyde (MDA) in grape leaves of the two experimental groups had no significant difference between 0 h and 3 h after high temperature treatment, and the MDA content in the AMF group was significantly lower than that in the uninoculated group after 6 h of high temperature treatment. The contents of soluble sugar and soluble protein in the AMF group were higher than those in the uninoculated group at all time periods, especially after 6 h of high temperature treatment. In addition, we found that VvHSP70, VvHSP17.9, VvGLOS1, VvHSFA2 genes all responded to high temperature stress, but there was no significant difference between the AMF group and the uninoculated group. It can be seen from the above that AMF can significantly enhance the adaptability of grape plants to high temperature stress by improving photosynthetic efficiency, antioxidant enzyme activity, soluble sugar and soluble protein content, and reduce Malondialdehyde (MDA) content, which provides guidance and theoretical basis for grape production.
Acinetobacter baumannii is an opportunistic pathogen and a major cause of nosocomial infections worldwide. This study aimed to isolate and characterize phages with lytic activity against multidrug-resistant A. baumannii strains to enable antibacterial alternatives. Eight phages (AKO8a, PS118, B612, MCR, IDQ7, 89P13, CRL20, and CIM23) were isolated and subjected to genomic, phylogenetic, and functional analyses. Antibacterial activity was assessed in vitro against A. baumannii strain AbAK04 by measuring optical density over 17 h at multiplicities of infection (MOIs) of 0.1, 1, and 10, using a repeated-measures design with time as a crossed factor and MOI as a nested factor. Tukey’s post-hoc test identified significant bacterial growth reductions of 57–72% (p < 0.001). Specifically, phages PS118 and 89P13 reduced growth by 71% at MOI 10; CIM23, B612, and CRL20 achieved 68% reduction at MOI 1; and MCR reduced growth by 64% at MOIs 0.1 and 1. Notably, lytic phage MCR encodes a glycosyl hydrolase family 58 (GH58) enzyme, potentially contributing to its antibacterial activity. Genomic analyses confirmed absence of virulence and antibiotic resistance genes, with all phages classified as novel species within the Kagunavirus genus. These findings support the use of these phages as promising candidates for in vivo evaluation.
T-cadherin (CDH13) is an atypical, glycosyl-phosphatidylinositol-anchored cadherin with functions ranging from axon guidance and vascular patterning to adipokine signaling and cell-fate specification. Originally identified as a homophilic cue for migrating neural crest cells, projecting axons, and growing blood vessels, it later emerged as a dual metabolic receptor for cardioprotective high-molecular-weight adiponectin and atherogenic low-density lipoproteins. We recently showed that mesenchymal stem/stromal cells lacking T-cadherin are predisposed to adipogenesis, underscoring its role in lineage choice. Emerging evidence indicates that CDH13 expression and function are fine-tuned by non-coding RNAs (ncRNAs). MiR-199b-5p, miR-377-3p, miR-23a/27a/24-2, and the miR-142 family directly bind CDH13 3′-UTR or its epigenetic regulators, affecting transcription or accelerating decay. Long non-coding RNAs (lncRNAs), including antisense transcripts CDH13-AS1/AS2, brain-restricted FEDORA, and context-dependent LINC00707 and UPAT, either sponge these miRNAs or recruit DNMT/TET enzymes to the CDH13 promoter. Circular RNAs (circRNAs), i.e.circCDH13 and circ_0000119, can add a third level of complexity by sequestering miRNA repressors or boosting DNMT1. Collectively, this ncRNA circuitry regulates T-cadherin across cardiovascular, metabolic, oncogenic, and neurodegenerative conditions. This review integrates both experimentally validated data and in silico predictions to map the ncRNA-CDH13 crosstalk between health and disease, opening new avenues for biomarker discovery and RNA-based therapeutics.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has been consistently linked to increased risk of cardiovascular disease (CVD). HDL lipoproteins may serve as a possible link in this association through their hepatic synthesis and atheroprotective properties. Serum samples were collected from 51 MASLD patients (diagnosed by abdominal ultrasound), 40 with coronary artery disease, and 50 healthy controls. HDL lipid profiles were investigated by proton nuclear magnetic resonance (1H NMR) spectroscopy. Patients with MASLD exhibit an increased percentage of lysophosphatidylcholine and sphingolipid content, mainly due to increased ceramides, and a reduced percentage of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol compared to controls. The % content of total and individual polyunsaturated fatty acids including linoleic, docosahexaenoic, eicosapentaenoic, and arachidonic acid was found to be reduced in patients with MASLD, while saturated fatty acid content was increased compared to the control group. These alterations in fatty acid composition were observed also in CAD patients compared to controls but were more pronounced in CAD patients. Compared to CAD patients, those with MASLD showed an increased content of sphingolipids, ceramides, and glycerolipids and a reduced content of phosphatidylinositol. Changes observed in the lipid composition of HDL lipoproteins in MASLD patients may impair the protective properties of HDL particles, contributing to increased CVD risk.
A series of new isatin hydrazones bearing phosphorus-containing moiety was synthesized through a simple, high-yield and easy work-up reaction of phosphine oxide (Phosenazide) or phosphinate (2-chloroethyl (4-(dimethylamino)phenyl)(2-hydrazinyl-2-oxoethyl)phosphinate, CAPAH) hydrazides with aryl-substituted isatins. The 31P NMR technique showed that, in most cases, out of 12 examples in solution, the ratio of the two spatial isomers varied from 1:1 to 1:3. Quantum chemical calculations confirmed the predominance of Z,syn form both in the gas phase and in solution. According to X-ray analysis data in crystals, they exist only in Z,syn form too. Most of the phosphine oxide derivatives and 5-methoxy- and 5-bromoaryl phosphinate analogs exhibit anti-aggregant activity at the level of acetylsalicylic acid but inhibit platelet activation processes more effectively. The 5-chloro type phosphinate derivative exhibits anti-aggregant properties more effectively than acetylsalicylic acid under the conditions of the tissue factor (TF)-activated thromboelastography (TEG) model, the ex vivo thrombosis model. Thus, all the obtained results can become the basis for future pharmaceutical developments to create effective anti-aggregation drugs with broad antithrombotic potential.
CD38, a nicotinamide adenine dinucleotide (NAD+) glycohydrolase, increases in old murine macrophages after infection compared to young controls. We aimed to determine whether the increase in CD38 in old murine macrophages after infection is directly associated with enhanced inflammation induced by the oral pathogens Aggregatibacter actinomycetemcomitans (Aa) or Porphyromonas gingivalis (Pg) when compared to young controls. Additionally, we determined the effects of a specific CD38 inhibitor (78c) on CD38, NAD+, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α expressions, and anti-oxidative responses in old murine macrophages induced by oral pathogens. Old and young murine macrophages were either uninfected or infected with the oral pathogens Aa or Pg for 1 to 24 h. Protein levels of CD38 and protein kinases, including nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs), NAD+, and inflammatory cytokine (IL-1β, IL-6, TNF-α) levels were evaluated. Additionally, old murine macrophages were treated with a vehicle or a CD38 inhibitor (78c) and cells were either uninfected or infected with Aa or Pg. CD38, NAD+, cytokine (IL-1β, IL-6, TNF-α) levels, reactive oxygen species (ROS), NAPDH oxidase 1 (Nox1), and anti-oxidative enzymes, including superoxide dismutase1 (Sod1), glutathione peroxidase 4 (Gpx4), Peroxiredoxin 1 (Prdx1), thioredoxin reductase 1 (Txnrd1), and catalase (Cat), were evaluated. The results showed that old murine macrophages significantly enhanced CD38 and reduced NAD+ levels 24 h after Aa or Pg infection compared to young controls. This enhanced CD38 in old murine macrophages was not directly correlated with the activation of protein kinases (NF-κB, PI3K, and MAPKs), nor the (IL-1β, IL-6, TNF-α) levels in macrophages. The inhibition of CD38 by 78c reduced CD38, enhanced NAD+ levels, attenuated IL-1β, IL-6 and TNF-α pro-inflammatory cytokine levels, reduced ROS and Nox1 expressions, and enhanced expressions of Sod1, Gpx4, Prdx1, Txnrd1, and Cat in old murine macrophages infected with Aa or Pg. These results suggest that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat aging-associated periodontitis.
Melatonin (MT) has been reported to alleviate chilling injury (CI) in postharvest tomato fruit during low-temperature storage. In the present study, the DNA methylation profile changes in the CpG islands of ethylene signaling genes regulated by MT in postharvest tomato fruit during low-temperature storage were detected. The MT treatment increased the content of total soluble solids (TSS) and enhanced the ethylene production of tomato fruit. Moreover, it decreased titratable acidity (TA) content, inhibited the activity of polygalacturonase (PG), and kept the firmness of tomato fruit under low-temperature storage. In the MT-treated tomato fruit, significant changes in DNA methylation of CpG island of SlACS10, LeCTR1, LeEIN3, SlERF-A1, and LeERT10 genes were induced; the expression of LeCTR1 was inhibited; and the expression of SlACS10, LeEIN3, and SlERF-A1 genes was increased, by which the ethylene signaling might be influenced and the CI was alleviated. The present results provide evidence that the CI of postharvest tomato fruit alleviated by MT might be related to the changes in DNA methylation of ethylene-signaling genes.
A growing global trend of adult obesity and the increasing prevalence of overweight/obesity in children indicate a higher risk in the future of adult diseases related to obesity. Current anti-obesity medications regulate appetite and metabolism by acting either in peripheral tissues or in the central nervous system. On the other hand, subsequent weight regain is a typical response to weight loss methods, and there is little evidence that current anti-obesity medications can help maintain long-term weight loss without causing a range of undesirable side effects. The combination of anti-obesity drugs targets multiple molecular pathways and structures in the central nervous system that are involved in weight regulation. This systematic review involves trials performed in pediatric populations, published up to 2025 and systematically searched on the ClinicalTrials.gov database, using “Glucagon like peptide-1 analog, Glucagon like peptide-1 receptor agonists” as the criterion for the “Intervention/treatment” category. We evaluated the entero-insular axis in pediatric patients with obesity, along with the mechanisms of action and therapeutic potential of the Glucagon like peptide-1receptor agonists. We analyzed incretin hormones and summarized the drugs approved by the Food and Drug Administration. Our objective is to identify new treatment strategies as we improve our understanding of the pathophysiology of obesity and the incretin axis.
Recent diagnostic advances reveal that lymphatic disease in Noonan syndrome (NS) and other NS-like RASopathies often stems from central conducting lymphatic anomalies (CCLAs). The RAS/MAPK-ERK pathway plays a central role in lymphangiogenesis. Targeting this pathway with MEK-inhibitor trametinib has emerged as a promising therapeutic strategy for managing CCLAs in patients with NS-like RASopathies. This case series assessed the clinical outcomes of trametinib therapy in eight patients with NS-like RASopathies and CCLA, each offering unique insights into the therapeutic efficacy of MEK inhibition. In infants, a lower dose of 0.01 mg/kg/day and earlier discontinuation of trametinib therapy effectively alleviated the symptoms of congenital chylothorax and rescued the lymphatic phenotype, compared to similar published cases. Moreover, four patients aged >11 y showed a slower response and did not achieve complete symptomatic recovery. In conclusion, it is advised to consider trametinib therapy for patients with severe, therapy-refractory CCLA in patients with NS-like RASopathies. However, individual responses to trametinib therapy may vary, with some patients demonstrating more favorable outcomes than others. Further investigation into potential enhancers and suppressors of the lymphatic phenotype is necessary for more accurate treatment predictions. While these factors are likely genetic, we cannot rule out other intrinsic or physiological factors.
From a previously performed proteomics screen, GPP130, or Golgi phosphoprotein of 130 kDa, was identified as a potential substrate of the proprotein convertase 7 (PC7; PCSK7). GPP130 is a type-II transmembrane protein with a luminal domain containing endosomal and Golgi-retrieval determinants, enabling a unique trafficking route. Most of the previous work on GPP130 relates to its binding and retrograde trafficking of the Shiga toxin. However, its cellular biology and its biochemical characterization remain understudied. Recently, GPP130 was reported to be implicated in cell cycle progression and cell proliferation in head and neck cancer cells. This led us to analyze the cBioPortal for Cancer Genomics, revealing that the GPP130/GOLIM4 gene is amplified in many cancers, including lung, ovarian, and cervical. This observation led us to use the A549 lung cancer cell line to investigate the growth-regulating roles of endogenous and overexpressed GPP130 and to analyze the impact of its cleavage/shedding by PC7 and/or Furin on cellular growth. Our cell-based assays suggest that GPP130 is a novel pro-protein convertase substrate that increases cell proliferation in A549, SKOV3, and HeLa cells, and that the latter activity is enhanced following its cleavage by PC7 and/or Furin into a membrane-bound N-terminal product and secreted C-terminal fragments. This novel work sheds light on the cell biology of the poorly characterized GPP130, its proliferative activity, and modulation upon its shedding by PC7 and Furin in lung cancer progression.
Mature dendritic cells (DCs) are known to activate effector immune responses, whereas steady state immature DCs can induce tolerance. Several studies have targeted immature murine quiescent DCs in vivo with antigen, including donor alloantigens, for the induction of tolerance. Receptors expressed by specific DC subsets have been also targeted with antibodies linked with antigens to induce tolerance; for instance, in vivo targeting of the DCIR2+ DC subset with donor alloantigen resulted in long-term survival of heart and skin transplants. DCs also express sialic acid immunoglobulin-like lectin (Siglec) receptors, and these have been successfully targeted with myelin oligiodendrocyte glycoprotein (MOG) antigen to induce tolerance in experimental autoimmune encephalomyelitis (EAE). We investigated, in a mismatched model of skin transplant (B6Kd into B6 recipient mice), whether targeting a sialylated alloantigen Kd (Sia-Kd) to Siglecs on recipient DCs promoted transplant survival. The injection of α2,3 Sia-Kd into B6 recipient mice prior to B6Kd skin transplantation, by binding to Batf3 dependent DCs, resulted in prolonged skin graft survival and an increase in CD4+CD62L+Foxp3+ Tregs. Targeting Siglecs on DC subsets in vivo represents a novel way of improving transplant survival.
Fragile X syndrome is characterized by the diminished expression of the fragile X messenger ribonucleoprotein (FMRP), a ubiquitously expressed RNA binding protein with numerous functions in cells. Our prior work found significant differences in physiological and behavioral outcomes as a function of FMRP levels and in response to diet in mice. Here, we assess protein biomarker levels as a function of FMRP levels, sex and matched casein and soy protein isolate-based purified ingredient diets in Fmr1KO and littermate mice. Brain regions (cortex, hippocampus, and hypothalamus) and blood plasma were analyzed by RayBiotech’s Quantibody® Mouse Cytokine Antibody Array 640 to quantitate the expression of 640 proteins. The main findings were the identification of numerous proteins that were differentially expressed in response to diet, sex and/or genotype. Of note, prolactin (PRL) levels in blood plasma were significantly elevated in Fmr1KO female mice as a function of genotype and sex selectively with the AIN-93G/casein diet. Also, using a moderately stringent significance cutoff, growth differentiation factor 9 (GDF-9) in plasma from mice fed AIN-93G/soy was the only protein studied by Quantibody arrays that was differentially expressed between WT and Fmr1KO male mice. When comparing the results from a pelleted infant formula study with AIN-93G-based diets, insulin-like growth factor binding protein 5 (IGFBP5) in plasma was the only protein differentially expressed as a function of soy in the diet. There was no overlap in statistically significant results when comparing tissue analyzed by mass spectrometry versus Quantibody arrays from mice maintained on AIN-93G-based diets. In conclusion, gene–diet interactions affect protein expression in Fmr1KO and littermate mice and need to be considered in study design.
Mesenchymal stem cell-derived exosomes (MSC-Exos) play a key role in tissue repair, immune regulation, and cancer biology. Due to limitations in MSC expansion and source variability, interest has shifted to induced pluripotent stem cell-derived MSCs (iMSCs) as a promising alternative. This study compares effects of exosomes derived from iMSCs (iMSC-Exos) and Wharton’s jelly MSCs (WJMSC-Exos) on MCF7 and A549 cancer cells. Both types of exosomes reduced MCF7 proliferation and induced a senescence-like state, rather than apoptosis, although the antiproliferative effect was transient in A549 cells. Notably, WJMSC-Exos promoted migration in both MCF7 and A549, whereas iMSC-Exos did not exhibit this effect. Overall, WJMSC-Exos had a more robust impact on cancer cell proliferation and migration. These findings highlight the diverse effects of exosomes on cancer and the development of a senescence-like state as an important response to Exos exposure. Moreover, these findings invite for more careful evaluation of the therapeutic role of iMSC-derived Exos.
Bovine alphaherpesvirus 1 (BoAHV-1) is a promising oncolytic virus that can infect the human lung carcinoma cell line A549. In an effort to adapt the virus to grow more rapidly in these cells through the serial passaging of viral progeny, we were unsuccessful. Here, we found that extracellular vesicles (EVs) secreted by BoAHV-1-infected A549 cells (referred to as EDVs) contain 59 viral proteins, including both viral structure proteins (such as gC and gD) and viral regulatory proteins (such as bICP4 and bICP22), as identified via a proteomic analysis. These EDVs can bind to and enter target cells, inhibit viral particles binding to cells, and stimulate the production of IFN-α and IFN-β in A549 cells. When EDVs are inoculated into rabbits via either the conjunctival sacs or intravenously, they can be readily detected in neurons within the trigeminal ganglia (TG), where they reduce viral replication and promote the transcription of IFN-γ. Furthermore, incorporation of the known anti-herpesvirus drug Acyclovir (ACY) into the EDVs leads to synergistically enhanced antiviral efficacy. Collectively, the EDVs exhibit antiviral effects by blocking viral binding to target cells and stimulating the innate immune response, thereby leading to the failure of the serial passaging of viral progeny in these cells, and these EDVs may serve as a promising vector for delivering drugs targeting TG tissues for antiviral purposes.
Familial hypercholesterolemia leads to the early development of cardiovascular diseases at a young age due to the prolonged exposure of the arterial vessel wall to high concentrations of atherogenic lipids. Serotonin plays a significant role in the development and progression of atherosclerotic processes. Monoamine has a damaging effect on the vascular wall, stimulates the proliferation of vascular smooth muscle cells and fibroblasts, and participates in platelet activation and aggregation. The aim of the work was the demonstration of the importance of serotonin, transporters, and receptors in the pathogenesis of atherosclerotic plaque formation. The study was performed on immature mice of the C57BL/6JGpt-Ldlrem1Cd82/Gpt (Ldlr+/−) line (main group) and C57BL/6 mice of comparable age and sex demographics (control group). Morphological manifestations of early signs of atherosclerosis (pre-lipid stage and lipoidosis stage, which were confirmed by Sudan III staining) in the gene-modified mice’s aorta were determined. Morphological changes in the aorta correlated with changes in the left ventricle of the heart, where lipid content also increased. No atherosclerotic changes in the control-group mice were detected. A statistically significant increase in the expression of the membrane serotonin transporter and 5HT2A and 5HT2B receptors in both the aorta and left ventricle was also found in the animals of the main group. Serotonin and its receptors and transporter may become new therapeutic targets for the treatment and prevention of atherosclerotic vascular lesion progression in children and adults.
Plastic overconsumption has emerged as a major environmental pollutant, with degraded micro- and nanoplastic (MNP) particles being consumed by a vast variety of species. MNPs, particles < 5 mm, contain endocrine-disrupting chemicals (EDCs), which can bind to hormone receptors and disrupt the proper endocrinological function of a variety of organs. This review explores the toxicological impact of MNPs on the hypothalamus, pituitary gland, thyroid, pineal body, ovaries, and testes, as well as the effects of the endocrinological regulatory axes, including the hypothalamic–pituitary–gonadal (HPG), hypothalamic–pituitary–thyroid (HPT), and hypothalamic–pituitary–adrenal (HPA) axes. The disruption of these hormonal feedback systems leads to reproductive dysfunction, neurotoxicity, cytotoxicity, immunotoxicity, and metabolic disorders. The gonads are particularly susceptible, with studies demonstrating oxidative stress, cellular apoptosis, and infertility due to MNP exposure. Given the widespread presence of MNPs and their impact on human health, further research is critical to understand their long-term effects and develop strategies to reduce exposure.
The gut microbiota constitutes a complex community of microorganisms (including bacteria, viruses, fungi, and protozoa) within the intestinal tract. Over the years, an increasing number of studies have highlighted the bidirectional communication between the gut microbiota and the central nervous system (CNS), a relationship commonly referred to as the “microbiota–gut–brain axis”. In particular, the crosstalk between the gut microbiota and the brain has been associated with the pathogenesis and progression of various CNS disorders. Phages, or bacteriophages, viruses that specifically infect bacteria, constitute the most abundant viral component within the gut microbiota. However, despite their abundance and significance in the gut microbial community, studies exploring the relationship between phages and the CNS remain surprisingly limited. This review examines the biological interplay between gut-resident phages and the CNS. Furthermore, we discuss the current literature linking phages to CNS-related pathologies.
4-coumarate-CoA ligase (4CL) plays a crucial role in the phenylpropanoid metabolic pathway and is a key enzyme involved in plant growth and stress responses. Black rot, caused by Xanthomonas campestris pv. campestris (Xcc) is a major bacterial disease affecting the production of global cruciferous crop-like cabbage (Brassica oleracea var. capitata). However, the role of 4CL genes in cabbage resistance to black rot remains unclear. In this study, transcriptome sequencing was conducted using resistant cabbage MY and susceptible cabbage LY at 0, 6, 24, and 48 h post-inoculation. KEGG analysis identified the enrichment of the phenylpropanoid biosynthesis pathway, and significant expression changes of 4CL genes were determined through the expression heat map. Further genome-wide analysis revealed 43 Bol4CL gene family members on the cabbage genome distributed across nine chromosomes. Gene structure and protein motif analysis revealed similarities in motifs within the same evolutionary branch, but variations in gene structure. A combination of Bol4CL gene expression profiles and differentially expressed genes (DEGs) from the transcriptome identified Bol4CL41 as a key gene for further study. Inoculation of overexpressed Bol4CL41 T2 generation stably expressed cabbage seedlings demonstrated significantly larger lesion areas compared to wild type cabbage, indicating that Bol4CL41 negatively regulates resistance to black rot in cabbage. The analysis of multi-time point transcriptomes in cabbage and the functional study of the Bol4CL gene family enhance our understanding of the mechanisms underlying plant disease resistance. This provides compelling evidence and experimental support for elucidating the mechanisms of black rot resistance in cabbage.
AVRO is an adjunctive four-drug regimen designed to increase the effectiveness of current standard treatment of glioblastoma (GB). AVRO is a repurposed drug regimen consisting of the antinausea drug aprepitant, the antidepressant vortioxetine, the emphysema treatment drug roflumilast, and the antipsychotic drug olanzapine. All four are EMA/FDA approved for nononcology indications, all four have strong research evidence showing inhibition of GB growth, and all four carry a low side effect risk. The goal of adding AVRO is to further retard GB growth, improving survival. Aprepitant is an antinausea drug that blocks NK-1 signaling, with a database of 59 studies showing growth inhibition in 22 different cancers, 12 of which were specific to GB. Fully 30 studies demonstrated that the SSRI class of antidepressants inhibited GB growth; accordingly, we chose one such agent, vortioxetine, to add to AVRO. Elevation of intracellular cAMP slowed GB growth in 21 independent studies. Accordingly, we added the emphysema treatment drug roflumilast, which inhibits cAMP degradation. Among the 27 currently marketed D2-blocking antipsychotic drugs, 24 have preclinical evidence of GB growth inhibition in a combined 84 independent study database. One of these 24 drugs is olanzapine, added to AVRO. Given the short median survival of GB as of mid-2025, the clinician and researcher community will benefit from wider awareness of the anti-GB effects of these four nononcology drugs.
Head and neck squamous cell carcinoma (HNSCC) remains challenging to treat despite multimodal therapeutic approaches. Cisplatin treatment is effective and cost-efficient, although chemoresistance and disease recurrence limit its efficacy. Understanding the mechanisms of cisplatin resistance and the identification of compounds to target resistant tumor cells are critical for improving patient outcomes. We have demonstrated that cisplatin-induced senescent HN30 HNSCC cells can be eliminated by ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor that has senolytic properties. Here, we report the development of a cisplatin-resistant cell line (HN30R) for the testing of ABT-263 and the PROTAC BET degraders ARV-825 and ARV-771. ABT-263 was ineffective in sensitizing HN30R cells to cisplatin, largely due to a lack of senescence induction. However, the BET degraders in combination with cisplatin promoted apoptotic cell death in both HN30 and HN30R cells. The effectiveness of ARV-825 did not appear to depend on the cells entering into senescence, indicating that it was not acting as a conventional senolytic. ARV-825 treatment downregulated BRD4 and its downstream targets, c-Myc and Survivin, as well as decreased the expression of RAD51, a DNA repair marker. These results suggest that the BET degraders ARV-825 and ARV-771 may be effective in improving the response of chemoresistant head and neck cancer to cisplatin treatment.
Metal nanostructure-assisted solar-driven interfacial evaporation systems have emerged as a promising solution to achieve sustainable water production. Herein, we fabricated photothermal films of a bumpy gold nanoshell with controlled shell thicknesses (11.7 nm and 16.6 nm) and gap structures to enhance their photothermal conversion efficiency. FDTD simulation of bumpy nanoshell modeling revealed that thinner nanoshells exhibited higher absorption efficiency across the visible–NIR spectrum. Photothermal films prepared by a three-phase self-assembly method exhibited superior photothermal conversion, with films using thinner nanoshells (11.7 nm) achieving higher surface temperatures and faster water evaporation under both laser and sunlight irradiation. Furthermore, evaporation performance was evaluated using different support layers. Films on PVDF membranes with optimized hydrophilicity and minimized heat convection achieved the highest evaporation rate of 1.067 kg m−2 h−1 under sunlight exposure (937.1 W/m2), outperforming cellulose and PTFE supports. This work highlights the critical role of nanostructure design and support layer engineering in enhancing photothermal conversion efficiency, offering a strategy for the development of efficient solar-driven desalination systems.
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. It is generally accepted that IBD is characterized by an inappropriate immune response to the intestinal microbiome in genetically susceptible individuals. Despite the available treatment options ranging from salicylates and corticosteroids, to immunosuppressants and biologics, there is still a high unmet medical need for patients who respond poorly to drugs or are not able to tolerate them. Microbiome-based therapeutics offer a valid treatment strategy for IBD with enhanced safety. A butyrate-producing consortium of six commensal strains (MH002) was evaluated in a series of in vitro, ex vivo, and in vivo experiments mimicking multiple IBD-related dysfunctions, namely disrupted intestinal permeability and immune activation. MH002 rapidly produced high levels of butyrate in fed-batch cultures, and significantly increased butyrate levels within one day after administration to IBD-derived gut microbial communities in vitro. Both in Caco-2/peripheral blood mononuclear cells (PBMCs) co-cultures, and IBD patients-derived organoids and colonic explants, MH002 reduced inflammation and restored epithelial barrier integrity. In addition, MH002 promoted wound repair in vitro. Finally, MH002 protected mice and rats from chemically induced colitis. Altogether, results showed that MH002 presents a novel therapeutic avenue for the treatment of IBD.
The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.
Hepatocellular carcinoma (HCC) presents significant intertumoral heterogeneity, complicating prognosis and treatment. To address this, we performed an integrated single-cell RNA-sequencing analysis of HCC specimens using Seurat and identified malignant cells via Infercnv. Through a systematic evaluation of 101 machine learning algorithms used in combination, we developed tumor-cell-specific gene signatures (TCSGs) that demonstrated strong predictive performance, with area under the curve (AUC) values ranging from 0.72 to 0.74 in independent validation cohorts. Risk stratification based on these signatures revealed distinct therapeutic vulnerabilities: high-risk patients showed increased sensitivity to sorafenib, while low-risk patients exhibited enhanced responses to immunotherapy and transarterial chemoembolization (TACE). Pharmacogenomic analysis with Oncopredict identified four chemotherapeutic agents, including sapitinib and dinaciclib, with risk-dependent efficacy patterns. Furthermore, CRISPR/Cas9-dependency screening prioritized SRSF7 as essential for HCC cell survival, a finding confirmed by the identification of protein-level overexpression in tumors via immunohistochemistry. This multi-omics framework bridges single-cell characterization to clinical decision-making, offering a clinically actionable prognostic system that can be used to optimize therapeutic selection in HCC management.
Bipolar disorder (BD) and schizophrenia (SCH) are results of the complex interactions between genetic and environmental factors, and the underlying pathophysiology is not yet completely understood. The current diagnostic criteria for psychiatric diagnosis are based purely on clinical phenomenology and they are limited to psychiatrist judgment after a standardized clinical interview, with no precise biomarkers used to discriminate between the disorders. Besides gaps in the understanding and diagnosis of these diseases, there is also a need for personalized and precise approaches to patients through customized medical treatment and reliable monitoring of treatment response. To fulfill existing gaps, the establishment of disorder biomarker sets is a necessary step. LC-MS lipidomic blood sample analysis is one of the ongoing omics approaches. In the last ten years, several studies have identified alterations in lipid metabolism associated with BD and SCH, and this review summarizes current knowledge on their lipidomic patterns, which is essential for identifying lipid biomarkers. Currently, findings indicate decreases in plasmalogens and acyl-carnitines, along with increases in certain triacylglycerol species, shared by both conditions. In contrast, serum LC-MS lipidomic profiles of sphingolipids including ceramides could be unique to BD, indicating the need for further investigation in future studies.
Yam (Dioscorea spp.) provides various nutritional and medicinal benefits, including a high starch content, dietary fiber, essential micronutrients, and bioactive compounds. The molecular mechanisms underlying tuber expansion have not yet been clarified. Rapid alkalinization factor (RALF) genes, which mediate various processes in plants, are thought to contribute to the regulation of tuber growth; however, their role in yam development, especially in gibberellin (GA)-mediated processes, remains unclear. Here, we characterized seven DrRALF genes in the yam genome. Analysis of gene duplication demonstrated that the expansion of DrRALF genes was primarily driven by whole-genome duplication or segmental duplication. Phylogenetic analysis revealed that DrRALF genes were concentrated in specific clusters, indicating that their functions are relatively conserved. DrRALF5 was specifically expressed in the roots, and DrRALF2, DrRALF3, DrRALF4, and DrRALF6 were highly expressed in flowers. DrRALF1, DrRALF2, DrRALF3, DrRALF4, DrRALF5, and DrRALF6 were shown to play a role in tuber expansion. Subsequent qRT-PCR validation of four selected DrRALF genes confirmed the regulation of DrRALF2, DrRALF4, DrRALF5, and DrRALF6 by GA and PP333 (paclobutrazol, a GA biosynthesis inhibitor). Yeast one-hybrid assays further showed that the DrRALF6 promoter region interacted with the GA-signaling protein, DrDELLA1. Our findings provide novel insights into the regulatory network controlling yam tuber expansion, especially through the interaction between DrRALF6 and GA signaling pathways. Our results clarify the molecular mechanisms involved in tuber growth and propose a promising strategy for improving yam production through genetic manipulation of the GA-RALF signaling pathway.
Ruxolitinib, a clinically approved JAK1/2 inhibitor used in the treatment of hematologic malignancies and inflammatory conditions, has been shown to interfere with the function of cytotoxic T lymphocytes (CTLs). Previous studies supported the involvement of the multidrug resistance transporter P-glycoprotein (Pgp/ABCB1) in CTL biology; however, the nature of its regulation remains unclear. To address this, we investigated the impact of ruxolitinib on Pgp expression and function in human CD8+ T cells. We demonstrate that CD8+ T lymphocytes express Pgp dynamically at both the mRNA and protein levels across naïve, short-term, and long-term activation states. Ruxolitinib increased the calcein accumulation in human Pgp-overexpressing NIH-3T3 cells and in CTLs and directly modulated Pgp function by increasing its basal ATPase activity in a concentration-dependent manner (10–100 μM), similar to the effect of the known Pgp substrate/modulator verapamil. Although measurable ATPase stimulation and transport inhibition were observed at supratherapeutic concentrations of ruxolitinib, its Pgp-mediated efflux may also occur at therapeutically relevant concentrations. In contrast, at therapeutically relevant plasma concentrations (1–3 μM), ruxolitinib significantly stabilized the mRNA expression of Pgp during early T-cell receptor (TCR) activation and inhibited the TCR-induced upregulation of Pgp, CD8, and PD-1 surface markers, suggesting its interference with activation-associated differentiation. At these same concentrations, ruxolitinib also impaired CCL19-directed transmigration of CTLs across human umbilical vein endothelial cell (HUVEC) monolayers, indicating disruption of lymphoid homing cues. Collectively, these findings demonstrate that ruxolitinib modulates Pgp at both the transcriptional and functional levels, with distinct concentration dependence. The ability of ruxolitinib to alter CTL activation and migration at clinically relevant plasma concentrations highlights the need for careful evaluation of JAK inhibitor–mediated immunomodulation and its implications for vaccination, transplantation, and T cell-based immunotherapies.
Gastroesophageal reflux disease (GERD) is associated with inflammatory and neoplastic changes in the esophageal epithelium. Despite widespread PPI use, esophageal adenocarcinoma (EAC) incidence continues to rise, implicating non-acidic reflux components such as pepsin in disease progression. We performed transcriptomic profiling to assess pepsin-induced changes and the protective effect of amprenavir in vitro. Het-1A (normal) and BAR-T (Barrett’s) cells (n = 3) were treated at pH 7.0 with pepsin and/or 10 μM amprenavir for 1 h. RNA-seq identified DEGs (FDR ≤ 0.05, |log₂FC| ≥ 0.375), and Ingenuity Pathway Analysis revealed enriched pathways. Pepsin exposure altered mitochondrial function, oxidative phosphorylation, epithelial integrity, signaling, and inflammatory pathways in both cell lines. Amprenavir attenuated these transcriptomic perturbations, preserving mitochondrial and stress-response pathways. Notably, BAR-T cells exhibited heightened activation of wound-healing and epithelial repair pathways, whereas Het-1A cells showed greater mitochondrial and systemic stress pathway alterations. Pepsin drives transcriptomic dysregulation in esophageal epithelial cells under non-acidic conditions, and amprenavir shows potential to counteract peptic injury. Further studies are needed to validate these findings and explore amprenavir’s therapeutic utility in GERD management and EAC prevention.
Marantodes pumilum (MP) is one of the traditional plants to which various medicinal properties are attributed. Studies on the medicinal properties of MP and its characteristics are becoming more extensive and are attracting more and more attention. In this review, the findings on the pharmacological properties of MP have been summarised and analysed. The results show that in addition to its phytoestrogenic effects on the female reproductive system, MP also has bone-remodelling properties, anti-obesity, anti-cancer, anti-gout, antimicrobial, anti-inflammatory and wound-healing effects, as well as effects on the cardiovascular system. These findings show that MP has great potential for the prevention and complementary treatment of various diseases. However, further research is needed to explore its full clinical potential.
Acetaminophen, or paracetamol (PCM), is a common painkiller used to treat aches, pain, and fever. Nevertheless, PCM has been reported to be hepatotoxic and nephrotoxic in humans. Thus, there is a need to identify how this side effect can be treated. Previous studies have shown that Leea species possess antioxidative, anthelmintic, anti-cytotoxic, hepatoprotective, and nephroprotective properties. However, the role of Leea guineensis (LG) in modulating PCM-induced hepatotoxicity or nephrotoxicity remains unknown. Herein, we investigate the possibility of Leea guineensis leaf extract (LGE) to ameliorate PCM toxic effects, evaluate hepatic and renal function, oxidative stress markers, and safety, and perform molecular docking to predict affinities of Leea guineensis extract compounds for their targets compared to PCM. An in vivo rat model was used for Leea guineensis extract or silymarin (SLM, standard drug) at various concentrations, and it was co-administered with PCM. We observed that Leea guineensis extract is rich in phytochemical constituents, and its treatment in rats did not significantly affect body weight. Our data showed that PCM increased bilirubin, creatinine, uric acid, Alanine aminotransferase (ALT), and cholesterol levels but decreased Aspartate aminotransferase (AST) in plasma. Moreover, it increased lipid peroxidation (MDA) levels in the liver and kidneys, while the total protein was elevated in the latter. Interestingly, Leea guineensis extract and SLM abrogated the elevated parameters due to PCM toxicity. Importantly, histopathological examination showed that Leea guineensis extract demonstrated the potential to ameliorate hepatic and renal lesions caused by PCM intoxication, thus demonstrating its safety. Furthermore, comparative molecular binding affinities of the study ligands binding the target corroborate the experimental findings. Our study shows that L. guineensis leaf extract, through its rich phytochemicals, can protect the liver and kidneys against the toxic effects of paracetamol in a dose-dependent manner.
Impulse control disorders (ICDs) are a debilitating non-motor symptom of Parkinson’s disease (PD), often associated with dopaminergic therapy. However, their occurrence in some patients but not others suggests additional biological mechanisms, including the gut microbiome. In this study, we analyzed 191 PD patients (14 with ICDs, 177 without) using 16S rRNA gene sequencing to explore the association between gut microbiota and ICDs. No significant differences were observed in alpha or beta diversity between groups, but several bacterial taxa showed differential abundances. Notably, Methanobrevibacter and Intestinimonas butyriciproducens were enriched in ICD patients. Functional pathway analysis revealed differences in metabolic pathways, including enrichment of xenobiotic degradation and nicotinate metabolism in the ICD group. These findings suggest that specific gut microbial taxa and their associated metabolic functions may contribute to ICDs in PD, highlighting a potential non-dopaminergic mechanism and opening new avenues for microbiome-targeted intervention.
This study develops a dual-mode antibacterial orthodontic adhesive by integrating quaternary ammonium salt-modified large-pore mesoporous silica nanoparticles (QLMSN@CHX). The material integrates two antibacterial mechanisms: (1) contact killing via covalently anchored quaternary ammonium salts (QACs) and (2) sustained release of chlorhexidine (CHX) from radially aligned macropores. The experimental results demonstrated that QLMSN@CHX (5 wt%) achieved rapid biofilm eradication (near-complete biofilm eradication at 24 h) and prolonged antibacterial activity, while maintaining shear bond strength comparable to commercial adhesives (6.62 ± 0.09 MPa after 30-day aging). The large-pore structure enabled controlled CHX release without burst effects, and covalent grafting ensured negligible QAC leaching over 30 days. The composite demonstrated good biocompatibility with human dental pulp mesenchymal stem cells at clinically relevant concentrations. This dual-mode design provides a clinically viable strategy to combat bacterial contamination in orthodontic treatments, with potential applications in other oral infections. Future studies will focus on validating efficacy in complex in vivo biofilm models.
To enhance the signal intensity of kynurenines, which are present at trace concentrations in biological fluids, a novel analytical approach was developed, combining pressure-assisted electrokinetic injection (PAEKI) with a mixed micelle system based on sodium dodecyl sulfate (SDS) and Brij-35. The method was applied to key compounds of the kynurenine pathway, including L-tryptophan, kynurenine, 3-hydroxykynurenine, and kynurenic acid, as well as to the aromatic amino acids (AAs) L-tyrosine and L-phenylalanine. PAEKI was performed by electrokinetic injection for 2 min at −6.5 kV (reversed polarity) and 0.5 psi (3.45 kPa) using a fused silica capillary (50 cm in length, 50 µm inner diameter). The background electrolyte (BGE) consisted of 20 mM Na2B4O7 (pH 9.2), 2 mM Brij-35, 20 mM SDS, and 20% (v/v) methanol (MeOH). The limit of detection (LOD) using a diode array detector (DAD) was 1.2 ng/mL for kynurenine and ranged from 1.5 to 3.0 ng/mL for the other analytes. The application of PAEKI in conjunction with micellar electrokinetic capillary chromatography (MEKC) and solid-phase extraction (SPE) of artificial urine samples resulted in a 146-fold increase in signal intensity for kynurenines compared to that observed using the hydrodynamic injection (HDI) mode. The developed method demonstrates strong potential for determining kynurenine pathway metabolites in complex biological matrices.
Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by progressive neuronal dysfunction and loss and represent a significant global health challenge. Oxidative stress, neuroinflammation, and neurotransmitter dysregulation, particularly affecting acetylcholine (ACh) and monoamines, are key hallmarks of these conditions. The current therapeutic strategies targeting cholinergic and monoaminergic systems have some limitations, highlighting the need for novel approaches. Metallodrugs, especially ruthenium and platinum complexes, are gaining attention for their therapeutic use. Among metal complexes, gold(I) and silver(I) N-heterocyclic carbene (NHC) complexes exhibit several biological activities, but their application in NDDs, particularly as monoamine oxidase (MAO) inhibitors, remains largely unexplored. To advance the understanding of this field, we designed, synthesized, and evaluated the biological activity of a new series of Au(I) and Ag(I) complexes stabilized by NHC ligands and bearing a carboxylate salt of tert-butyloxycarbonyl (Boc)-N-protected proline as an anionic ligand. Through in silico and in vitro studies, we assessed their potential as acetylcholinesterase (AChE) and MAO inhibitors, as well as their antioxidant and anti-inflammatory properties, aiming to contribute to the development of potential novel therapeutic agents for NDD management.
Loop diuretics like furosemide are commonly used in heart failure (HF) treatment, but their effects on disease progression are still unclear. Furosemide treatment accelerates HF deterioration in a swine model, but the mechanism of acceleration is poorly understood. We hypothesized that furosemide activates inflammatory signaling in the failing left ventricular (LV) myocardium, leading to adverse remodeling of the extracellular matrix (ECM). A total of 14 Yorkshire pigs underwent permanent transvenous pacemaker implantation and were paced at 200 beats per minute; 9 non-instrumented pigs provided controls. Seven paced animals received normal saline, and seven received furosemide at a dose of 1 mg/kg intramuscularly. Weekly echocardiograms were performed. Furosemide-treated animals reached the HF endpoint a mean of 3.2 days sooner than saline-treated controls (mean 28.9 ± 3.8 SEM for furosemide and 32.1 ± 2.5 SEM for saline). The inflammatory signaling protein transforming growth factor-beta (TGF-β) and its downstream proteins were significantly (p ≤ 0.05) elevated in the LV after furosemide treatment. The regulatory factors in cell proliferation, mitogen-activated protein kinase signaling pathway proteins, and matrix metalloproteinases were elevated in the furosemide-treated animals (p ≤ 0.05). Our data showed that furosemide treatment increased ECM remodeling and myocardial fibrosis, reflecting increased TGF-β signaling factors, supporting prior results showing worsened HF.
DNA-deaminase AID plays a pivotal role in adaptive immunity, antibody diversification and epigenetic regulation. AID catalyzes cytidine deamination in immunoglobulin genes, facilitating somatic hypermutation (SHM), class-switch recombination (CSR) and gene conversion (GC). However, the dysregulation of AID activity can lead to oncogenic mutations and immune disorders such as hyper-IgM syndrome type 2 (HIGM2). At present the number of studies investigating the role of AID polymorphic variants in the promotion of pathology is low. The current review examines the structural and functional aspects of AID, focusing on the impact of amino acid substitutions—both natural polymorphisms and artificial mutations—on its catalytic activity, substrate binding and interactions with regulatory proteins. Additionally, a bioinformatic analysis of single-nucleotide polymorphisms of AID deposited in the dbSNP database was performed. SNPs leading to amino acid substitutions in the primary protein structure were analyzed. The bioinformatic analysis of SNPs in the AID gene predicts that among 208 SNPs causing amino acid substitutions in the primary protein structure, 62 substitutions may have significant negative impact on the functioning of AID. The integration of computational predictions with experimental data underscores the importance of AID regulation in maintaining immune homeostasis and highlights potential markers for immune-related pathologies. This comprehensive analysis provides insights into the molecular mechanisms of AID dysfunction and its implications for disease.
Vitamins are chemical compounds, or a group of closely related compounds known as vitamers, which are crucial for an organism’s metabolic functions. Vitamins are categorized as either water-soluble or fat-soluble, with this second group composed of vitamins A, D, E, and K. The low aqueous solubility of these compounds often necessitates the use of pharmaceutical excipients to benefit from their medicinal efficiency. A successful example of this is the formation of the inclusion complexes with cyclodextrins (CDs), a group of cyclic oligosaccharides, composed of glucose subunits forming a macrocyclic ring. CD complexes with fat-soluble vitamins have been consistently utilized to accomplish diverse objectives, with CDs predominantly employed as solubilizers and absorption enhancers. This article examines studies detailing the synthesis and the biological, physicochemical, and structural characteristics of the inclusion complexes formed between fat-soluble vitamins and different cyclodextrins. This research demonstrates that although the fat-soluble vitamins form stable complexes with various CDs, the kind of CDs employed significantly influences the resultant properties of the complex formed.
Osteosarcoma (OSA) is the most common primary bone malignancy in dogs, characterized by aggressive growth and high metastatic potential. Despite advances in treatment, the prognosis for affected animals remains poor, mainly due to metastatic disease. Metastasis is a complex process that involves forming new blood vessels in the primary tumor (angiogenesis), intravasation, the transport of cancer cells to other locations, extravasation, and the growth of cancer cells in the secondary site. Gold nanoparticles (AuNPs), due to their unique physicochemical properties, are considered promising tools in cancer therapy, both as drug delivery systems and potential anti-metastatic agents. Previously, it has been demonstrated that 500 µg/mL glutathione-stabilized gold nanoparticles (Au-GSH NPs) inhibit cancer cell extravasation—one of the steps of the metastatic cascade. This study aimed to evaluate the anti-metastatic properties of Au-GSH NPs through their influence on OSA cell migration, proliferation, and colony formation in vitro, as well as their antiangiogenic properties on the chick embryo chorioallantoic (CAM) model. Additionally, we investigated whether these effects are associated with changes in alpha-2-macroglobulin (A2M) expression, as it was previously demonstrated to play an essential role in the metastatic cascade. Au-GSH NPs significantly inhibited migration and colony formation in canine osteosarcoma cells (from OSCA-8, OSCA-32, and D-17 cell lines) at 200 µg/mL concentrations. Interestingly, at 500 µg/mL, Au-GSH NPs inhibited angiogenesis on the CAM model and cancer cell migration, but fewer colonies were formed. These results may be directly related to the higher efficiency of Au-GSH NPs uptake by OSA cells at the dose of 200 μg/mL than at the dose of 500 μg/mL, as demonstrated using Microwave Plasma Atomic Emission Spectroscopy (MP-AES). Moreover, this is the first study that demonstrates a significant increase in A2M expression in cancer cells after Au-GSH NPs treatment. This study provides new insight into the potential use of Au-GSH NPs as anti-metastatic agents in canine osteosarcoma, indicating that their anti-metastatic properties may be related to A2M. However, further in vitro and in vivo studies are needed to explore the molecular mechanism underlying these effects and to evaluate the clinical relevance of AuNPs in veterinary oncology.
Necrotizing enterocolitis (NEC) is a serious GI disease of premature infants, marked by intestinal inflammation and necrosis. Recent research has highlighted the potential role of oxidative stress (OS) and ferroptosis in its pathogenesis. We previously identified a deficiency in Glutathione Peroxidase (GPX) 4 and lipid radical accumulation, prompting further investigation. Human intestinal tissue from a prior study was processed, and it underwent RNA and protein isolation, Immunohistochemistry, Immunofluorescence, and acid digestion for iron and selenium analysis via Inductively coupled mass spectrometry (ICP-MS). NEC was induced in human enteroids using lipopolysaccharide (LPS) and hypoxia, followed by RNA/protein isolation and lipidomic analysis. Humans with NEC had significantly higher levels of GPX2 (p = 0.0003). Enteroids exposed to NEC conditions had significantly decreased amounts of NADPH compared to initial controls (p = 0.0091), but similar levels compared to post-24 h controls (p = 0.3520). Patients with NEC had significantly higher levels of iron compared to controls via the bathophenanthroline-based assay (p = 0.0102) and with ICP-MS (p = 0.0148). There were several significant alterations in lipid distribution between NEC and control patients, but not in the fatty acid profiles. Our study suggests that oxidative stress, iron dysregulation, and altered lipid metabolism contribute to NEC pathogenesis.
Multiple myeloma (MM) is frequently associated with cytogenetic abnormalities, with high-risk cytogenetics linked to poorer survival. Acute kidney injury (AKI) is common in MM, but its relationship with high-risk cytogenetics remains underexplored. This study aimed to assess the association between high-risk cytogenetics and AKI in newly diagnosed MM patients and to evaluate their impact on overall survival, relapse-free survival, and progression to chronic kidney disease (CKD) in the first two years after diagnosis. We conducted a single-center retrospective cohort study including patients newly diagnosed with MM between 2018 and 2022. We enrolled 122 patients. AKI was observed in 36.9% of patients, rising to 62.3% among those with high-risk cytogenetics. High-risk cytogenetics (OR: 3.32; 95% CI: 1.17–6.40; p = 0.024), CKD (OR: 9.14; 95% CI: 2.92–18.65; p < 0.001), kappa free light chains, hypercalcemia, difference in free light chain (dFLC), and bone marrow plasmocyte percentage were independently associated with AKI. Both AKI (HR: 2.71; 95% CI: 1.18–6.23; p = 0.019) and high-risk cytogenetics (HR: 3.33; 95% CI: 1.13–9.76; p = 0.029) were independently associated with lower overall survival. Among survivors without prior CKD, progression to CKD was higher in those with AKI (30.7% vs. 9.3%; p = 0.041). High-risk cytogenetics were significantly associated with AKI in MM patients. Both factors independently predict worse survival and increased risk of CKD progression.
Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting.
Alcoholic liver disease (ALD) is a type of liver disease with complex pathogenic factors. In 2019, alcohol caused 11 million life-years to be lost globally, and the mortality rate has continued to rise. This study aims to explore the exclusive gene profile of AH and construct an mRNA-lncRNA regulatory network through an integrative analysis and database validation to reveal potential key biomarkers. We obtained expression data for alcoholic hepatitis from the GEO database; screened differentially expressed genes (DEGs) through a weighted gene co-expression network analysis (WGCNA); conducted a GO&KEGG analysis; and focused on the enrichment pathways for the top 20 genes. Hub genes were selected using cytoHubba and MCODE to construct the mRNA-lncRNA regulatory network, and key genes were confirmed using GSE167308 and GSE28619. We obtained 2552 differentially expressed mRNAs and 555 differentially expressed lncRNAs from three databases. Differentially expressed genes are mainly involved in pathways such as lipid metabolism disorders, complement activation, the activation of cancer-related pathways, the excessive activation of inflammatory immunity, and the initiation of cell adhesion and fibrosis. Based on the hub gene analysis, we screened out 43 key genes. By constructing the key mRNA-lncRNA–pathway network, we identified 12 mRNAs (AQP1, ELOVL7, ITPR3, KRT19, KRT23, LAMC2, MMP7, PROM1, SPINT1, STK39, TNFRSF21, and VTCN1) and 14 lncRNAs that play an important role in the occurrence and development of alcoholic hepatitis. To sum up, this article mainly expounds upon the key genes in the occurrence and development of alcoholic hepatitis. The key genes are mainly concentrated within signaling pathways such as metabolic pathways, fatty acid metabolism, and cancer pathways. Twelve differentially expressed mRNAs in the co-expression network can be used as biomarkers and intervention targets for the diagnosis and treatment of alcoholic hepatitis.
Glioblastoma (GBM), a highly malignant brain tumor, arises within a complex microenvironment that plays a critical role in facilitating tumor progression, ensuring survival, and enabling immune evasion, ultimately contributing to therapeutic resistance. Cancer-associated fibrosis is increasingly recognized as a key factor in the tumor pathophysiology, particularly in extracranial cancers, and reported therapeutic strategies in several cancers consist of the current use of the standard-of-care treatment combined with anti-fibrotic drugs. However, it remains unclear how the fibrotic changes associated with the GBM microenvironment contribute to the transformation of GBM from a chemosensitive state to a chemoresistant one. Here, we developed an in vitro model that mimics a fibrosis-like mechanism using the U-87MG GBM cell line. To achieve this, we identified the optimal experimental conditions (i.e., U-87MG cultured in serum-deprivation medium in the presence of recombinant TGF-B1 at 5 ng/mL for 72 h) that effectively induced fibrosis, as suggested by the counter-regulated expression of E- and N-cadherin and sustained levels of α-SMA and collagen I. As expected, U-87MG fibrotic cells were demonstrated to be more resistant to TMZ (predicted EC50 = 35 µM) as compared to the non-fibrotic counterpart (EC50 not achieved here; predicted EC50 = 351 µM). Accordingly, the anti-fibrotic uPAcyclin—a new derivative cyclic compound inspired as a A6 decapeptide drug—showed a significant cytotoxic effect, sensitizing resistant U-87MG fibrotic cells to TMZ. This highlights that targeting fibrosis may help to overcome TMZ resistance in GBM.
About a quarter of COVID-19 patients develop acute kidney injury (AKI), worsening prognosis and increasing mortality. Severe COVID-19 often triggers a hyperactive immune response, influencing disease outcomes. This study examined the correlation between kidney injury biomarkers, inflammatory mediators, and mortality in COVID-19 patients. Blood samples from 390 COVID-19 patients were collected at admission and before the outcome. Serum Cystatin C (CysC), albumin, and plasma NGAL were measured via nephelometry, while inflammatory mediators (IL-4, IL-6, IL-10, IL-15, IFN-γ, TNF-α, and IL-1β) were assessed by ELISA. Most patients were male, with hypertension and diabetes as common comorbidities, and a high ICU admission rate. Lower albumin and elevated CysC and NGAL were linked to mortality. Increased inflammatory mediators correlated with lower albumin and higher CysC and NGAL, reinforcing the connection between systemic inflammation and kidney dysfunction. Elevated cytokines and kidney injury biomarkers, including NGAL, CysC, and low albumin, are strongly associated with higher mortality in COVID-19 patients. These findings highlight the role of inflammation and kidney function markers in identifying high-risk individuals, improving patient management, and mitigating complications. Monitoring these biomarkers remains crucial for managing long-term health impacts and future outbreaks
Gonadotropin-Releasing Hormone (GnRH) is a crucial neuropeptide that regulates reproductive functions in vertebrates. The study identifies and characterizes (GnRH) in the brain of Tenualosa ilisha, an iconic and lucrative Clupeiform fish from River Ganga, India. The current study aimed to analyze the GnRH gene in T. ilisha using an in silico study. The GnRH gene of T. ilisha comprises a full-length nucleotide sequence of 605 base pairs with an open reading frame of 312 base pairs, which encodes 103 deduced amino acids (aa), respectively. It was found that leucine (L) is the most abundant amino acid in the GnRH protein. Additionally, the ligand interactions of the GnRH were analyzed using computational approaches. The structural validation showed an excellent stereochemical quality of the GnRH protein sequence, with over 88% of residues in Ramachandran plot-favored regions. The binding site prediction revealed 6 ligand-binding pockets, with the largest pocket containing 12 amino acids. After ADME screening, 16 drug-like compounds were docked to GnRH protein. Top five ligands N-Ac-(4-Cl-Phe)-Trp-Lys-AlaNH2, LHRH_LYS (6), Seabream_GnRH, Leuprolide, and LHRH_Des-tyr (5) had binding affinities ranging from −7.5 to −5.6 kcal/mol. The stable binding site was confirmed by 100 ns molecular dynamics simulations, with RMSD values below 10 Å and key residues retaining ligand contacts. The GnRH-protein resulted in the development of a suitable peptide sequence of T. ilisha, showing similarity with the similar anadromous American shad (Alosa sapidissima). This will certainly aid in future therapeutic and captive breeding advances, thereby fostering the culture and conservation of the wild species.
Protein C (PC) is the main anticoagulant protein of the hemostasis system. It can inhibit the blood clotting cascade before the formation of a thrombus, while its concentration can decrease significantly during strong activation of blood clotting. The PC concentration was found to decrease during systemic lupus erythematosus (SLE) (with a median of 75%) and depended heavily on the inflammation index. It was also associated with the accumulation of soluble fibrin monomeric (SFMCs) (with a median of 7 µg/mL). A low PC level was detected during severe ischemic heart disease (IHD) (with medians of 60 and 63%, respectively). These pathologies also were associated with clotting activation. During abdominal aortic aneurysm (AAA), the PC level in blood plasma before surgery was found to range from 40% to 119%. A decrease in the PC level in the blood plasma of patients with AAA before surgery, lower than 78%, was associated with high blood loss (more than 1.5 L). A decrease in the PC level can lead to an imbalance between coagulation and anticoagulation. Thus, during the treatment of complex pathologies associated with the activation of coagulation, specific attention should be paid not only to classic markers of thrombus formation but also to the state of the anticoagulant link.
Uncomplicated hypertension (UH) during pregnancy represents a common condition, worsening maternal and fetal prognosis. However, no single biomarker has proven optimal for determining the risk of UH. We developed an early risk multivariate model for UH, integrating hemodynamics with biochemistry, focusing on the relationship between blood pressure (BP) indices, uric acid (UA), and angiogenesis-related factors (AF). We collected and analyzed data on 24 h ambulatory BP monitoring, demographic, epidemiological, clinical, and laboratory variables from 132 pregnancies. The main predictors were BP indices and serum UA and AF levels. Uncomplicated hypertension, defined as the presence of gestational hypertension or worsening of essential hypertension beyond the 20th week, was the main outcome. The combined second-degree polynomial transformation of UA and the AF (sFlt-1/PIGF) ratio, called the UA-AF Index, consistently showed a positive association with UH. The models incorporating nighttime BP indices combined with the UA-AF Index outperformed the others, with the best-performing model based on the nocturnal systolic BP (SBP). Specifically, in the best-fitting model (nighttime SBP + UA-AF Index as predictors), each 1 mmHg increase in nocturnal SBP was associated with a 10% higher risk of UH, while each one-unit increase in the UA-AF Index raised the likelihood of UH by more than twofold (accuracy: 0.830, AUC 0. 874, SE 0.032, p-value < 0.001, 95%CI 0.811–0.938). The combination of nighttime blood pressure indices, serum uric acid, and angiogenesis-related factors may provide added value in the assessment of uncomplicated hypertension during pregnancy.
Staphylococcus lugdunensis is a coagulase-negative staphylococcus known for its significant pathogenic potential, often causing severe infections such as endocarditis and bacteremia, with virulence comparable to S. aureus. Despite general susceptibility to most antibiotics, the emergence of oxacillin-resistant strains is increasingly concerning. This study conducted whole-genome sequencing on 20 S. lugdunensis isolates from Chang Gung Memorial Hospital to explore their genetic diversity, antimicrobial resistance mechanisms, and mobile genetic elements. The lugdunin biosynthetic operon, essential for antimicrobial peptide production, was present in multilocus sequence typing (MLST) types 1, 3, and 6 but absent in STs 4, 27, and 29. Additionally, IS256 insertion elements, ranging from 7 to 17 copies, were identified in four strains and linked to multidrug resistance. CRISPR-Cas systems varied across STs, with type III-A predominant in ST1 and ST6 and type IIC in ST4, ST27, and ST29; notably, ST3 lacked CRISPR systems, correlating with a higher diversity of SCCmec elements and an increased potential for horizontal gene transfer. Phage analysis revealed stable phage–host associations in ST1, ST6, and ST29, whereas ST4 displayed a varied prophage profile. Phenotypic resistance profiles generally aligned with genomic predictions, although discrepancies were observed for aminoglycosides and clindamycin. These findings highlight the complex genetic landscape and evolutionary dynamics of S. lugdunensis, emphasizing the need for genomic surveillance to inform clinical management and prevent the spread of resistant strains.
The possibilities of small-cell lung cancer (SCLC) therapy were strictly limited for years, leading to high patient mortality rates. New approaches to SCLC treatment are being proposed, including chemoimmunotherapy. However, biomarkers enabling appropriate personalization of therapy in SCLC patients have not been identified yet. Even though molecular subtyping (ASCL1, NEUROD1, POU2F3, and YAP1) seems pivotal in the management of SCLC, expression of other genes might be potentially valuable during patients’ stratification. Due to their crucial role in tumorigenesis and SCLC invasiveness, benefits arising from MET and SLFN11 gene evaluation are suggested. Our study was designed to evaluate the relationship between the mRNA expression of these genes and chemoimmunotherapy efficacy in SCLC patients. A total of 35 patients with extensive-stage SCLC (ES-SCLC) treated with first-line chemoimmunotherapy were involved in the study. mRNA expression of MET and SLFN11 genes was evaluated using the RT-qPCR technique in FFPE tissue collected from all patients. Molecular results were correlated with clinicopathological features and outcome of disease (OS, PFS). We detected SLFN11 expression in 60% (21 of 35) of the samples. SLFN11 expression was higher in patients with longer PFS (p = 0.05) and with the T4 feature in the TNM scale (p = 0.08). MET mRNA was expressed in all FFPE tissues. We observed that risk of progression and death was higher in patients with higher expression of MET mRNA (p = 0.06 and p = 0.04, respectively). Our study showed that MET and SLFN11 expression might serve as additional biomarkers for prediction of chemoimmunotherapy efficacy in ES-SCLC patients.
Anthozoa is a species-rich class with an innate immune system that acts as a defensive tool and shares many of its cellular pathways with mammalian immune responses. In addition to immune-related strategies (e.g., allorecognition and xenorecognition), anthozoans have evolved to use compounds or toxins for chemical communication, defense, or predation, which may exhibit biological activities useful for human health, mainly antiviral, antibacterial, anti-inflammatory, anticancer, and antitumor properties of pharmaceutical interest. These compounds/toxins can be alkaloids, amino acids, proteins, ceramides, diterpenes, and sesquiterpenes and are mainly distributed into Hexacorallia and Octocorallia. Anthozoans are enriched in defensive enzymes, which can either be found in anthozoan species or their symbionts and help them survive in hostile conditions. Studies related to genomics and transcriptomics using advanced sequencing efforts revealed the presence of genetic elements in anthozoans that help them survive against abiotic and biotic stressors in the marine environment. This review presents developments and highlights the current state of knowledge about anthozoans’ chemical weaponry that can drive further bioprospection of anthozoan species producing compounds and toxins which may be useful in biotechnological applications. Omics research in Anthozoa is still nascent, and more efforts are required to fully understand the chemical ecology, diversity, and possible biotechnological applications of cnidarian genes and their products.
Sepsis remains a critical global health challenge characterized by life-threatening organ dysfunction arising from a dysregulated host response to infection. Immunothrombosis refers to the intersection of immune activation and coagulation pathways, particularly relevant in the context of sepsis. A growing body of evidence identifies immunothrombosis, a tightly interwoven process between innate immunity and coagulation. While immunothrombosis serves as a host defense mechanism under physiological conditions, its aberrant activation in sepsis precipitates microvascular thrombosis, organ ischemia, and progression toward disseminated intravascular coagulation (DIC). This review provides a comprehensive overview of the cellular contributors to immunothrombosis, including neutrophils, monocytes, platelets, and endothelial cells, and elucidates the signaling cascades, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and inflammasome activation, that govern their interplay. We further highlight emerging molecular mediators, including extracellular traps, tissue factor expression, and cytokine amplification loops, that collectively promote pathological thromboinflammation. A deeper understanding of these interconnected pathways offers critical insights into the pathogenesis of sepsis and unveils potential targets for timely intervention. Ultimately, this review aims to bridge immunological and hematological perspectives to inform the development of novel therapeutic strategies against sepsis-induced coagulopathy.
Acute kidney injury (AKI) resulting from ischemia/reperfusion (I/R) poses a significant clinical challenge due to its high mortality and complex pathophysiology. Here, the protective actions of Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced adenosine triphosphate depletion and recovery (ATP-D/R) injury in human kidney-2 (HK2) cells are examined. During ATP-D/R, expression levels of CHCHD2 were significantly reduced. The overexpression of CHCHD2 substantially reduced the levels of ROS, lipid peroxidation, apoptosis, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), whereas the knockdown of CHCHD2 exacerbated cellular injury. Mechanistic studies further demonstrated that overexpression of CHCHD2 restored Nrf2 expression under ATP-D/R conditions, facilitated its nuclear translocation, and upregulated the downstream antioxidant enzyme HO-1. In contrast, the knockdown of Nrf2 reduced the cytoprotective actions of CHCHD2. These findings indicate that CHCHD2 reduces cellular damage by enhancing antioxidant defenses and reducing apoptosis through activating the Nrf2 axis, underscoring its potential as a therapeutic target for AKI.
Pheochromocytoma, a rare catecholamine-secreting tumor, poses significant perioperative challenges due to its potential for severe hemodynamic instability. Careful management of patients with pheochromocytoma is critical for patient safety and favorable outcomes. The diagnostic workup focuses on biochemical analysis of plasma or urinary metanephrines, followed by imaging for tumor localization and genetic testing to identify hereditary syndromes. Preoperative management emphasizes adequate alpha-adrenergic blockade followed by beta-blockade to stabilize cardiovascular function. Anesthetic planning requires meticulous attention to volume status, cardiovascular optimization, and intraoperative monitoring to mitigate the risks of hypertensive crises and hypotension. Postoperative care must account for ongoing hemodynamic and metabolic fluctuations. A multidisciplinary, protocol-driven approach is essential to improve outcomes in patients undergoing pheochromocytoma resection. This paper provides a comprehensive overview of the genetic, biochemical, clinical, and anesthetic considerations involved in the diagnosis and perioperative management of pheochromocytoma.
Alzheimer’s disease (AD) is characterized by progressive cognitive decline strongly associated with impaired adult hippocampal neurogenesis (AHN). Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)—such as transcriptional alterations in quiescent states—and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-β and Tau pathology, supporting their potential as early biomarkers of disease progression. In this review, we synthesize recent advances in therapeutic strategies aimed at restoring AHN, encompassing pharmacological agents, natural products, and non-pharmacological interventions such as environmental enrichment and dietary modulation. Emerging approaches—including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions—highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)—a novel composite metric that quantifies hippocampal neurogenic capacity relative to amyloid burden, while adjusting for demographic and cognitive variables. By integrating neurogenic potential, cognitive performance, and pathological load, NII provides a framework for stratifying disease severity and guiding personalized therapeutic approaches. Despite ongoing challenges—such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies—this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments.
This study presents an integrated experimental and theoretical investigation of two pharmacologically significant neolignans—magnolol and honokiol—with the aim of characterizing their structural and spectroscopic properties in detail. Experimental Fourier-transform infrared (FT-IR), ultraviolet–visible (UV-Vis), and nuclear magnetic resonance (1H NMR) spectra were recorded and analyzed. To support and interpret these findings, a series of density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were conducted using several hybrid and long-range corrected functionals (B3LYP, CAM-B3LYP, M06X, PW6B95D3, and ωB97XD). Implicit solvation effects were modeled using the CPCM approach across a variety of solvents. The theoretical spectra were systematically compared to experimental data to determine the most reliable computational approaches. Additionally, natural bond orbital (NBO) analysis, molecular electrostatic potential (MEP) mapping, and frontier molecular orbital (FMO) visualization were performed to explore electronic properties and reactivity descriptors. The results provide valuable insight into the structure–spectrum relationships of magnolol and honokiol and establish a computational benchmark for further studies on neolignan analogues.
Wound healing is a complex biological process that benefits from advanced biomaterials capable of modulating inflammation and promoting tissue regeneration. In this study, cerium oxide nanoparticles (CeO2NPs) were green-synthesized using Hemerocallis citrina extract, which served as both a reducing and stabilizing agent. The CeO2NPs exhibited a spherical morphology, a face-centered cubic crystalline structure, and an average size of 9.39 nm, as confirmed by UV-Vis spectroscopy, FTIR, XRD, and TEM analyses. These nanoparticles demonstrated no cytotoxicity and promoted fibroblast migration, while significantly suppressing the production of inflammatory mediators (TNF-α, IL-6, iNOS, NO, and ROS) in LPS-stimulated RAW264.7 macrophages. Gene expression analysis indicated M2 macrophage polarization, with upregulation of Arg-1, IL-10, IL-4, and TGF-β. Aligned polycaprolactone/polylactic acid (PCL/PLA) nanofibers embedded with CeO2NPs were fabricated using electrospinning. The composite nanofibers exhibited desirable physicochemical properties, including porosity, mechanical strength, swelling behavior, and sustained cerium ions release. In a rat full-thickness wound model, the CeO2 nanofiber-treated group showed a 22% enhancement in wound closure compared to the control on day 11. Histological evaluation revealed reduced inflammation, enhanced granulation tissue, neovascularization, and increased collagen deposition. These results highlight the therapeutic potential of CeO2-incorporated nanofiber scaffolds for accelerated wound repair and inflammation modulation.
Heterozygous mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase (GCase), are major risk factors for Parkinson’s Disease (PD). Ambroxol, a small chaperone originally used as a mucolytic agent, has been shown to cross the blood–brain barrier, enhance glucocerebrosidase activity, and reduce α-synuclein levels, making it a promising therapeutic candidate for disease-modifying effects in GBA1-associated PD (GBA1-PD). This study aimed to develop a method to quantify ambroxol levels in human plasma and cerebrospinal fluid (CSF) using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Ambroxol was determined by online solid-phase extraction (SPE), coupled with LC-MS/MS, by gradient elution on a monolithic column. Detection employed a 3200 QTRAP tandem mass spectrometer in the positive electrospray ionization mode. Calibration curves exhibited linearity across the analyzed ranges in both plasma and CSF. The recovery rate ranged from 106.7% to 113.5% in plasma and from 99.0% to 103.0% in CSF. No significant matrix effect was observed. Intra-day and inter-day precisions were below 11.8% in both matrices, and accuracy ranged from 89.9% to 103.1% in plasma and from 96.3% to 107.8% in CSF. We evaluated and confirmed the stability of the analyte in plasma and CSF across various storage conditions. The method was successfully validated according to European Medicine Agency (EMA) guidelines and its applicability was confirmed in the context of a multicenter, randomized, double-blind, placebo-controlled, phase II study, designed to monitor the ambroxol levels in the plasma and CSF of GBA1-PD.
WRN helicases play a key role in DNA replication, repair, and other processes in a variety of tumors. It has become one of the hot targets of genotoxic drugs, but the effect and mechanism of targeting WRN against prostate cancer is still unclear. In our previous study, we found a quinazoline compound kzl052, which has a WRN-dependent inhibitory effect on prostate cancer cells, but its molecular mechanism needs to be further explored. In this study, kzl052 significantly inhibited the growth of PC3 (IC50 = 0.39 ± 0.01 μM) and LNCaP (IC50 = 0.11 ± 0.01 μM) cells in vitro and showed a good inhibition effect on PCa in vivo. It inhibits PC3 cell growth by binding to WRN proteins and affecting its non-enzymatic function. Then the mechanism of kzl052 against prostate cancer progression was revealed to be by regulating the stability of DNA replication forks and the RB pathway. This study will provide a theoretical basis and treatment strategy for targeting WRN helicase in the treatment of prostate cancer.
Several studies suggest a relationship between phthalates (PAEs) and allergic diseases in children. Therefore, we speculated that PAE exposure may be an important environmental factor causing allergic diseases. The present study employed meta-analysis and network toxicology to analyze the interactions and assess potential pathogenic pathways between prenatal and postnatal PAE exposure and childhood allergic diseases. This study found that prenatal PAEs exposure was positively associated with childhood wheezing and eczema (OR = 1.03, 1.05), and postnatal PAEs exposure was positively associated with childhood wheezing, eczema, and rhinitis (OR = 1.10, 1.05, 1.06). PAE exposure from dust may elicit distinct effects compared to direct exposure to PAEs. Furthermore, a large number of overlapping genes between disease targets and PAEs were identified. Enrichment analysis highlighted the association of PAE-targeted genes with biological pathways integral to allergic diseases. Molecular docking results indicated a strong link between the PAEs and the core proteins, such as SRC, AKT1, and HSP90AA1. These proteins are critically involved in the regulation of immune–inflammatory processes underlying allergic diseases. This discovery not only enhances our understanding of the relationship between environmental pollutants and child health but also provides a robust reference for experimental studies on the induction of childhood diseases by early-life exposure to environmental pollutants.
Recently, marketing authorizations were granted by the Federal Drug Administration (FDA) for pegcetacoplan and avacincaptad pegol, which inhibit C3 and C5 complement components, respectively. These two drugs were demonstrated to slow down the growth of atrophic areas in the retina. These authorizations represent a huge breakthrough for patients suffering from geographic atrophy (GA), the late stage of the dry form of Age-related Macular Degeneration (AMD). Until then, no treatment was available to treat this blinding disease. However, these two new compounds inhibiting the complement system are still not available for patients outside of the United States, and they are not devoid of drawbacks, including a poor effect on vision improvement, an increased risk of occurrence of the neovascular form of AMD and the burden of patients receiving recurrent intravitreal injections. Thus, the important medical need posed by GA remains incompletely answered, and new therapeutic options with alternative modes of action are still required. Oxidative stress and inflammation are two major potential targets to limit the progression of atrophic retinal lesions. Dimethyl fumarate, dimethyl itaconate and other activators of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) display antioxidants and immunomodulatory properties that have shown evidence of efficacy in in vitro and in vivo models of dry AMD. Tecfidera®, whose active principle is dimethyl fumarate, is already commercialized for the treatment of autoimmune diseases such as multiple sclerosis and psoriasis. The aim of this review is to present the rationale and the design of the clinical trial we initiated to test the effectiveness and safety of repurposing Tecfidera®, which could represent a new therapeutic alternative in patients with the dry form of AMD.
Peptidylarginine deiminase 4 (PAD4) catalyzes protein citrullination, a post-translational modification implicated in type 1 diabetes mellitus (T1DM). This study examined PAD4 expression and activity in the pancreas of streptozotocin (STZ)-induced diabetic Wistar rats. Animals were divided into three groups: (A) STZ-induced diabetic rats (60 mg/kg, i.p.), (B) non-diabetic controls, and (C) diabetic rats treated with Cl-amidine (5 mg/kg), a pan-PAD inhibitor, from week six post-induction. Analyses included PAD4 mRNA and protein expression, citrullinated histone H3 (CitH3), calcium concentration, and neutrophil elastase activity. Diabetic rats exhibited increased PAD4 expression, CitH3 levels, and NETosis markers, alongside reduced pancreatic calcium, suggesting calcium consumption during PAD4 activation. Cl-amidine treatment attenuated NETosis. These results implicate PAD4 in T1DM pathogenesis via NETosis and support the utility of STZ-induced diabetic rats as a model for PAD4-targeted studies. Cl-amidine may represent a promising therapeutic approach to reduce pancreatic inflammation in T1DM.
Throughout human history, wild plant resources have played an invaluable role, serving as critical sources of food, medicine, and industrial materials. This study examined the callus cultures of Cistanche deserticola Y.C. Ma, a medicinal desert plant, by subjecting them to abiotic stress under controlled in vitro conditions. The secondary metabolite profiles were then analyzed using GC-MS and qTOF-UHPLC-MS. The GC-MS analysis revealed several bioactive compounds of pharmaceutical interest, such as γ-sitosterol and homovanillyl alcohol. PhGs, including echinacoside and salidroside, were quantified for the first time across 16 callus samples exposed to various stress treatments. The application of 0.1% Na2CO3 for 50 days resulted in the highest accumulation of echinacoside (13,378.9 µg/mL), and heavy metal stress notably increased salidroside levels to 27.0 µg/mL. There was a clear correlation between callus pigmentation and metabolic activity: orange and white calli produced significantly more PhGs than dark calli. These results suggest that C. deserticola callus cultures could be a sustainable, controllable platform for producing high-value secondary metabolites. This reinforces the importance of wild plant resources in modern science and industry.
Cortisol, the main glucocorticoid in teleost, plays a central role in mediating the physiological response to stress by regulating metabolism, immune function, and growth. While its transcriptional effects are well known, its role in modulating chromatin accessibility in fish skeletal muscle remains poorly understood. In this study, we investigated the epigenomic and transcriptomic changes induced by cortisol in a juvenile rainbow trout’s (Oncorhynchus mykiss) skeletal muscle using ATAC-seq and RNA-seq. Fish were treated with a single intraperitoneal dose of cortisol (10 mg/kg) or vehicle, and muscle samples were collected 3 h post-treatment. ATAC-seq analysis revealed a total of 163,802 differentially accessible regions (DARs), with an important enrichment of open regions near transcription start sites and promoters. A total of 1612 and 1746 differentially accessible genes (DAGs) were identified in the cortisol and control groups, respectively. Motif enrichment analysis identified 89 transcription factors to be significantly enriched, among which key stress-responsive regulators such as Fos, AP-1, FoxO1/3, Mef2a/b/c, Klf5/10, and ATF4 were prominently represented. RNA-seq analysis identified 4050 differentially expressed genes (DEGs), with 2204 upregulated genes involved in autophagy, mitophagy, and FoxO signaling, while 1864 downregulated genes were enriched in spliceosome and chromatin remodeling pathways. Integrative analysis revealed 174 overlapping genes between ATAC-seq and RNA-seq datasets, highlighting pathways linked to autophagy and ATP-dependent chromatin remodeling. Four selected DEGs (sesn1, sesn2, cullin3, samtor) were validated by qPCR, showing high concordance with transcriptomic data. These findings provide new insights into cortisol-mediated regulation of chromatin dynamics and gene expression in teleost skeletal muscle and underscore the importance of epigenetic mechanisms in fish stress responses.
Hemophilia, an X-linked bleeding disorder, is characterized by a deficiency in coagulation factors. It manifests as spontaneous bleeding, leading to severe complications if not properly managed. In contrast, acquired hemophilia is an autoimmune condition marked by the development of inhibitory antibodies against coagulation factors. Both forms present significant diagnostic and therapeutic challenges, highlighting the need for advanced genetic, molecular, laboratory, and clinical assessments. Recent advances in artificial intelligence have opened new avenues for the management of hemophilia. Machine learning and deep learning technologies enhance the ability to predict bleeding risks, optimize treatment regimens, and monitor disease progression with greater precision. Artificial intelligence-driven applications in medical imaging have also improved the detection of joint damage and hemarthrosis, ensuring timely interventions and better clinical outcomes. Moreover, the integration of artificial intelligence into clinical practice holds the potential to transform hemophilia care through predictive analytics and personalized medicine, promising not only faster and more accurate diagnoses but also a reduction in long-term complications. However, ethical considerations and the need for data standardization remain critical for its widespread adoption. The application of artificial intelligence in hemophilia represents a paradigm shift towards precision medicine, with the promise of significantly improving patient outcomes and quality of life.
Skin cancer, particularly melanoma, remains a major public health concern due to its high mortality rate. Current treatment options, including chemotherapy with dacarbazine and doxorubicin, have shown limited efficacy, achieving only a 20% objective response rate over six months, along with severe side effects such as cardiotoxicity. Given these limitations, there is a growing interest in herbal medicine as a source of novel anticancer compounds. Bambusa stenostachya, a bamboo species native to Taiwan, was investigated for its potential anti-melanoma properties using network pharmacology and molecular docking. LC-MS analysis identified seven bioactive compounds, including quinic acid and isovitexin, which satisfied Lipinski’s drug-likeness criteria. Among the seven bioactive compounds identified, five belong to the flavonoid family, while two are classified as phenolic compounds that modulate signaling pathways related to cancer and exhibit antioxidant activity, respectively. Through pathway enrichment analysis, four key melanoma-associated genes (PIM1, MEK1, CDK2, and PDK1) were identified as potential therapeutic targets. Ensemble docking results demonstrated that naringin-7-rhamnoglucoside exhibited the highest binding affinity (−6.30 kcal/mol) with phosphoinositide-dependent kinase-1, surpassing the affinities of standard chemotherapeutic agents. Additionally, the average docking scores for naringin-7-rhamnoglucoside and the remaining three proteins were as follows: PIM1 (−5.92), MEK1 (−6.07), and CDK2 (−5.26). These findings suggest that the bioactive compounds in B. stenostachya may play a crucial role in inhibiting melanoma progression by modulating metabolic and signaling pathways. Further in vitro and in vivo studies are necessary to validate these computational findings and explore the potential of B. stenostachya as a complementary therapeutic agent for melanoma.
Understanding the binding interactions between protein-bound uremic toxins (PBUTs) and human serum albumin (HSA) is critical for advancing treatments for chronic kidney disease (CKD). While previous studies have suggested that putrescine, a diamine PBUT, exhibits moderate binding affinity to HSA, this study provides evidence of the contrary. Using isothermal titration calorimetry and saturation transfer difference nuclear magnetic resonance , we demonstrate that putrescine’s interaction with HSA is weak, non-specific, and thermodynamically negligible in the range of conditions studied. Unlike earlier studies relying on spectroscopy techniques such as UV–visible absorption and fluorescence, which may overestimate binding strength, the results presented here highlight the limitations of indirect methodologies and underscore the importance of more sensitive approaches for accurate energy characterization. Our findings suggest that putrescine only weakly interacts non-specifically with HSA and may bind more preferentially to other plasma proteins, contributing to its accumulation in CKD patients.
Biotechnology has increasingly focused on cyanobacteria as these microorganisms are a rich source of secondary metabolites with significant potential for various industries. Cyanobacterial metabolites have been described to have a wide range of biological activities, including cytotoxicity in cancer cells, inhibition of pathogenic bacteria and fungi, and inhibition of various enzymes, demonstrating a great diversity of bioactive compounds. The cyanobacterium Microcystis aeruginosa is well known for its toxicity and production of the cyanotoxin microcystin. However, another peptide produced by this cyanobacterium, microginins, has significant biotechnological potential. These linear pentapeptides were initially discovered for their angiotensin-converting enzyme (ACE) inhibitory activity. Subsequent studies have explored the full potential of this peptide, revealing its ability to inhibit other enzymes as well. This review aims to compile and systematize the microginins with biotechnological potential described in the literature, as well as outline their main structural characteristics and the predominant methodologies for their isolation and identification.
Advancing age in men significantly contributes to declining sperm fertility. Information on age-related proteomic changes in spermatozoa is limited. This study involved normal fertile Arab men in three age groups: young adult (21–30 years; n = 6), late adult (31–40 years; n = 7), and advanced age (40–51 years; n = 5). Gradient-purified spermatozoa were analyzed using LC-MS/MS and proteomic data were processed using Progenesis QI (QIfp) v3.0 and UniProt/SwissProt. Significantly enriched annotations and clustering of proteins in the proteomic datasets were identified (2-fold change; p < 0.05). A total of 588 proteins were identified, with 93% shared across the three groups. Unique proteins were MYLK4 for the young adult group, PRSS57 for the late adult group, and HMGB4, KRT4, LPGAT1, OXCT2, and MGRN1 for the advanced age group. Furthermore, 261 (44%) proteins were differentially expressed (p < 0.05) across the three groups. Functional enrichment analysis suggested an aging-related significant increase in pathways associated with neurodegenerative diseases and protein folding, alongside decreases in glycolysis/gluconeogenesis, flagellated sperm motility, acetylation, phosphoprotein modifications, oxidation processes, and Ubl conjugation. Cluster analysis highlighted significantly upregulated proteins in young adults (e.g., H2BC1, LAP3, SQLE, LTF, PDIA4, DYNLT2) and late adults (e.g., ATP5F1B, ODF2, TUBA3C, ENO1, SPO11, TEX45, TEKT3), whereas most proteins in the advanced age group exhibited downregulation (e.g., SPESP1, RAB10, SEPTIN4, RAB15, PTPN7, USP5, ANXA1, PRDX1). In conclusion, this study revealed aging-associated proteomic changes in spermatozoa that impact critical processes, including spermatogenesis, motility, metabolism, and fertilization, potentially contributing to fertility decline. These changes provide a molecular framework for developing therapies to preserve sperm proteostasis and enhance fertility in older men.
Extracellular vesicles (EVs) are lipid membrane-enclosed particles released by all cells and can be isolated from various sources, even from solid tissues. This study focuses on isolating and characterizing EVs from mouse lymph nodes (LNs). Male C57BL/6 mice were injected with complete Freund’s adjuvant, with or without ovalbumin. Inguinal and popliteal LNs were incised 9 days after immunization, and EV isolation was carried out using a combination of differential centrifugation and size-exclusion chromatography. The characteristic morphology of small and large EVs was confirmed by transmission electron microscopy. Particle size distribution and concentration were determined by nanoparticle tracking analysis, while protein and lipid contents were measured by bicinchoninic acid assay, and sulfo-phospho-vanillin assays, respectively, to calculate the protein-to-lipid ratio. Immune and EV markers were analyzed by using flow cytometry and Western blot assay, revealing significant changes between immunized mice compared to controls. This study establishes a novel protocol for isolating and characterizing EVs from LNs and highlights the impact of immunization on EV properties, offering insights into their roles in immune processes.
Among the fundamental pathological processes, tumorigenesis is arguably the most complex [...]
The study aimed to identify the variants of SARS-CoV-2 (Severe Acute Respiratory Syndrome related coronavirus-2) virus isolates within the window of March 2021 to February 2022 in Bangladesh and investigate their comparative mutational profiles, preferences and phylogenetics. After the collection of the sample specimen and RNA extraction, the genome was sequenced using Illumina COVID Seq, and NGS data analysis was performed in DRAGEN COVID Lineage software (version 3.5.9). Among the 96 virus isolates, 24 (25%) were from Delta (clade 21A (n = 21) and 21J (n = 3)) and 72 (75%) were from Omicron (clade 20A (n = 6) and 20B (n = 66)). In Omicron and Delta, substitutions were much higher than deletions and insertions. High-frequency nucleotide change patterns were similar (for C > T, and A > G) in both of the variants, but different in some (i.e., G > T, G > A). Preferences for specific amino acids over the other amino acids in substitutions and deletions were observed to vary in different proteins of these variants. Phylogenetic analysis showed that the most ancestral variants were from clade 21A and clade 20A, and then the other variants emerged. The study demonstrates noteworthy variations of Omicron and Delta in mutational pattern and preferences for amino acids and protein, and further study on their biological functional impact might unveil the reason behind their mutational strategies and behavioral changes.
Plastics pollution is a critical global environmental issue, with growing concern over the increasing presence of nanoplastic particles. Plastics are major environmental pollutants that adversely affect human health, particularly when plastics from food sources enter the body and pose potential risks to reproductive health. Echinacea purpurea is an immunologically active medicinal plant containing phenolic acids and alkylamides. Nanoparticles present a promising approach to enhance the effectiveness, stability, and bioavailability of Echinacea purpurea ethanol extract (EE) active components. This study aimed to determine the protective effects of chitosan-silica-Echinacea purpurea nanoparticles (CSE) against reproductive injury induced by polystyrene nanoplastics (PS-NPs) in male rats. The results showed that CSE dose-dependently reduced oxidative damage and protected intestinal and reproductive health. Furthermore, CSE improved gut microbiota dysbiosis, preserved barrier integrity, and attenuated PS-NPs-induced inflammation in the colon, brain, and gonads. Inflammatory factors released from the gut can enter the bloodstream, cross the blood–brain barrier, and potentially modulate the hypothalamic–pituitary–gonadal (HPG) axis. CSE has also been shown to elevate neurotransmitter levels in the colon and brain, thereby repairing HPG axis dysregulation caused by PS-NPs through gut–brain communication and improving reproductive dysfunction. This study enhances our understanding of CSE in modulating the gut–brain and HPG axes under PS-NPs-induced damage. CSE demonstrates the capacity to provide protection and facilitate recovery by mitigating oxidative stress and inflammation, restoring gut microbiota balance, and preserving hormone levels in the context of PS-NPs-induced injury.
Glycogen synthase kinase-3 (GSK-3)—particularly the GSK-3β isoform—plays a pivotal role in regulating dendritic cell (DC) functions, including maturation, cytokine production, and antigen presentation. In immature DCs, GSK-3β is continuously active, and its inhibition has been shown to enhance DC maturation and function. As a key upstream kinase of β-catenin, GSK-3 inhibition activates β-catenin in both human and murine DCs—a pathway traditionally linked to its immunomodulatory effects. However, our recent findings challenge this paradigm by uncovering β-catenin-independent, dual roles of GSK-3β in DCs. Our study reveals that while GSK-3β enhances DC-mediated cross-priming of CD8 T cells, it concurrently impairs the generation of memory CD8 T cells. These findings have significant implications for vaccine development and cancer immunotherapy, where both effective T-cell priming and durable memory responses are critical. This mini-review provides an in-depth analysis of mechanistic insights into GSK-3β’s paradoxical functions and discusses potential strategies to fine-tune GSK-3 activity for optimized immunotherapeutic outcomes.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex multisystem conditions that pose significant challenges in healthcare. Accumulated research evidence suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating potential shared metabolic dysfunctions. This study aims to systematically explore shared metabolic disturbances in the muscle tissue of patients. Utilizing genome-wide metabolic modeling, we identified key metabolic irregularities in the muscle of patients with ME/CFS, notably the downregulation of the alanine and aspartate metabolism pathway and the arginine and proline metabolism pathway. Further, in silico knockout analyses suggested that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. In addition, assessments of metabolomic levels in Long COVID patients also showed the significant downregulation of ASP during post-exertional malaise (PEM) in both muscle and blood. Consequently, we propose that a combination of l-ornithine and l-aspartate (LOLA) is a potential candidate to alleviate metabolic symptoms in ME/CFS and Long COVID for future clinical trials.
Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are related diseases with poorly understood pathophysiology. While therapy options for IBD have increased, treatment options for PSC remain limited. Galectin-3 is a multifunctional lectin expressed in intestinal epithelial cells, and is abundant in immune cells such as macrophages, with roles in cell adhesion, apoptosis, inflammation and fibrosis being associated with IBD and PSC disease development and progression. In addition, galectin-3 is also a visceral fat-derived protein whose systemic levels are increased in obese individuals, the latter correlating with a poorer prognosis in IBD and PSC patients. On the other hand, decreased galectin-3 expression in the inflamed mucosal tissues of mice and patients with IBD possibly indicate a protective role of this lectin in IBD. However, galectin-3 loss or inhibition is protective in most animal models of liver fibrosis but exacerbates the severity of autoimmune liver disease. Hence, with PSC being a slowly progressing autoimmune hepatobiliary disease closely related to IBD, further studies evaluating galectin-3 as a therapeutic target or biomarker for the severity of IBD and the occurrence of PSC are still needed. This review summarizes studies that have analyzed expression patterns and functions of galectin-3 in IBD and PSC. Current evidence suggests that strategies to block galectin-3 are not advised for patients with IBD and PSC-IBD.
Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations.
Antimicrobial food packaging is considered a promising technology to improve food safety by inhibiting or reducing the growth of food microorganisms and minimizing the need for preservatives. This study aimed to develop and evaluate carboxymethyl cellulose (CMC) films integrated with bacteriocins for antibacterial efficacy. Plantaricin W was assessed as a potential bacteriocin for activation of CMC to control the dangerous food-borne pathogen, Listeria monocytogenes. Minced beef samples were inoculated with L. monocytogenes ATCC BAA-679 and treated with plantaricin W-activated food packaging. The results showed a significant reduction of the target pathogen by approximately 1 log cycle compared to the control group. Enterocin F4-9 is a novel bacteriocin that acts on Gram-negative microbes that were not affected by plantaricin W. Therefore, a novel food packaging activated with plantaricin W and enterocin F4-9 was developed to broaden their antimicrobial activity. The effect of this film on meat-associated microbes was investigated. The results demonstrated that the film significantly reduced the counts of mesophilic and psychotropic bacteria by 86.67% and 96.67%, respectively. Additionally, the pH values of the treated meat samples were significantly lower than those of the untreated controls. The obtained findings indicated that bacteriocin-activated CMC films could potentially be utilized as antimicrobial packaging in modern food technology.
The intrauterine environment is increasingly recognised as a critical period for the emergence of mental health vulnerabilities. This review explores how adverse maternal exposures, such as psychological stress, infection, malnutrition, and environmental toxins, can disrupt foetal neurodevelopment via epigenetic mechanisms, contributing to the risk of psychiatric and neurodevelopmental disorders. Focusing primarily on human studies, we synthesise evidence on DNA methylation, histone modifications, and non-coding RNAs as key pathways through which the intrauterine environment influences gene regulation in the developing brain. We examine how timing of exposure, foetal sex, and gene–environment interactions modulate these effects, with particular attention to disorders such as schizophrenia, autism spectrum disorder, depression, and anxiety. The placenta emerges as a central mediator, both reflecting and shaping epigenetic changes in response to maternal signals. We also discuss the reversibility of epigenetic marks and highlight emerging interventions, including nutritional supplementation and maternal mental health support, that may buffer or reverse prenatal epigenetic programming. Methodological challenges are addressed, including tissue specificity and causal inference, and future directions are proposed toward integrating epigenetic biomarkers into early risk assessment and precision mental health and psychiatry. This review emphasises the importance of the prenatal period as a window of vulnerability and opportunity for shaping lifelong mental health.
ABCG2 is a crucial ATP-binding cassette (ABC) transporter involved in multidrug resistance and essential physiological and pharmacological processes. In recent years, multiple ABCG2 structures have been resolved using cryo-electron microscopy (cryo-EM), providing significant insights into its conformational states during its transport cycle. However, even more than 25 years after its description, a high-resolution X-ray crystallographic structure is still unavailable, limiting the understanding of its dynamic transitions, as well as leaving aspects of the transport cycle unresolved and open to discussion. Given the complexity of ABCG2, a multidisciplinary approach is essential in order to fully elucidate its mechanism. This review compiles recent advances in ABCG2 structural biology, highlights unresolved controversies, and explores future directions to bridge the gap between structure and function. Moving forward, integrating multiple structural and functional approaches will be key to uncovering the intricate workings of this enigmatic transporter. In particular, detailed structural insights will be crucial to identifying new ABCG2 substrates and designing selective inhibitors, with important implications for therapeutic development.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of rare diseases characterized by autoimmune-associated inflammation and vessel damage. Based on the clinical manifestations and involvement of immune components, three disease syndromes are distinguished: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In this review, we present the current data on the epidemiology, the clinical manifestations of each syndrome, and the most up-to-date classification criteria. The role of the underlying genetic and epigenetic abnormalities, as well as their interplay, is described. The immunological diversification of AAV is also described, with a focus on the immune cell dysfunctions detected in patients. In conclusion, we emphasize the urgent need to unravel the sophisticated mechanisms of this disease, which would enable the development of new, effective therapeutic strategies.
Cannabinoid receptor 1 (CB1) signalling is critical for weight gain and for milk intake in newborn pups. This is important as in humans, low birth weight increases the risk for attention-deficit hyperactivity disorder (ADHD). Moreover, some children with ADHD also have Tourette syndrome (TS). However, it remains unclear if insufficient CB1 receptor signalling may promote ADHD/TS-like behaviours. Here, ADHD/TS-like behaviours were studied from postnatal to adulthood by exposing postnatal wild-type CB1 and Cannabinoid receptor 2 (CB2) knockout mouse pups to SR141716A (rimonabant), a CB1 receptor antagonist/inverse agonist. Postnatal disruption of the cannabinoid system by SR141716A induced vocal-like tics and learning deficits in male mice, accompanied by excessive vocalisation, hyperactivity, motor-like tics and/or high-risk behaviour in adults. In CB1 knockouts, rearing and risky behaviours increased in females. In CB2 knockouts, vocal-like tics did not develop, and males were hyperactive with learning deficits. Importantly, females were hyperactive but showed no vocal-like tics. The appearance of vocal-like tics depends on disrupted CB1 receptor signalling and on functional CB2 receptors after birth. Inhibition of CB1 receptor signalling together with CB2 receptor stimulation underlie ADHD/TS-like behaviours in males. This study suggests that the ADHD/TS phenotype may be a single clinical entity resulting from incorrect cannabinoid signalling after birth.
Emerging evidence suggests that the timing of eating and exercise over the course of the day is paramount to metabolism and physical function. This review highlights seminal studies showing that adipocyte AMPKα2 signaling controls circadian adipose tissue–skeletal muscle communication. Day-restricted feeding has been shown to improve exercise performance via adipocyte-specific activation of AMPKα2, which controls fat–muscle crosstalk in a time-of-day dependent manner. This review also discusses corroborating experimental studies designating mesenchymal stem cells as key cellular mediators, showing that exercise in the afternoon leads to better metabolic effects in humans, and illustrating how incorrect timing of food intake leads to leptin resistance and metabolic dysregulation. Multi-omics strategies have shed light on the molecular mechanisms underlying such effects of time, showing the circadian control of metabolic processes across tissues. These results advance our knowledge of chronometabolism and offer exciting temporal intervention treatments for metabolic diseases, such as time-restricted feeding, timed exercise, and chronopharmacological targeting of AMPK. Fat–muscle crosstalk, physical performance, and metabolic health outcomes can possibly be optimized by synchronizing dietary and exercise timing with endogenous circadian rhythms.
Helicobacter pylori (H. pylori) infection is a leading cause of gastritis, peptic ulcers, and gastric cancer, affecting more than half of the global population. Its persistence in the acidic gastric environment and its ability to evade host immunity present major treatment challenges. Although antibiotics remain the standard therapy, rising antimicrobial resistance has reduced treatment efficacy, prompting the search for alternative and adjunct approaches. Emerging therapies include probiotics, antimicrobial peptides (AMPs), and plant-derived compounds, which target H. pylori through membrane disruption, immunomodulation, or direct antimicrobial activity. Novel drug delivery systems and microbiota-sparing interventions are also being investigated. Additionally, vaccine development offers a promising strategy for long-term protection, though challenges related to antigenic variability and host-specific responses remain. Despite these advances, treatment variability and the limited clinical validation of alternatives hinder progress. A multifaceted approach integrating microbiome research, host–pathogen interactions, and new therapeutic agents is essential for future success.
Secreted bacteriolytic proteases L1 and L5 of the Gram-negative bacterium Lysobacter capsici XL hydrolyze peptide bridges in bacterial peptidoglycans. Such specificity of action determines the prospects of these enzymes for medicine with the view of creating new antimicrobial drugs to combat antibiotic-resistant strains of pathogens. This research concerns the development of successful expression systems for producing active enzymes L1 and L5 in sufficient amounts for comprehensive studies. Based on L. capsici XL strains with deletions in the alpA (enzyme L1) and alpB (enzyme L5) genes and the constructed expression vectors pBBR1-MCS5 PT5–alpA and pBBR1-MCS5 PT5–alpB, we obtained expression strains L. capsici PT5–alpA and L. capsici PT5–alpB, respectively. The yields of enzymes L1 and L5 in the developed strains increased by 4 and 137 times, respectively, as compared to the wild-type strain. The cultivation of the expression strains was successfully scaled up under non-selective conditions in a 10-L bioreactor. After fermentation, the yields of enzymes L1 and L5 were 35.48 mg/L and 57.11 mg/L, respectively. The developed homologous expression systems of bacteriolytic proteases L1 and L5 have biotechnological value as compared to those obtained by us earlier based on heterologous expression systems, which have lower yields and labor-intensive purification schemes.
The FIC domain-containing protein Sofic has recently been shown to provide robust protection to bacteria against phage infection. Sofic acts as a toxic protein, inducing abortive infection through the AMPylation of target proteins during phage invasion. However, the molecular mechanisms regulating Sofic’s toxic activity remain elusive. In this study, we identified a small gene encoding a short protein located downstream of Sofic in the genome, named AS1 (anti-Sofic1), which functions as an antitoxic protein to counteract Sofic’s toxicity. The crystal structure of Sofic revealed that the protein functions as a dimer in solution, with dimerization being indispensable for its toxic activity. Importantly, structural analysis indicated that ATP binding induces a conformational change in the C-terminal domain (CTD) of Sofic, underscoring the critical role of the CTD in mediating its toxic effects. In vitro colony-forming assays confirmed that the interaction between the CTD and the Amylase domain is crucial for Sofic’s toxic activity. Overall, our results provide molecular insights into the regulatory mechanisms of Sofic in antiviral immunity.
Bacterial cellulose (BC), an extracellular polysaccharide synthesized by various bacterial strains. It exhibits high tensile strength, water retention, crystallinity, and biocompatibility, making it valuable in biomedical, cosmetic, food, textile, and paper industries. This study examined the effects of six carbon sources on BC production by Komagataeibacter sucrofermentans, identifying fructose as the most effective. A Box–Behnken experimental design was employed to investigate the effects of three variables (fructose concentration, temperature, and cultivation time) on cellulose yield. The optimized cultivation conditions were: fructose concentration of 227.5 g/L, temperature of 28.0 °C, and cultivation time of 295 h, resulting in a BC yield of 63.07 ± 2.91 g/L. Subsequently, BC’s potential as a bacteriophage carrier was assessed. Escherichia coli phage T4 and Staphylococcus aureus phage vB_SauS_CS1 (CS1) were immobilized within BC hydrogels, and their antibacterial activities were assessed through in vitro experiments. These findings suggest BC’s promise as a phage delivery platform for biomedical applications.
Breast cancer remains a leading cause of mortality among women worldwide. Surgery, radiation therapy, chemotherapy, and hormone-based treatments are standard therapeutic approaches, but drug resistance and adverse effects necessitate the search for novel anticancer agents. Quinazolinedione derivatives have emerged as potential anticancer compounds due to their cytotoxic and apoptosis-inducing properties. This study aimed to evaluate the apoptotic induction of previously reported quinazolinedione derivatives on MCF-7 breast cancer cells. The cytotoxic effect was assessed using the MTT assay, apoptosis was quantified by Annexin V-PE/7AAD staining and flow cytometry, and apoptosis-related protein expression was analyzed via multiplexed bead-based immunoassays. These findings indicate that two derivatives in the series significantly reduced the cell viability in a dose-dependent manner. Apoptosis was induced primarily through the intrinsic apoptotic pathway as evidenced by the upregulation of caspase-9 and p53 and the downregulation of Bcl-2 and p-Akt. These results highlight quinazolinedione derivatives as promising candidates for breast cancer therapy prompting further investigation into their molecular mechanisms and potential clinical applications.
The prevalence, pathogenesis, and long-term consequences of hypertension differ significantly across the sexes, and pregnancy is a special physiological stress test that can reveal a woman’s underlying cardiovascular sensitivity. In addition to being direct risks to the health of the mother and fetus, hypertensive disorders of pregnancy (HDPs), especially preeclampsia, are also reliable indicators of future hypertension and cardiovascular disease in those who are afflicted. Fetal sex has a substantial impact on maternal vascular adaptation, according to new data from placental transcriptomics and epigenetics. This may be due to variations in the expression of angiogenic, immunomodulatory, and vasoactive genes. Sex-specific patterns of placental function, inflammation, and endothelium control are specifically influenced by X-linked gene dosage, escape from X-inactivation, and sex chromosomal composition. These biological variations highlight the placenta’s potential function as a mediator and indicator of maternal cardiovascular risk, and they may help to explain why the incidence and severity of hypertensive pregnancy challenges vary depending on the fetal sex. The purpose of this review is to summarize the state of the art regarding how placental genetics and fetal sex influence maternal hypertensive risk both during and after pregnancy. Additionally, it will investigate how these findings may influence sex-specific cardiovascular screening, prediction, and prevention methods.
The biological complexity of sarcopenia presents a major challenge for therapeutic intervention due to the wide range of degenerative changes it induces in skeletal muscle. This study demonstrates the potential of liposomal controlled release systems to address these challenges by combining two bioactive agents with complementary actions: caffeine (CAF), encapsulated in DMPC-based liposomes, and hyaluronic acid methacrylate (HAMA), encapsulated in DOPC-based liposomes. A hybrid system was also developed to deliver both substances simultaneously, aiming to restore tissue function through combined metabolic, anti-inflammatory, and regenerative effects. The liposomes exhibited nanoscale dimensions, spherical morphology, and intact membrane structure, as confirmed by electron microscopy. DLS analysis indicated good colloidal stability and monodisperse size distribution across all formulations, with improved stability observed in the hybrid system. Drug release studies showed a time-dependent profile, with HAMA releasing rapidly and CAF releasing gradually, supporting a dual-action therapeutic approach tailored to the multifactorial pathology of sarcopenia. The biological assays, performed in an established in vitro sarcopenia model, revealed the potential of liposomes co-delivering caffeine and HAMA to mitigate oxidative stress, preserve mitochondrial function, and reduce apoptosis in H2O2-damaged myotubes.
MiaA is responsible for the addition of the isopentyl modification to adenine 37 in the anticodon stem loop of specific tRNAs in Escherichia coli. Mutants in miaA have pleotropic effects on the cell in E. coli and play a role in virulence gene regulation. In addition, MiaA is necessary for stress response gene expression by promoting efficient decoding of UUX-leucine codons, and genes with elevated UUX-leucine codons may be a regulatory target for i6A-modified tRNAs. Understanding the temporal nature of the i6A modification status of tRNAs would help us determine the regulatory potential of MiaA and its potential interplay with leucine codon frequency. In this work, we set out to uncover additional information about the synthesis of the MiaA. MiaA synthesis is primarily driven at the transcriptional level from multiple promoters in a complex operon. However, very little is known about the post-transcriptional regulation of MiaA, including the role of sRNAs in its synthesis. To determine the role of small RNAs (sRNAs) in the regulation of miaA, we constructed a chromosomal miaA-lacZ translational fusion driven by the arabinose-responsive PBAD promoter and used it to screen against an Escherichia coli sRNA library (containing sRNAs driven by the IPTG-inducible PLac promoter). Our genetic screen and quantitative β-galactosidase assays identified CsrB and its cognate protein CsrA as potential regulators of miaA expression in E. coli. Consistent with our hypothesis that CsrA regulates miaA post-transcriptional gene expression through binding to the miaA mRNA 5′ UTR, and CsrB binds and regulates miaA post-transcriptional gene expression through sequestration of CsrA levels, a deletion of csrA significantly reduced expression of the reporter fusion as well as reducing miaA mRNA levels. These results suggest that under conditions where CsrA is inhibited, miaA mRNA translation and thus MiaA-dependent tRNA modification may be limited.
Maturity-onset diabetes of the young (MODY)—a monogenic form of diabetes—accounts for approximately 1–2% of all diabetes cases, with GCK-MODY being the second most commonly diagnosed type. Although the inherited nature of the disease implies that the interplay between maternal glycemia and fetal genotype directly influences neonatal outcomes, clinical guidelines for MODY-complicated pregnancies remain underdeveloped. A systematic literature search in the PubMed, Scopus, Web of Science, and Cochrane databases was conducted following the PRISMA guidelines. The study protocol has been logged in the PROSPERO registry with the identification number CRD42024609390. Data, such as MODY type, the gestational age at delivery, mode of delivery, insulin administration, mutational status of the fetus, fetal birthweight (FBW), occurrence of small-/large-for-gestational age fetus, shoulder dystocia, and neonatal hypoglycemia, were extracted and evaluated. Among 19 studies selected for the final analysis, 15 investigated perinatal outcomes in the GCK-MODY variant. Women diagnosed with GCK-MODY treated with insulin delivered approximately 1–2 weeks earlier than those managed with diet alone. FBW was significantly higher in GCK-negative as compared to GCK-positive offspring. Accordingly, fetal macrosomia was notably more common among unaffected neonates. In GCK-affected fetuses, insulin therapy was associated with a significantly lower FBW. Fetal genotype critically modifies perinatal outcomes in GCK-MODY pregnancies. In the absence of fetal genotyping, conservative management should be prioritized to mitigate the risks of fetal growth restriction and iatrogenic prematurity. As data regarding other types of MODY in pregnancy remain sparse, there is an urgent need for more research in this area.
Interest in metformin as a potential anticancer agent for colorectal cancer (CRC) has increased. However, compelling epidemiological links and strong preclinical evidence suggest that metformin has variable efficacy in patients with CRC. This variability highlights the need to identify the patients who are most likely to benefit from effective stratification. We aimed to review the evidence concerning the diverse roles of metformin in CRC prevention and treatment, focusing on identifying and validating the predictive biomarkers essential for selecting patient subgroups that are likely to respond positively. We explored the various molecular pathways through which metformin acts and investigated how these diverse mechanisms might explain the observed differences in patient responses. Epidemiological studies and large meta-analyses have consistently reported reduced CRC incidence and improved survival among patients with diabetes treated with metformin. However, successfully extending these benefits broadly across all patients with CRC or achieving predictable outcomes in advanced disease settings remains a significant challenge. This review consolidates the current knowledge, highlights how different mechanisms interact, critically assesses clinical evidence in light of patient heterogeneity, and advocates for the development and implementation of biomarker-guided personalized therapeutic strategies as key to optimally utilizing the potential of metformin in CRC management. The current challenges and vital future research priorities in this critical area are also outlined.
Exposure to extremely low-frequency magnetic fields (ELF-MF) can induce biological alterations in human cells, including peripheral blood mononuclear cells (PBMCs). However, the molecular mechanisms and key regulatory factors underlying this cellular response remain largely unknown. In this study, we analyzed the proteomic profiles of PBMCs isolated from three human subjects. PBMCs were exposed to 50 Hz, 1 mT of ELF-MF for 24 h and compared to unexposed PBMCs from the same individuals. ELF-MF exposure altered the expression levels of several PBMC proteins without affecting cell proliferation, cell viability, or cell cycle progression. A total of 51 proteins were upregulated, 36 of which were intercorrelated and associated with the Cellular Metabolic Process (GO:0044237) and Metabolic Process (GO:0008152). Among them, solute carrier family 25 member 4 (SLC25A4), which catalyzes the exchange of cytoplasmic ADP for mitochondrial ATP across the inner mitochondrial membrane, was consistently upregulated in all ELF-MF–exposed samples. Additionally, 67 proteins were downregulated, many of which are linked to T cell costimulation (GO:0031295), Cell activation (GO:0001775), and Immune system processes (GO:0002376) included ASPSCR1, PCYT1A, PCYT2, QRAS, and REPS1. In conclusion, ELF-MF exposure induces metabolic reprogramming in human PBMCs, characterized by the upregulation of mitochondrial proteins and downregulation of immune-activation-related proteins, without compromising cell viability or proliferation.
This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications.
Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K+ (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC’s effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS.
Gene therapy for hemophilia B offers the advantage of a single administration with sustained therapeutic effects. This study evaluated the systemic safety, efficacy, biodistribution, and immunogenicity of AAV8-FIX-TripleL, a recombinant adeno-associated virus type 8 (AAV8) vector encoding a modified factor IX (FIX) variant with increased activity. In this good laboratory practice (GLP)-compliant study, 180 male FIX-knockout hemophilia B mice were randomized into 12 groups (n = 15) and received intravenous AAV8-FIX-TripleL at therapeutic (5 × 1011 VG/kg) or supraphysiological (5 × 1012 VG/kg) doses on Day 1. The mice were sacrificed on Days 2, 15, 28, and 91 for comprehensive evaluations, including hematological and biochemical assessments, histopathological examination, FIX protein/activity analysis, immunogenicity assessment, and vector biodistribution via quantitative polymerase chain reaction (qPCR) in major organs. AAV8-FIX-TripleL demonstrated dose-dependent increases in FIX activity and protein levels, with FIX activity exceeding physiological levels and the maintenance of a favorable safety profile. Biodistribution analysis confirmed predominant hepatic accumulation and vector persistence up to 91 days post-injection, with minimal off-target distribution. These findings indicate that AAV8-FIX-TripleL is a promising gene therapy candidate for hemophilia B, as it has robust expression, sustained efficacy, and a favorable safety profile, and that further translational studies are warranted.
This study aimed to design dual-responsive chitosan–polylactic acid nanosystems (PLA@CS NPs) for controlled and targeted ledipasvir (LED) delivery to HepG2 liver cancer cells, thereby reducing the systemic toxicity and improving the therapeutic selectivity. Two formulations were developed utilizing ionotropic gelation and w/o/w emulsion techniques: LED@CS NPs with a size of 143 nm, a zeta potential of +43.5 mV, and a loading capacity of 44.1%, and LED-PLA@CS NPs measuring 394 nm, with a zeta potential of +33.3 mV and a loading capacity of 89.3%, with the latter demonstrating significant drug payload capacity. Since most drugs work through interaction with DNA, the in vitro affinity of DNA to LED and its encapsulated forms was assessed using stopped-flow and other approaches. They bind through multi-modal electrostatic and intercalative modes via two reversible processes: a fast complexation followed by a slow isomerization. The overall binding activation parameters for LED (cordination affinity, Ka = 128.4 M−1, Kd = 7.8 × 10−3 M, ΔG = −12.02 kJ mol−1), LED@CS NPs (Ka = 2131 M−1, Kd = 0.47 × 10−3 M, ΔG = −18.98 kJ mol−1) and LED-PLA@CS NPs (Ka = 22026 M−1, Kd = 0.045 × 10−3 M, ΔG = −24.79 kJ mol−1) were obtained with a reactivity ratio of 1/16/170 (LED/LED@CS NPs/LED-PLA@CS NPs). This indicates that encapsulation enhanced the interaction between the DNA and the LED-loaded nanoparticle systems, without changing the mechanism, and formed thermodynamically stable complexes. The drug release kinetics were assessed under tumor-mimetic conditions (pH 5.5, 10 mM GSH) and physiological settings (pH 7.4, 2 μM GSH). The LED@CS NPs and LED-PLA@CS NPs exhibited drug release rates of 88.0% and 73%, respectively, under dual stimuli over 50 h, exceeding the release rates observed under physiological conditions, which were 58% and 54%, thereby indicating that the LED@CS NPs and LED-PLA@CS NPs systems specifically target malignant tissue. Release regulated by Fickian diffusion facilitates tumor-specific payload delivery. Although encapsulation did not enhance the immediate cytotoxicity compared to free LED, as demonstrated by an in vitro cytotoxicity in HepG2 cancer cell lines, it significantly enhanced the therapeutic index (2.1-fold for LED-PLA@CS NPs) by protecting non-cancerous cells. Additionally, the nanoparticles demonstrated broad-spectrum antibacterial effects, suggesting efficacy in the prevention of chemotherapy-related infections. The dual-responsive LED-PLA@CS NPs allowed controlled tumor-targeted LED delivery with better selectivity and lower off-target toxicity, making LED-PLA@CS NPs interesting candidates for repurposing HCV treatments into safer cancer nanomedicines. Furthermore, this thorough analysis offers useful reference information for comprehending the interaction between drugs and DNA.
Organisms respond to environmental stress primarily through the autonomic nervous system and hypothalamic–pituitary–adrenal (HPA) axis, regulating metabolism, psychological states, and immune function and modulating memory, reward processing, and immune responses. The HPA axis plays a central role in stress response, exhibiting distinct activation patterns under acute versus chronic social defeat stress. However, differences in physiological impacts and regulatory pathways between these stress conditions remain understudied. This study integrates RNA sequencing and behavioral analyses to reveal that acute social defeat stress triggers transient anxiety-like behaviors, accompanied by systemic inflammation and immediate-early gene (IEG) activation. In contrast, chronic social defeat stress induces long-term behavioral and physiological alterations, including neurotransmitter imbalance (e.g., reduced GABA and increased glutamate), sustained activation of maladaptive pathways (e.g., IL-17 signaling), and disrupted corticosterone synthesis. These findings highlight the dynamic regulatory role of the HPA axis under varying stress conditions, providing novel insights into mental health disorders such as anxiety and depression. The study identifies potential therapeutic targets to mitigate chronic social defeat stress effects and offers a theoretical foundation for personalized interventions.
The wolf fish Hoplias malabaricus is a Neotropical species characterized by remarkable karyotypic diversity, including seven karyomorphs (KarA-G) with distinct sex chromosome systems. This study investigated the homologous XY (KarF) and XY1Y2 (KarG) sex chromosome systems present in this species by integrating cytogenetics and genomics to examine sex chromosomes’ composition through characterization of repeatome (satellite DNA and transposable elements) and sex-linked markers. Our analysis indicated that both karyomorphs are little differentiated in their sex chromosomes content revealed by satDNA mapping and putative sex-linked markers. Both repeatomes were mostly composed of transposable elements, but neither intra- (male versus female) nor interspecific (KarF x KarG) variations were found. In both systems, we demonstrated the occurrence of sex-specific sequences probably located on the non-recombining region of the Y chromosome supported by the accumulation of sex-specific haplotypes of HmfSat10-28/HmgSat31-28. This investigation offered valuable insights by highlighting the composition of homologous XY and XY1Y2 multiple sex chromosomes. Although homologous, the large Y chromosome in KarF corresponds to two separate linkage groups (Y1 and Y2) in KarG implying a specific meiotic arrangement involving the X chromosome in a meiotic trivalent chain. This scenario likely influenced recombination rates and, as a result, the genomic composition of these chromosomes.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), utilizes its spike protein to infect host cells. In addition to angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1), AXL acts as a spike protein receptor and mediates infection, especially in respiratory cells with low ACE2 expression. Angiotensin II (1–8) can be cleaved into shorter peptides within the biological system. Antibody-based binding assays showed that angiotensin II causes a two-fold increase in the binding between the spike protein and AXL, but not ACE2 or NRP1. While a longer peptide, angiotensin I (1–10), did not affect the spike–AXL binding, shorter lengths of angiotensin peptides exhibited enhancing effects. The C-terminal deletions of angiotensin II to angiotensin (1–7) or angiotensin (1–6) resulted in peptides with enhanced activity toward spike–AXL binding with a similar capacity as angiotensin II. In contrast, the N-terminal deletions of angiotensin II to angiotensin III (2–8) or angiotensin IV (3–8) as well as the N-terminal deletions of angiotensin (1–7) to angiotensin (2–7) or angiotensin (5–7) produced peptides with a more potent ability to enhance spike–AXL binding (2.7-fold increase with angiotensin IV). When valine was substituted for tyrosine at position 4 in angiotensin II or when tyrosine at position 4 was phosphorylated, spike–AXL binding was increased, suggesting that modifications to tyrosine trigger enhancement. Angiotensin IV also enhances spike protein binding to ACE2 and NRP1. Thus, angiotensin peptides may contribute to COVID-19 pathogenesis by enhancing spike protein binding and thus serve as therapeutic targets.
Glioblastoma multiforme (GBM) is a highly aggressive, treatment-resistant grade IV brain tumor with poor prognosis that grows rapidly and invades surrounding tissues, complicating surgery and frequently recurring. Although the crucial role of endogenous peptides has been highlighted for several tumors, the specific peptidomic profile of GBM remains unexplored to date. This study aimed to perform a preliminary characterization of the low molecular mass proteome fraction of Cavitron Ultrasonic Surgical Aspirator (CUSA) fluid collected from different tumor zones, i.e., the core and tumor periphery of newly diagnosed (ND) and recurrent (R) GBM. The samples, pooled by tumor type and collection zone, were centrifuged through molecular cut-off filter devices to collect the non-retained fraction of the proteome <10 kDa for direct full-length LC-MS analysis. A total of 40 and 24 peptides, fragments of 32 and 18 proteins, were marked as ND and R GBM COREs, respectively, while 132 peptides, fragments of 46 precursor proteins, were identified as common and included proteins which were cancer-related or involved in GBM pathophysiology. Besides providing a preliminary overview of the unexplored peptidome of GBM, this pilot study confirms peptidomics as a promising tool to discover potential GBM biomarkers in the perspective of clinical applications increasingly oriented towards a precision medicine approach. Data are available via ProteomeXchange with the identifier PXD060807.
Self/non-self-discrimination is a fundamental aspect of adaptive immunity, which helps prevent harmful autoimmune responses. However, infectious agents can also act as environmental catalysts for autoimmune diseases. In this study, we investigated the role of molecular mimicry to self-antigens in epitope recognition in relation to infectious and autoimmune diseases. To this end, we performed BLAST searches against the human proteome, utilizing known virus-specific B and T cell peptide epitopes identified in association with autoimmune or infectious diseases in humans as our queries. Additionally, similar control analyses were carried out using non-B and non-T cell epitopes, consisting of random viral peptide sequences. Overall, our results endorsed a major role of molecular mimicry in instigating or sustaining autoimmunity associated with viral infections and challenged the prevailing view on self/non-self-discrimination for T cells. Additionally, we uncovered many virus-specific epitopes among those identified in association with infectious diseases with high similarity to self-antigens, which are primarily derived from human coronaviruses and various flaviviruses. Recognition of these epitopes could lead to autoimmunity against human proteins that are in cellular components concerning cell motility, cell membrane projections, and cellular synapses.
Retinal ribbon synapses are continuously active chemical synapses. The eponymous synaptic ribbon is anchored to the active zone neurotransmitter release sites of ribbon synapses, recruits synaptic vesicles and guides ribbon-associated synaptic vesicles to the release sites. RIBEYE is the major protein component of synaptic ribbons. But likely, additional proteins contribute to ribbon synapse function. The synaptic ribbon of photoreceptor synapses is embedded into a highly polarized microtubule cytoskeleton. Interestingly, proteins of the photoreceptor primary cilium, such as NPHP4 and other ciliary proteins, including KIF3A, were shown to be localized to photoreceptor synaptic ribbons. Previous studies demonstrated that the microtubule motor protein KIF13B catalyzes secretory vesicle transport to the plus ends of microtubules and identified an interaction of KIF13B with NPHP4 at primary cilia. However, the localization of KIF13B, a kinesin-3 family motor protein, in the retina is still unknown. In the present study, we used two different antibodies against KIF13B and high-resolution confocal microscopy, super-resolution structured illumination microscopy (SR-SIM), and post-embedding immunogold electron microscopy to determine the localization of KIF13B in retinal photoreceptors. Apart from its localization at the primary photoreceptor cilium, we found a strong enrichment of KIF13B at photoreceptor synaptic ribbons. The synaptic ribbon is needed for the synaptic enrichment of KIF13B as shown by analyses of synaptic ribbon-deficient RIBEYE knockout mice. These findings suggest that KIF13B performs vesicle trafficking functions at the photoreceptor synaptic ribbon complex at the interface between the synaptic ribbon and the presynaptic microtubule transport system.
Immunoglobulin A vasculitis (IgAV), previously known as Henoch–Schönlein purpura (HSP), is a type of non-thrombocytopenic small-vessel vasculitis. HSP is the most common systemic vasculitis in pediatric patients, and it is characterized by purpura, arthritis or arthralgia, gastrointestinal pain, and renal dysfunction. This retrospective analysis also examines a range of demographic factors, including sex, geographic and environmental influences, age, and medication, to evaluate their potential effects on the pediatric population affected by HSP. The five-year hospital-based retrospective analysis included 138 hospitalized children diagnosed with HSP during hospitalization. Blood sample analysis was conducted to assess various immunological parameters, including levels of immunoglobulins (IgA and IgE), complement components (C3 and C4), C-reactive protein, fibrinogen, the erythrocyte sedimentation rate (ESR), and allergen panels. Elevated IgE levels and normal IgA serum concentrations were found to be strongly associated with infectious diseases in pediatric HSP patients. Patients with recurrent infectious diseases consistently exhibited elevated IgE levels and normal IgA levels during treatment despite no identified allergens, alongside an increased risk of disease recurrence.
In the original publication [...]
B cells contribute to innate and adaptive immunity. In the former, Toll-like receptor (TLR) activation promotes the expansion of inflammatory B cells. In the latter, B cell receptor (BCR) activation results in the production of antibodies or autoantibodies. Antigen processing and presentation are closely associated with major histocompatibility class II (MHC-II) and its companion protein, class II invariant peptide (CLIP). The impact of autophagy on the regulation of these unique mechanisms of B cell activation and subset expansion has not been fully explored. The results from the current study show that activating autophagy with rapamycin (RAPA) or inhibiting autophagy with hydroxycholoroquine (HCQ) differentially influences the TLR9 and BCR activation of B cells. These differences include the selective expansion of B1 and B2 B cell subsets, the regulation of the cell-surface expression of MHC-II and CLIP, and the ability of distinct B cell subsets to present peptide antigens. These novel findings demonstrate that the unique B cell activation mechanisms induced by TLR9 and BCR activation are differentially influenced by RAPA and HCQ, owing to the selective modulation of B cell subset expansion, and antigen processing and presentation by MHC-II proteins.
Network-based GWAS (NetWAS) has advanced brain imaging research by identifying genetic modules associated with brain alterations. However, how imaging risk genes exert functions in brain diseases, particularly their mediation through imaging quantitative traits (iQTs), remains underexplored. We propose a module-level polygenic risk score (MPRS)-based NetWAS framework to uncover genetic modules associated with Alzheimer’s disease (AD) through the mediation of an iQT, using amygdala density as a case study. Our framework integrates genotype data, brain imaging phenotypes, clinical diagnosis of AD, and protein–protein interaction (PPI) networks to identify AD-relevant modules (ADMs) influenced by iQT-associated genetic variants. Specifically, we conducted a genome-wide association study (GWAS) of amygdala density (N=1515) to identify variants associated with iQT. These variants were mapped onto a PPI network and network propagation was performed to prompt amygdala modules. The meta-GWAS of AD (N1=63,926; N2=455,267) was used to calculate MPRS to further identify AD-relevant modules (ADMs). Four modules that showed significant differences in MPRS between AD and controls were identified as ADM. Post-hoc analyses revealed that these ADMs demonstrated strong modularity, showed increased sensitivity to early stages of AD, and significantly mediated the link between ADMs and AD progression through the amygdala. Furthermore, these modules exhibited high tissue specificity within the amygdala and were enriched in AD-related biological pathways. Our MPRS-based framework bridges genetics, intermediate traits, and clinical outcomes and can be adapted for broader biomedical applications.
Environmental pollution remains a significant challenge in animal production. The “ideal protein” concept refers to an amino acid profile that precisely meets the animal’s nutritional requirements, optimizing nutrient utilization and minimizing waste excretion. This study applied untargeted metabolomics to explore metabolic changes induced by limiting AA. Two experimental diets were used in 47-day-old growing rabbits: Met+ (with a methionine level balanced to its optimal utilization) and Met− (with a methionine level that was clearly limiting). A total of 68 blood samples were taken for untargeted metabolomics analysis and 88 were taken for targeted plasmatic urea nitrogen analysis, collected at 08:00 (in ad libitum feeding animals) and 21:00 (after a feeding event in 10 h fasting animals). Our results revealed that both sampling time and diet (at each time point) exerted a significant modulatory influence on the metabolome. Interestingly, the difference between the metabolomes obtained with the different diets was less pronounced at 08:00, likely due to the caecotrophy effect, compared to 21:00, when higher intake and lower caecotrophy frequency were observed. This study identifies pseudourine, citric acid, pantothenic acid, and enterolactone sulfate as promising metabolites that could be targeted in order to refine the ideal protein concept, thus improving nutrient efficiency and reducing the environmental impact of animal production.
HIKESHI-related hypomyelinating leukodystrophy (HHL) is a life-threatening disorder caused by homozygous pathogenic variants in HIKESHI. Symptoms include infantile onset progressive spastic dystonic quadriplegia, nystagmus, failure to thrive, diffused hypomyelination, and severe morbidity or death following febrile illness. V54L variants in HIKESHI are particularly prevalent within the Ashkenazi Jewish population. Here, we identified a novel P78S disease-causing variant in HIKESHI in a patient of Christian Arab origin, presenting with clinical and radiologic features characteristic of HHL. In silico analysis suggests that the mutated residue may affect the HIKESHI protein’s dimerization domain. We generated a comprehensive set of induced pluripotent stem cells (iPSCs) from the index case and two additional HHL patients. To investigate mechanisms potentially linked to febrile illness in HHL, we used these cells to study the heat shock (HS) response. HHL-iPSCs showed dramatically decreased levels of HIKESHI compared with healthy controls following HS. In addition, they exhibited increased HSP70 mRNA levels in response to HS, suggesting an increased sensitivity. HHL-iPSCs had impaired HSP70 translocation to the nucleus. Our results provide a human-relevant model for HHL.
The rising prevalence of type 2 diabetes is linked to an increased risk of cardiovascular diseases, with the diabetic heart being particularly vulnerable to ischemia–reperfusion (IR) injury. Chronic hyperglycemia contributes to an increase in reactive oxygen species and impacts the homeostasis of biochemical pathways, including the polyol pathway, increasing susceptibility to damage. Aldose reductase (AR), a key enzyme in this pathway, has been targeted for therapeutic intervention, with AR inhibitors showing potential in mitigating diabetic complications. This study investigated IR injury in cardiomyocytes following high glucose exposure and assessed the AR inhibitor Epalrestat as a protective agent. Cardiomyocyte function was evaluated by measuring lactate dehydrogenase (LDH) release, FM1-43 membrane incorporation, cell viability, intracellular calcium accumulation, and superoxide anion formation. High glucose exposure and simulated IR led to increased LDH release, FM1-43 incorporation, intracellular calcium, and superoxide levels, alongside reduced cell viability in a dose-dependent manner. However, Epalrestat treatment during high glucose exposure significantly reduced IR-induced injury. These findings suggest that high glucose exacerbates IR injury in cardiomyocytes, with the polyol pathway playing a critical role. Targeting this pathway with AR inhibitors like Epalrestat may offer a protective strategy against diabetic heart complications.
Dendritic cells (DCs) play a central role in the immunopathogenesis of rheumatoid arthritis (RA), yet their regulation by tumor necrosis factor alpha (TNF) and associated receptors remains poorly characterized. We applied a single-cell multi-omics approach (CITE-seq) to profile peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors, before and after in vitro TNF stimulation. Using integrated analysis of surface protein expression and transcriptomic data, we focused on phenotypic and transcriptional changes in dendritic cell populations. DCs from RA patients exhibited elevated surface expression of CD14 and CD16, indicative of an inflammatory phenotype, and showed marked responsiveness to TNF. Upon stimulation, RA-derived DCs upregulated genes involved in antigen presentation (CD83, LAMP3), lymph node migration (CCR7, ADAM19), and inflammation (TRAF1, IL24) whereas such activation was absent in healthy controls. Our data reveal a TNF-responsive, pro-inflammatory transcriptional program in dendritic cells from RA patients and underscore the relevance of the TNF receptor profile in shaping DC function. These findings provide new insights into the immunobiology of RA and identify dendritic cells as potential targets for personalized immunomodulatory therapy.
Multiple myeloma (MM or plasma cell myeloma) is a heterogenous B-cell malignant tumor that typically exhibits a high recurrence rate, resistance to drugs, and molecular diversity of tumor subclones. Given the limited efficacy of standard therapy options, cellular immunotherapy featuring a chimeric antigen receptor (CAR) has proven tangible potential in treatment for relapsed and refractory forms of MM. The rational choice of a tumor target which shows high selectivity, stable expression, and biological significance is key to the successful implementation of CAR therapy. This review has summarized and analyzed data from the literature on biological properties, the features of expression, and the clinical development stages of CAR cell products for MM treatment which target BCMA, GPRC5D, FcRH5, SLAMF7, CD38, CD138, TACI, APRIL, CD19, TNFR2, CD44v6, CD70, NKG2D ligands, etc. Special focus is on strategic approaches to overcoming antigenic escape, such as multi-specific CAR constructs, logical activation sequences, and controlled safety systems. The analysis underscores the need for integrating the molecular selection of targets with cutting-edge bioengineering solutions as a key trend for raising the efficacy, stability, and safety of cellular therapy in the case of MM.
Duchenne muscular dystrophy (DMD) manifests as a hereditary condition that diminishes muscular strength through the progressive degeneration of structural muscle tissue, which is brought about by deficiencies in the dystrophin protein required for the integrity of muscle cells. DMD is among four different types of dystrophinopathy disorders. Current studies have established that long non-coding RNAs (lncRNAs) play a significant role in determining the trajectory and overall prognosis of chronic musculoskeletal conditions. LncRNAs are different in terms of their lengths, production mechanisms, and operational modes, but they do not produce proteins, as their primary activity is the regulation of gene expression. This research synthesizes current literature on the role of lncRNAs in the regulation of myogenesis with a specific focus on certain lncRNAs leading to DMD increments or suppressing muscle biological functions. LncRNAs modulate skeletal myogenesis gene expression, yet pathological lncRNA function is linked to various muscular diseases. Some lncRNAs directly control genes or indirectly control miRNAs with positive or negative effects on muscle cells or the development of DMD. The research findings have significantly advanced our knowledge about the regulatory function of lncRNAs on muscle growth and regeneration processes and DMD diseases.
Granulosa cells (GCs) are essential for follicular growth and development, and their functional state critically impacts folliculogenesis. TAp73α, a transcriptionally active isoform of the p73 gene, is crucial for maintaining follicular integrity. In this study, we demonstrate that TAp73α overexpression promotes ferroptosis in bovine GCs by downregulating SLC7A11, depleting intracellular glutathione (GSH), and enhancing lipid peroxidation, particularly under Erastin treatment. By contrast, TAp73α knockdown restores antioxidant capacity, elevates GSH levels, and attenuates ferroptosis. To elucidate the underlying mechanism, untargeted metabolomic profiling revealed that TAp73α overexpression significantly altered the metabolic landscape of GCs, with marked enrichment in the glutathione metabolism pathway. Notably, betaine—a metabolite closely linked to redox homeostasis—was markedly downregulated. Functional assays confirmed that exogenous betaine supplementation restored SLC7A11 expression, increased GSH levels, and alleviated oxidative damage induced by either H2O2 or TAp73α overexpression. Moreover, betaine co-treatment effectively reversed lipid peroxide accumulation and mitigated TAp73α-induced ferroptosis. Collectively, our findings identify a novel mechanism by which TAp73α promotes ferroptosis in granulosa cells through the suppression of betaine and glutathione metabolism, highlighting betaine as a key metabolic modulator with promising protective potential.
Nitric oxide (NO), a simple yet remarkably versatile molecule, stands today as a pivotal player in virtually all body systems and cellular compartments [...]
In this study, we investigated the solvent performance of six heavy oils from Xinjiang, China, for coal–oil co-liquefaction (COCL). Autoclave experiments revealed that shale oil vacuum residue (SOVR) provided the best liquefaction performance. The oils were characterized using FT-IR, 13C-NMR, 1H-NMR, and column chromatography, which revealed that they were mainly composed of aliphatic compounds, with minor aromatic and substituted aromatic compounds. The pyrolytic degradation quality indices (PDQIs), solubility parameter (δC), and polycyclic aromatic hydrocarbon content (HA2 + HA3) were calculated and correlated with liquefaction performance. The results showed a strong linear relationship between HA2 + HA3 and oil yield (R2 = 0.90), and the aromatic content (AR) was also positively related to oil yield. This study suggests that AR content and HA2 + HA3 are effective indicators for evaluating the solvent performance of heavy oils in COCL.
We have previously reported on a novel monoclonal antibody (mAb) we designated F5, which was raised against a glycopeptide derived from the tandem repeat (TR) region of Mucin-4 (MUC4), a heavily O-glycosylated protein that is overexpressed in many pancreatic cancer cells. This mAb was highly specific for the MUC4 glycopeptide antigen in glycan microarrays, ELISA and SPR assays, selectively stained tissue derived from advanced-stage tumors, and bound MUC4+ tumor cells in flow cytometry assays. The mAb was also unique in that it did not cross-react with other commercial anti-MUC4 mAbs that were raised in a similar but non-glycosylated TR sequence. Here we describe the selective conjugation of a novel near-infrared dye to this mAb and in vivo biodistribution of this labeled mAb to various MUC4-expressing tumors in mice. The labeled mAb were selectively distributed to both cell-derived xenograft (CDX) flank tumors and patient-derived xenograft (PDX) tumors that expressed MUC4 compared to those that were MUC4-negative. Organ distribution analysis showed high uptake in MUC4+ relative to MUC4− tumors. These results suggest that mAb F5 may be used to develop MUC4-targeted, passive antibody-based immunotherapies against Pancreatic Ductal Adenocarcinomas (PDACs) which are notorious for being refractory to many chemo- and radiotherapies
Programmed Death-Ligand 1 (PD-L1) is a major target for immunotherapy using checkpoint inhibitors (CPIs), particularly in lung cancer treatment. Tumoral PD-L1 expression has been recognized as a natural predictor of CPI response. This predictive relationship is primarily due to its upregulation by interferon-gamma, which is released by immune cells (mainly T lymphocytes and natural killer cells) in proximity to tumor cells, driving an immune resistance mechanism. However, PD-L1 expression is modulated at multiple levels, including oncogenic signaling pathways, and transcriptional and post-transcriptional regulations, potentially leading to false positive predictions. Conversely, variable glycosylation of PD-L1 may compromise the accuracy of immunohistochemical measurements, resulting in false negative predictive data. In addition, PD-L1 expression demonstrates relative instability throughout treatment courses (e.g., chemotherapy and tyrosine kinase inhibitors), further limiting its clinical utility. In this review, we focused on the molecular mechanisms governing PD-L1 expression with a special emphasis on lung cancer. We also discussed biomarker strategies for optimizing patient selection for checkpoint inhibitor therapy where multimodal/multi-omics meta-biomarker approaches are emerging. Such comprehensive PD-L1-enriched biomarker strategies require evaluation through large-scale prospective studies, particularly in lung cancer, where numerous competing predictive candidates exist for CPI response.
Aberrant DNA methylation is a hallmark of colorectal cancer (CRC), contributing to tumor progression through the silencing of tumor suppressor genes and activation of oncogenes. Indicaxanthin (IND), a dietary betalain pigment from Opuntia ficus indica, has shown antiproliferative effects in CRC models, yet its epigenetic impact remains unexplored. In this study, we investigated the effects of IND on the methylome of Caco-2 cells using Reduced Representation Bisulfite Sequencing (RRBS). IND induced a global hypermethylation profile, particularly at gene promoters and CpG islands. Among the differentially methylated genes, 60% were protein-coding, and 10% encoded transcription factors, including PAX5 and TFAP4, both hypermethylated at active enhancers. Functional enrichment analysis revealed pathways beyond canonical intestinal functions, suggesting altered cell identity and plasticity. Transcription factor targets (SOX10, NFKB1, AHR, ARNT) were significantly enriched among the affected genes, several of which are involved in transdifferentiation processes. Methylation changes also indicated potential reprogramming toward epithelial cell types from pulmonary or neuroectodermal origin. Moreover, IND induced selective hypomethylation of Alu elements on chromosome 21 and hypermethylation of rDNA loci, hinting at suppressed ribosomal biogenesis. Overall, these findings highlight the epigenetic remodeling potential of IND and its possible role in modulating cell fate and metabolism in CRC cells.
A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence or presence of the ester group, showed the strongest cytotoxic effect towards all tested cancer cell lines with the IC50 0.68–2.88 µM. In addition, it was demonstrated that these compounds inhibit cancer cell proliferation by inducing G2/M phase arrest in HeLa cells. The structure–activity relationship was analyzed and it confirmed the importance of the core structural features like a dioxolane ring and free-rotating trimethoxyphenyl group for cytotoxicity. Moreover, the R configuration of the ester group at the C-8′ position proved to be substantial since its epimer was inactive. The molecular docking studies revealed that the most potent compounds have a different binding mode to β-tubulin than podophyllotoxin; however, the benzothiazole fragment docked in a similar location as the trimethoxyphenyl group of podophyllotoxin, exhibiting similar hydrophobic interactions. These findings clearly indicate that podophyllotoxin–benzothiazole derivatives could be addressed for further pharmacological studies in anticancer research.
Zebrafish is a well-recognized model for studying human genetic disorders. Recently, we proposed the homozygous cdkl5sa21938 mutant zebrafish as a model of CDKL5 deficiency disorder (CDD), a developmental epileptic encephalopathy with diverse symptoms. This study aimed to explore Cdkl5-associated molecular mechanisms in zebrafish and assess their similarity to those in mammals. We conducted RNA sequencing on whole cdkl5−/− zebrafish and wild-type siblings at 5 and 35 days post-fertilization (dpf) to compare their gene expression profiles. Most significant differentially expressed genes (DEGs) were related to muscle, neuronal, and visual systems which are affected in CDD. Gene Ontology analysis revealed downregulated DEGs enriched in muscle development, extracellular matrix, and actin cytoskeleton functions at both stages, while upregulated DEGs were enriched in eye development functions at 35 dpf. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of downregulated DEGs in focal adhesion and extracellular matrix (ECM)-receptor interaction pathways at both stages. Neuronal development DEGs were mainly downregulated at both stages, while synaptic signaling DEGs were upregulated at 35 dpf. Crossing cdkl5−/− mutants with the Hb9:GFP transgenic line showed fewer motor neuron cells with shorter axons compared to the wild type, which may explain the impaired motor phenotype observed in zebrafish and CDD patients. Moreover, we identified key downregulated DEGs related to cartilage development at both stages and bone development at 35 dpf, potentially explaining the skeletal defects seen in zebrafish and CDD individuals. In conclusion, Cdkl5 loss in zebrafish leads to dysregulation of genes involved in CDKL5-associated functions in mammals, providing new insights into its less studied functions and phenotypes.
Bullous pemphigoid (BP) and pemphigus vulgaris (PV) represent the most prevalent conditions among autoimmune bullous skin diseases, considered a major cause of severe morbidity and, in certain cases, mortality. The hallmark of the two diseases is the presence of autoantibodies directed against proteins located in the basement membrane of the skin, which determines the formation of blisters. In recent years, interest in the role of microbiota in relation to health-disease status has progressively increased. In particular, based on the gut–skin axis, accumulating evidence has emerged on the potential association between the composition and diversity of microbial communities in the gut, skin, and even in the oral cavity and the risk of developing BP and PV. Dysbiosis, characterized by a generally higher relative abundance of Firmicutes and a depletion of probiotics/beneficial species, might contribute to the pathogenesis of both diseases. Despite the still limited number of studies and the need for further large-scale multicenter studies, the knowledge gathered so far is suggestive of a novel modifiable risk factor representing a potential target for adjuvant treatments of these disabling and life-threatening conditions.
Rosavin, a glycoside isolated from Rhodiola rosea, exhibits various biological activities, including potential modulation of metabolic pathways. Despite promising findings in animal models, its effects on many human bone cells remain unexplored. This study aimed to investigate, for the first time, the in vitro effects of rosavin on human osteoblasts (HOBs), focusing on BMP-2 expression, cell morphology, and culture confluence as indicators of osteogenic activity. HOB cultures were treated with 50 µM or 100 µM rosavin for 21 days. BMP-2 expression was measured by ELISA, collagen production was assessed via Sirius Red staining, and cell morphology and confluence were evaluated using phase-contrast microscopy. A significant increase in BMP-2 expression was observed in the 100 µM rosavin group compared to the mineralization control (p < 0.05), particularly on days 14 and 21. Both rosavin-treated groups exhibited higher confluence than controls, with the 50 µM group showing unexpectedly greater confluence than the 100 µM group. Rosavin at 50 µM also promoted a cuboidal morphology characteristic of active HOBs. The presence of collagen validated both the successful progression of the mineralization process and the correct implementation of the experimental protocol. Rosavin enhances BMP-2 expression and supports HOB proliferation and morphological maturation in vitro. These findings suggest its potential as a supportive agent in the prevention or treatment of metabolic bone diseases. Further research is necessary to determine its bioavailability, safety profile, and therapeutic relevance in clinical settings.
Systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS), are traditionally characterized by chronic inflammation and immune-mediated damage to joints and other tissues. However, many patients also experience symptoms such as widespread pain, persistent fatigue, cognitive dysfunction, and autonomic disturbances that cannot be attributed directly or entirely to peripheral inflammation or structural pathology. These conditions suggest the involvement of interactions between the nervous and immune systems, which probably include both peripheral and central components. This review summarizes the current knowledge of neurological and neuroimmune mechanisms that may contribute to these symptoms in SARDs. Glial cell activation and neuroinflammation within the central nervous system (CNS), small-fiber neuropathy (SFN) affecting peripheral nociceptive pathways, central pain sensitization, and autonomic nervous system dysfunction will be discussed. In addition, the role of molecular mediators, including cytokines, neuropeptides, and microRNAs, that could potentially modulate neuroimmune signaling will be highlighted. Integrating findings from pathology, immunology, and neuroscience, this review seeks to provide a useful framework for understanding neuroimmune dysregulation in SARDs. It also highlights the clinical relevance of these mechanisms and summarizes new directions for diagnosis and treatment.
SARS-CoV-2, a β-coronavirus, primarily affects the lungs, with non-specific lesions and no cytopathic viral effect in the skin. Cutaneous antiviral mechanisms include activation of TLR/IRF pathways and production of type I IFN. We evaluated the antiviral mechanisms involved in the skin of COVID-19 patients, including skin samples from 35 deceased patients who had contracted COVID-19 before the launch of the vaccine. Detection of SARS-CoV-2 in the skin was performed using transmission electron microscopy and RT-qPCR. Microscopic and molecular effects of the virus in skin were evaluated by histopathology, RT-qPCR, and immunohistochemistry (IHC). The results revealed the presence of SARS-CoV-2 and microscopic changes, including microvascular hyaline thrombi, perivascular dermatitis, and eccrine gland necrosis. There was increased transcription of TBK1 and a reduction in transcription of TNFα by RT-qPCR in the COVID-19 group. IHC revealed reduced expression of ACE2, TLR7, and IL-6, and elevated expression of IFN-β by epidermal cells. In the dermis, there was decreased expression of STING, IFN-β, and TNF-α and increased expression of IL-6 in sweat glands. Our results highlight the role of type I IFN in the skin of COVID-19 patients, which may modulate the cutaneous response to SARS-CoV-2.
Peptides are currently vital components in nutrition with physiological advantages beyond a basic diet. This systematic review aims to explain their significance in metabolic, behavioral, and musculoskeletal health, focusing on their therapeutic benefits, molecular mechanisms, and bioactivities. This systematic review analyzed clinical trials from PubMed and Scopus databases in the time range of 2019 to 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, that investigated the role of peptides in human nutrition. Eight randomized clinical trials (RCTs) met the predefined metabolic, behavioral, and musculoskeletal health inclusion criteria. Peptides are derived from various sources, including milk, fish, and plants, and show various bioactive characteristics such as anti-inflammatory effect, improved muscle protein synthesis, and immune modulation. Some important findings emphasize their potential to govern metabolic processes, defend against chronic diseases, and enhance gut health. For instance, glucagon-like peptide (GLP-1) controls taste perception and appetite stimulation, and collagen peptides strengthen the musculoskeletal system. Peptides display intriguing potential as nutrients for addressing global health challenges, including behavioral responses, aging, and metabolic syndrome. Future investigations would focus on bioavailability, optimizing dosage, and demographic-specific treatments.
This review highlights recent findings on the versatile serpin protein, pigment epithelium-derived factor (PEDF), in relation to cancer diagnosis, treatment and prognosis. PEDF was initially discovered in the eye but has since been reported to be relevant to various biological roles in the body, and when awry, to clinically lead to various disease states such as neoplasia. At the preclinical stage, potent effects have been reported in studies focussing on apoptosis, metastasis, oxidative stress, immune stimulation and metabolism. Apart from full-length proteins, short peptides based on PEDF have shown promise against cancer. For diagnosis and prognosis, PEDF levels in tumour specimens or in circulation have the potential to serve as biomarkers, most probably in combination with other biomarkers of cancer initiation and progression. Lastly, this review discusses the growing list of studies that point out the perceived pro-cancerous effects of PEDF, though this is clearly outweighed by the anticancer publications. Thus, this review provides a comprehensive and balanced listing of the oncological studies associated with this protein to date, drawing conclusions on whether this potent antiangiogenic protein and its peptides can be used in the future for better cancer treatment, especially against metastasis.
Growing evidence underscores the pivotal roles of both in situ-resident and -non-resident cardiac cells in the repair mechanisms following myocardial infarction (MI). MI continues to be a predominant cause of death and disability, posing a significant threat to global health and well-being. Despite advances in medical care, current therapies remain insufficient in preventing ventricular remodeling and heart failure post-MI. We seek to clarify the underlying regenerative mechanisms by which distinct cell types contribute to the repair of MI injury and to systematically assess the translational potential and therapeutic efficacy of these cell-based approaches in clinical applications. This review conducts a comprehensive analysis of recent research progress on the roles of non-cardiac stem cells in situ and cardiac cells derived from explants in MI repair. These cells contribute to the repair process through multiple mechanisms, including cell proliferation and differentiation, angiogenesis, paracrine signaling, immune regulation and fibrosis modulation. Our analysis reveals the intricate mechanisms of MI repair and highlights the necessity for developing age-specific therapeutic strategies for certain cell types. This review offers novel insights into cell-based treatment for MI and provides a scientific foundation for future clinical trials of cardiac regenerative medicine.
Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in Aβ1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application.
The global obese population accounts for approximately 30% of the total population and continues to increase. White adipocytes, which accumulate in the body for energy storage, are associated with obesity. Mechanisms that activate browning of white adipocytes are an attractive therapeutic target for obesity and metabolic disorders. Exosomes are nano-sized biovesicles that play a role in cell-to-cell communication though the transfer of cargos such as microRNAs. Although milk exosomes contain many endogenous microRNA molecules, the role of microRNAs in milk exosomes is limited. Therefore, the aim of this study was to investigate the effects of milk exosomes on the browning of white adipocyte. Mouse pre-adipocytes (3T3-L1) and human adipose-derived stem cells (hADSCs) were differentiated and exposed to milk exosomes. Compared to control, milk exosomes promoted the expression of thermogenic genes and cellular mitochondrial energy metabolism in both 3T3-L1 cells and hADSCs. Additionally, milk exosomes were orally administered to mice fed a high-fat diet. As the intake of milk exosomes increased, the mice’s body weight decreased. Milk exosomes also increased the protein levels of thermogenic genes and mitochondrial-related genes in mouse adipose tissue. The overexpression of miR-11987, which is abundant in milk exosomes, in both 3T3-L1 cells and hADSCs led to the increased expression of thermogenic genes and mitochondrial activity. Our results support that bovine-specific miR-11987 in milk exosomes promotes the browning of white adipocytes. Therefore, milk exosome and milk exosomal miR-11987 could have significant clinical implications for obesity and metabolic syndrome.
Prostate cancer (PCa) therapy faces challenges due to tumor heterogeneity, plasticity, and progression. Metabolic reprogramming, a dynamic process, has emerged as a key focus in PCa treatment. However, conventional therapies targeting cancer-specific metabolic pathways or employing chemosensitizers are often limited by compensatory mechanisms and metabolic complexity. This review highlights the roles of transcription factors, including AR, p53, c-Myc, HIF-1, Nrf2, and PPARγ, in regulating PCa metabolism by influencing signaling pathways, enzymes, and gene expression. Multi-target compounds, particularly natural products, show potential for disrupting multiple metabolic enzymes, opening up new research possibilities. Notable examples include β-elemene, juglone, tannic acid, and withaferin A, which target critical metabolic processes through enzyme inhibition, transcription factor modulation, epigenetic changes, and protein interaction disruption. Naturally derived metabolites can elicit transversal responses in diverse metabolic pathways, particularly in p53 and MYC transcription factors. Additionally, compounds such as pentacyclic terpenoids (ursolic acid with ursane skeleton), sulforaphane, and isothiocyanate-related moieties may induce metabolic and epigenetic changes through S-adenosyl methionine (SAM) and acetyl-CoA modulation, potentially affecting new areas of research through metabolic processes. We propose a cooperative crosstalk between metabolic reprogramming and transcription factors/epigenetic modulation in PCa. This approach holds potential for expanding PCa therapeutics and opening new avenues for research.
Complete chloroplast genome sequences are widely used in the analyses of phylogenetic relationships among angiosperms. As a species-rich genus, species diversity centers of Saxifraga L. include mountainous regions of Eurasia, such as the Alps and the Qinghai–Tibetan Plateau (QTP) sensu lato. However, to date, datasets of chloroplast genomes of Saxifraga have been concentrated on the QTP species; those from European Alps are largely unavailable, which hinders comprehensively comparative and evolutionary analyses of chloroplast genomes in this genus. Here, complete chloroplast genomes of 19 Saxifraga species were de novo sequenced, assembled and annotated, and of these 15 species from Alps were reported for the first time. Subsequent comparative analysis and phylogenetic reconstruction were also conducted. Chloroplast genome length of the 19 Saxifraga species range from 149,217 bp to 152,282 bp with a typical quadripartite structure. All individual chloroplast genome included in this study contains 113 unique genes, including 79 protein-coding genes, four rRNAs and 30 tRNAs. The IR boundaries keep relatively conserved with minor expansion in S. consanguinea. mVISTA analysis and identification of polymorphic loci for molecular markers shows that six intergenic regions (ndhC-trnV, psbE-petL, rpl32-trnL, rps16-trnQ, trnF-ndhJ, trnS-trnG) can be selected as the potential DNA barcodes. A total of 1204 SSRs, 433 tandem repeats and 534 Large sequence repeats were identified in the 19 Saxifraga chloroplast genomes. The codon usage analysis revealed that Saxifraga chloroplast genome codon prefers to end in A/T. Phylogenetic reconstruction of 33 species (31 Saxifraga species included) based on 75 common protein coding genes received high bootstrap support values for nearly all identified nodes, and revealed a tree topology similar to previous studies.
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that severely impacts patients’ quality of life. Although current therapies have improved symptom management, they often fail to alter disease progression and are associated with immunosuppressive side effects. This study evaluated the immunomodulatory potential of resolvin D2 (RvD2), a pro-resolving lipid mediator, using a murine model of colitis and the ex vivo treatment of intestinal mucosal biopsies from CD patients, comparing its effects to those of conventional anti-TNFα therapy. To determine the optimal concentration of RvD2 for application in human tissue explant cultures, an initial in vitro assay was conducted using intestinal biopsies from mice with experimentally induced colitis. The explants were treated in vitro with varying concentrations of RvD2, and 0.1 μM emerged as an effective dose. This concentration significantly reduced the transcriptional levels of TNF-α (p = 0.004) and IL-6 (p = 0.026). Intestinal mucosal biopsies from fifteen patients with CD and seven control individuals were analyzed to validate RNA-sequencing data, which revealed dysregulation in the RvD2 biosynthetic and signaling pathways. The real-time PCR confirmed an increased expression of PLA2G7 (p = 0.02) and ALOX15 (p = 0.02), while the immunohistochemical analysis demonstrated the reduced expression of the RvD2 receptor GPR18 (p = 0.04) in intestinal tissues from CD patients. Subsequently, samples from eight patients with active Crohn’s disease, eight patients in remission, and six healthy controls were used for the serum analysis of RvD2 by ELISA, in vitro treatment of intestinal biopsies with RvD2 or anti-TNF, followed by transcriptional analysis, and a multiplex assay of the explant culture supernatants. The serum analysis demonstrated elevated RvD2 levels in CD patients both with active disease (p = 0.02) and in remission (p = 0.002) compared to healthy controls. The ex vivo treatment of intestinal biopsies with RvD2 decreased IL1β (p = 0.04) and TNFα (p = 0.02) transcriptional levels, comparable to anti-TNFα therapy. Additionally, multiplex cytokine profiling confirmed a reduction in pro-inflammatory cytokines, including IL-6 (p = 0.01), IL-21 (p = 0.04), and IL-22 (p = 0.009), in the supernatant of samples treated with RvD2. Altogether, these findings suggest that RvD2 promotes the resolution of inflammation in CD and supports its potential as a promising therapeutic strategy.
Osteogenesis imperfecta (OI) is a rare bone dysplasia that occurs with a frequency of 1/15,000–20,000 live births. It is characterized by increased susceptibility of bone fractures, skeletal deformities, low stature, and low bone mass. It results in impaired production of type I collagen. About 90% of people with OI have heterozygous mutations in the COL1A1 and COL1A2 genes. Fibroblast growth factor 23 (FGF23) is a protein involved in the regulation of phosphate and 1,25-dihydroxyvitamin D3 metabolism on a negative feedback basis. FGF23 is secreted by osteocytes in response to increased serum calcitriol and phosphorus. The purpose of this study was to evaluate the concentration of FGF23 among children with osteogenesis imperfecta and the differences in reference values in a healthy population of children and adolescents. Then, this study sought to evaluate how the course of osteogenesis imperfecta, including type of disease, number of bone fractures, and bone mineral density, are related to FGF23 concentration. The study included 47 children aged 3 to 17 years with a diagnosis of osteogenesis imperfecta, confirmed by genetic tests. The patients were hospitalized at the Department from August 2019 to September 2020 and were treated with intravenous infusions of sodium pamidronate. The course of the disease was analyzed, including the number of bone fractures, clinical symptoms, and anthropometric parameters, and bone densitometry was performed by dual X-ray absorptiometry (DXA) in Total Body Less Head (TBLH) and Spine options with Z-score evaluation. FGF23 concentration was determined by the ELISA method. The study was prospective in nature. Results: The mean level of FGF23 in the study group of patients was 645.09 pg/mL and was within the reference values for the developmental age population. There was no significant correlation between FGF23 concentration and anthropometric measurements: body weight (p = 0.267), height (p = 0.429), gender (p = 0.291), or pubertal stage (p = 0.223) in the study group of patients. FGF23 levels were not related to the number of fractures (p = 0.749), the number of sodium pamidronate cycles administered (p = 0.580), bone mineral density parameters (Z-score), the form of osteogenesis imperfecta (p = 0.156), or the genetic test result (p = 0.573). FGF23 levels decrease with age (r = −0.32, p = 0.030) and BMI (r = −0.34, p = 0.020). The level of FGF23 in patients with osteogenesis imperfecta is lower among older children and those having a higher BMI. This index cannot be a diagnostic tool in this group of patients, for no differences were found between the concentrations in patients with osteogenesis imperfecta and the developmental age population.
Clinacanthus nutans (Burm.f.) Lindau is a Southeast Asian medicinal plant traditionally used for treating skin inflammation and infections. This study evaluated its wound-healing potential through anti-inflammatory, cytoprotective, and antiviral mechanisms. HPLC-DAD analysis identified schaftoside as the major flavonoid in the 95% ethanolic leaf extract. In the lipopolysaccharide (LPS)-stimulated murine macrophage cell line (RAW 264.7), both C. nutans extract (5 and 50 μg/mL) and its flavonoid schaftoside (5 and 20 μg/mL) significantly downregulated the expression of pro-inflammatory genes, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2), under both pre-treatment and post-treatment conditions. ELISA confirmed dose-dependent inhibition of human COX-2 enzymatic activity, reaching up to 99.3% with the extract and 86.9% with schaftoside. In the endothelial cell models (CCL-209), the extract exhibited low cytotoxicity and effectively protected cells from LPS-induced apoptosis, preserving vascular integrity critical to tissue regeneration. Antiviral assays demonstrated suppression of HSV-2 replication, particularly during early infection, which may help prevent infection-related delays in wound healing. Collectively, these findings suggest that C. nutans and schaftoside promote wound repair by attenuating inflammatory responses, supporting endothelial survival, and controlling viral reactivation. These multifunctional properties highlight their potential as natural therapeutic agents for enhancing wound-healing outcomes.
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In this study, utilizing ex vivo, in silico, and in vitro approaches, we investigated the LCS1269 effects on two potential targets, DNA and Top I. We also elucidated the influence of LCS1269 on signaling pathways and GBM cell viability. Based on our docking data and competition studies results, we demonstrated that LCS1269 may bind to DNA, demonstrating selectivity toward AT-rich regions. We also showed that LCS1269 could dock both Top I/DNA binary complex and Top I active sites. LCS1269 caused Top I dysfunction and downregulated the expression of Top I. Moreover, the LCS1269 treatment of GBM cells facilitated DNA damage and the activation of the ATM/Chk1/BRCA1/Rad51 pathway. Meanwhile, DNA damage response induction and ATM/Chk1/BRCA1/Rad51 pathway activation were insufficient to prevent GBM cell death triggered by LCS1269 treatment. Our work shows that DNA and Top I are promising molecular targets of LCS1269, thus providing insight on several novel mechanisms of its anti-tumor activity. Nonetheless, we did not perform a biophysical validation of the LCS1269–DNA interaction, which is a limitation of our study.
Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated calmodulin (CaM) variants, the cellular mechanism(s) underlying this posttranslational modification was investigated in cultured cardiomyocytes. Whole-cell LTCCs decreased by ≈75% after silencing the gene coding for casein kinase 2 (CK2), a constitutively active kinase in cardiomyocytes, or after its pharmacological inhibition. The overexpression of the dominant negative phosphoresistant single, double T79A/S81A, or triple T79A/S81A/S101A CaM variants resulted in a similar inhibition. In contrast, the overexpression of CaM WT or its double T79D/S81D and triple T79D/S81D/S101D phosphomimetic variants curtailed the downregulation of LTCCs caused by CK2 partial knockdown, suggesting that CK2 is responsible for the posttranslational modification of these CaM target residues. Catecholamines, triggering the protein kinase A (PKA) cascade, partially rescued LTCCs treated with siRNA without or after the overexpression of either CaM WT or stimulating CaM phosphomimetic variants. More importantly, they thwarted the negative impact of the phosphoresistant CaM variants, altogether arguing that CK2 and PKA are acting in synergy to regulate the activity of LTCCs. We conclude that CK2-mediated phosphorylation processes exacerbate the Ca2+ load associated with heart failure.
The parathyroid and thymus glands are key components of the endocrine and immune systems, respectively, with intriguing developmental, anatomical, and functional interrelationships. This study starts from the hypothesis that, given their shared embryological origin, it is plausible that the thymus and parathyroid glands interact functionally and may share pathological pathways. The present study explores the developmental pathways, spatial proximity, and potential cross-talk between these glands. Recent studies suggest that parathyroid hormone (PTH) may influence thymic function, including T-cell maturation and immune regulation, while thymic signaling molecules could impact calcium homeostasis and parathyroid activity. Understanding the functional and etiopathogenical relations between these endocrine glands offers new insights into endocrine–immunological crosstalk, and therapeutic approaches targeting disorders such as hypoparathyroidism, thymomas, myasthenia gravis and thymic hypoplasia. Perspectives and conclusion: Future research is essential to discover the molecular mechanisms underpinning this dynamic interrelation and its broader implications for health and disease. Because there is still very little data on this interaction, in-depth studies are necessary on large groups of patients. This research proposes a cross-study of the receptors for the main substances secreted by the two categories of endocrine glands. At the same time, it is essential to carry out an in-depth study on the cervico-pericardial ligaments through the lens of this glandular interaction. These ligaments could contain the main blood and nerve communication pathway between the parathyroids and the glands.
The GLABROUS1 enhancer-binding protein (GeBP) gene family, a plant-specific class of transcriptional regulators, is involved in multiple biological processes, including the formation of trichomes, plant growth, and environmental adaptation. However, the functional characterization of SlGeBP genes in tomato remains poor, particularly regarding their roles in regulating developmental processes and stress response mechanisms. In this study, 11 SlGeBP family members were identified from the tomato genome and 97 GeBP proteins from six species were classified into three groups. A wide range of elements linked to phytohormone, stress, and plant development were presented on the promoter sequences. Gene expression profile analysis revealed a comprehensive expression during the vegetative and immature fruit development stages. Analysis of the expression level under nine hormones and seven stresses can help us to understand the responsiveness of SlGeBP genes associated with hormone induction and stress tolerance. Subcellular localization analysis exhibited that SlGeBP1 and SlGeBP5 were localized in the nucleus, and the yeast two-hybrid assay confirmed that SlGeBP1 could interact with SlGeBP5. This study will help us to understand the potential function of the SlGeBP family and may establish a basis for further research on phytohormone signaling and stress resistance.
The study investigated the antinociceptive effects of four compounds (F1–F4) based on a 1H-isoindole-1,3(2H)-dione core, using various in vivo pain models—tonic (formalin test), neurogenic (capsaicin and glutamate tests), neuropathic (oxaliplatin-induced model of peripheral neuropathy as well as the streptozotocin-induced model of painful diabetic neuropathy), and inflammatory (carrageenan-induced). Pharmacokinetic parameters were also assessed. In the capsaicin test, F1, F2, and F4 (5–20 mg/kg) significantly reduced pain, while compound F3 was only active at 20 mg/kg. In the glutamate test, F1, F2, and F3 (5–20 mg/kg) demonstrated the most pronounced effect. In phase I of the formalin test, compounds F1 and F2 were active at doses of 5 and 10 mg/kg, respectively, while F3 and F4 exhibited activity only at the 20 mg/kg dose. In phase II, a dose-dependent reduction in pain was observed, with the weakest effect noted at F4. At a dose of 20 mg/kg, the compounds significantly reduced edema and carrageenan-induced pain, but to a lesser extent than ketoprofen. The compounds tested (10 mg/kg) showed significant anti-allodynic activity in the oxaliplatin- and streptozotocin-induced neuropathy pain models. All compounds demonstrated favorable pharmacokinetic results. The results of this study indicate that the compounds have a broad analgesic spectrum of activity.
Pasta, due to its convenience, follows bread as the most common cereal product in the human diet. Typical wheat pasta is a high-energy product, since it contains a large amount of starch; at the same time, it is characterized by a low content of health-promoting ingredients, such as dietary fiber, minerals, vitamins, and polyphenols. Food industry by-products, or even waste, can be applied as a source of many bioactive substances, thus enriching pasta with bioactive ingredients. Two by-products, Cherry Pomace (CP) and Red Potato Pulp (RPP) were applied as health-promoting supplements for wheat pasta, at three levels (10, 20, and 30%). The antioxidant potential of the resulting pasta was examined (by DPPH, ABTS, FRAP, and FOMO methods), and the antioxidant’s content was also tested. The amount of polyphenols determined by HPLC was higher in the case of CP than in RPP, and the main ones were 5-O-Caffeoylquinic acid and Cyanidin 3-O-rutinoside in CP, whereas for RPP it was Pelargonidin 3-(4‴-p-coumaroylrutinoside)-5-glucoside. Fortified pasta samples were characterized by a higher content of total polyphenols and phenolic acids, flavonoids, flavanols, and anthocyanins. In pasta with a share of CP, some polyphenols were unstable during pasta production. Pasta with a share of CP was characterized by very high antioxidant activity due to a high level of phenolic acids and anthocyanins acting synergistically. It was also characterized by a higher content of phytosterols. A 30% addition of CP into pasta is considered the most beneficial in terms of increasing the health-promoting properties of such a product.
Spinal cord injury (SCI) results in a significant loss of motor, sensory, and autonomic function, imposing substantial biosocial and economic burdens. Traditional approaches, such as stem cell therapy and immune modulation, have faced translational challenges, whereas neuromodulation and digital brain–spinal cord interfaces combining brain–computer interface (BCI) technology and epidural spinal cord stimulation (ESCS) to create brain–spine interfaces (BSIs) offer promising alternatives by leveraging residual neural pathways to restore physiological function. This review examines recent advancements in neuromodulation, focusing on the future translation of clinical trial data to clinical practice. We address key considerations, including scalability, patient selection, surgical techniques, postoperative rehabilitation, and ethical implications. By integrating interdisciplinary collaboration, standardized protocols, and patient-centered design, neuromodulation has the potential to revolutionize SCI rehabilitation, reducing long-term disability and enhancing quality of life globally.
The ocular surface is susceptible to a wide spectrum of inflammatory, degenerative, and neurotrophic diseases that can impair vision. The complex pathophysiology and limited therapeutic options associated with these conditions continue to pose significant clinical challenges. Nerve Growth Factor (NGF), a neurotrophin initially recognized for its role in neuronal survival and differentiation, has emerged as a key regulator of ocular surface homeostasis and repair. Beyond its neurotrophic functions, NGF is suggested to influence epithelial proliferation, immune responses, tear secretion, and angiogenesis. Experimental and clinical studies have implicated NGF in both the pathogenesis and potential treatment of various ocular surface diseases, including allergic conjunctivitis, neurotrophic keratopathy (NK), immune-mediated and herpetic keratitis, and dry eye disease (DED), as well as post-surgical corneal wound healing. Notably, recombinant human NGF (rhNGF, cenegermin) has been approved as the first topical biologic therapy for NK. Despite encouraging clinical outcomes, challenges such as high treatment costs, limited long-term data, and potential proangiogenic effects remain. This review consolidates current evidence on the role of NGF in ocular surface health and disease, highlighting its biological mechanisms, clinical applications, and future therapeutic potential.
Coagulation factor XII (FXII), the initiator of the intrinsic coagulation pathway, is not involved in hemostasis but is associated with pathological thrombosis. Bacterial infections activate coagulation cascades, although the underlying mechanisms remain not fully understood. Here, we revealed that FXII exhibits antibacterial activity through its heavy chain (hFXII) against Pseudomonas aeruginosa (P. aeruginosa), a Gram-negative bacterium. We constructed an FXII-deficient (FXII−/−) mouse model and demonstrated that FXII plays a critical role in antibacterial functions. FXII and hFXII significantly reduced bacterial loads via intravenous injection, confirming their antibacterial activity in FXII−/−. To further investigate the pathophysiological implications of FXII in the P. aeruginosa-induced disseminated intravascular coagulation (DIC) mouse model, FXII and hFXII effectively reduced DIC-related bacterial infections, alleviated organ damage, and decreased fibrin deposition, consequently improving survival rates. This study indicates that FXII exhibits both in vitro and in vivo antibacterial activity, primarily mediated through its heavy chain. In thrombotic diseases triggered by Gram-negative bacterial infections, the antibacterial functions of FXII may influence the progression of the disease. These results not only redefine the critical role of the intrinsic coagulation pathway in innate immune defense but also provide novel insights into the prevention and treatment of severe infection-related diseases.
Liver fibrosis can progress to irreversible cirrhosis if the underlying causes remain, and this can in turn develop into hepatocellular carcinoma (HCC). Despite these adverse outcomes, liver fibrosis can be reversed. Consequently, research has focused on substances that target liver fibrosis to prevent or reduce its progression. This study deals with the potential anti-fibrotic action of 3-hydroxy-β-ionone (3-HBI), a bioactive compound found in many plants. To assess the putative effects of 3-HBI, pro-inflammatory cytokine production and the expression of genes and proteins associated with the TGF-β/SMAD2/3 pathway were monitored following exposure to 3-HBI. Initially, cells of the human hepatic stellate cell line LX-2 were treated with TGF-β1 to simulate fibrogenesis. Following the exposure of activated LX-2 cells to 3-HBI, the production of pro-fibrotic substances was significantly reduced. Molecular docking studies revealed that 3-HBI exhibited a high binding affinity for key proteins in the TGF-β/SMAD2/3 pathway. Analyses using qRT-PCR and Western blotting revealed that 3-HBI suppressed the expression of TIMP1, MMP2, MMP9, COL1A1, COL4A1, SMAD2, SMAD3, SMAD4, MMP2, and ACTA2. Together, these findings demonstrate that 3-HBI inhibited the activation of LX-2 cells and significantly reduced the proinflammatory responses triggered by TGF-β1. Accordingly, we confirmed the noteworthy potential of 3-HBI as a therapeutic agent to prevent and treat liver fibrosis, effected by its modulation of the TGF-β/SMAD2/3 signaling pathway.
Hereditary α-tryptasemia (HαT)—a genetic trait caused by increased α-tryptase-encoding typtase alpha/beta-1 (TPSAB1) copy number—is associated with adult mastocytosis. The primary objective was to assess the association between α-tryptase and pediatric mastocytosis. We also want to evaluate whether the KIT p.D816V mutation in peripheral blood leukocytes (PBLs) reliably predicts systemic mastocytosis (SM) in children. A prospective cohort of 68 children from a referral center in Slovenia with cutaneous mastocytosis (CM) underwent tryptase genotyping by droplet digital PCR and examination for KIT p.D816V in PBL using a sensitive PCR test. A significant majority of patients (57 of 68; [83.8%]) had at least one α-tryptase-encoding gene; none had HαT. 7 of the 68 (10.3%) who were positive for KIT p.D816V in PBL, one fulfilled diagnostic criteria for indolent SM, and another was diagnosed with monoclonal mast cell activation syndrome. One of those individuals had an increased basal serum tryptase (BST) level (14.5 ng/mL). We found a high presence of germline α-tryptase in children with CM, but not HαT. By employing sensitive examination for KIT p.D816V in PBL, in combination with clinical data and other examinations, our study suggests that KIT p.D816V in PBL may indicate systemic disease in children with CM.
The limited efficacy of antipsychotics in treating the negative and cognitive symptoms of schizophrenia has prompted the exploration of adjuvant therapies. Several drugs developed for other indications—including caffeine, metformin, and furosemide—have shown procognitive potential. This study evaluated the effects of these agents on behavioral parameters using the reward-based Ambitus test, and on the cerebral D2 dopamine receptor (D2R) expression and binding. The drugs were administered individually and in combination in a schizophrenia-like triple-hit animal model (Lisket rats), derived from the Long Evans (LE) strain. Lisket rats received 14 days of drug treatment via drinking water; water-drinking LE rats served as the controls. The Ambitus test was conducted before treatment and on days 11–14. Caffeine enhanced activity without affecting learning or memory. Metformin and furosemide reduced exploratory behavior but improved reference memory; these effects were inhibited by caffeine co-administration. Although no statistically significant behavioral differences were found compared to water-treated Lisket rats, a trend toward reduced exploratory visits was observed in the triple-combination group. Lisket rats exhibited moderately reduced D2R binding in the cortex and increased binding in the hippocampus. Caffeine alone and in combination enhanced hippocampal D2R binding, while furosemide increased cortical D2R expression. This study is the first to highlight the behavioral and molecular effects of these non-antipsychotic agents in a schizophrenia model, supporting their potential for adjunctive use.
This study aimed to develop polylactic acid (PLA)-based membranes incorporating tramadol (TMD) using air jet spinning (AJS), ensuring stable physicochemical properties and biocompatibility. Two groups were fabricated: 10% PLA membranes (control) and 10% PLA membranes loaded with TMD in an 80:1 ratio (experimental). Characterization included scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-VIS), and biocompatibility assays with human osteoblasts using resazurin, crystal violet staining, and 5-chloromethylfluorescein diacetate for fluorescence microscopy. SEM revealed a homogeneous, randomly distributed fiber pattern, with diameters under 5 µm and no structural voids. DSC and TGA indicated that TMD was uniformly incorporated, increased the thermal capacity, and slightly lowered the onset and inflection degradation temperatures. FT-IR confirmed the chemical compatibility of TMD with PLA, showing no structural alterations. UV-VIS detected sustained TMD release over 72 h. Biocompatibility tests showed no cytotoxic effects; cell viability and proliferation in TMD-loaded membranes were comparable to controls. Statistical analysis used ANOVA and Wilcoxon tests. 10% PLA membranes loaded with TMD at an 80:1 ratio exhibited stable physicochemical characteristics and favorable biocompatibility, supporting their potential use in drug delivery systems.
The field of colloid systems is still a developing scientific area, but a very promising one for many practical applications [...]
The essential micronutrient zinc is known to inhibit gastric acid secretion (GAS), where its homeostasis is strictly regulated. We hypothesized that the gastric bitter taste receptors, TAS2Rs, regulate the following: (i) zinc-modulated proton secretory activity (PSA) as a key mechanism of GAS and (ii) zinc homeostasis in immortalized parietal cells. To confirm this hypothesis, human gastric tumor cells (HGT-1) were exposed to 100–1000 µM of zinc salts for 30 min in order to quantitate their TAS2R-dependent PSA and intracellular zinc concentration using a fluorescence-based pH sensor and ICP-MS, respectively. Thereby, we identified TAS2R43 as a key player in parietal cell PSA and zinc homeostasis, with both conclusions being verified by a CRISPR-Cas9 knockout approach. Moreover, by regulating the zinc importer protein ZIP14, TAS2R43 proved to perform a protective role against excessive zinc accumulation in immortalized parietal cells.
Rare genetic movement disorders usually manifest early in life with dystonia, parkinsonism, chorea, or a combination thereof. These are often associated with neurodevelopmental delay, intellectual disability, speech problems, retinal abnormalities, seizures, ataxia, spasticity, or systemic features. Due to their vast number and pheno–genotypic heterogeneity, the diagnosis of these disorders can be challenging. However, recognising their core motor phenomenology as well as clinical, laboratory, and neuroradiological clues can expedite appropriate diagnostic workup, molecular diagnosis, and adequate treatment. In this review, we outline diagnostic clues to rare movement disorders (RMDs), focusing on those that present mainly with dystonia, parkinsonism, or paroxysmal dyskinesia due to genetic causes. Additionally, we provide a decision tree approach linking clinical, genetic, and imaging testing. Finally, we highlight selected RMDs that should not be missed, as they possess established treatments that can hinder their progression, prevent irreversible or life-threatening sequelae and, in certain cases, lead to complete symptom remission.
Salt accumulation in arable lands causes significant abiotic stress, resulting in a 10% loss in global arable land area and jeopardizing food production and agricultural sustainability. In order to attain high and sustainable food production, it is imperative to enhance traditional agricultural practices with modern technology to enable the restoration of arable lands afflicted by salinity. This review consolidates recent rice-specific advancements aimed at enhancing salt stress resilience through integrated strategies. We explore the functions of primary and secondary metabolic pathways, organic amendments, microbial symbiosis, and plant growth regulators in reducing the negative impacts of salt. Furthermore, we highlight the significance of emerging genetic and epigenetic technologies, including gene editing and transcriptional regulation, in developing salt-tolerant rice cultivars. Physiological studies reveal salt stress responses in rice plants, biochemical analyses identify stress-related metabolites, microbial investigations uncover beneficial plant–microbe interactions, and molecular approaches enable the identification of key genes—together providing essential insights for developing salt-tolerant rice varieties. We present a comprehensive overview of the multilayered strategies—ranging from agronomic management and physiological adaptations to molecular breeding and microbial applications—that have been developed and refined over recent decades. These approaches have significantly contributed to understanding and improving salinity tolerance mechanisms in rice. This review provides a foundational framework for future research and practical implementation in stress-resilient rice farming systems.
Lactylation and PANoptosis are emerging modes of tumor progression regulation; however, their interplay and effect on the prognosis for lung adenocarcinoma (LUAD) remain unclear. This research analyzed both bulk and single-cell transcriptomic profiles of LUAD and identified 506 potential markers related to lactylation and PANoptosis. Employing 117 machine learning approaches and 5 LUAD datasets, lactylation and PANoptosis-related signatures (LAPRS) and further predictive nomograms were constructed with 85 prognostic genes. The performance of LAPRS was validated with multifaceted validation, including Kaplan–Meier analysis, time-dependent ROC curves and comparison with 55 existing LUAD models. LAPRS enabled the stratification of LUAD patients into high- and low-risk subgroups. Through additional investigation, high-risk individuals showed elevated genomic alterations, reduced immune infiltration, and poorer immunotherapy response, while low-risk individuals showed better drug sensitivity and a higher tumor mutation burden. Further analysis via 18 models and experimental validation revealed APOL1 as a poor prognostic factor, potentially interacting with the lactylation-related gene VIM through TNF signaling. This research clarifies the mechanistic roles of lactylation and PANoptosis in LUAD and proposes APOL1 as a novel prognostic marker, offering insights for therapeutic stratification.
Lymphangioleiomyomatosis (LAM) is a rare progressive disease that affects women of reproductive age and is characterized by cystic lung destruction, airflow obstruction, and lymphatic dysfunction. Current diagnostic methods are costly or lack sufficient specificity, highlighting the need for novel non-invasive approaches. Exhaled breath analysis using real-time proton mass spectrometry (PTR-MS) presents a promising strategy for identifying disease-specific volatile organic compounds (VOCs). This cross-sectional study analyzed exhaled breath samples from 51 LAM patients and 51 age- and sex-matched healthy controls. PTR-time-of-flight mass spectrometry (PTR-TOF-MS) was employed to identify VOC signatures associated with LAM. Data preprocessing, feature selection, and statistical analyses were performed using machine learning models, including gradient boosting classifiers (XGBoost), to identify predictive biomarkers of LAM and its complications. We identified several VOCs as potential biomarkers of LAM, including m/z = 90.06 (lactic acid) and m/z = 113.13. VOCs predictive of disease complications included m/z = 49.00 (methanethiol), m/z = 48.04 (O-methylhydroxylamine), and m/z = 129.07, which correlated with pneumothorax, obstructive ventilation disorders, and radiological findings of lung cysts and bronchial narrowing. The classifier incorporating these biomarkers demonstrated high diagnostic accuracy (AUC = 0.922). This study provides the first evidence that exhaled breath VOC profiling can serve as a non-invasive additional tool for diagnosing LAM and predicting its complications. These findings warrant further validation in larger cohorts to refine biomarker specificity and explore their clinical applications in disease monitoring and personalized treatment strategies.
The SNCA gene, encoding alpha-synuclein, is implicated in the pathogenesis of Parkinson’s disease (PD), with several single-nucleotide polymorphisms (SNPs) linked to increased risk. This study systematically evaluated the association between common SNCA polymorphisms and PD through a meta-analysis of cohort and case–control studies published before 20 November 2023. Eligible studies were identified via comprehensive searches of PubMed, Scopus, and Web of Science, and pooled odds ratios with 95% confidence intervals were calculated under allelic, dominant, and recessive models. Heterogeneity and publication bias were assessed, and subgroup and sensitivity analyses were performed. Twenty-seven studies were included. SNP rs11931074 showed consistent associations with PD across all models, with low heterogeneity and no evidence of publication bias. rs356219 and rs356165 were also significantly associated with PD, although regional differences contributed to heterogeneity. In contrast, rs2583988 showed marginal significance in the allelic model, which was lost after sensitivity analyses. No associations were found under dominant or recessive models for this SNP. These findings confirm rs11931074 as a robust PD risk variant and support the roles of rs356219 and rs356165 while suggesting weaker evidence for rs2583988. Large, multi-ethnic studies are warranted to elucidate underlying mechanisms and support precision medicine in PD.
Precision prevention strategies for cervical cancer that integrate genetic biomarkers provide opportunities for personalized risk assessment and optimized preventive measures. An HPV infection–Precancerous–Cancer risk assessment model incorporating genetic polymorphisms and DNA methylation was developed to better understand the regression and progression of cervical lesions by HPV infection status. Utilizing a virtual cohort of 300,000 Taiwanese women aged 30 years and older, our model simulated the natural history of cervical cancer, capturing transitions from a healthy state through precancerous lesions (LSILs and HSILs) to invasive carcinoma and incorporating the possibility of regression between states. Genetic and epigenetic markers significantly influenced disease transitions, demonstrating heterogeneous risks among women with distinct molecular biomarker profiles. Guided by these individual risk profiles, tailored preventive strategies including varying intervals for Pap smear screening, HPV DNA testing, and HPV vaccination showed improved efficiency and effectiveness in reducing cervical cancer incidence compared to uniform approaches. The proposed dynamic transition model of cervical neoplasms incorporating genetic biomarkers can facilitate the development of an individualized risk-based approach for guiding precision prevention towards the goal of cervical cancer elimination.
Antibody-mediated rejection (ABMR) remains a major cause of renal graft dysfunction and loss. The histological hallmark of antibody-mediated rejection is progressive tissue damage, in which extracellular matrix turnover plays an important role. This turnover is mainly regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Recent studies suggest that MMP/TIMP imbalance may favor the progression of renal damage, inflammation, and fibrosis, but the utility of these molecules as a biomarker of antibody-mediated turnover has not been fully explored. We measured plasma MMP and TIMP levels by ELISA in 15 patients with antibody-mediated renal transplant rejection and 12 patients without rejection. There was a significant increase in MMP-1, MMP-2, and MMP-3 concentrations in the plasma of patients with rejection, directly correlating with the severity of different renal lesions. In contrast, TIMP-3 levels were elevated in patients without rejection, showing a negative correlation with the severity of histopathological lesions. The concentrations of these molecules demonstrated good diagnostic capacity for patients with rejection. Our results show that MMP-1, MMP-2, MMP-3, and TIMP-3 could be potential biomarkers of rejection.
One of the most prevalent types of cancer among women is ovarian cancer. The search for ovarian cancer markers is constantly ongoing. Evaluation of LAG-3 and TIM-3 protein expression in ovarian cancer tissue and its role in distinguishing the clinical signs stated were the objectives of this study. Methods: A total of 58 ovarian cancer patients were recruited for this study. The cohort was split into two groups: one for high-grade serous ovarian cancer (HGSOC) and another for ovarian cancer that was not HGSOC (non-HGSOC). LAG-3 and TIM-3 protein expression in ovarian cancer tissue samples was evaluated by immunohistochemistry. StatView 5.0 software (Carry, NC, USA) was used for all statistical analyses. Both LAG-3 and TIM-3 proteins mostly showed positive, moderately positive, or strongly positive expression. This study shows that LAG-3 could be a marker associated with BMI in the non-HGSOC group. TIM-3 may be a marker associated with age in a group of all ovarian cancers. LAG-3 expression is associated with TIM-3 expression in the total cohort and the HGSOC and non-HGSOC groups.
Wild fruits are distributed worldwide, but are consumed mainly in developing countries, where they are an important part of the diet. Still, in many other countries, they are consumed only locally. Blackthorn (Prunus spinosa L.) is an underutilized species rich in fibres and phenolic compounds, making it suitable as a potential functional food for supporting human health. Cold (Cw) and hot (Hw) water-extracted (poly)phenolic polysaccharide–protein complexes, differing in carbohydrate, phenolic and protein contents, were isolated from blackthorn fruits and characterized. The complexes exhibited molecular weights of 235,200 g/mol (Cw) and 218,400 g/mol (Hw), and were rich in pectic polymers containing galacturonic acid, arabinose, galactose and rhamnose, indicating a dominance of homogalacturonan (HG) [→4)-α-D-GalA(1→4)-α-D-GalA(1→]n and a low content of RGI [→2)-α-L-Rha(1→4)-α-D-GalA(1→2)-α-L-Rha(1→]n sequences associated with arabinan or arabinogalactan. Minor content of glucan, probably starch-derived, was also solubilized. Pectic polysaccharides were highly esterified and partly acetylated. Pharmacological testing was performed in male Dunkin–Hartley guinea pigs, a model with human-like airway reflexes. Both complexes affected airway defense mechanisms. Particularly, Hw significantly suppressed citric acid-induced cough, similar to codeine, and reduced bronchoconstriction comparably to salbutamol in a dose-dependent manner. These findings support further exploration of Hw as a natural antitussive and bronchodilatory agent.
Endometriosis is a complex gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to chronic pain and infertility. Immunohistochemistry (IHC) serves as a vital technique for elucidating the molecular and cellular differences between ectopic endometriotic tissues and eutopic endometrium. IHC reveals significant variations in the expression of inflammatory markers, adhesion molecules, and cell cycle regulators. This literature review compiles findings from various studies that assess the role of key proteins, such as leukemia inhibitory factor (LIF), cyclooxygenase-2 (COX-2), and b-cell lymphoma 2 (BCL-2), across different menstrual phases and lesion types. Notably, elevated LIF levels and increased mast cell activity in ectopic tissues underscore the inflammatory landscape of endometriosis. Additionally, altered expression of adhesion molecules like integrins and cluster of differentiation 44 (CD44) suggests modified cellular interactions, while apoptotic markers reveal a survival advantage for ectopic cells. These insights enhance our understanding of endometriosis pathophysiology.
AbstractMild repetitive head injury is a serious health problem with long-term negative consequences. Changes in brain neurobiology were assessed with MRI in a model of head injury designed to reflect the human experience. Rats were maintained on a reverse light-dark cycle and head impacted daily at 24 h intervals over three days while fully awake under red light illumination. There was no neuroradiological evidence of brain damage. Rats were imaged for changes in blood brain barrier permeability, edema and gray matter microarchitecture, and resting state functional connectivity. Data were registered to a 3D MRI rat atlas with 173 segmented brain areas providing site-specific information on each imaging modality. Changes in BBB permeability were minimal and localized to the hippocampus and cerebellum. There was evidence of cytotoxic edema in the basal ganglia, thalamus, and cerebellum. There was a global decrease in connectivity and an increase in gliosis in the thalamus, cerebellum, and hippocampus. This study shows a sequelae of neuropathology caused by mild repetitive head injury that is commonly observed in clinical practice using MRI in patients. As such, it may serve as a model for testing the efficacy of new therapeutics using any or all of the measures as biomarkers to assess drug efficacy.
AbstractClinical investigations have suggested a potential link between cataracts and Alzheimer’s disease (AD). However, whether cataract has an impact on the progression of AD remains unclear. The objective of this research was to determine the relationship between cataracts and AD. A cataract model was established in APP/PS1 [mutant amyloid precursor protein (APP) and a mutant presenilin-1 (PS1) gene] micevialens puncture. Behavioural assays were used to evaluate cognitive function. Immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assays (ELISA) were applied to detect AD-related pathology. Visual signals were markedly obstructed following surgery to induce cataracts, and these mice presented an increased cerebral amyloid-beta (Aβ) load, while no significant alterations in the levels of enzymes associated with Aβ metabolism were detected. In addition, compared with control mice, cataract model mice presented increased astrogliosis and microgliosis, along with elevated levels of proinflammatory factors. Moreover, cataract model mice presented more pronounced cognitive impairments than did control mice. Our study offers experimental confirmation that cataract considerably contributes to the pathogenesis of AD, thereby emphasizing the importance of visual signals in maintaining cognitive well-being.
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AbstractEpisodic memory, our ability to recall past experiences, is supported by structures in the medial temporal lobe (MTL) particularly the hippocampus, and its interactions with fronto-parietal brain regions. Understanding how these brain regions coordinate to encode, consolidate, and retrieve episodic memories remains a fundamental question in cognitive neuroscience. Non-invasive brain stimulation (NIBS) methods, especially transcranial magnetic stimulation (TMS), have advanced episodic memory research beyond traditional lesion studies and neuroimaging by enabling causal investigations through targeted magnetic stimulation to specific brain regions. This review begins by delineating the evolving understanding of episodic memory from both psychological and neurobiological perspectives and discusses the brain networks supporting episodic memory processes. Then, we review studies that employed TMS to modulate episodic memory, with the aim of identifying potential cortical regions that could be used as stimulation sites to modulate episodic memory networks. We conclude with the implications and prospects of using NIBS to understand episodic memory mechanisms.
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AbstractNeuronal injury in glaucoma persists despite effective intraocular pressure (IOP) control, necessitating neuroprotective strategies for retinal ganglion cells (RGCs). In this study, we investigated the neuroprotective role of the γ-hydroxybutyrate analog HOCPCA in a glaucoma model, focusing on its effects on CaMKII signaling, oxidative stress, and neuroinflammatory responses. Retinal tissue from high IOP animal models was analyzedviaproteomics.In vitromouse retinal explants were subjected to elevated pressure and oxidative stress, followed by HOCPCA treatment. HOCPCA significantly mitigated the RGC loss induced by oxidative stress and elevated pressure, preserving neuronal function. It restored CaMKIIα and β levels, preserving RGC integrity, while also modulating oxidative stress and neuroinflammatory responses. These findings suggest that HOCPCA, through its interaction with CaMKII, holds promise as a neuroprotective therapy for glaucoma.
AbstractThe advancement of tissue clearing technology has significantly propelled neuroscience research. Nevertheless, the fluorescent proteins used in traditional transgenic mouse strains were not specifically optimized for tissue clearing procedures, resulting in a substantial decrease in fluorescent intensity after clearing. In this study, we developed theCi1reporter mouse strain (where Ci stands for the Chinese Institute for Brain Research, CIBR) based on the bright red fluorescent protein mScarlet. TheCi1reporter exhibits no fluorescence leakage in various organs or tissue types and can be readily crossed with multiple tissue-specific Cre lines. Compared to theAi14mouse strain, theCi1reporter strain demonstrates lower non-specific leakage, stronger fluorescence intensity in different tissues, and better preservation of fluorescence following tissue clearing treatment. The creation of theCi1reporter provides a more effective tool for both neuroscience and other biomedical research applications.
AbstractGrowth and differentiation factor 15 (GDF15) is a significant player in cellular stress and energy homeostasis. GDF15 is elevated in cancer cachexia, chemotherapy-induced anorexia, hyperemesis gravidarum, and mitochondrial disorders. Here we analyze GDF15 in anorexia nervosa (AN), a psychiatric disorder characterized by low weight and persistent restriction of food intake. While no significant difference in plasma GDF15 concentration was seen across the three included groups; active AN, recovered AN, and healthy controls, a subgroup of study participants with high GDF15 plasma was noted to a significantly higher extent in the AN groups. Sparse partial least squares discriminant analysis (sPLS-DA) identified six markers related to inflammatory processes or cellular stress from a set of 74 markers that distinguished AN with high GDF15 from the rest, with fibroblast growth factor 21 (FGF21) being the most important contributor. Moreover, FGF21 plasma concentration was significantly higher in the group with high GDF15, suggesting an involvement of mitochondrial dysfunction. In fact, mitochondrial polygenic risk score (PRS) was significantly associated with AN risk in a large AN case-control cohort. In line with this, we also report elevated liver expression of GDF15 in theanx/anxmouse displaying anorexia associated with mitochondrial dysfunction. We conclude that mitochondrial dysfunction should be further explored in AN. Clinical trials of GDF15 immunoneutralization in patients with AN and high levels of GDF15 are worthy of consideration.
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AbstractIn attention-deficit/hyperactivity disorder (ADHD), emotional features account for heterogeneity and exacerbate severity of behavioral and functional impairments, beyond cognitive and comorbidity features. Yet, debate remains about the extent to which, in ADHD, such emotional features are a “core feature”, i.e. whether ADHD should be conceptualized as encompassing difficulties with regulating not only activity, attention, and impulses but also processing and regulating emotions. We aimed to address this issue by examining the extent to which in adolescents, ADHD polygenic scores (PGSs) are associated with electrophysiological indices of affective-motivational processing, measured during a monetary punishment/reward feedback paradigm. ADHD PGSs were negatively associated, inn= 166 adolescents (Mage= 15.76 years,SD= 1.07; 42.77% girls), with amplitude values of an occipitoparietal event-related potential (i.e. late positive potential) and were positively associated, inn= 84 adolescents (Mage= 15.76 years,SD= 1.05; 41.67% girls), with fronto-centro-parietal alpha event-related desynchronization. Across analyses, covariates were anxiety, depression, and ADHD with comorbid disruptive behavior disorder PGSs; ADHD, internalizing, and oppositional defiant disorder severity; childhood maltreatment; current ADHD medication; and baseline values of the outcome. Findings were replicated in sensitivity analyses with blocks of conceptually related covariates entered separately. In adolescents, electrophysiological indices of affective-motivational processing are associated principally with genetic liability for ADHD but not comorbidity genetic liability or comorbidity manifest symptoms.
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AbstractBackgroundIn order to appraise the risk-benefit balance of the three available dual orexin receptor antagonists (DORAs; daridorexant, lemborexant, and suvorexant) for the management of adults with insomnia, we conducted a systematic review and random-effects model network meta-analysis.MethodsIncluded were all published double-blind, randomized, placebo-controlled trials of these agents. Outcomes included subjective time to sleep onset at month 1 (sTSO, primary), subjective total sleep time at month 1 (sTST, co-primary), subjective wake after sleep onset at month 1, Insomnia Severity Index scores at month 1, all-cause discontinuation, discontinuation due to adverse events, and the incidence of individual adverse events such as somnolence, dizziness, falls, headache, nasopharyngitis, and upper respiratory tract infection.ResultsThis meta-analysis included eight trials (5198 adults, average age = 56.33 years, 67.84% female). The treatment arms included daridorexant 25 mg/day (DAR25), daridorexant 50 mg/day (DAR50), lemborexant 5 mg/day (LEM5), lemborexant 10 mg/day (LEM10), suvorexant 20 mg/day (15 mg/day for people ≥65years, SUV20/15), and placebo. All active-treatments outperformed placebo in terms of all efficacy outcomes. The standardized mean difference (95% CI) in primary outcomes ranged from; sTSO: −0.430 (−0.568, −0.292) for LEM10 to −0.164 (−0.296, −0.031) for SUV20/15 and sTST: −0.475 (−0.593, −0.357) for DRA50 to −0.206 ( −0.330, −0.082) for LEM5. An additional sensitivity analysis suggested that DRA25, LEM10, and SUV20/15 were associated with a higher incidence of somnolence compared to a placebo.ConclusionsConsidering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults.
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AbstractSchizophrenia (ScZ) is characterized by prominent perceptual abnormalities. A deeper understanding of the neural mechanisms underlying these abnormalities is crucial for developing precise treatment strategies. Our study aimed to address the following primary questions. First, the functional role of various sub-oscillations within the alpha band remains unclear. Second, we aimed to identify biomarkers for the diagnostic purposes of ScZ. Third, the broader question of whether the diagnostic biomarker can also function as a treatment biomarker remains unknown. Resting-state EEG data from 55 ScZ patients and 61 healthy controls were analyzed to compare different sub-oscillations in the alpha band and their correlation with clinical symptoms (as measured by the general psychopathology scale). We discovered that distinct topographic patterns in low (~8 Hz) and high (~12 Hz) alpha may serve specific diagnostic and evaluative purposes respectively. Moreover, a pronounced gender bias was also observed. Low-alpha-band activity appeared to have more diagnostic relevance in females. On the other hand, the high-alpha difference was more relevant for evaluating the severity of symptoms in ScZ males. Our research has brought new insights into the neural oscillation mechanism of schizophrenia, which could substantially assist the formulating diagnosis of ScZ and the development of its treatment strategies.
AbstractSerum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P< 10−5) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P< 5 × 10−8) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.
AbstractPost-traumatic stress disorder (PTSD) is a delayed-onset or prolonged persistent psychiatric disorder caused by individuals experiencing an unusually threatening or catastrophic stressful event or situation. Due to its long duration and recurrent nature, unimodal neuroimaging tools such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and electroencephalography (EEG) have been widely used in the diagnosis and treatment of PTSD for early intervention. However, as compared with an unimodal approach, a multimodal imaging approach can better capture integrated neural mechanisms underlying the occurrence and development of PTSD, including predisposing factors, changes in neural activity, and physiological mechanisms of symptoms. Moreover, a multimodal neuroimaging approach can aid the diagnosis and treatment of PTSD, facilitate searching for biomarkers at different stages of PTSD, and explore biomarkers for symptomatic improvement. However, at present, the majority of PTSD studies remain unimodal, while the combination of multimodal brain imaging data with machine learning will become an important direction for future research.
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AbstractDepression and anxiety are disabling and high incidence mental disorders characterized by phenotypic heterogeneity. Currently available treatments show severe limitations. Thus, there is an urgent need for effective treatments in this population. In the search for novel rapid-acting antidepressants, the psychedelic psilocybin has emerged as a promising therapy in several clinical trials. However, its antidepressant mechanism of action is still not well understood. The aim of the present study was to evaluate the therapeutic potential of psilocybin in ameliorating the adverse behavioural and neurochemical consequences of chronic stress. To this end, a chronic unpredictable mild stress (CUMS) animal model was used, and psilocybin treatment was administered (two doses of 1 mg/kg, i.p., administered 7 days apart). Psilocybin reversed impairments in anhedonia and behavioural despair dimensions of depressive phenotype but not in apathy-related behaviour. Psilocybin administration was also able to exert an anxiolytic-like effect on treated animals. Physiological alterations caused by stress, indicative of a hyperactive hypothalamic-pituitary-adrenal axis (HPA), were not reversed by psilocybin. When neuroplasticity-related proteins were assessed in cerebral cortex, brain-derived neurotrophic factor (BDNF) was found to be decreased in stressed animals, and treatment did not reverse such impairment. Psilocybin administration increased the expression and function of serotonin-2A-receptor (5HT2AR) in brain cortex of control and CUMS groups. Furthermore, psilocybin treatment caused a selective increase in the expression of glucocorticoid-receptor (GR) in brain cortex of CUMS mice. In conclusion, psilocybin was able to rescue impairments in the depressive phenotype, and to induce anxiolytic-like effects. Furthermore, an enhancement in sensitivity to psilocybin-induced HTR was observed following a booster dose. Altogether, this work provides new knowledge on the putative benefit/risk actions of psilocybin and contributes to the understanding of the therapeutic mechanism of action of psychedelics.
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AbstractConsidering the complexity of serotonergic influence on emotions, we conducted a comprehensive investigation of the interplay between emotion processing and the serotonergic system using simultaneous functional and molecular neuroimaging during pharmacological challenge while disentangling the effects of serotonin transporter (SERT) binding, genotype, and diagnosis of major depressive disorder (MDD). Herein, 153 subjects (44 with MDD) performed a facial emotion processing task during functional magnetic resonance imaging (fMRI) before and after an acute intravenous application of 8 mg citalopram or placebo. Patients with MDD were assessed again after at least three months of antidepressant treatment. Citalopram administration resulted in a reduced fMRI activation in regions involved in fear processing, including the anterior cingulate cortex (ACC), when viewing fearful faces contrasted against happy or neutral faces. ACC activation correlated negatively with striatal/thalamic SERT availability across drug conditions as measured by [11 C]DASB positron emission tomography. Across groups, citalopram-induced changes in ACC activation correlated with emotional attribution, indicating stronger reductions for subjects with higher self- versus other- attribution. Moreover, striatal SERT availability mediated the influence of the number of 5-HTTLPR/rs25531 LAalleles on ACC activation under placebo. Patients with MDD exhibited increased activations in the intraparietal and superior frontal sulcus in response to fearful versus happy faces at baseline, and along the parieto-occipital/calcarine fissure after treatment. We interpret our findings on multiple levels of the serotonergic-emotional interaction within the context of enhanced passive coping and acute anxiolytic effects of citalopram following potential changes in serotonin or SERT availability.
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AbstractMajor depressive disorder (MDD) ranks among the leading causes of disability worldwide. An additional burden arises from treatment-resistance, defined by a lack of response to two or more adequate pharmacotherapeutic treatment trials. Unlike in MDD, where the serotonin 1A receptor subtype (5-HT1A) has commonly been used to study pathophysiological alterations, treatment-resistant depression (TRD) subjects represent a less investigated cohort. In this cross-sectional study, 5-HT1Areceptor binding was assessed in 33 subjects with TRD with stable medication and 44 healthy control (HC) subjects. Positron emission tomography scans with the radioligand [carbonyl-11C]WAY-100635 were acquired and 5-HT1Areceptor nondisplaceable binding potential (BPND) was quantified using the multilinear reference tissue model 2. Regional BPNDin amygdala, anterior cingulate cortex, hippocampus, insula, orbitofrontal cortex, dorsal raphe nucleus and median raphe nucleus was assessed using a multivariate analysis of covariance (MANCOVA). The MANCOVA showed a significant effect of group (F = 3.349,p< 0.05) and sex (F = 2.428,p< 0.05). The subsequent pairwise comparison revealed a lower BPNDby 17.45% in the TRD group in the dorsal raphe nucleus (mean difference ± SE = −0.59 ± 0.24,p< 0.05) and by 18.39% in the median raphe nucleus (mean difference ± SE = −0.71 ± 0.30,p< 0.05). Our results extend previously reported alterations of 5-HT1Areceptor distribution in non-resistant depression to TRD. Ultimately, this knowledge may contribute to clarifying the role of serotonin and help to address the urgent issue of treatment resistance in depression.
AbstractA delay in brain maturation is a hypothesized pathomechanism of attention-deficit/hyperactivity disorder (ADHD). Differences in emotion regulation are associated with phenotypic and prognostic heterogeneity in ADHD. The development of emotion regulation is driven, in part, by brain maturation. Whether the difference between an individual’s brain age predicted by machine-learning algorithms trained on neuroimaging data and that individual’s chronological age, i.e. brain-predicted age difference (brain-PAD) predicts differences in emotion regulation, and whether ADHD problems add to this prediction is unknown. Using data from the Adolescent Brain Cognitive Development Study, we examined, in 2711 children (Mage= 120.09 months,SD= 7.61; 54.15% female; 61.23% white), whether adjusting for action cancellation (inhibition), age, sex assigned at birth, psychotropic treatment, and pubertal status, brain-PAD in late childhood predicts self-reported emotion regulation in early adolescence (at 3-year follow-up), and whether parent-reported ADHD problems predict self-reported emotion regulation above and beyond brain-PAD. Greater brain-PAD predicted greater expressive suppression (b= 0.172,SE= 0.051,pFDR= 0.004), whereas ADHD problems did not (b= 0.041,SE= 0.022,pFDR= 0.124), model marginalR2= 0.020. This pattern of results was replicated across sensitivity tests. Neither brain-PAD, nor ADHD problems predicted cognitive reappraisal,pFDRs = 0.734. Clinically, consistent with earlier findings linking greater brain-PAD to psychopathology, we observed that greater brain-PAD in childhood—but not ADHD problems—predicted expressive suppression in early adolescence. Expressive suppression is implicated in the etiology, maintenance, and treatment of numerous psychopathologies, highlighting the relevance of brain-PAD in understanding developmental risk mechanisms. Conceptually, these findings further validate brain-PAD as a valuable tool for advancing developmental neuroscience.
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AbstractCellular prion protein (PrPC) and tau are highly expressed in the brain and overlap at the cellular level in neurons. Both proteins contribute directly to neurodegeneration processes in a misfolding state, although in their natural conformation, they play important roles in neurogenesis that could have a common link according to the recent literature. In this sense, it is well known that the proteinase-K resistant PrPCisoform (PrPSc), the prion, is the causal agent of prionopathies. And misfolded tau, which is responsible for tauopathies, is considered “prion-like” because it displays similar behavior to prions in terms of self-aggregation and spreading properties. At the physiological level, PrPCpotentiates neuronal differentiation while tau intervenes in axonal maturation and elongation. Likewise, recent studies from our laboratory reported that PrPCdirectly affects the alternative splicing of tau through inhibition of GSK3β while tau, in turn, can regulatePRNPtranscription. In this review, we first describe the biology and physiological roles of PrPCand tau in the central nervous system (CNS). Second, in the effort to improve our understanding of a possible cooperation between them in various cellular circumstances, we also discuss the molecular convergence points between PrPCand tau in neurodegeneration and in natural neuronal physiology.
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AbstractNeuropathic pain is a serious neurological disorder caused by lesioned somatosensory neurons characterized by multiple pathologies. Transient receptor potential vanilloid 1 (TRPV1) channels and opioid receptors are co-expressed in dorsal root ganglia (DRG) and play a crucial role in the development of neuropathic pain. Here, we investigated the possible involvement of TRPV1 channels and µ-opioid receptors in mediating the antinociception of the KATPopener, nicorandil, in neuropathic pain in four nociceptive models: chronic constriction injury of the sciatic nerve (CCI), formalin, capsaicin, and acetic acid writhing tests. Nicorandil (150 mg/kg, twice, 2 h apart, PO) administered to male rats (i) reversed the effects of CCI on nociceptive threshold and cumulative scores assessed by von Frey and acetone test, respectively; (ii) reduced licking time and number of flinches in biphasic formalin and capsaicin tests, and (iii) reduced the number of writhes in the acetic acid test; and (iv) combined nicorandil-capsaicin abolished acetic acid induced writhing response. Similarly, ipsilateral intraplantar injection of nicorandil (37.5 mg/paw, twice, ipl) inhibited nociceptive responses induced by capsaicin, formalin, and acetic acid. Immunohistochemical analysis revealed that nicorandil blunted the CCI-induced elevation of TRPV1 protein expression in DRG. The beneficial effects of nicorandil in all models were attenuated by naloxone. Molecular docking supported the interaction between nicorandil and TRPV1. Histologically, nicorandil improved the pathological changes induced by CCI in the sciatic nerve and DRG. Collectively, these results demonstrate that nicorandil exhibits antinociceptive effects in neuropathic and nociceptive pain via mechanisms involving TRPV1 modulation and opioid receptor signaling. Further investigation is warranted to explore the mechanism of action of nicorandil as an alternative treatment option for neuropathic pain.
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AbstractCerebral ischemia–reperfusion injury (CIRI) induces significant microglial inflammation. V-type immunoglobulin domain–containing suppressor of T cell activation (VISTA), a novel inhibitory immune checkpoint, participates in myeloid cell metabolism. This study aims to investigate the molecular mechanisms of VISTA’s protective effects on CIRI by modulating microglial metabolism. In this study, differentially expressed genes (DEGs) were extracted from GSE77986 to identify hub gene VISTA. Transient middle cerebral artery occlusion (tMCAO) and oxygen–glucose deprivation and reoxygenation (OGD/R) were conducted to mimic CIRI. AAVMG1.2-VSIR was injected intracerebroventricularly into Cx3cr1Cremice, while over-expression plasmids were transfected into BV2 to intervene VISTA. The mice underwent LONGA scoring, H&E, Nissl, and TTC staining. Western blot and qRT-PCR were conducted for VISTA, IL-6, TNFα, IL-1β, and IL-10. Microglial proliferation was assessed by Edu staining and CCK8. RNA-sequencing (RNA-seq) analysis was used to investigate downstream pathways. Tricarboxylic acid (TCA) cycle intermediates were measured using ELISA. ACOD1/IκBα/NF-κB pathway was validated by Western blot. Eight DE-ICGs were identified through differential analysis, with VSIR exhibiting the highest expression. Additionally, VISTA was found decreased in microglia around the infarction site. Compared with CIRI group, VISTA reduced the infarct volume, improved neurological deficit, and decreased IL-6, TNFα, and IL-1β, while increasing IL-10, and suppressing microglia proliferation. RNA-seq showed that the DEGs primarily participated in microglial glucose metabolism and the IκBa/NF-κB pathway. VISTA promoted ACOD1 expression and itaconate (ITA). The protective function on CIRI and inhibitory effect on IκBa/NF-κB of VISTA were abrogated by ACOD1 knockdown.
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AbstractRetrospective diagnosis of a seizure type is pivotal for effective management and treatment of epilepsy. Previously, we demonstrated that RNA signatures could discriminate between non-epileptic spells and epileptic seizures. Here, we investigate the utility of alternative RNA splicing to distinguish generalized versus focal epileptic seizures. Blood samples were collected at baseline, 4–6 h post-seizure, and at discharge from 27 patients undergoing video-electroencephalogram (vEEG) monitoring at the Emory University Hospital. Epileptologists determined seizure classification through vEEG data review. RNA was extracted, sequenced, and analyzed for RNA expression and transcript usage. Classification models were generated to distinguish between patients who had a focal or generalized seizure. The study shows transcriptomic profile changes following EEG-verified focal and generalized seizures. Compared to baseline, focal seizure exhibits limited changes in transcriptomic expression 4–6 h post-seizure and discharge samples. In contrast, generalized seizures demonstrated a broader transcript response, with 74 differentially expressed transcripts at 4–6 h and 70 at discharge. The changes were also evident across different time points between focal and generalized seizure. The study for the first time described the landscape of isoform switching in seizure type. Notably, significant isoform switching without differences in gene expression was observed. We identified 2689 isoform switches linked to 1249 genes among which 742 genes were sensitive to nonsense-mediated mRNA decay (NMD). Significant switches were observed in genes such as CORO1C, ZBTB44, SNHG1, and RPS17. Notably, we also observed novel isoforms, including CD300 (MSTRG.26116.1), RNF216 (MSTRG.52862.7), and RN7SL1 (MSTRG.17010.3) which exhibited significant switching, revealing potential new regulators of gene expression. Differentially expressed transcripts were utilized as classifiers for machine learning (ML) modeling using random forest (rf) and radial support vector machine (rSVM) algorithms, achieving ~ 83% accuracy in classifying generalized seizures, and multivariate adaptive regression splines (mars) algorithm achieving 100% accuracy in identifying focal seizure events. Our findings of blood transcript expression changes, including isoform switch analysis, underscore the potential of blood-based transcriptome analysis for retrospectively distinguishing seizure types and identifying biomarkers for epilepsy management.
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AbstractAttention-deficit/hyperactivity disorder, or ADHD, is a neurodevelopmental disorder with poorly understood molecular mechanisms. Recent studies have proposed that gene expression involved in regulating synaptic transmission in the striatum may play a role in ADHD pathogenesis. To explore the molecular basis of ADHD, we utilized proteomic analysis using whole striatal tissues from early adult thyroid hormone-responsive protein-overexpressing (THRSP-OE) mice, which displayed defining characteristics of predominantly inattentive ADHD (ADHD-PI). We focused on the striatal brain region due to its critical role in the regulation of attention, motivation, and reward processing. Moreover, the striatum modulates dopaminergic pathways that are known to be impaired in ADHD. Our analysis revealed an innate overexpression of Snap25 protein in THRSP-OE mice, indicating possible alterations in the SNARE protein complex and potential neurotransmitter dysregulation. Furthermore, a binding affinity study showed reduced dopamine D1 receptor binding concentrations and pronounced low dopamine levels in THRSP-OE mice. Repeated seven-day injections of methylphenidate improved the low dopamine levels, reducing the EEG theta/beta ratio in this animal model. These findings suggest new markers specific to the ADHD-PI presentation and further support the role of Snap25 dysregulation and possible SNARE protein complex alterations in ADHD-PI.
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AbstractMetformin is an anti-diabetic drug used in the management of type 2 diabetes (T2D). Metformin has different pleiotropic effects, such as anti-inflammatory, antioxidant, antithrombotic, and vasculoprotective. Metformin has neuroprotective effects against neurodegenerative diseases and ischemic stroke. Conversely, metformin may exacerbate the pathogenesis of ischemic stroke. This controversial point may be related to the impact of metformin on the different signaling pathways, such as AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15). Many studies have reported the effect of metformin on ischemic stroke, with AMPK signaling only. However, little has been explored about the impact of metformin on the GDF-15 signaling in ischemic stroke. Accordingly, this review aims to discuss the role of metformin in the neuropathology of ischemic stroke regarding the AMPK and GDF-15 signaling pathways.
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AbstractThe cognitive and regulatory processes within higher-order brain structures that regulate the hypothalamic–pituitary–adrenal (HPA) axis and the limbic system orchestrate a complex stress response system. In order to address this, we collected 48 tissue samples from the amygdala (Amy), hippocampus (Hip), thalamus (Tal), hypothalamus (HT), pituitary gland (PG) and adrenal gland (AG). We applied ATAC-seq, a method for profiling accessible chromatin, to map the epigenetic landscape of these brain and endocrine tissues in pigs and generate foundational baseline chromatin accessibility datasets that can serve as a reference for future studies. A total of 321,584 consensus peaks, representing open chromatin regions across various samples and tissues in the pig genome, were identified. Screening for transcription factor binding motifs within these chromatin-accessible regions revealed 377 significantly enriched motifs in at least one tissue (p≤ 0.001). Among the 93 motifs enriched in only one tissue, some showed concordant expression of their corresponding transcription factors, includingGRHL2andKLF5in the PG, andGATA4/6, andHAND2in the AG. Differentially accessible regions (DARs), particularly in promoter regions, between brain and endocrine tissues were identified, with functional specificities in the AG, including cortisol synthesis and secretion, as well as tyrosine metabolism. The cytokine-cytokine receptor interaction and neuroactive ligand-receptor interaction pathways showed greater enrichment and open chromatin accessibility in brain regions compared to endocrine tissues (PG or AG). This study provides valuable insights into brain transcriptional regulation and adds a novel layer of information for future research on genetic improvement and animal welfare.
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AbstractExcitotoxic damage caused by high extracellular levels of glutamate in the spinal cord results in neuronal loss and severe locomotor impairment. This study investigates the efficacy of NeuroAiD II (MLC901), an herbal formulation, in promoting nerve regeneration following spinal cord injury (SCI) induced by kainic acid (KA). KA, a potent glutamate receptor agonist, causes excitotoxic damage in the spinal cord, leading to neuronal loss and locomotor impairment. To explore the potential of MLC901, KA-injured rats were treated with MLC901, and nerve regeneration was evaluated using various techniques. In this study, KA was administered intrathecally between the T12 and T13 vertebrae in rats, resulting in incomplete paraplegia. MLC901 was then tested for its neuro-regenerative potential. Various assessments were conducted to evaluate the effects of MLC901 treatment, including behavioral, electrophysiological, and histopathological analyses. Behavioral tests, such as the Basso, Beattie, and Bresnahan (BBB) open field test, running wheel, grid walk, inverted grid, and sensory tests, showed significant improvements in locomotor activity in treated rats. Electrophysiological recordings indicated that, while KA injection caused reduced amplitude and delayed latency, MLC901 treatment helped restore lost connections on days 14 and 28. Histopathological and immunohistochemical analyses also revealed improved tissue integrity and neuron survival. The study concludes that MLC901 significantly enhances locomotor recovery, somatosensory evoked potentials, and tissue preservation following SCI. These findings suggest that MLC901 holds promise as a neuro-regenerative therapy for spinal cord injuries.
AbstractParkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor and non-motor symptoms. PD neuropathology is due to the progressive deposition of mutant alpha-synuclein (α-Syn) in the dopaminergic neurons of the substantia nigra pars compacta (SNpc). This effect initiates oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis of the dopaminergic neurons in the SNpc. PD neuropathology, which is closely associated with inflammatory and oxidative disorders, disrupts different vital cellular pathways. Notably, the current anti-PD medications only relieve the symptoms of PD without averting the underlying neuropathology. Thus, it is advisable to search for novel drugs that attenuate the progression of PD neuropathology. It has been shown that phosphatidylinositol 3-kinase (PI3K), AKT, and glycogen synthase kinase 3 beta (GSK3β) signaling pathways are affected in PD. PI3K/AKT pathway is neuroprotective against the development and progression of PD. However, the over-activated GSK3β signaling pathway has a detrimental effect on PD neuropathology by inducing inflammation and oxidative stress. Dysregulation of the PI3K/AKT/GSK3β signaling pathway provokes brain insulin resistance (BIR), neuroinflammation, and neuronal apoptosis, the hallmarks of PD and other neurodegenerative diseases. However, the mechanistic role of the PI3K/AKT/GSK3β signaling pathway is not fully clarified. Therefore, in this review, we intend to discuss the role of the PI3K/AKT/GSK3β signaling pathway in PD pathogenesis and how PI3K/AKT activators and GSK3β inhibitors have helped effectively manage PD.
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AbstractSH-SY5Y cells are widely used as an in vitro neuronal model, yet reliable differentiation protocols tailored for tauopathy research remain limited. Effective differentiation is essential for studying tau aggregation, propagation, and neurodegenerative mechanisms. Here, we present an optimized two-step differentiation protocol for TauP301L-expressing SH-SY5Y cells that enhances neuronal maturation and tauopathy modeling, providing a physiologically relevant system for investigating tau seeding. SH-SY5Y cells expressing TauP301L-EGFP under an inducible system were differentiated using a two-step protocol consisting of retinoic acid (RA) for 72 h, followed by brain-derived neurotrophic factor (BDNF) and RA for 72 h. Differentiated neurons were then exposed to exogenous P301L tau peptide fibrils to assess their susceptibility to tau seeding and aggregation. Differentiation resulted in increased neurite outgrowth, cholinergic marker expression (ChAT upregulation, TH downregulation), and upregulation of the mature 2N4R tau isoform. Western blot analysis showed increased T22 and pSer262 tau immunoreactivity in seeded cells, consistent with tau conformational changes and pathological phosphorylation. These findings may reflect early stages of tau misfolding but do not confirm oligomer formation. Seeding also induced neurite remodeling, varicosity formation, and reduced neurite diameter—features consistent with tau-mediated pathology involving cytoskeletal changes, organelle accumulation, or axonal transport defects. This optimized differentiation protocol provides an experimentally tractable tauopathy model for investigating tau propagation and neuronal dysfunctions in a controlled human cell context. Compared to existing SH-SY5Y differentiation methods, our system provides faster neuronal maturation, controlled TauP301L induction, and enhanced tau isoform expression, making it a valuable platform for studying early tau misfolding events and therapeutic interventions in tauopathies.
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AbstractMultiple sclerosis (MS) is an autoimmune neurodegenerative disorder, with relapsing–remitting MS (RRMS) being the most common subtype. Interferon-γ (IFN-γ) plays a dual role in MS pathogenesis. MicroRNAs (miRNAs) have emerged as potential diagnostic biomarkers. This study examined the effect of relative expression of hsa-miR-24-3p and hsa-miR-181d-3p, plasma IFN-γ levels, and theIFNGrs2069727 T/C variant on MS risk, evaluating their interrelationships and diagnostic potential. This case–control study comprised two overlapping groups—a genetic polymorphism group (330 RRMS, 330 healthy controls (HCs)) and a miRNA group (25 glatiramer acetate (GA)-treated RRMS patients, 25 treatment-naïve RRMS patients, and 25 HCs)- collected at the Ankara Bilkent City Hospital Neurology Polyclinic. TheIFNGrs2069727 T/C variant did not display a statistically significant disparity between RRMS patients and HCs. Significantly elevated hsa-miR-24-3p and hsa-miR-181d-3p relative expression levels were observed in GA-treated and treatment-naïve RRMS patients compared to HCs. Conversely, age-adjusted plasma IFN-γ concentrations were markedly lower in GA-treated and treatment-naïve RRMS patients versus HCs. Individuals with low plasma IFN-γ levels (≤ 1.311 pg/mL) demonstrated significantly elevated hsa-miR-24-3p relative expression compared to the high IFN-γ group (> 1.311 pg/mL). Conversely, subjects with low hsa-miR-181d-3p levels (≤ 2.90) exhibited significantly higher plasma IFN-γ concentrations relative to those with high hsa-miR-181d-3p levels (> 2.90). In the GA-treated group, EDSS negatively correlated with age-adjusted plasma IFN-γ. This study identified age-adjusted plasma IFN-γ, hsa-miR-24-3p, and hsa-miR-181d-3p expression as potential blood-based biomarkers for RRMS diagnosis and analyzed them alongside disability scores. The miRNAs in this study can be further evaluated as prospective therapeutic targets.
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AbstractPanax ginseng (PG)is a medicinal plant used for many years to treat many diseases. The current study aimed to investigate the possible prophylactic and therapeutic effects of PG extract on doxorubicin (DOX)-induced testicular toxicity in rats. 32 adult male Sprague–Dawley rats (200–250 g) were used in the experiment. The experimental groups were designed as control (normal saline, intraperitoneal), DOX (18 mg/kg, intraperitoneal), PG (200 mg/kg, gavage), and PG + DOX (200 mg/kg, gavage). After treatment, serum levels of testosterone, interleukin-1β (IL-1β), glutathione (GSH), luteinizing hormone (LH), superoxide dismutase (SOD), lactate dehydrogenase (LDH), catalase (CAT), follicle stimulating hormone (FSH), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) were measured. Then, gene expression, histopathological, and immunohistochemical analyses were performed on testicular tissues. Compared to DOX, treatment with PG + DOX showed a significant improvement in serum levels of FSH, testosterone, LH, TNF-α, IL-1β, MDA, SOD, LDH, GSH, and CAT. It was also observed that PG + DOX decreased nuclear factor-κB and cyclooxygenase-2 expression levels, increased androgen receptor expression, restored testicular histopathological structure, and significantly improved spermatogenesis. The results of the present study showed that PG may have an ameliorative effect against DOX-induced male reproductive toxicity, as DOX causes male reproductive toxicity. It can be concluded that PG is one of the effects that protect against DOX-induced testicular toxicity in rats by reducing lipid peroxidation and activating the antioxidant system. In light of this information, PG may be a useful agent to prevent the testicular toxicity observed in men receiving DOX treatment.
AbstractParkinson’s disease (PD) pathogenesis involves complex interactions between genetic factors. We employed two-sample Mendelian randomization (MR) integrating tissue-specific gene regulatory networks to identify causal genes and regulatory elements modulating PD risk. Two-sample MR analysis identified 79 putative causal genes for PD. A subset of the 79 causal genes was enriched within chr17q21.31 and chr16p11.2 cytobands that have been previously linked to neurodevelopmental disorders. Functional enrichment analysis of the 79 genes revealed autophagosome-lysosome fusion as a key process. Ten genes (ELOVL7,HSD3B7,PLEKHM1,PRSS53,SNCA,STX1B,STX4,ZSWIM7,LINC02210, andRP11-1072 A3.3) showed causal associations with tissue-specific expression patterns driving risk or protection for PD. Further investigation into their tissue-specific isoform expression profile revealed isoform-specific contributions to disease risk (or protection). These findings highlight the critical role of isoform-specific expression of causal genes in modulating PD risk, particularly relating to autophagosome-lysosome fusion. While our findings provide new insights into PD susceptibility, we acknowledge that the observed isoform-specific changes may, in part, reflect sample selection bias. Therefore, further experimental verification is needed to confirm the importance of incorporating tissue-specific gene isoform profiles in understanding PD causal mechanisms.
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AbstractLong non‐coding RNAs (lncRNAs) play an important role in the regulation of skeletal muscle transcriptional processes, but their involvement in spaceflight‐ or inactivity‐induced muscle atrophy remains poorly understood. To address this gap we simulated the space environment by combining microgravity, irradiation and stress in a mouse model. This simulation resulted in the differential expression (threshold set atP< 0.01) of 6191 protein‐coding genes (3525 downregulated and 2666 upregulated compared to controls) and 465 lncRNAs, of which 27% were downregulated and 73% upregulated compared to controls. Particularly several previously identified lncRNAs involved in muscle regulation were affected, including H19 (log fold change, logFC: −2.0), Gm29773 (logFC: −1.4), Pvt1 (logFC: 0.63), Kcnq1ot1 (logFC: 0.31) and Lncpint (logFC: 0.86). To determine whether similar changes occurred in humans, we examined the expression of lncRNAs during long‐term (3 months) head‐down tilt bed rest, a model for microgravity‐induced muscle atrophy. We found that Kcnq1ot1 and Lncpint (human homologues KCNQ1OT1 and LINC‐PINT) were upregulated in response to simulated microgravity. In addition KCNQ1OT1 was increased in a human 3‐Din vitromodel of muscle atrophy. These results are the first to demonstrate the involvement of lncRNAs in spaceflight‐ and severe inactivity‐induced muscle atrophy, in particular KCNQ1OT1 and LINC‐PINT. Our study provides novel insights into the contribution of lncRNAs to muscle atrophy caused by the space exposome and has broader implications for understanding and combating muscle atrophy in clinical scenarios of prolonged inactivity. Future research can build on these findings to investigate the therapeutic potential of lncRNAs in muscle atrophy.imageKey pointsThe combination of unloading, irradiation and stress led to a significant reduction in skeletal muscle mass and marked transcriptional responses (6191 differentially expressed genes) in the skeletal muscle of mice.The simulated space exposome led to the differential expression of 465 long non‐coding RNAs (lncRNAs) in mouse skeletal muscle.Two lncRNAs upregulated in mice – Kcnq1ot1 and Lncpint – were also upregulated in human muscle after 3 months of bed rest (human homologues KCNQ1OT1 and LINC‐PINT).KCNQ1OT1, but not LINC‐PINT, was upregulated in a human 3‐Din vitromodel of muscle atrophy.This study offers fundamental insights into the role of lncRNAs in muscle atrophy induced by the space exposome. These findings have broader implications for understanding and mitigating muscle atrophy in clinical settings, such as prolonged inactivity.
AbstractHistomorphometric differences in cell‐matrix properties were analysed between ascending thoracic aortic aneurysm (ATAA), dissection (ATAAD) and non‐aneurysmal patients, as well as across the circumference of the aneurysms in ATAA cases. Fresh anterior aortic wall samples were collected during surgery. A significant radius‐to‐intima‐media thickness (IMT) ratio variation was observed among ATAA patients, indicating patient‐specific adaptive responses. The radius‐IMT ratio was significantly lower in ATAAD patients. The quantity and quality of elastin and the quantity of collagen were particularly reduced in ATAAD compared to ATAA and non‐aneurysmal aortas. Matrix degradation was accompanied by an increase in the density of vascular smooth muscle cells (VSMCs), albeit with reduced expression of VSMC contractile markers (calponin and α‐smooth muscle actin (α‐SMA)). Concomitantly ATAA and ATAAD samples exhibited increased markers (matrix metalloproteinase (MMP)‐2/9) of proteolysis. Based on radius‐IMT ratios we roughly identified ‘thickening’ and ‘thinning’ (i.e. hypertrophic and hypotrophic) aneurysm variants to capture the substantial variation in the loss of mechanical homoeostasis in ATAA. Interestingly we did not find conspicuous differences along the circumference of excised aneurysms in ATAA, except for an increased IMT heterogeneity in ‘thinning’ aneurysms. We conclude that during aneurysm formation wall stress homoeostasis may remain partially intact, particularly in ‘thickening’ ATAA. Our study underscores the current critique that aneurysm dimensions are poor risk predictors; therefore there is a crucial need for better‐informed preventive intervention in ATAAD.imageKey pointsAscending thoracic aortic aneurysm (ATAA) variants can be categorised as aortic medial thickening (hypertrophic) or aortic medial thinning (hypotrophic) based on the radius‐to‐intima‐media thickness (IMT) ratio, reflecting distinct disruptions in mechanical homoeostasis.Morphological patterns arise from dynamic interactions in the aortic medial layer between vascular smooth muscle cells (VSMCs) and the extracellular matrix (ECM).Increased number of synthetic VSMCs in the medial layer of ATAA patients is a compensatory response to maintain vessel elasticity and structural integrity.In acute type A aortic dissection (ATAAD) aortas with medial thinning are characterised by ECM breakdown and maladaptive remodelling.ATAA development is circumferentially homogeneous, despite the occurrence of inter‐ and intrapatient variability in vascular architecture, composition and VSMC characteristics.
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AbstractElevated cytoplasmic [Ca2⁺] and protein kinase C (PKC) activation are key signalling events driving secretion in pancreatic acinar cells after stimulation by the secretagogues cholecystokinin (CCK) and acetylcholine (ACh). Although both ACh and CCK binding to their cognate receptors activates Gq/11proteins, leading to inositol 1,4,5‐trisphosphate (IP₃)‐mediated Ca2⁺ release and diacylglycerol (DAG)‐dependent PKC activation, it has been proposed that physiological CCK stimulation bypasses this canonical pathway, instead mobilizing Ca2⁺ via production of nicotinic acid adenine dinucleotide phosphate (NAADP). We reassessed the role of Gq/11signalling in CCK‐induced responses using a bioluminescence resonance energy transfer (BRET) assay, demonstrating that both CCK1 (CCK1R) and muscarinic M3 receptors (M3R) engage Gq/11along with other Gα subunits. Importantly YM‐254890, a Gq/11antagonist, inhibited coupling through Gq/11but did not alter the interactions of CCK1R or M3R with other G protein families. YM‐254890 eliminated CCK1R‐ and M3R‐induced Ca2⁺ signals in isolated acinar cells. Consistent with thein vitrodata, systemic CCK injection, intrinsic neural stimulation or feeding failed to elicit Ca2⁺ responsesin vivoin mice pre‐treated with YM‐254890, indicating that physiological stimulation of Ca2+signalling events requires Gq/11activation. Additionally YM‐254890 suppressed Ca2⁺‐activated Cl⁻ currents, a key event underlying fluid secretion, and amylase secretion in acini after CCK or ACh stimulation. These findings establish that CCK‐ and ACh‐induced exocrine pancreatic secretion strictly requires Gq/11activation, leading to IP₃ generation, DAG production and downstream signalling that is essential for physiological function.imageKey pointsAn increase in cytoplasmic Ca2+and PKC activity after CCK and ACh stimulation following feeding is a pivotal event in the activation of fluid secretion and exocytosis from pancreatic acinar cells.In contrast to ACh, it has been suggested that at physiological concentrations, CCK stimulation results in the production of nicotinic acid dinucleotide adenine phosphate, without activating the canonical Gq/11pathway, and the production of inositol 1,4,5,‐trisphosphate (IP3) and diacylglycerol (DAG).After having established that YM‐254890 is an exquisitely selective Gq/11inhibitor, we show that Ca2+signals stimulatedin vitroandin vivoin response to both M3R and CCK1R stimulation are completely inhibited by YM‐254890.YM‐254890 completely abrogates Ca2+‐activated Cl−current activation, pivotal for fluid secretion together with amylase secretion stimulated by both M3R and CCK1R activation.We conclude that ACh and CCK stimulation results in Gq/11 activation, an increase in IP3and DAG, and this event is fundamentally important for exocrine function.
AbstractElectrophysiological mapping is essential for understanding these mechanisms and guiding therapeutic treatments. However, approaches such as invasive electrical mapping, body surface mapping and electrocardiographic imaging face challenges, including low spatial resolution, far‐field interference and signal processing limitations. By contrast, panoramic optical mapping, using fluorescent dyes, offers high spatial resolution and allows direct measurement of cellular action potentialex situ. Can the integration of panoramic optical mapping with electrical mapping overcome the limitations of the above‐cited techniques and provide deeper insights into arrhythmic mechanisms? To investigate this, we developed an experimental setup that combines 3‐D panoramic optical mapping with multi‐electrode epicardial electrical mapping and non‐invasive electrical mapping (torso‐tank setup) for electrocardiographic imaging in Langendorff‐perfused rabbit hearts. Our results confirm the feasibility of using simultaneous optical and electrical mapping under sinus rhythm, as well as in atrial and ventricular arrhythmias, using time, frequency and phase analyses. During sinus rhythm and ventricular tachycardia, wavefront propagation showed concordance between modalities, where diverges are observed for atrial arrhythmias. Dominant frequency analysis could recover the frequency of activation better than the inverse of cycle length, and outcomes from all mapping modalities agreed. Reconstructed electrograms presented a good similarity compared to electrograms. By correlating optical and electrical mapping, clinically relevant arrhythmia markers and targets for ablation, from invasive and non‐invasive mapping can be better understood and localised. This platform could also serve as a test bed for studying drug effects, connecting changes from cellular action potential levels to whole‐heart electrophysiology.imageKey pointsCardiac arrhythmias are still a significant challenge in electrophysiology, with advancements in experimental and clinical research improving our understanding of mechanisms and target for ablation.Current electrical mapping technology, both invasive and non‐invasive, is used in science and by commercial systems to identify arrhythmic episodes and mechanisms, but has several limitations mimicking the true electrophysiology behaviour.Optical mapping uses fluorescent dyes to measure transmembrane action potentials with high spatial resolution. When combined with electrical mapping, it can enhance cardiac arrhythmia studies and mapping technologies.A novel 3‐D platform that integrates panoramic and electrical mapping techniques (epicardium, non‐invasive torso‐tank and electrocardiographic imaging) is presented and validated in isolated rabbit hearts, highlighting that the mapping strategies do not always agree, helping to further improve commercial systems.
AbstractDisruptions in both circadian clock and mitochondrial dynamics in the skeletal muscle (SkM) have been associated with insulin resistance and sarcopenia. Emerging evidence, in resting conditions and in response to metabolic challenges like exercise, suggests the intricate interplay between the circadian clock, mitochondrial dynamics and SkM function. However the molecular mechanisms that connect the circadian clock to mitochondrial dynamics and SkM function remain poorly understood. This review focuses on the role of circadian clock proteins, particularly brain and muscle Arnt‐like protein‐1 (BMAL1), in regulating mitochondrial dynamics and examines how their dysregulation contributes to metabolic and SkM deterioration. By exploring their interaction we aim to identify potential therapeutic targets that could improve metabolic health and muscle function.image
AbstractBlindness is a significant condition that triggers the ability of the brain to adapt to environmental changes through plasticity processes. This study examined somatosensory processing, multisensory integration, kinesthetic motor imagery (MI) and mirror neuron system (MNS) activity in response to auditory stimuli in visually impaired (VI) individuals. The study included 21 individuals with total vision loss, and the findings were compared with 21 participants with normal vision. The somatosensory temporal discrimination threshold (STDT) was used to evaluate somatosensory processing, while transcranial magnetic stimulation (TMS) was employed to measure kinesthetic MI activity and MNS activity in response to auditory stimuli. The results showed that VI individuals had significantly lower STDT values than the control group in conventional STDT measurements. STDT values measured 50, 100 and 300 ms after auditory stimuli in the auditory–tactile sensory integration paradigm. VI participants have significantly lower STDT values than the control group in the auditory–tactile sensory integration test. Most of the participants, who were congenitally blind, exhibited TMS activity during MI processes similar to that of sighted individuals. However, no TMS measurements indicative of MNS activation in response to auditory stimuli were detected in VI individuals using the stimulus paradigm applied in the study. The findings suggest that VI individuals perform better than sighted individuals in both somatosensory processing and multisensory integration while exhibiting similar MI performance to sighted individuals.imageKey pointsVisually impaired (VI) individuals have better somatosensory processing capacity than sighted individuals.The multisensory processing capacities of VI individuals are superior to those of sighted individuals.The enhanced sensory processing and multisensory integration capacities observed in VI individuals may be related to secondary cross‐modal plasticity that develops due to vision loss.
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AbstractN‐Methyl‐d‐aspartate receptors (NMDARs) are a family of ligand‐gated ionotropic glutamate receptors that mediate a slow, calcium‐permeable component to excitatory neurotransmission. The GluN2D subunit is enriched in GABAergic inhibitory interneurons in cortical tissue. Diminished levels of GABAergic inhibition contribute to multiple neuropsychiatric conditions, suggesting that enhancing inhibition might have therapeutic utility, thus making GluN2D modulation an attractive drug target. Here, we describe the actions of a GluN2C/GluN2D‐selective positive allosteric modulator, (+)‐EU1180‐453, which has improved drug‐like properties, such as increased aqueous solubility, in comparison to the first‐in‐class GluN2C/GluN2D‐selective prototypical positive allosteric modulator, (+)‐CIQ. (+)‐EU1180‐453 doubles the NMDAR response at lower concentrations and produces a greater degree of maximal potentiation at 30 µM compared with (+)‐CIQ. Usingin vitroelectrophysiological recordings, we show that (+)‐EU1180‐453 potentiates triheteromeric NMDARs containing at least one GluN2C or GluN2D subunit and is active at both exon5‐lacking and exon5‐containing GluN1 splice variants. (+)‐EU1180‐453 increases glutamate efficacy for GluN2C/GluN2D‐containing NMDARs both by prolonging the deactivation time and by potentiating the peak response amplitude. We show that (+)‐EU1180‐453 selectively increases synaptic NMDAR‐mediated charge transfer onto postnatal day 11–15 CA1stratum radiatumhippocampal interneurons but is without effect on CA1 pyramidal cells. This increased charge transfer enhances inhibitory output from GABAergic interneurons onto CA1 pyramidal cells in a GluN2D‐dependent manner. (+)‐EU1180‐453 also shifts excitatory‐to‐inhibitory coupling towards increased inhibition and produces enhanced gamma‐band power from carbachol‐induced field potential oscillations in hippocampal slices. Thus, (+)‐EU1180‐453 can enhance overall circuit inhibition, which could prove therapeutically useful for the treatment of anxiety, depression, schizophrenia and other neuropsychiatric disorders.imageKey points(+)EU‐1180‐453 is a GluN2C/GluN2D positive allosteric modulator and is active at triheteromeric receptors.(+)EU‐1180‐453 is active at exon5‐containing and exon5‐lacking GluN1‐containing receptors.(+)EU‐1180‐453 selectively potentiates the interneuron network and can enhance carbachol‐induced gamma‐band power.
AbstractGravity changes with respect to the 1gterrestrial condition induce several cardiovascular alterations, from fluid shift and blood volume reduction to orthostatic hypotension and venous pooling. Micro‐gravity and hyper‐gravity exposure characterizes space missions and aeronautical flights, as well as terrestrial analogues such as centrifuges, bed rest studies, and parabolic flights. Despite a growing number of clinical measures becoming available, cardiac function in these extreme conditions is still incomplete and difficult to obtain. Thus, computational haemodynamics provides a powerful and reliable tool to understand the cardiac response. We propose a 0D‐1D multiscale cardiovascular model to investigate the steady‐state acute cardiac response to gravity changes (from 0gto 3g). The model combines a 1D description of the coronary circulation and arterial tree, with a 0D parameterization of the peripheral microcirculation, the venous return, the cardiopulmonary and the cerebrovascular‐ocular circulations. The overall model is equipped with short‐term regulation mechanisms, and accounts for gravity and posture changes. After a thorough validation using measured data from literature involving the most common central haemodynamic parameters (i.e. HR, MAP, SV and CO), the model provides an in‐depth description of the cardiac response from micro‐ (0g) to hyper‐gravity (3g), highlighting: (i) a different behaviour between left and right heart haemodynamics; (ii) an improvement in cardiac efficiency and cardiac performance in micro‐gravity; (iii) a worsening of cardiac efficiency and an energy supply/demand impairment both at heart and coronary levels in hyper‐gravity. Therefore, the modelling approach proves to be an important tool in shedding light on space medicine.imageKey pointsGravity changes from micro‐ to hyper‐gravity induce several cardiovascular alterations, from fluid shift and blood volume reduction to orthostatic hypotension and venous pooling.Although the overall cardiovascular response is clear, details of the cardiac function in these extreme conditions are still incomplete and difficult to obtain.We propose a validated multiscale cardiovascular model to investigate the steady‐state acute cardiac response to gravity changes (from 0gto 3g).After a thorough validation against the most common central haemodynamic parameters in literature, present results show: (i) a different behaviour between left and right heart haemodynamics; (ii) an improvement of cardiac efficiency and cardiac performance in micro‐gravity; (iii) an energy supply/demand impairment in hyper‐gravity.The computational approach is a useful and reliable tool in exploring the response of cardiac parameters which are difficult to investigate experimentally, aiming to shed light on the cardiac function under altered gravitational force.
AbstractParkinson's disease (PD) is a complex, progressive neurodegenerative disorder driven by multiple pathogenetic factors, including oxidative stress, mitochondria dysfunction, neuroinflammation and ion imbalance. Recent evidence highlights the significant role of potassium channels in the pathophysiology of PD. We recently identified a PD‐linked genetic mutation in theKCNJ15gene (KCNJ15p.R28C), encoding the inwardly rectifying potassium channel Kir4.2, within a four‐generation family with familial PD. However, the role of the Kir4.2 channel in neurodegenerative diseases remains largely unexplored. This study aimed to elucidate the impact of theKCNJ15p.R28C(Kir4.2R28C) mutation on the biophysical and biochemical properties of Kir4.2. Employing Kir4.2‐overexpressing HEK293T cells as a model, we investigated how the mutation affects the channel's functional properties, total protein expression, intracellular processing in the endoplasmic reticulum and lysosomes and plasma membrane trafficking. Patch clamp studies revealed that the Kir4.2R28Cmutation results in loss of channel function with significant dominant‐negative effects. This dysfunction is partially attributed to the substantial reduction in overall mutant channel protein expression compared to the wild‐type (Kir4.2WT). We observed that both Kir4.2WTand Kir4.2R28Cproteins undergo glycosylation during the post‐translational modification process, albeit with differing protein turnover efficiencies. Furthermore, the Kir4.2R28Cmutant exhibits reduced stability and compromised plasma membrane trafficking capacity compared to Kir4.2WT. These findings suggest that the Kir4.2R28Cmutant has unique biomolecular and biophysical characteristics distinct from the Kir4.2WTchannel, which potentially elucidates its role in the pathogenesis of PD.imageKey pointsInwardly rectifying potassium channels are increasingly recognized for their critical role in the complex pathogenesis of Parkinson's disease (PD).We previously identified a genetic mutation, Kir4.2R28C, in the inwardly rectifying potassium channel Kir4.2, which strongly segregates with familial PD in a multi‐generational pedigree.This study confirms Kir4.2R28Cas a loss‐of‐function mutation with significant dominant‐negative effects, impairing channel activity even in heterozygous conditions.The Kir4.2R28Cmutation significantly reduces overall protein levels, impairs protein stability and disrupts plasma membrane trafficking inin vitrocell models.
AbstractThe circadian‐regulated transcriptional repressor REV‐ERB‐α is a key mediator of skeletal muscle oxidative capacity, enhancing exercise performance when activated. Conversely its global genetic ablation leads to impaired performance. Simultaneously the kynurenine (KYN) pathway, involved in tryptophan degradation, produces neurotoxic metabolites under stress and inflammation, contributing to CNS dysfunction and fatigue. These mechanisms may underlie the fatigue and performance impairments caused by exhaustive exercise (EE). This study investigated the interplay between REV‐ERB‐α and the KYN pathway in acute and chronic EE models. Time course analyses revealed that EE downregulated REV‐ERB‐α in skeletal muscle, correlated with KYN pathway alterations. Notably KYN metabolism shifted towards a neurotoxic profile, characterized by reduced KYN aminotransferase 1 (KAT1) and increased KYN 3‐monooxygenase (KMO) expression in skeletal muscle, with increased KYN levels in the hippocampus.In vitroexperiments using C2C12 myoblasts showed that REV‐ERB‐α knockout upregulated KAT1 and KMO, whereas overexpression selectively reduced KMO. Pharmacological activation of REV‐ERB‐α with SR9009 upregulated KAT1 in skeletal muscle and reduced KMO in the hippocampus of mice. These findings reveal a dynamic relationship between REV‐ERB‐α and the KYN pathway, linking peripheral and central responses to EE. This study highlights REV‐ERB‐α and the KYN pathway as critical regulators of exercise‐induced fatigue and suggests potential therapeutic targets to mitigate its effects, offering novel insights into the molecular basis of performance impairments associated with EE.imageKey pointsExcessive exercise can impair performance and induce fatigue; however the underlying biological mechanisms remain incompletely understood.Although REV‐ERB‐α activation enhances skeletal muscle oxidative capacity and exercise performance, its deletion impairs both parameters.This study demonstrates that excessive exercise decreases REV‐ERB‐α levels in skeletal muscle and disrupts the kynurenine (KYN) pathway by downregulating KYN aminotransferase 1 (KAT1), an enzyme involved in a neuroprotective branch of the pathway.These alterations affect both skeletal muscle and the brain, suggesting a potential link between physical fatigue and brain function.REV‐ERB‐α suppresses KYN 3‐monooxygenase (KMO), a key enzyme in the KYN pathway that promotes the formation of potentially neurotoxic metabolites, thereby revealing a novel mechanism and a potential therapeutic target.
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AbstractAtrial fibrillation (AF) is the most common arrhythmia, characterized by irregular atrial electrical activity resulting in asynchronous atrial contraction. AF is accompanied by extensive structural remodelling of atria, including extracellular matrix expansion (fibrosis), which affects both AF maintenance and treatment outcomes. However, no fibrosis‐specific therapies are currently available for AF. To identify the prominent pathways in atrial fibroblasts (Fb) that modulate atrial fibrosis and arrhythmogenesis, we developed the first atrial Fb signalling network model. This expands on the well‐established ventricular model by integrating atrial‐relevant elements involved in fibrogenesis and/or differentially expressed in chronic AF (vs. normal sinus rhythm) patients and connections based on experimental evidence in an Fb‐related context. Our findings indicate that under high profibrotic signals, e.g. angiotensin‐II (AngII) and transforming growth factor β, inhibition of Ca2+fluxes reduced the abundance of key fibrotic markers such as collagen I, collagen III, periostin, plasminogen activator inhibitor‐1, connective tissue growth factor and α‐smooth muscle actin, via modulation of the Ca2+/calmodulin‐dependent protein kinase II/Smad3 pathway and extra domain A of fibronectin via the calcineurin pathway. Mechanistically, we found that the Ca2+‐dependent regulation of collagen I and III is primarily at the level of gene transcription, with collagen I and collagen III exhibiting similar dynamics in the Fb model. Overall, our study highlights the pivotal role of Ca2+signalling in the evolution of AF‐associated fibrogenesis and provides novel insights into potential anti‐AF therapeutic strategies targeting fibrotic responses. Future work will investigate in greater detail the upstream mechanisms driving Ca2+increases in atrial Fbs during AF.imageKey pointsA fibroblast signalling network was developed incorporating new atrial‐informed elements and reactions to identify the prominent pathways that modulate atrial fibrosis and associated arrhythmogenesis, including atrial fibrillation (AF).The model was validated against experimental data in cardiac fibroblasts. For atrial‐specific validation, we focused on the model responses to AF‐relevant profibrotic inputs, i.e. angiotensin‐II (AngII) and transforming growth factor β (TGFβ).The analysis underscores the critical role of Ca2+signalling in mediating profibrotic responses under AF‐relevant stimuli, AngII and TGFβ and shows that Ca2+/calmodulin‐dependent protein kinase II/Smad3 and calcineurin mediate the Ca2+‐dependent upregulation of key fibrotic markers.
AbstractHigh‐frequency mossy fibre (MF) inputs trigger a sustained increase in excitability to perforant pathway (PP) inputs in CA3 pyramidal cells (CA3‐PC) by reducing Kv1.2 levels at distal apical dendrites, known as long‐term potentiation of intrinsic excitability (LTP‐IE). LTP‐IE enhances excitatory postsynaptic potential (EPSP)‐to‐spike coupling at PP synapses, facilitating Hebbian LTP of synaptic weights. Prolonged hyperexcitability is detrimental, yet it is little understood how LTP‐IE is restored in CA3‐PCs. Here we show that MF‐induced LTP‐IE can be reversed through the burst firing of a CA3‐PC elicited by PP or recurrent synaptic inputs. This reversal was impeded by the oxidative bias of cellular redox state or intracellular Zn2+signalling. Because high‐frequency PP inputs to MF‐primed CA3 pyramidal cells not only induce homosynaptic LTP but also restore hyperexcitability, this input‐specific bidirectional regulation of intrinsic excitability may provide a cellular basis for understanding ensemble dynamics in the CA3 network.imageKey pointsIntrinsic excitability plays a pivotal role in recruiting principal cells to neuronal memory ensembles.Mossy fibre inputs prime hippocampal CA3 pyramidal cells by enhancing their intrinsic excitability and excitatory postsynaptic potential (EPSP)‐to‐spike coupling at perforant path (PP) synapses.High‐frequency PP inputs to such primed cells not only induce long‐term potentiation of synaptic weights but also restore the high excitability state to baseline.This input‐specific bidirectional regulation of intrinsic excitability may offer a cellular basis for understanding the ensemble dynamics in the hippocampal CA3 network.
AbstractMetformin is increasingly used to treat diabetes in pregnancy, but the effects on adult offspring health remain under‐explored. The present study investigated the long‐term cardiovascular effects in male and female offspring of maternal metformin treatment using a well‐established mouse model of obese glucose intolerant pregnancy. Female mice were given chow, or an obesogenic diet with/without 300 mg kg−1day−1oral metformin during gestation. At 3, 6 and 12 months of age, male and female offspring were studied longitudinally with tail‐cuff plethysmography and echocardiography. At 12 months, tissues were collected for wire myography, histology and molecular analyses. Female offspring of obese dams had elevated blood pressure throughout life, cardiac diastolic dysfunction at 3 months, and increased femoral vasoconstrictor reactivity and aortic wall remodelling at 12 months. Metformin treatment did not ameliorate these effects and led to obesity‐induced hypertension at 12 months. Irrespective of metformin, male offspring of obese pregnancy had cardiac diastolic dysfunction from 6 months without changes in blood pressure. Male metformin‐exposed offspring also showed cardiomegaly, increased cardiac collagen and vascular sympathetic hyperreactivity, suggesting metformin exposure worsened the cardiovascular phenotype. These findings show that maternal obesity caused sex‐specific cardiovascular aberrations in aged offspring. Maternal metformin was not corrective and introduced further sex‐dependent cardiovascular alterations. Further long‐term offspring follow up of both sexes is needed for informed decisions about metformin during pregnancy.imageKey pointsThe oral medication metformin is increasingly used to treat diabetes in pregnancy.Metformin readily crosses the placenta, and long‐term effects on offspring cardiovascular health remain unexplored in human and animal studies.In a mouse model of maternal diet‐induced obesity with impaired glucose tolerance, female and male offspring developed hypertension and diastolic cardiac dysfunction, respectively, by 12 months of age (equivalent to middle age in humans).Maternal metformin treatment worsened the cardiovascular phenotype and introduced further sex‐dependent cardiovascular alterations in both male (cardiac stiffening, vascular dysfunction) and female (obesity‐induced hypertension) offspring.This work highlights that long‐term cardiovascular follow up in offspring of both sexes from human pregnancies treated with metformin is crucial to make more informed decisions about metformin use in diabetic pregnancy.
AbstractMicroglia are resident immune cells critical in maintaining brain homeostasis via their surveillance and phagocytosis function. Under disease contexts such as seizures and epilepsy, microglial phagocytic signalling is activated in response to both inflammatory and non‐inflammatory cell death. This process involves a range of well‐characterized ‘find me’ and ‘eat me’ signals, phagocytic receptors, and less well‐characterized intracellular signalling pathways. In addition, epigenetic and transcriptional regulators orchestrate microglial responses to seizures, including the integration of phagocytic and inflammatory pathways. Interestingly, although inhibiting phagocytosis has been shown to improve neuronal survival and cognitive performance after seizures, it paradoxically increases the risk of developing spontaneous recurrent seizures. Reconciling these dual effects requires a deeper understanding the spatiotemporal dynamics of microglial phagocytosis. The objective of this review is to examine the mechanisms and impact of microglial phagocytosis in the context of epilepsy and to highlight unresolved questions that warrant further investigation in this emerging field.image
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AbstractPeak inspiratory pressure‐generating capacity is preserved in themdxmouse model of Duchenne muscular dystrophy in early disease, despite profound diaphragm muscle weakness and reduced electrical activation, revealing adequate compensation by extra‐diaphragmatic muscles. Respiratory system compensation is lost as disease progresses, with the emergence of reduced peak inspiratory pressure‐generating capacity in advanced disease. We hypothesised that extra‐diaphragmatic inspiratory muscles compensate for diaphragm dysfunction in early dystrophic disease, supporting the maintenance of peak respiratory performance inmdxmice. We reasoned that extra‐diaphragmatic muscle dysfunction would emerge with progressive disease, leading to the loss of peak inspiratory pressure‐generating capacity in advanced dystrophic disease. We measured ventilation, inspiratory pressure, and obligatory (diaphragm, intercostal and parasternal) and accessory (sternomastoid, cleidomastoid, scalene and trapezius) respiratory muscle form, function and EMG activity in early (4 months) and advanced (16 months) dystrophic disease. Despite obligatory and accessory muscle dysfunction, including structural remodelling, weakness and reduced EMG activity, peak inspiratory pressure‐generating capacity and ventilation are preserved in early disease. Obligatory and accessory muscle dysfunction progressively declines with advanced disease, with the emergence of reduced peak inspiratory pressure‐generating capacity. However, although there was evidence of progressive accessory muscle dysfunction, more profound remodelling was seen in the diaphragm muscle comparing early and advanced dystrophic disease. In conclusion, in early dystrophic disease, peak inspiratory performance is compensated. A progressive decline in diaphragm and extra‐diaphragmatic muscles contributes to respiratory system compromise in advanced disease. Further loss of compensation afforded by extra‐diaphragmatic muscles probably contributes to end‐stage respiratory failure.imageKey pointsWe characterised obligatory and accessory respiratory muscle form, function and control in early and advanced disease in themdxmouse model of Duchenne muscular dystrophy.Profound diaphragm muscle remodelling, immune cell infiltration, elevated cytokine concentrations and dysfunction present in early disease, but peak inspiratory performance is fully compensated. The burden of breathing is shared across many muscles, revealed as remodelling, elevated cytokine concentrations, weakness and impaired control in several obligatory and accessory muscles.Peak inspiratory performance declines in advanced disease with evidence of progressive remodelling in the diaphragm muscle with extensive fibrosis and further decline in the form, function and control of accessory muscles of breathing.Diaphragm remodelling with profound fibrosis, more so than progressive accessory muscle remodelling (although evident), is the striking phenotype at 16 months of age when the decline in peak inspiratory performance appears.The progressive decline to end‐stage disease (∼20–22 months of age inmdxmice) probably relates to continued profound loss of diaphragm contractile function and loss of compensatory support provided by extra‐diaphragmatic muscles. Logistically convenient models of rapid, progressive muscular dystrophy are required to facilitate the study of end‐stage disease.
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AbstractIt is unclear whether cortical and spinal excitability modulations contribute to enhanced stretch–shortening cycle (SSC) performance. Therefore, this study investigated cortical and spinal excitability modulations during and following shortening of SSC contractions compared with pure shortening (SHO) contractions. Participants (n= 18) performed submaximal voluntary plantar flexion contractions while prone on the dynamometer bench. The right foot was strapped onto the dynamometer's footplate attachment, and the resultant ankle joint torque and crank arm angle were recorded. Cortical and spinal excitability modulations of the soleus muscle were analysed by eliciting compound muscle actional potentials via electrical nerve stimulation, cervicomedullary motor‐evoked potentials (CMEPs) via electrical stimulation of the spinal cord, and motor‐evoked potentials (MEPs) via magnetic stimulation of the motor cortex. Mean torque following stretch was significantly increased by 7 ± 3% (P =0.029) compared with the fixed‐end reference (REF) contraction, and mean torque during shortening of SSC compared with SHO was significantly increased by 12 ± 24% (P =0.046). Mean steady‐state torque was significantly lower by 13 ± 3% (P =0.006) and 9 ± 12% (P =0.011) following SSC compared with REF and SHO, respectively. Mean steady‐state torque was not significantly different following SHO compared with REF (7 ± 8%,P= 0.456). CMEPs and MEPs were also not significantly different during shortening of SSC compared with SHO (P≥ 0.885) or during the steady state of SSC, SHO and REF (P≥ 0.727). Therefore, our results indicate that SSC performance was not associated with cortical or spinal excitability modulations during or after shortening, but rather driven by mechanical mechanisms triggered during active stretch.imageKey pointsA stretch–shortening cycle (SSC) effect of 12% was observed during EMG‐matched submaximal voluntary contractions of the human plantar flexors.The SSC effect was neither associated with cortical or spinal excitability modulations nor with stretch‐reflex activity.The SSC effect was likely driven by mechanical mechanisms related to active muscle stretch, which have long‐lasting effects during shortening.Residual force depression following SSC was not attenuated by the long‐lasting mechanical mechanisms triggered during active muscle stretch.Steady‐state torques were lower following shortening of SSCsversuspure shortening and fixed‐end contractions at the same final ankle joint angle, but the torque differences were not correlated with cortical or spinal excitability modulations.
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AbstractElectrical tuning allows auditory, vestibular, and electrosensory receptor cells to filter sensory signals and selectively transmit specific stimulus frequencies. In auditory hair cells, electrical tuning results from membrane potential resonance produced by voltage‐gated Ca and K(Ca) channels, with variable kinetics that generate different tuning properties. Such resonance has been observed only up to ∼1 kHz, however. Additionally, in most species that employ electrical tuning, hearing is constrained to this relatively low‐frequency range, raising the question of whether electrical tuning can extend to higher frequencies. Here we investigated this possibility by studying tuning and transduction properties of Knollenorgans, a class of tuberous electroreceptors of mormyrid electric fish. These organs, which generate spike‐like receptor potentials, detect species‐specific electric organ discharges (EODs). To test whether fish with brief EODs had correspondingly high‐frequency electrical tuning, we recorded tuning curves from Knollenorgans of three species,Brevimyrus niger, Gnathonemus petersii, andPollimyrus adspersus, which have EODs with spectral components exceeding 5 kHz. All species had receptors tuned to a range of frequencies tiling the species‐specific EOD spectrum, with best frequencies extending beyond 10 kHz inP. adspersus. We also computed the impulse response of each Knollenorgan by reverse‐correlating spikes elicited by white noise stimuli. After incorporation of a spike threshold non‐linearity, convolving the impulse response with arbitrary stimulus waveforms successfully predicted spike patterns experimentally evoked by these inputs. These analyses demonstrate that differential electrical tuning properties of Knollenorgans produce distinct, well‐timed spike responses that reliably encode time‐varying electrical signals at frequencies up to 20 kHz.imageKey pointsKnollenorgans, among the tuberous electroreceptors of mormyrid electric fish, are modified hair cells that transduce electrical signals into spike‐like receptor potentials.Knollenorgans in three species of mormyrids are tuned to frequencies matched to the frequencies present in the species‐typical electric organ discharges, suiting them for electric communication.The frequency of highest sensitivity of Knollenorgans can extend well beyond 10 kHz, far exceeding the limit for electrical tuning mechanisms estimated from mechanosensitive hair cells.The timing and probability of spiking by Knollenorgans are accurately predicted by a model composed of linear filtering followed by non‐linear rectification and spike thresholding.Differential filtering by different Knollenorgans produces distinct outputs to the same input, with high‐tuned receptors effectively transmitting well‐timed spikes, on a microsecond time scale, in response to electrical stimuli up to 20 kHz.
AbstractLow cardiorespiratory fitness increases the risk for cardiometabolic disease. Endurance exercise training promotes cardiorespiratory fitness and improves cardiometabolic risk factors, but with great heterogeneity. Here, we tested the hypothesis that the metabolic phenotype imparted by low parental (inborn) cardiorespiratory fitness would be overcome by early‐life exercise training, and that exercise adaptations would be influenced in part by inborn fitness. At 26 days of age, male and female rat low‐capacity runners (LCR,n =20) and high‐capacity runners (HCR,n =20) generated by artificial selection were assigned to either sedentary control (CTRL,n =10) or voluntary wheel running (VWR,n =10) for 6 weeks. Post‐intervention, whole‐body metabolic phenotyping was conducted, and the respiratory function of isolated skeletal muscle and liver mitochondria was assayed. Transcriptomic and proteomic profiling of these tissues was performed using RNA‐sequencing and mass spectrometry, respectively. Daily VWR volume was 1.8‐fold higher in HCR‐VWR compared to LCR‐VWR. In LCR, VWR reduced adiposity and enhanced glucose tolerance, coincident with elevated total energy expenditure. Although intrinsic skeletal muscle mitochondrial respiratory function was unchanged, estimated skeletal muscle oxidative capacity increased in VWR groups. In liver mitochondria, VWR increased both maximal oxidative capacity and ATP‐linked respiration only in HCR. Transcriptomic and proteomic profiling revealed extensive remodelling of skeletal muscle and liver tissue by VWR, elements of which were both shared and distinct based on inborn fitness. Early‐life exercise partly offsets the metabolic effects of low inborn fitness, but molecular adaptations to VWR are dependent on inborn fitness, with potential implications for personalized exercise medicine.imageKey pointsLow cardiorespiratory fitness is a heritable trait associated with increased risk for cardiometabolic disease.Endurance exercise training promotes cardiorespiratory fitness and metabolic health but how genetic (inborn) fitness influences exercise‐induced adaptations is unclear.We used rats selectively bred for low (LCR) or high running capacity (HCR) to test whether: (1) early‐life voluntary wheel running (VWR) could offset poor metabolic health in LCR rats and (2) inborn fitness modulates adaptations to VWR.VWR improved body composition and glucose tolerance in LCR rats but did not alter mitochondrial respiratory function.Molecular analyses revealed that VWR induced shared and distinct changes in skeletal muscle and liver depending on inborn fitness, highlighting individualized biological responses.These findings suggest that genetic factors linked to fitness influence how the body adapts to exercise, with implications for personalized exercised medicine.
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AbstractNeuroscientists, behavioural scientists, mechanical engineers and roboticists collaborate in the broad field of whisker science to investigate tactile sensing and movement in mammals. Much of this research is focussed on the study of laboratory rodents, with important insights already gained from studying their whisker movements, control behaviours and the sensory processing of whisker signals. The findings of whisker behaviour studies in the laboratory have also formed the foundation for research in other captive settings, such as in zoos. However, without inspiration from more natural environments and stimuli, researchers are probably missing out on describing other important whisker behaviours, which may in turn give researchers better insights into the brain areas, signals and behaviours associated with active whisker touch sensing. Taking inspiration from recent findings from the field and zoo, developing more social and active foraging tasks for the laboratory would probably enrich whisker behaviour studies, as would including a wider variety of species. In the longer‐term, a more integrated approach, with collaboration across laboratory, captive and field settings, will help to develop more natural behavioural tasks representative of what an animal experiences in the real world, which would give us greater insights into the natural sensory behaviours of mammals. This has implications for the fields of neuroscience, sensory biology and evolutionary biology, as well important applications for captive mammal health and welfare.image
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AbstractHyperpolarization‐ and cyclic nucleotide‐activated channels (HCN orIhchannels) play an important role for the integrative dynamics of many types of neurons. In the retina, the multiple types of bipolar cells constitute parallel channels that connect the outer and inner retina. Differences in synaptic inputs and differential expression and localization of specific voltage‐gated ion channels shape and modulate bipolar cell visual responses. Here, we examined the expression and function of HCN2‐mediatedIhin rod bipolar cells (RBCs) of rat retina. Using immunolabelling, we observed HCN2 channels in dendrites, cell bodies and axon terminals of RBCs. With whole‐cell voltage‐clamp recording, we observed that ZD7288 and Cs+blockedIhin RBCs, and from activation/deactivation data, we developed a Hodgkin–Huxley‐type kineticIhmodel that closely reproduced physiological responses. Applying a ZAP current stimulus, we found that the bandpass frequency–response characteristics of RBCs were blocked by Cs+, could be restored by dynamic clamp injection of a positiveIhconductance (in Cs+) and could be eliminated by injecting a negativeIhconductance (in control), suggesting thatIhis necessary and sufficient for bandpass filtering properties in the examined voltage range. Implementing our kinetic model forIhin morphologically realistic compartmental models closely mimicked physiological bandpass characteristics, with little influence of the subcellular location of theIhconductance. Our results demonstrate how the specific kinetic properties ofIhin RBCs determine their frequency–response properties, supporting an important role ofIhin the functional dynamics of RBC visual responses.imageKey pointsHyperpolarization‐ and cyclic nucleotide‐activated (HCN) channels are found throughout the nervous system and contribute to physiological activities including rhythmic neuronal behaviour and control of the resting membrane potential.Unlike most voltage‐gated channels, HCN channels are activated by hyperpolarizing voltages and, in some cells, generate bandpass behaviour, thereby amplifying certain frequencies of transmitted signals.We demonstrate that HCN2 channels are located at the dendrites, soma and axon terminals of rod bipolar cells, which are important for transmitting visual signals at night.Chemically blocking or electronically subtracting the HCN channels eliminates bandpass behaviour, whereas electronically adding the channels restores bandpass behaviour.We have implemented a Hodgkin–Huxley‐type kinetic model for HCN channels that allows for computer simulations with realistic models of rod bipolar cells.We demonstrate that HCN channels are necessary and sufficient to confer bandpass properties and thus contribute to understanding how these voltage‐gated ion channels generate diverse visual signals.
AbstractAcute intermittent hypercapnic hypoxia (IHH) evokes persistent increases in vascular sympathetic activity and blood pressure. Whether myocardial contractility is enhanced to contribute to this pressor response is unknown. We hypothesized that IHH would augment left ventricular systolic function. Twenty‐four healthy participants (nine females; aged 25 ± 4 years) underwent 40 consecutive 1 min bouts of 40 s of hypercapnic hypoxia (: 48 mmHg; : +5 mmHg) and 20 s of normocapnic normoxia. Cardiac, haemodynamic, respiratory and sympathetic measurements were made at rest and during three 5 min stages of progressive lower body negative pressure (LBNP) (−15, −30 and −45 mmHg) before and after IHH. Following IHH, stroke work [Δ: 64 mJ; 95% confidence interval (CI) = 14–113;P= 0.007], longitudinal strain (Δ: −0.9%; CI = −0.1 to −1.7;P= 0.007) and single‐beat estimates of preload‐recruitable stroke work (PRSWsb; Δ: 0.9 mJ mL−1; CI = 0.2–1.5;P= 0.004) were enhanced. Across LBNP stages, IHH further enhanced ejection fraction (Δ: 1.0%; CI = 0.0–2.0;P= 0.041), stroke work (Δ: 44 mJ; CI = 23–66;P< 0.001), longitudinal strain (Δ: −0.5%; CI = 0.0 to −0.9;P= 0.047), end‐systolic elastance (Δ: 0.15 mmHg mL−1; CI = 0.05–0.25;P= 0.004) and PRSWsb(Δ: 0.60 mJ mL−1; CI = 0.36–0.85;P< 0.001). Linear end‐systolic pressure–volume relationships (+0.13 ± 0.06 mmHg mL−1,P= 0.024) and preload‐recruitable stroke work slopes (+0.83 ± 0.17 mJ mL−1,P< 0.001) were also increased post‐IHH. Ventricular stiffness (E/E′ratio) and relaxation (peak diastolic strain rate) were unaltered by IHH (P> 0.236), whereas the passive/active diastolic filling (E/A) ratio was reduced (P= 0.022), potentially via increased atrial kick contribution (P= 0.068). We demonstrate that increased left ventricular systolic function following acute IHH contributes to the pressor response in addition to the established vasopressor arm in humans.imageKey pointsAcute intermittent hypercapnic hypoxia evokes persistent sympathoexcitation and increased arterial pressure, known to be mediated by increased vasoconstrictor signalling.Chronic intermittent hypoxia increases cardiac contractility associated with cardiac sympathetic and structural remodelling. However, whether increases in contractility manifest acutely following intermittent hypercapnic hypoxia is unknown.We show increases in indices of cardiac systolic performance at rest and across progressive hypovolaemia following acute intermittent hypercapnic hypoxia.Diastolic relaxation was unchanged, but reductions in the ratio of passive filling to atrial kick during diastole, potentially as a result of increased mitral inflow velocity during atrial filling, suggest that the increases in contractility may extend to the atria.
AbstractTendons are collagen‐rich tissues that are necessary for movement and, as such, are exposed to mechanical forces. Mechanical loading impacts tendon formation, homeostasis and injury. Frequent injury and poor healing of tendon is a major clinical issue. An improved understanding of how tendon cells respond to mechanical forces is needed to advance new therapies to treat tendon injuries and limit degeneration caused by aberrant mechanical loading. In this review, we highlight recent discoveries in how mechanical stimulation impacts tendon and enthesis formation during development, as well as tendon maintenance and degradation during adulthood. We focus on understanding the cell‐level mechanotransduction mechanisms, which include calcium signalling, activation of specific cell receptors and ion channels, and the effect on primary cilia and other downstream cell signalling pathways. These recently identified mechanotransducers in tendon cells show promise as future therapeutic targets, which can be leveraged for tendon healing.image
AbstractIt has long been established that microglia are integral to the CNS immune system. Their surveying and adaptive nature is key in brain development and maintaining homeostasis as well as in the manifestation and progression of neuropathology. However with advancing technology it is becoming increasingly recognised that they do not serve this role in isolation. Previously most work has focused on microglia‐derived signalling, with less attention on the sensing and signalling capacity of macroglia (astrocytes, oligodendrocytes). Recent developments in single‐cell transcriptomics have allowed extensive analysis of cell profiles in health and disease; these studies have drawn attention to the capacity of macroglia to also engage in immune signalling pathways. This is particularly relevant in neuropathologies, including in Alzheimer's disease (AD), where specific disease‐associated profiles of glia (DAGs) have been established. These changes are predominantly related to immune pathways, which were long considered limited to immune cells, including cytokine and chemokine production, antigen presentation and phagocytosis. There is an increasing body of evidence that glia should be considered as active components of the CNS immune system forming a glia‐specific immune‐like network, whereby macroglia, acting as sensors of the CNS microenvironment, function within this network to co‐ordinate diverse CNS effect(s)/function(s). To gain an in‐depth understanding of AD pathology, the intimate molecular dialogue of glia needs to be elucidated. This review aims to examine the evidence for macroglia‐derived immune signalling and its relevance in health and disease.image
AbstractCa2+‐dependent exocytosis initiates with the formation of fusion pores comprising thesolubleN‐ethylmaleimide‐sensitive factorattachment proteinreceptor (SNARE) complex. Although cellular signalling typically occurs in transient oscillations on the order of tens of seconds, it remains unclear how such rapid SNARE phosphorylation influences fusion pore kinetics, analogous to transient regulation observed in ion channels. Here we demonstrate that protein kinase A (PKA)‐mediated phosphorylation of SN25b (the neuronal isoform of synaptosome‐associated protein of 25 kD) modulates secretion rate and fusion pore kinetics in PC12 cells (rat pheochromocytoma derivatives). Upon acute application of KCl and forskolin, cells overexpressing SN25b exhibited a reduced secretion rate compared to the control. This reduction was occluded by overexpressing a PKA‐phosphodeficient mutant, SN25b‐T138A, rather than a PKA‐phosphomimetic mutant, SN25b‐T138E. Notably, SN25b, SN25b‐T138A or SN25b‐T138E did not alter the fraction of incomplete fusion events or quantal size compared to the control. Further kinetic analysis indicated that SN25b‐T138A destabilized initial fusion pores by promoting the closure and dilatation of fusion pores. Mechanistically,in situproximity ligation assays showed that SN25b‐T138A reduced its interaction with the other t‐SNARE syntaxin‐1 compared to the control and SN25b, correlating with destabilized fusion pores. Moreover, compared to SN25b‐T138E, SN25b‐T138A decreased whole‐cell Ca2+currents and weakened its interaction with synaptobrevin‐2 and L‐type Ca2+channel subunits. These changes in interaction were associated with increased secretion and full‐fusion rate, implying efficient disassembly after dilatation. Together, PKA‐mediated phosphorylation of SN25b rapidly modulates fusion pore kinetics in response to transient signalling oscillations, thereby fine‐tuning exocytotic efficiency in real time.imageKey pointsProtein kinase A (PKA)‐mediated SNAP‐25 phosphorylation rapidly reduces the rate of secretion.PKA‐phosphodeficiency of SNAP‐25 destabilizes the kinetics of initial fusion pores, correlating with its decreased interaction with syntaxin‐1.PKA‐phosphodeficiency of SNAP‐25 decreases the interaction with synaptobrevin‐2 and the L‐type calcium channel subunit, leading to efficient priming.PKA‐mediated SNAP‐25 phosphorylation rapidly regulates fusion pore kinetics and shapes exocytotic kinetics on the order of tens of seconds.
AbstractCardiovascular disease is the predominant cause of mortality globally, with both morbidity and mortality rates escalating annually. Non‐coding RNAs are essential in the regulation of cardiovascular disease. Exosomes are lipid bilayer vesicles that are released by many types of cells. They carry biomolecules such as proteins and nucleic acids (e.g. microRNAs, circular RNAs and long non‐coding RNAs). The physiological condition of the mother cell significantly affects their composition and biological activity. In cardiovascular disorders, macrophages generate exosomes that facilitate intercellular communication, potentially resulting in new therapeutic strategies for these conditions. In this article, we examine the impact of exosomal non‐coding RNAs derived from macrophages on the functionality and condition of immune cells, vascular smooth muscle cells, endothelial cells, cardiomyocytes and cardiac fibroblasts. They facilitate intercellular communication via several mechanisms. Non‐coding RNAs generated from macrophage exosomes significantly influence cellular functional states and might offer new approaches for preventing and treating cardiovascular disorders. Owing to insufficient clinical evidence, additional extensive investigations are required to assess the therapeutic potential of these non‐coding RNAs in cardiovascular disorders.image
AbstractAnatomical changes associated with intra‐uterine growth restriction (IUGR) have been observed in different age groups and linked to cardiovascular complications. This study analysed the electrocardiogram (ECG) in pre‐adolescents with severe IUGR, comparing QRS complex and T‐wave biomarkers with controls. Computer simulations explored links between anatomical re‐modelling and ECG biomarkers, providing insights into the potential cardiovascular risk associated with IUGR‐induced re‐modelling. Clinical recordings were analysed using principal component analysis (PCA) to compute spatially transformed leads, enhancing QRS complex and T‐wave delineation for depolarization and repolarization assessment. Transformed leads analysis revealed a 4‐ms increase in QRS complex duration (QRS ) and a 2‐ms increase in the T peak‐to‐end interval (T ) in IUGR subjects compared to controls. We conducted electrophysiologicalin silicosimulations using anatomical models based on clinical IUGR data. These models, derived from a reference control, incorporated key geometric changes associated with IUGR, the apex‐base length, basal diameter, wall thickness () and ventricular tissue volume, to assess their impact on depolarization and repolarization intervals.In silicoPCA leads showed increased QRS , QRS amplitude and T in globular models, consistent with clinical data. Despite the QRS increase, the QT interval increases but is not linearly related to the change. These findings suggest that cardiac re‐modelling primarily influences the depolarization cycle, notably QRS , while repolarization intervals increase but are not directly related to the increase. The study highlights the impact of geometric and volumetric changes in IUGR‐related cardiac re‐modelling, also emphasizing the need for further research on electrophysiological re‐modelling and its effects on cardiac function.imageKey pointsIntrauterine growth restriction (IUGR) is associated with long‐term cardiovascular complications, including changes in the heart's electrical activity.Cardiac re‐modelling as a consequence of IUGR can lead to electrical changes that can be assessed through an electrocardiogram (ECG).This study analysed ECGs in pre‐adolescents with severe IUGR, revealing prolonged depolarization duration (QRS complex duration) and repolarization (T peak‐to‐end interval) compared to healthy controls.Computational models incorporating clinically observed anatomical changes, such as increased ventricular wall thickness and altered heart geometry, were used to assess their impact on electrical function, and determine whether these structural modifications contribute to the ECG alterations observed in clinical data.Both clinical data analysis and simulation findings showed significant shifts in depolarization‐based biomarkers and smaller, and non‐linear changes to geometrical changes, in repolarization intervals, highlighting how cardiac re‐modelling in IUGR affects heart function as measured by ECG.
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AbstractThe intestinal mucosa has evolved to facilitate interactions between the host and the constellation of intestinal microbes, collectively termed the microbiota. A well‐orchestrated balance exists in the healthy mucosa where microbes and microbial products first encounter a barrier formed by a single layer of intestinal epithelial cells (IECs). This homeostasis exists at a harsh interface between the highly vascularized mucosa and the anaerobic intestinal lumen. This steep oxygen gradient establishes ‘physiological hypoxia’ as a central metabolic characteristic of the mucosa. Recently, interest in understanding the dynamic host–microbe interplay has identified microbial metabolites that support host functions at several different levels. Of singular relevance are short‐chain fatty acids, particularly butyric acid. Studies have demonstrated that IECs have evolved to benefit from butyrate through a plethora of functions, including energy procurement, metabolism, barrier and wound healing regulation, production of antimicrobial peptides, etc. Butyrate is consumed by differentiated colonic epithelial cells preferentially for energy, creating a distinct butyrate gradient along the intestinal cryp‐tvillus axis. The depletion of butyrate and butyrate‐producing microbes during active inflammation, termed dysbiosis, promotes disease and attenuates tissue healing responses. Furthermore, in a disease state, the butyrate gradient is disrupted leading to reduced utilization of butyrate and inhibition of proliferation of colonic stem cells. Emerging studies suggest that chemical modifications to butyrate could be useful in targeting select IEC functions for particular benefits to the host. In this review, we consider how butyrate molecular mimicry may play out in the setting of mucosal health and disease and discuss current discoveries on endogenous and synthetic butyrate‐like compounds and their pathways.image
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AbstractHysteresis is a ubiquitous phenomenon and a salient feature of the adaptation of cardiac ventricular repolarization (VR) duration to changes in heart rate (HR), an expression of ultra‐rapid cardiac memory. Against a background of a handful of previous studies, this review focuses on non‐invasive electrophysiological assessment of the adaptation of VR duration and heterogeneity (aka dispersion) to changes in HR. Four different modalities were used: atrial pacing (incremental and step up/down), ventricular pacing (step up/down), and atropine‐induced continuous HR increase in healthy subjects and patients who either had permanent pacemakers or were scheduled for ablation of supraventricular tachycardia or had long QT syndrome type 1 (LQT1). Vectorcardiography according to Frank, with orthogonal leadsX,Y, andZ, was used for signal recording and beat‐to‐beat analysis. The RR interval (instantaneous HR) was the input. VR duration was assessed by the QT and QTpeakintervals and VR dispersion by T amplitude, T area, and the ventricular gradient. The main results were that independent of modality, VR duration adaptation follows a mono‐exponential pattern, is reproducible, and at a stable HR it takes 2–3 min to reach steady state. In contrast, VR dispersion adaptation is more rapid and roller‐coaster‐like, presumably due to local differences in adaptation time. In LQT1 patients, VR duration adaptation time is reduced giving less time for electro‐mechanical adaptation and coronary perfusion at HR increase. In conclusion, the patterns of adaptation of VR duration and VR dispersion differ, and further studies might provide information on these phenomena of both pathophysiological and therapeutic relevance.image
AbstractEnhanced untrained muscle strength and force steadiness following unilateral resistance training (i.e.cross‐education) are attributed to neural responses. However, the mechanisms of these adaptations for spinal motoneurons remain underexplored. Therefore, we examined maximal voluntary force (MVF), steady force variability (CovF) and longitudinally tracked motor unit adaptations in 10 individuals completing a 4 week unilateral strength intervention compared to nine controls. High‐density surface EMG was recorded from the biceps brachii during steady (10% MVF) and trapezoidal (35% MVF) contractions. The relative proportion of common synaptic input (CSI) to motoneurons and its variability (CSI‐V) were estimated using coherence and spectral analysis. Indirect estimates of persistent inward currents using firing rate hysteresis (∆F) and motor unit recruitment thresholds (MURTs) were assessed during ramps (35% MVF). MVF increased in both the trained (+14%,P< 0.001) and untrained limbs (+6%,P= 0.004), and CovF decreased in both limbs (P< 0.001). Greater CSI was observed on both sides (P< 0.01), concomitant with reduced CSI‐V (P< 0.01). ∆Fincreased exclusively in trained limbs [+1.61 ± 0.71 pulse per second (pps);P< 0.001], and both sides exhibited lower MURTs (P< 0.001). In trained limbs, MVF gains were strongly associated with changes in CSI, MURT and ∆F(R2> 0.70,P< 0.01), while the contralateral muscle MVF increase was associated exclusively with CSI and MURT (R2> 0.65,P< 0.01). In both limbs, lower CovF was strongly associated with reduced CSI‐V (R2> 0.70,P< 0.01). Our findings suggest that enhanced untrained muscle force and steadiness are mediated by increased relative strength of shared synaptic input with respect to independent noise and decreased variability of this shared input, with trained muscle MVF gains being associated with ∆F.imageKey pointsUnilateral resistance training improves strength and force steadiness in the contralateral untrained limb, suggesting neural adaptations without directly overloading the muscle.Despite established force‐related modifications, specific untrained limb responses in the relative shared synaptic input distribution and intrinsic motoneuron properties remain largely unknown.A 4 week unilateral training intervention enhanced muscle strength and force steadiness in the untrained limbs of 10 individuals, alongside a greater proportion of shared synaptic input, reduced variance in common input and lower motor unit recruitment thresholds.We demonstrated that the neural mechanisms underlying improved strength and force steadiness in muscles without mechanical overloading are associated with a higher relative shared input to motoneurons and reduced variance in these common input components.
AbstractCentral terminals of primary afferents and dorsal horn neurons usually exhibit spontaneous activity, the two phenomena being interrelated. Spontaneous activity may constitute a system for adjusting the level of excitation of spinal circuits and the processing of somatosensory information. Superficial dorsal horn neurons fire action potentials in a coordinated form, giving rise to population events. These population events are altered by peripheral inflammation, suggesting their implication in central sensitisation. In this work, we aimed to define the role of primary afferents in the occurrence of this coordinated activity. Channelrhodopsin‐2, archaerhodopsin‐3 or the hM4Di‐DREADD receptor were expressed in primary afferents by Cre‐recombination under control of the advillin promoter. Dorsal roots and superficial dorsal horn neurons were simultaneously recorded usingin vitrospinal cord slices from neonatal mice. Depolarisation of primary afferents by activation of channelrhodopsin‐2 inhibited dorsal root activity and the coordinated firing of dorsal horn neurons. DREADD activation reduced the activity in the afferents and depressed coordinated activity in dorsal horn neurons. In contrast, hyperpolarisation of afferents by archaerhodopsin‐3 augmented dorsal root responses and increased the coordinated activity of spinal neurons. The present results demonstrate a direct implication of primary afferents in the generation of coordinated spontaneous firing in superficial dorsal horn neurons.imageKey pointsThe input of somatosensory information through primary afferents is a process subjected to regulation at the level of the spinal cord, even before it reaches second‐order neurons.Primary afferent and spinal cord neurons exhibit spontaneous activity, which is altered in pathological models of pain.This study demonstrates the role of primary afferents as a fundamental coordinating element for the spontaneous activity of dorsal horn neurons.These results show that modulating the activity of the central terminals of primary afferents may have profound implications in both the excitability of spinal cord circuits and the processing of somatosensory information.
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AbstractDehydration is prevalent and adversely affects exercise performance; however, its influence on cellular responses to exercise remains unclear. Thus, this study examined the intramuscular responses to resistance‐exercise (RE) in RE‐trained men under dehydrated and euhydrated states. Eleven men (21 ± 1 years, 175.9 ± 6.2 cm, 79.2 ± 12.3 kg, 18.4% ± 6.7% fat) completed two identical lower‐body RE sessions, either with (DEHY) or without (EUHY) fluid‐restriction from 24 h before to 3 h after RE. At pre‐RE (PRE), 1 h, and 3 h post‐RE, muscle samples were collected and analysed for protein content of AKT/mTOR/p70S6K/rpS6 and their corresponding phosphorylation sites, REDD1 and selected autophagy markers, cathepsin L, H2O2concentration, fibre cross‐sectional area (CSA), and muscle water content. Significant time × condition interaction effects revealed that p‐rpS6S240/244was greater in DEHY than EUHY at PRE and increased from PRE to 1 h and 3 h in both conditions. In DEHY, REDD1 increased from PRE to 1 h and 3 h, active‐cathepsin L decreased from 1 h to 3 h and was greater than EUHY at 1 h, and muscle water content increased from 1 h to 3 h. Significant condition main effects revealed that p‐S6KT389and H2O2were greater, and CSA was smaller, in DEHYversusEUHY. Significant time main effects revealed that p‐AKTS473and p‐mTORS2448increased from PRE to 1 h and 3 h, LC3‐I decreased from PRE and 1 h to 3 h, LC3‐II decreased from PRE to 1 h and 3 h, and LC3‐II/LC3‐I decreased from PRE to 1 h and increased from 1 h to 3 h. These results suggest that performing RE in a dehydrated state imposes additional stress on the muscle, leading to greater cellular stress and growth signalling.imageKey pointsDehydration can negatively impact exercise performance, overall health, and cognitive function in humans.Water makes up about 70% of muscle mass, and dehydration has been shown to decrease muscle size in humans. However, the mechanisms by which dehydration affects muscle response on anabolic and catabolic signalling have only been observed inin vitrostudies, leaving the processes in humans still not fully understood.Following 24 h of dehydration, there was an increase in the activation of rpS6 at rest. Additionally, young men exhibited greater activation of S6K during resistance exercise (RE) while dehydrated compared to when they were adequately hydrated.Concurrently, stress (H2O2and REDD1) and proteolytic (active‐cathepsin L) responses were elevated after RE in a dehydrated state compared to an adequately hydrated state.Our research offers new insights into the importance of hydration in muscle responses to exercise, particularly for individuals who are frequently dehydrated.
AbstractIn the activation process of Kv channels, the S4 segment of the voltage‐sensing domain (VSD) moves in the outward direction. A conserved phenylalanine in the transmembrane S2 helix of the VSD is viewed as operating as a charge transfer centre (CTC) that interacts with a positively charged arginine of the S4 helix. This phenylalanine is highly sensitive to diverse substitutions. Kv2.1 subunits can form functional homotetrameric channels on their own whereas ‘silent’ Kv6.4 subunits can only contribute to functional heterotetrameric channels. We used concatenated dimers of Kv2.1 and Kv6.4 subunits to define the stoichiometry and position of these subunits in functional heterotetrameric channels. Our results demonstrate that mutating the phenylalanine F273 of the Kv6.4 subunits in Kv 2.1_6.4 channels built of dimers to diverse other amino acids at the CTC affects steady‐state activation only moderately whereas it strongly shifts steady‐state inactivation by 40 mV toward more depolarized potentials compared to Kv2.1_6.4 wild‐type channels. Mutating the Kv6.4 subunits in this heterotetramer slowed down the recovery from closed‐state inactivation without impacting open‐state inactivation. Moreover, results with the specific Kv2.1 blocker guangxitoxin suggest that Kv6.4 subunits may partly activate Kv2.1_6.4 channels. It is concluded that F273 in the silent Kv6.4 subunit of Kv2.1_6.4 channels has a unique role in controlling activation and the recovery from inactivation.imageHighlightsThis study quantifies the functional effects of Kv6.4 mutations in Kv2.1_6.4 channels on activation and inactivation.Highly diverse mutations of the phenylalanine in the charge transfer centre of Kv6.4 reveal its unique role in Kv2.1_6.4 channels in closed state inactivation.The specific Kv2.1 blocker guangxitoxin unmasks that Kv6.4 subunits can partly activate Kv2.1_6.4 channels.
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AbstractSudden unexpected death in epilepsy (SUDEP) is the most extreme consequence of epilepsy. SUDEP typically occurs at night. Because humans sleep at night, these nighttime deaths are often attributed to seizures arising from sleep. Nocturnal mice also experience more seizure‐associated deaths during the nighttime. This could represent timing that is under circadian control. To examine this, male and femaleScn1aR1407X/+mice, a model of the epileptic encephalopathy Dravet syndrome, in which patients experience spontaneous seizures that often result in death, were housed in constant darkness and the timing of seizure associated death was assessed. We found that the timing of sudden death following seizures persists in constant darkness and peaks during the subjective nighttime. This circadian rhythm of death was independent of the timing of potentially fatal seizures and more frequently occurred while awake. Potentially fatal seizures resulted in prolonged unconsciousness, which also exhibited a circadian rhythm peaking during the subjective night. These findings provide support for circadian regulation, independent of seizure timing and sleep, in the nighttime risk of seizure‐associated death. Nighttime seizures may increase risk of SUDEP via multiple mechanisms, as evident by peak spontaneous sudden death and profoundly impaired consciousness following seizures during the subjective night.imageKey pointsSudden unexpected death in epilepsy, or SUDEP, is a devastating outcome of intractable epilepsy.Converging lines of evidence indicate that there is a time‐of‐day preference for SUDEP, with more SUDEP occurring during the night.Several animal models of the epileptic encephalopathy Dravet syndrome (DS), including the one employed in our study, recapitulate key features of DS in patients, including a high rate of seizure‐related death and more of the deaths occurring at night.Here, we removed light/dark photocycles, by housing animals in constant darkness, and identify nighttime preponderance of death, suggesting that this is under circadian regulation.We further carefully characterize fatalvs. non‐fatal seizures in our animals and identify features that may prove to be useful biomarkers to predict which seizures may become fatal.
AbstractThe spontaneous, phasic contractions of collecting lymphatic vessels are critical for lymph transport and interstitial fluid homeostasis. Phasic contractions are initiated by action potentials in lymphatic muscle and conduct along the vessel to trigger contraction waves. Contractions are regulated by pressure and shear stress (SS), but only limited aspects of that regulation are understood. Numerical models predict that pressure promotes retrograde propagation of contraction waves, whereas nitric oxide (NO) production associated with phasic contractions (pulsatile NO) promotes antegrade conduction and extends the pressure range over which contractions propel lymph. These predictions were tested using 3−4‐valve segments of rat mesenteric lymphatic vessels using pressure myography and protocols that imposed forward flow, elevated inflow pressure (Pin) or elevated outflow pressure (Pout), each with/without intact NO signalling. NO bioavailability and flow‐induced responses were enhanced byl‐arginine supplementation. Spatiotemporal maps generated from video images were used to quantify the direction and extent of contraction wave conduction. Our results show that (1) contraction waves are normally biased towards retrograde conduction at equalPin/Poutlevels. (2)Pinelevation promotes antegrade conduction, whereasPoutelevation promotes retrograde conduction. (3) Imposed flow is inhibitory, reducing contraction amplitude and frequency and limiting the extent of contraction wave conduction without a significant effect on conduction direction. (4) Pulsatile NO does not significantly influence the conduction direction or extend the pressure range over which spontaneous contractions occur. Our findings support the idea that pressure is the dominant regulator of lymphatic pacemaking and pumping, with pulsatile NO having only minimal influence.imageKey pointsThe degree to which spontaneous, phasic contractions of lymphatic collecting vessels are regulated by pressure and shear stress is not fully understood.Numeric models predict that nitric oxide (NO) production associated with phasic contractions (pulsatile NO) promotes antegrade conduction of contraction waves, whereas pressure elevation promotes retrograde conduction; pulsatile NO production is also thought to extend the pressure range over which phasic contractions occur.Ex vivomethods were used to control pressure/flow in 3−4 valve segments of collecting lymphatics from rat mesentery, with preserved or inhibited NO signalling.The relatively long vessel segments limited the absolute levels of imposed flow/SS, sol‐arginine supplementation was used to enhance NO bioavailability.Our findings support a scheme whereby pressure is by far the dominant mechanism determining the pacemaking site of lymphatic collectors, and challenge existing dogma about the importance of pulsatile NO production in regulating their behaviour.
The hippocampal formation (HF) plays a key role in avian spatial navigation. Previous studies suggest that the HF may serve different functions at various stages in pigeons’ long-distance outdoor homing flight. However, it remains unclear whether the HF exhibits specific neural responses during these stages. In this study, we employed a wearable bimodal data recording system to simultaneously capture flight trajectories and hippocampal local field potential (LFP) signals of pigeons (either sex) during outdoor homing navigation. Our results revealed significant differences in hippocampal neural responses across the initial decision-making (DM) and en route navigation (ER) stages. Specifically, elevated LFP power in theta (4–12 Hz) and beta (12–30 Hz) bands was detected during the DM stage compared to the ER stage, while the high gamma (60–120 Hz) band exhibited the opposite pattern. In addition, we examined typical theta-beta phase-amplitude coupling (PAC) during the ER stage. Additionally, stage-specific hippocampal responses remained consistent across release sites. Notably, the difference in hippocampal responses across stages diminished along with the accumulation of homing experience. These results offer new insights into the role of the avian HF in homing flight navigation and suggest parallels between avian and mammalian hippocampal mechanisms in spatial learning.Significance StatementIt remains unclear whether the hippocampal formation (HF) exhibits specific neural responses during various stages in the long-distance outdoor navigation of pigeons. By recording hippocampal local field potentials (LFPs) and positional data during natural outdoor flights, we reveal distinct neural response patterns that differentiate between initial decision-making and sustained navigation stages. We detected band-specific power and coupling responses between different navigation stages, consistent across multiple release sites. Additionally, we found that the LFP responses differences across stages gradually diminish along with the accumulation of the homing experience. Our study offers new insights into the role of the avian HF in outdoor homing flight.
Recent evidence highlights the importance of glutamatergic neurons in the basal forebrain (BF) in promoting cortical activity; however, whether BF glutamatergic neurons are involved in regulating general anesthesia and the underlying neural circuits remains unclear. Here, the authors show that the activity of BF glutamatergic neurons decreased during the induction of isoflurane anesthesia and restored during the emergence in mice. Optogenetic activation of BF glutamatergic neurons accelerated the emergence from isoflurane anesthesia, decreased isoflurane sensitivity, and increased arousal score of mice. Moreover, optogenetic activation of BF glutamatergic neurons decreased EEG delta power and burst-suppression ratio, while increased pupil size and respiration rate of mice during isoflurane anesthesia. Similar results were observed during the optogenetic activation of BF glutamatergic terminals in the ventral tegmental area (VTA). Additionally, the authors found that the activity of BF glutamatergic neurons and VTA glutamatergic neurons synchronously fluctuate during isoflurane anesthesia, and optogenetic activation of BF glutamatergic terminals in the VTA potently increased the calcium signals of VTA glutamatergic neurons during isoflurane anesthesia. Collectively, their study illustrated that BF glutamatergic neurons promote isoflurane anesthesia emergence via activating VTA glutamatergic neurons. Both male and female mice were used in this study.Statement of SignificanceGeneral anesthesia is widely used in modern medicine; however, its specific neural mechanisms remain poorly understood. The basal forebrain (BF) is a critical component of the ascending arousal system, and its glutamatergic neurons were implicated in sleep–wake behavior and cortical activity. Here, we report that optogenetic activation of BF glutamatergic neurons significantly promoted cortical activation, behavioral emergence and physiological indicators in mice under isoflurane anesthesia. Photostimulation of BF glutamatergic terminals in the ventral tegmental area (VTA) produced similar effects, and significantly increased the activity of VTA glutamatergic neurons. Our findings illustrated that BF glutamatergic neurons promote emergence from isoflurane anesthesia via VTA glutamatergic neurons, highlighting a potential target for attenuating anesthesia depth and accelerating anesthesia emergence in clinical anesthesia.
Microsaccades are miniature saccades performed during visual fixation that were shown to play a pivotal role in active sensing. Recent studies suggested that pre-microsaccadic attention may underlie the enhanced visual processing at the stimulus site. However, the neuronal mechanism underlying this phenomenon at the foveal scale remains unknown. Using voltage-sensitive dye imaging we investigated the neural responses to uninstructed, spontaneous microsaccades in the fovea of the primary visual cortex (V1) in behaving monkeys (macaque, male). We found that prior to microsaccades onset toward a small visual stimulus, the neuronal activity at the current and future landing stimulus sites was enhanced relative to microsaccades away from the stimulus. This enhancement was spatially confined to the current and future landing stimulus sites, which appeared to merge along the microsaccades ( < 1 deg ) trajectory in V1. Finally, we found a pre-microsaccadic increased synchronization at the current stimulus site. Our findings shed new light on neural modulations preceding microsaccades and suggest a link to neural signatures of attention.Significance statementMicrosaccades are miniature eye-movements that occur during visual fixation. Behavioral studies have suggested that pre-microsaccadic attention enhances visual processing in the fovea. However, the underlying neuronal mechanisms at the foveal scale remain unknown. Using voltage-sensitive dye imaging in monkeys, we investigated how microsaccades influence neural activity in the foveal region of the primary visual cortex. Just before a microsaccade toward a small visual stimulus, neural activity was enhanced at both the current and future landing stimulus locations, compared to microsaccades directed away. This enhancement appeared over the microsaccade path and was accompanied by increased synchronization at the current stimulus location. Our findings reveal novel neural modulations preceding microsaccades, and suggest a link between microsaccades and neural signatures of attention.
Structural neuroimaging studies of typical development reveal increases in grey matter volume during childhood, followed by shrinkage in adolescence and early adulthood. With neuropil constituting the bulk of grey matter, these developmental changes may reflect neuropil reorganization accompanied by alterations in cellular membranes, as well as changes in related energy demand. Phosphorus magnetic resonance spectroscopy (31P MRS) allows in vivo assessment of changes in the brain’s high-energy phosphates – phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) - as well as metabolites associated with synthesis and degradation of membrane phospholipids (MPLs) – phosphocholine (PC) and phosphoethanolamine (PE), and their breakdown products, glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE). Forty-nine children and adolescents aged 6 to 14 years at baseline (37 boys, 12 girls) were assessed on up to three occasions approximately 12 months apart. MPL precursor levels decreased across all examined regions over time, including cortical and subcortical gray matter and two major white matter tracts. Breakdown products increased in the prefrontal cortex (PFC) in younger children but decreased in their older counterparts. While ATP and Pi decreased across most regions, PCr changes were heterochronic and regional: Hippocampal increases were more pronounced in older children, whereas most of the remaining regions showed no change. Changes in MPL precursors were positively associated with change in PFC cortical thickness, suggesting that the expansion and contraction of neuropil are coupled with structural brain changes during childhood and adolescence. Thus, in vivo31P MRS provides new insights into the neurobiological mechanisms of normal brain development.Significance StatementIn childhood and adolescence, structural neuroimaging reveals marked changes in the brain’s grey matter, most likely indicating contraction and expansion of its main component – the neuropil. The neurobiological mechanisms of these changes are, however, poorly understood. In the first of its kind longitudinal study of 6- to 14-year-old children, we examined in vivo changes in metabolites associated with brain energetics and the synthesis and degradation of membrane phospholipids using phosphorus magnetic resonance spectroscopy. We identify developmental changes in the metabolites associated with contraction and expansion of the neuropil and their coupling with structural changes in late-to-mature brain regions of the prefrontal cortex, indicating candidate mechanisms of brain development.
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Rhythms at a population level are a defining characteristic of both normal and pathological cortical activity, but it is unclear howsuch rhythms interactwith activity of specific neurons to impact task performance on a trial-by-trial basis. We address this by employing a challenging visual detection task in which male rhesus macaques must signal the presentation of a shape embedded in a noisy background. We analyzed the rhythmic activity in the local field potential (LFP) and single neuron activity in area V4, a brain area strongly implicated in shape perception, prior to such presentations and focused on two different frequency ranges: alpha/beta (10-30 Hz), in which coherence was particularly strong and spatially extensive, and gamma (50-70 Hz), which has traditionally been strongly associated with single unit activity. We find that within sessions there were periods of time during which successful detection was associated with the absence of rhythmic activity prior to shape presentation in either frequency range. During these periods, rhythmic activity in both frequency bands could predict whether the shape would be detected by the animal at the time of, as well as before, shape presentation on a trial-to-trial basis with high accuracy. Importantly, for both frequency ranges, the individual neurons carrying the most relevant information with regard to the task had the weakest coupling to the LFP rhythms. These results are consistent with spatially-distributed rhythmic activity acting as a source of decision noise in the context of rapid visual detection by reducing the moment-to-moment reliability of task-relevant information carried by individual neurons.Significance StatementAlthough rhythmic activity in the brain has been studied for over 100 years, its relevance to information processing remains unresolved. In this study we show for the first time that, in the context of a challenging visual detection task, rhythmic activity in local populations of neurons prior to appearance of the visual stimulus can predict mistakes on a trial-by-trial basis. Furthermore, this activity is linked to task-relevant signals at a neuronal level because the individual neurons with the weakest coupling to these rhythms are the most reliable.
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Negative and cognitive symptoms impair functioning in patients with psychotic illnesses (i.e., schizophrenia spectrum disorders (SZ) and bipolar I disorder with psychotic features (BD)). Disruptions in mesocorticolimbic circuitry are hypothesized to underpin negative symptoms and cognitive impairment in patients with psychosis and may also facilitate reward-motivational deficits. In male and female patients with psychosis (N=44) and healthy controls (HC=27), we used neuroimaging to define gray matter morphology and white matter microstructure. We examined negative symptom severity with the Clinical Assessment Interview for Negative Symptoms (CAINS), effort allocation during reward processing with the Effort Expenditure for Rewards Task (EEfRT), and cognitive performance with the MATRICS Cognitive Consensus Battery (MCCB). Reduced nucleus accumbens volumes in patients with psychosis were associated to higher CAINS total and Motivation and Pleasure subscale scores as well as lower effort expenditure for medium (50%) and high (88%) reward probability conditions during the EEfRT. The fornix showed reduced fractional anisotropy in patients with psychosis. Negative associations were present between CAINS Motivation and Pleasure subscores and MCCB composite and subscale scores. Lower gray matter volume in cerebellar lobule VI corresponded with impaired effort allocation during medium and high reward probability conditions and lower cognitive performance. However, lobule VI was not correlated with CAINS scores. While nucleus accumbens volume may serve as marker of negative symptoms in psychotic illnesses, cerebellar lobule VI morphology may inform on cognitive impairment in patients with SZ and BD. The nucleus accumbens and lobule VI may each contribute to reduced effort allocation during reward processing.Significance StatementImproving negative symptoms and cognitive impairment in SZ and BD remains an unmet clinical need. This study reveals that, in SZ and BD, structural changes in the nucleus accumbens and cerebellar lobule VI are associated with negative symptoms and cognitive impairments, respectively. The current findings also suggest that reductions in nucleus accumbens and cerebellar lobule VI volume may also underpin impaired reduced effort allocation during reward processing. This study provides impetus for further probing supratentorial and cerebellar circuitry to further understand negative and cognitive symptoms experienced by patients with psychotic illness and their associations with reward-motivational deficits.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by death of lower and upper motor neurons. Although the mechanism behind the selective neuron loss is still unclear, several heterogenous genes have been causally linked to ALS.KIF5Aencodes for a neuronally enriched kinesin involved in protein transport and mutations within this gene have been causally linked to different motor neuron diseases. The mutations identified in ALS patients are mostly predicted to alter its mRNA splicing, leading to a frameshift mutation and an aberrant 39 amino acid-long sequence in the C-terminal domain of KIF5A.Here we found that ALS-related KIF5A mutations induce the accumulation of the mutant form of the protein in human motoneurons, which are also characterized by the cytosolic mislocalization of TDP-43. This ALS hallmark was even exacerbated upon overexpression of the ALS-KIF5A protein in cells differentiated from healthy controls and primary neurons, suggesting a pathological connection between the cellular load of the mutant protein and TDP-43 pathology. While the terminal domain of the WT isoform is characterized by an acid isoelectric point (pI), the ALS variant presents a basic pI due to the altered aminoacidic composition of this sequence. We thus generated a KIF5A ALS isoform that retained part of the aberrant sequence but with lower pI. The overexpression of this mutated variant led to significantly lower protein aggregation and TDP-43 mislocalization than the ALS mutant. Our data show that re-establishing the correct pI rescues KIFA aggregation and significantly reduces the cytoplasmic mislocalization of TDP-43.Significance StatementAmyotrophic Lateral Sclerosis is a lethal neurodegenerative disease to which no cure is still known. Heterogenous genes have been causally linked to ALS, yet, the exact pathomechanism responsible for neuronal death remains unclear. One such gene is KIF5A which encodes for a neuronally enriched kinesin. Identified mutations cause incorrect mRNA splicing resulting in an aberrant C-terminal aminoacidic sequence. Here, we identified TDP-43 cytosolic enrichment, a hallmark common to many ALS models, in two distinct hiPSC-derived motoneuron lines harboring the ALS mutation KIF5Ac2993-1 G>A. Moreover, we generated a KIF5A isoform that retained most of the aberrant sequence but did not promote protein aggregation nor TDP-43 mislocalization upon overexpression. These results shed further light on the pathobiochemistry of the ALS-KIF5A cases.
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning, alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca²⁺) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca2+ATPase (SERCA) pump may help to stabilize cytosolic Ca2+levels and exert neuroprotective effects in AD neurons. In the current manuscript we demonstrate synaptoprotective properties of several SERCA PAMs using anin vitromodel of amyloid toxicity. Based onin vitroexperiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer’s disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.Significance statementAlzheimer’s disease (AD) is a significant medical and social burden, yet no treatment currently exists. One of the hallmarks of AD is disrupted Ca²⁺ signaling, which contributes to neuronal dysfunction and degeneration. In the current study, we demonstrate the potential of the SERCA pump positive allosteric modulators (PAMs) as promising disease-modifying agents. Through anin vitroscreening, we identified NDC-9009 as the most effective SERCA PAM, promoting robust cytosolic calcium clearance and exhibiting neuroprotective properties. Furthermore, using miniature fluorescence in vivo imaging, a significant restoration of hippocampal neuronal ensembles activity and cognitive function after chronic administration of NDC-9009 in the transgenic AD mouse model was demonstrated.
Prestin’s voltage-driven motor activity confers sound-elicited somatic electromotility on auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in ∼50 dB hearing threshold shifts across frequency, supporting the causal association of the prestin-coding gene,SLC26A5, with hereditary hearing loss, DFNB61. However, ∼50% reduction in prestin-mediated OHC electromotility barely affects cochlear function, and it is currently unknown how much electromotility is minimally required to support normal hearing. We generated mouse models harboring two deafness-associated prestin variants, p.A100T and p.P119S, and found that these missense variants do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to 70-80% reductions in OHC electromotility. Homozygous and compound heterozygous mice of either sex for these missense variants suffered congenital hearing loss; however, they still retained relatively low hearing thresholds at lower frequencies, pointing to the clinical possibility that a small augmentation of OHC electromotility could benefit those with DFNB61 hearing loss. These mice were also found to be prone to audiogenic seizures. This study thus provides insights into the minimum OHC electromotility required for normal cochlear operation and reveals the unappreciated importance of prestin for central gain control.Significance statementPrestin is abundantly expressed in the auditory outer hair cells and is essential for normal cochlear operation. Hence, reduction of prestin expression is often taken as indicative of reduced cochlear function in diseased or aged ears. However, this assumption overlooks the fact that cochlear function can tolerate surprisingly large reductions in prestin motor activity. DFNB61 mouse models generated and characterized in this study provide an opportunity to gauge the amount of prestin motor activity needed to sustain normal hearing sensitivity. This knowledge is crucial not only for understanding the pathogenic roles of deafness-associated variants that impair OHC electromotility but also for unraveling how prestin contributes to cochlear amplification.
A major challenge in cerebellar physiology is determining how the stereotypic, conserved circuitry of the cerebellar cortex, with its dominant parasagittal and transverse architectures, underlies its fundamental computations and contributions to behavior. Recent advances have allowed for the resolution of Purkinje cell dendritic activity at large scales, but the full roles of these Purkinje cell dynamics during behavior remain undetermined. To interrogate Purkinje cell dynamics at the population level during behavior, we implemented a novel approach for awake, chronic, wide-field Ca2+imaging of the cerebellar cortex. We performed wide-field cerebellar recordings in mice of both sexes exhibiting sparse expression of the Ca2+indicator GCaMP6s, which importantly allowed for the resolution of both dendritic and somatic Purkinje cell activity. Blind source separation of wide-field dynamics using spatial independent component analysis (sICA) extracts components consisting of either Purkinje cell dendrites or somata, with distinct activity and spatial properties. These independent components (ICs) tend to be either parasagittally organized and likely reflective of dendritic activity, or more spatially distributed populations of Purkinje cell somata. We observe broad, bilateral activation of both these dendritic and somatic ICs during behavior, but they exhibit distinct and divergent patterns of spatial correlations occurring primarily along the parasagittal and transverse directions, consistent with the main geometry of the cerebellar cortex. Somatic correlation dynamics are robustly modulated by prediction errors and reflect ultimate behavioral outcomes. These results provide a novel link between cerebellar structure and function, with the correlation dynamics of Purkinje cell activity a key feature during behavior.Significance statementThe cerebellar cortex exhibits highly conserved, elegant cytoarchitecture, but a full understanding of how this organization contributes to cerebellar processing is limited. We performed wide-field Ca2+recordings of the primary output neurons of the cerebellar cortex, Purkinje cells, and find that they are organized into distinct networks, which are either parasagittally organized or distributed populations of somatic activity. While both networks are highly engaged during behavior, they exhibit distinct spatial correlation dynamics consistent with the main geometry of the cerebellar cortex, with somatic correlation dynamics conveying information about prediction error and behavioral outcomes. Together, these results provide new insights into the functional organization of Purkinje cells and implicate somatic network correlation dynamics as a key feature of cerebellar processing.
Puberty triggers significant changes. However, besides the pruning of synapses, little is known about more long-range alterations during brain maturation. Actin filament formation – a process ignited by actin nucleators - is crucial for life and also a driving force behind cellular morphology changes. Yet, the physiological importance of especially the more recently discovered, evolutionary younger actin nucleators largely remain elusive. We demonstrate the consequences of deficiency for the actin nucleator Cobl in the mouse brain. We identify remarkably layer- and age-restricted corticalCoblKO phenotypes in dendritic arborization that first transiently emerge in layer V in rather young adolescent male mice and then manifested in a similar but more pronounced manner in layer II/III during the age of emerging adulthood.CoblKO phenotypes were observed in the somatosensory cortex, prefrontal cortex and motor cortex. In WT mouse cortices, we discovered an increase in dendritic arbor complexity occurring during emerging adulthood and thereby identified a long-range process for cortical rewiring upon brain maturation. This dendritic arbor expansion is transient and largely erased during mature adulthood. The transient dendritic arbor expansion during emerging adulthood was accompanied by transient length changes of dendritic spines. Molecularly, the process thus seems to relate to alterations in actin dynamics. Importantly, both of these changes were completely absent inCoblKO mice. Increased risk-taking ofCoblKO mice point towards a lack of maturity. These observations revealed the actin nucleator Cobl as first molecular component crucial for the identified emerging adulthood-related changes of neurons towards brain maturation.Significance statementPuberty triggers significant changes. We discovered a transient increase in dendritic arbor complexity occurring during emerging adulthood. This identified a long-range process for cortical rewiring during the age of emerging adulthood. Also dendritic spines were transiently rearranged. Both processes turned out to be dependent on the actin nucleator Cobl. We discovered remarkably layer- and age-specific corticalCoblKO phenotypes in dendritic arborization. These first transiently emerged in layer V in adolescent mice and then manifested in a similar but more pronounced manner in layer II/III during the age of emerging adulthood. This identified the actin nucleator Cobl as the first crucial component for the discovered reorganizations towards brain maturation.
Crows, renowned for advanced cognitive abilities and vocal communication, rely on intricate auditory systems. While the neuroanatomy of corvid auditory pathways is partially explored, the underlying neurophysiological mechanisms are largely unknown. This study used functional ultrasound imaging (fUSi) to investigate sound-induced cerebral blood volume (CBV) changes in the field L complex of the auditory telencephalon in two female crows. FUSi revealed frequency-specific CBV responses, showing a tonotopic organization within the field L complex, with low frequencies in posterior dorsal region and high frequencies in the anterior ventral region. Machine learning analyses showed fUSi signals could be used to classify sound types accurately, in both awake and anesthetized states. Variable CBV responses to longer sound stimuli suggest a delineation of subregions within the field L complex. Together, these findings highlight the potential of fUSi for providing high-resolution insights into functional systems in corvids, enabling future exploration of experimental task-related cognitive dynamics.Significance StatementThis study highlights the use of functional ultrasound imaging (fUSi) to explore auditory processing in crows, marking the first application of this technique in songbirds. By revealing the frequency map of the crow's auditory system and demonstrating the ability of fUSi to classify sound types, the research uncovers the neural dynamics supporting complex auditory functions. The findings suggest conserved auditory organization across avian species and provide insights into the evolution of audio-vocal behaviors in birds. This work paves the way for future studies on the neural underpinnings of cognition and communication in corvids, offering significant implications for comparative neuroscience and neuroethology.
Music can effectively induce emotional arousal, which is associated with the release of stress hormones that are important for the emotional modulation of memory. Thus, music may serve as a powerful modulator of memory and mood, making it a promising therapeutic tool for memory and mood disorders such as Alzheimer’s disease or depression. However, music’s impact on memory depends on its features, timing, and ability to elicit emotional arousal. In the current study, we manipulated various features of music played during post-encoding memory consolidation to elicit emotional arousal and impact subsequent memory in men and women. We found that larger increases and moderate decreases in post-encoding music-induced emotional arousal from baseline resulted in gist vs. detail trade-offs in memory, with improved general memory but impaired detailed memory, while moderate increases in arousal from baseline corresponded to improved detailed memory, but impaired general memory. Importantly, relative to controls, music-induced emotional arousal demonstrated unique impacts on detailed memory that are crucial in supporting episodic memory. These findings suggest that music intervention does not uniformly impact memory and has important implications in developing personalized music-related interventions for those with memory and mood impairments.Significance StatementMusic may be a powerful tool for modulating memory and mood, offering therapeutic potential for disorders like Alzheimer’s and depression. We found that individual differences in emotional arousal following music exposure influenced both general memory and detailed memory performance. Compared to controls, music specifically impacted memory for details, highlighting its potential to target specific memory aspects. These findings suggest that music interventions may not uniformly enhance memory, emphasizing the need for personalized approaches in treating memory and mood impairments.
Rapid eye movement (REM) sleep is primarily regulated by the brainstem pons. In particular, the sublaterodorsal tegmentum (SubLDT) in the dorsal pons contains neurons whose activity is selective to REM sleep. Elucidation of the precise identities of these neurons and their roles in REM sleep regulation is challenging, however, due to the functional and molecular heterogeneity of the SubLDT. A recent study revealed that corticotropin-releasing hormone-binding protein (Crhbp)-positive neurons in the SubLDT projecting to the medulla play a crucial role in REM sleep regulation and that loss of theseCrhbp-positive neurons underlies sleep deficits observed in Parkinson’s disease. The firing patterns of these neurons during sleep/wake, however, remained unknown. Here, we used an opto-tagging method and conducted cell-type-specific recordings fromCrhbp-positive neurons using a glass pipette microelectrode in unanesthetized male mice. We recorded 58Crhbp-positive neurons and found that many of these neurons are REM sleep-active neurons (41.4%) and that the remaining neurons are mostly either wake-active, wake/REM sleep-active, or NREM sleep-active. In addition, projection-specific recordings revealed that the medulla-projectingCrhbp-positive neurons are mostly REM sleep-active neurons (75.0%). Based on clustering analysis and spike waveform analysis, REM sleep-activeCrhbp-positive neurons can be further divided into different subtypes according to their electrophysiological properties, suggesting thatCrhbp-positive neurons play diverse roles in REM sleep regulation.Significance statementReduced REM sleep is a risk for dementia and mortality, suggesting it has critical roles in health. The mechanisms and functions of REM sleep, however, remain largely elusive. Classical electrophysiological studies identified neurons in the pons that are active during REM sleep, and a recent study revealed thatCrhbp-positive neurons within the same area contribute to REM sleep regulation. The relationship between the neurons identified in each study, however, remained unknown. Loss ofCrhbp-positive neurons underlies sleep deficits in Parkinson’s disease, underscoring the importance of characterizing these neurons. Our study revealed that many of theCrhbp-positive neurons are REM sleep-active and comprise distinct subtypes in regard to firing patterns, suggesting their diverse roles in REM sleep regulation.
Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.Significance statementHistone deacetylase 3 (HDAC3) is a negative regulator of synaptic plasticity and memory. However, the mechanism that regulates HDAC3 activity remains poorly understood. This study demonstrates the pivotal nature of Serine 424 of HDAC3 to bidirectionally regulate long-term potentiation, a form of synaptic plasticity, and long-term memory formation. Serine 424 is a phosphorylation site, suggesting that phosphorylation of HDAC3 is a key regulatory mechanism controlling its regulation of gene expression required for long-term memory. Indeed, expression of a Serine 424 phospho-null in the aging brain ameliorated age-dependent long-term synaptic plasticity and long-term memory deficits in aging male and aging female mice. Thus, this study provides new insight into the regulation of HDAC3 activity involved in cognitive processes.
Evoked responses in the mouse primary visual cortex can be modulated by the temporal context in which visual inputs are presented. Oddball stimuli embedded in a sequence of regularly repeated visual elements have been shown to drive relatively large deviant responses, a finding that is generally consistent with the theory that cortical circuits implement a form of predictive coding. These results can be confounded by short-term adaptation effects, however, that make interpretation difficult. Here we use various forms of the oddball paradigm to disentangle temporal and ordinal components of the deviant response, showing that it is a complex phenomenon affected by temporal structure, ordinal expectation, and event frequency. Specifically, we use visually evoked potentials to show that deviant responses occur over a large range of time in male and female mice, cannot be explained by a simple adaptation model, scale with predictability, and are modulated by violations of both first and second-order sequential expectations. We also show that visual sequences can lead to long-term plasticity in some circumstances.Significance StatementVisual experience and temporal context can modulate evoked responses in mouse V1. There remains disagreement about whether this reflects predictive coding in visual circuits and whether visual mismatched negativity, which has important cross-over implications for human clinical work, constitutes evidence supporting this theory or reflects simple neural adaptation. This work strongly supports the former interpretation by demonstrating complex experience-dependent deviant responses that cannot be easily explained by a simple adaptation model. We use statistically rigorous analysis of the local field potential to show that oddball evoked deviance signals reflect relative timing, event frequency, 1stand 2ndorder sequence expectations and scale as a function of event probability.
Chronic neuropathic pain is a persistent and debilitating outcome of traumatic central nervous system injury, affecting up to 80% of individuals. Post-injury pain is refractory to treatments due to the limited understanding of the brain-spinal cord circuits that underlie pain signal processing. The corticospinal tract (CST) plays critical roles in sensory modulation during skilled movements and tactile sensation; however, a direct role for the CST in injury-associated neuropathic pain is unclear. Here we show that complete, selective CST transection at the medullary pyramids leads to hyperexcitability within lumbar deep dorsal horn and hindlimb allodynia-like behavior in chronically injured adult male and female mice. Chemogenetic regulation of CST-targeted lumbar spinal interneurons demonstrates that dysregulation of activity in this circuit underlies the development of tactile allodynia in chronic injury. Our findings shed light on an unrecognized circuit mechanism implicated in CNS injury-induced neuropathic pain and provide a novel target for therapeutic intervention.Significance StatementCNS injury-induced neuropathic pain affects millions of people worldwide. A significant challenge in developing efficient therapeutics is the lack of suitable animal models that accurately replicate key features of human conditions, such as chronic onset of allodynia. We found a nuanced temporal evolution of sensory responses following a selective corticospinal tract (CST) lesion. Initially, there was a reduced tactile response, which later progressed to an exaggerated response characterized by increased mechanical hypersensitivity, a key feature of allodynia. We further identified a heterogenous population of CST-targeted spinal interneurons in the deep dorsal horn that modulate tactile sensory responses. These findings reveal a pivotal role for the CST in the development of CNS injury-induced chronic neuropathic pain.
Humans use multiple sensory systems to estimate body orientation in space. Sensory contributions change depending on context. A predominant concept for the underlying multisensory integration (MSI) is the linear summation of weighted inputs from individual sensory systems. Changes of sensory contributions are typically attributed to some mechanism explicitly adjusting weighting factors. We provide evidence for a conceptually different mechanism that performs a multisensory correction if the reference of a sensory input moves in space without the need to explicitly change sensory weights. The correction is based on a reconstruction of the sensory reference frame motion (RFM) and automatically corrects erroneous inputs, e.g., when looking at a moving train. The proposed RFM estimator contains a nonlinear dead-zone that blocks corrections at slow velocities. We first demonstrate that this mechanism accounts for the apparent changes in sensory contributions. Secondly, using a balance control model, we show predictions of specific distortions in body sway responses to perturbations caused by this nonlinearity. Experiments measuring sway responses of 24 subjects (13 female, 11 male) to visual scene movements confirmed these predictions. The findings indicate that the central nervous system resolves sensory conflicts by an internal reconstruction of the cause of the conflict. Thus, the mechanism links the concept of causal inference to shifts in sensory contributions, providing a cohesive picture of MSI for the estimation of body orientation in space.Significance statementHow the central nervous system (CNS) constructs body orientation in space from multiple sensory inputs is a fundamental question in neuroscience. It is a prerequisite to maintain balance, navigate and interact with the world. To estimate body orientation, the CNS dynamically changes the contribution of individual sensory inputs depending on context and reliability of the cues. However, it is not clear how the CNS achieves these dynamic changes. The findings in our study resolve major aspects of this question. Importantly, the proposed solution using nonlinear multisensory feedback contrasts with traditional approaches assuming context-dependent gain-scaling of individual inputs. Thus, our findings demonstrate how complex, intelligent, and unintuitive behavior can emerge from a comparably simple nonlinear feedback mechanism.
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The removal of no-longer-relevant information from visual working memory (WM) is important for the functioning of WM, given its severe capacity limitation. Previously, with an “ABC-retrocuing” WM task, we have shown that removing information can be accomplished in different ways: by simply withdrawing attention from the newly irrelevant memory item (IMI; i.e., via “passive removal”); or by or “actively” removing the IMI from WM (Shan and Postle, 2022). Here, to investigate the neural mechanisms behind active removal, we recorded electroencephalogram (EEG) signals from human subjects (both sexes) performing the ABC-retrocuing task. Specifically, we tested the hijacked adaptation model, which posits that active removal is accomplished by a top-down-triggered down-modulation of the gain of perceptual circuits, such that sensory channels tuned to the to-be-removed information become less sensitive. Behaviorally, analyses revealed that, relative to passive removal, active removal produced a decline in the familiarity landscape centered on the IMI. Neurally, we focused on two epochs of the task, corresponding to the triggering, and to the consequence, of active removal. With regard to triggering, we observed a stronger anterior-to-posterior traveling wave for active versus passive removal. With regard to the consequence(s) of removal, the response to a task-irrelevant “ping” was reduced for active removal, as assessed with ERP, suggesting that active removal led to decreased excitability in perceptual circuits centered on the IMI.Significance StatementThe removal of no-longer-relevant information from working memory is critical for the flexible control of behavior. However, to our knowledge, the only explicit accounts of this operation describe the simple withdrawal of attention from that information (i.e., “passive removal”). Here, with measurements of behavior and electroencephalography (EEG), we provide evidence for a specific mechanism for the active removal of information from WM–hijacked adaptation–via the top-down triggering of an adaptation-like down-regulation of gain of the perceptual circuits tuned to the to-be-removed information. These results may have implications for disorders of mental health, including rumination, intrusion of negative thoughts, and hallucination.
The error negativity or error-related negativity (Ne/ERN), a correlate of errors in choice tasks, is related to post-error adjustments indicating that it signals the need for behavioral adjustments following errors. However, little is known how the error monitoring system selects appropriate post-error adjustments for a given error to ensure that future errors are effectively prevented. This could be achieved by monitoring error precursors indicating potential error sources and then scale the Ne/ERN according to the strength of the error precursor upon error occurrence. We isolated such an error precursor in alpha oscillations and tested whether it predicts the size of the Ne/ERN. 28 Participants (23 female, 5 male) had to classify a target in one hemifield but ignore a distractor in the opposite hemifield. Because responding to the distractor always led to an error, misallocating spatial attention to the distractor as reflected in posterior alpha was a viable error precursor in this paradigm. We found that an alpha asymmetry reversal indicated a shift of spatial attention to the distractor on error trials and predicted the Ne/ERN on a single-trial level. The Ne/ERN in turn predicted alpha asymmetry on the next trial indicating a shift of spatial attention away from the distractor. This is consistent with the idea that the error monitoring system scales the Ne/ERN according to the strength of error precursors to select appropriate post-error adjustments of behavior.Significance StatementThis study reports evidence that the error monitoring system uses misallocation of spatial attention to distracting information as an error precursor to scale error signals in the brain. This ensures that error signals convey information about the type and strength of behavioral post-error adjustments that are necessary for a given error. The idea of monitoring error precursors that reflect specific error sources significantly extends existing theories of error monitoring mechanisms in the brain.
Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer’s disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule, has been shownin vitroto interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice (both sexes) develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target.Significance StatementNeuronal endosome dysfunction appears early in Alzheimer’s disease (AD) and is linked to memory loss. Genes and risk factors associated with AD often increase rab5 activity, a protein that disrupts endosomal signalling when hyperactivated. APPL1, a key rab5 partner, worsens this dysfunction via its interaction with APP-βCTF, a protein fragment associated with AD. To explore APPL1’s role, we created a genetically modified mouse that overexpresses APPL1 in neurons. This model provides the first in vivo evidence that APPL1 overexpression triggers key AD-like effects: rab5 hyperactivation, enlarged early endosomes, loss of cholinergic neurons, reduced synaptic plasticity in memory-related brain regions, and memory deficits. These findings highlight APPL1’s role in AD pathogenesis and its potential as a therapeutic target.
Juvenile zebra finches learn to sing by imitating conspecific songs of adults during a sensitive period early in life. Area X is a basal ganglia nucleus of the song control circuit specialized for song-related sensory-motor learning during song development. The structural plasticity and the molecular mechanisms regulating neuronal structure in Area X during song development and maturation are unclear. In this study, we examined the structure of spiny neurons, the main neuron type in Area X, at key stages of song development in male zebra finches. We report that dendritic arbor of spiny neurons expands during the sensitive period for song learning, and this initial growth is followed by pruning of dendrites and spines accompanied by changes in spine morphology as the song circuit matures. Previously, we showed that overexpression of miR-9 in Area X impairs song learning and performance and alters the expression of many genes that have important roles in neuronal structure and function (Shi et al., 2018). As an extension of that study, we report here that overexpression of miR-9 in spiny neurons in juvenile zebra finches reduces dendritic arbor complexity and spine density in a developmental stage-specific manner. We also show that miR-9 regulates structural maintenance of spiny neurons in adulthood. Together, these findings reveal dynamic microstructural changes in the song circuit during the sensitive period of song development and provide evidence that miR-9 regulates neuronal structure during song development and maintenance.Significance StatementSong development in juvenile zebra finches provides a model to study sensitive period plasticity for language development and related neural developmental disorders in humans. Area X is a basal ganglia nucleus essential for song-related sensory-motor learning in the zebra finch. We show that dendritic arbor of spiny neurons in Area X undergoes an initial growth and expansion followed by pruning of dendrites and spines during song development, and that this process is regulated by miR-9 in a developmental stage specific manner. These findings reveal the temporal profiles of structural development of key neurons in the basal ganglia song circuit and reveal a possible molecular mechanism for restricting sensitive period plasticity during vocal development.
Opioid abuse poses a major healthcare challenge. To meet this challenge, the brain mechanisms underlying opioid abuse need to be more systematically characterized. It is commonly thought that the addictive potential of opioids stems from their ability to enhance the activity of ventral tegmental area (VTA) dopaminergic neurons. Indeed, activation of mu opioid receptors (MORs) dis-inhibits VTA dopaminergic neurons projecting to the nucleus accumbens, providing a substrate for the rewarding effects of opioids. However, the abuse potential of opioids has also been linked to their ability to suppress pain and aversive states. Although medial VTA dopaminergic neurons are commonly excited by aversive stimuli, the effects of MOR signaling on this circuitry have not been systematically explored. To fill this gap, a combination of anatomical, optogenetic, and electrophysiological approaches were used to study the afferent circuitry of paranigral VTA (pnVTA) dopaminergic neurons and its modulation by MOR signaling in male and female mice. These studies revealed that aversion-linked glutamatergic neurons in the lateral hypothalamus, ventrolateral periaqueductal gray, and lateral habenula innervated a subset of pnVTA dopaminergic neurons and that activation of presynaptic MORs suppressed their ability to drive pnVTA spiking. A distinct set of pnVTA dopaminergic neurons were innervated by lateral hypothalamus GABAergic neurons, which also were subject to MOR modulation. Thus, MORs robustly inhibit the ability of brain circuits coding aversive states to drive the activity of pnVTA dopaminergic neurons, suggesting that the addictive potential of opioids may stem in part from their ability to act as negative reinforcers.Significance StatementOpioid abuse is a severe, worldwide problem. The ventral tegmental area (VTA) is part of the brain circuitry underlying opioid dependence. Previous work has shown that opioid activation of mu opioid receptors (MORs) suppresses GABAergic inhibition of VTA dopaminergic neurons, enhancing dopamine release and reward. However, the central mechanisms responsible for the ability of opioids to alleviate pain are less clear. Here we demonstrate that MORs suppress the ability of neurons in three aversion-related brain regions to drive spiking in dopaminergic neurons located in the paranigral region of the VTA – a sub-region linked to pain perception. Thus, these studies add a new dimension to our understanding of the central actions of opioids and their potential role in opioid abuse.
Spinal interneurons shape motor neuron activity. Gata3+V2b neurons are a major inhibitory spinal population. These neurons are present at multiple spinal levels in mice, suggesting an important function in motor control. In zebrafish, our previous work showed that V2b neurons are evenly distributed along the spinal cord, where they act to slow down locomotion. However, the timing of V2b activity during locomotion, their postsynaptic targets other than motor neurons, and their recruitment across different behaviors remain unknown. In this study, we address these questions using larval zebrafish. First, via optogenetic mapping of output in the rostrocaudal axis, we demonstrate that V2b neurons robustly inhibit motor neurons and other major spinal populations, including V2a, V1, commissural neurons and other V2b neurons. V2b inhibition is patterned along the rostrocaudal axis, providing long-range inhibition to motor and V2a neurons but more localized inhibition of V1 neurons. Next, by recording V2b activity during different visually and electrically evoked movements, we show that V2b neurons are specifically recruited for forward swims and turns, but not for fast escape movements. Furthermore, a subset of V2b neurons also exhibited short-latency sensory-evoked activity preceding motor initiation. Finally, we show that V2b inhibition occurs in phase with the leading edge of the motor burst, in contrast to V1 inhibition which occurs in phase with the falling edge of the motor burst. Taken together, these data show that in axial motor networks, V2b neurons act via multiple targets to produce in phase, leading inhibition during locomotion.Significance statementSpinal interneurons are critical for executing and regulating movements. However, it has been challenging to understand their functions and interconnections because the spinal cord circuit is complex, with many long-range connections that are challenging to map. Using optogenetics in the larval zebrafish, we mapped the connectivity and activity of an inhibitory spinal population: V2b neurons. We show that V2b neurons not only inhibit motor neurons but also other major excitatory and inhibitory populations. With electrophysiology and calcium imaging, we recorded V2b activity during different behaviors and found that V2b neurons inhibit their targets on the rising phase of motor bursts, preferentially during slow locomotion. These results suggest that V2b neurons have a distinctive role in motor control.
The nature of motor deficits in Parkinson disease (PD) and aspects of their improvements with ʟ-DOPA replacement therapy (LDRT) offer potential insights into striatal dopamine actions. The defining and most LDRT responsive feature of PD, bradykinesia, is a complex phenomenon exhibiting impairments of both simple and complex limb movements. LDRT significantly remediates the former but not the latter. LDRT pharmacodynamics has two major components, the Short Duration Response (SDR), with a time course of seconds to minutes, and the Long Duration Response (LDR), with a time course of days to weeks. LDRT pharmacodynamics suggests different striatal dopamine actions on different time scales. While many studies used PD subjects to investigate striatal dopamine actions, few take LDRT pharmacodynamics into account. Correlating bradykinesia features and LDRT pharmacodynamics with our present understanding of striatal dopamine actions suggests that LDRT failure to improve complex movement performance reflects loss of phasic dopaminergic signaling. The SDR is likely a result of partially restored tonic/volume striatal dopamine neurotransmission. There is no existing explanation for the LDR. Recent experiments isolating the LDR cast doubt on prior accounts of how LDRT remediates bradykinesia. Interactions between the SDR and LDR may give rise to novel properties. Longer duration effects of striatal dopaminergic signaling need to be incorporated into studies of striatal dopamine actions in both preclinical and clinical experiments. Careful studies of PD bradykinesia and LDRT pharmacodynamics offer potential avenues for future explorations of striatal dopamine actions. Systematic preclinical experiments are needed to optimize design of clinical experiments.
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Opioid use disorder (OUD) is a chronic disease of the brain, and it currently continues at crisis proportions in the United States. Opioid physical withdrawal is a major driver of compulsive drug-taking behavior, triggering short-term relapse of opioid addiction. Early pharmacological evidence shows that midbrain periaqueductal gray (PAG) plays an important role in morphine withdrawal (MW). However, we still know few details about the underlying molecular mechanisms. Improving our understanding of such mechanisms will enable increasingly safe and effective treatments for patients with OUD. Here, MW was induced by the naloxone precipitation after chronic intraperitoneal administration of morphine for a period of 5 days in Sprague-Dawley male rats. MW increased phosphorylation of cAMP response element binding protein (pCREB, a primary marker of CREB functional activation), NMDA glutamate receptor 2B subunit (NR2B), and mitochondrial calcium uniporter (MCU) within the ventrolateral PAG (vlPAG). Inhibition of pCREB, NR2B, or MCU within this brain region reduced the severity of MW. Chromatin immunoprecipitation (ChIP) assay and luciferase report assay demonstrated that pCREB mediated the transcription of theGrin2b(glutamate ionotropic receptor NMDA type subunit 2B, encoding NR2B) andCcdc109a(encoding MCU) genes. These findings describe the role of pCREB inGrin2bandCcdc109a genetranscription levels in the vlPAG during MW. The study may provide a novel therapeutic approach for OUD.Significant StatementDependence on opioids is a part of OUD symptoms. Evidence shows that the midbrain periaqueductal gray (PAG) plays an important role in morphine withdrawal (MW). However, we still know few details about the exact molecular mechanisms of MW. Here we found that naloxone-precipitated MW increased the levels of pCREB, NR2B, and MCU in the vlPAG. ChIP and luciferase report assays demonstrated that pCREB mediated the expression of theGrin2b(glutamate ionotropic receptor NMDA type subunit 2B, encoding NR2B) andCcdc109a(encoding MCU) genes on the transcriptional level in the vlPAG.
Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN), similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task in male mice. Conversely, inhibiting CRHPVNneurons during stress reduces stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRHPVNneurons activate neurons in the lateral hypothalamus (LH), and that CRHPVNprojections to the LH regulate stress-induced memory deficits and sleep disruptions. Our results suggest that CRHPVNneuronal pathways regulate the adverse effects of stress on memory and sleep - an important step toward improving sleep and ameliorating cognitive deficits associated with stress-related disorders.Significance statementStress significantly affects both sleep and memory, with spatial memory being particularly vulnerable. In this study, we combine acute restraint stress with optogenetic manipulations and a spatial object recognition task to investigate how corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN), and their projections to the lateral hypothalamus (LH), influence memory performance and sleep-wake states following stress. Our findings reveal that activating CRHPVNneurons impairs memory performance and increases wakefulness, whereas inhibiting CRHPVNneurons during stress improves memory and sleep. Inhibiting CRHPVNneuronal projections to the LH similarly improves memory performance and sleep. This work highlights the role of CRHPVNneurons and their projections to the LH in modulating stress-induced alterations in memory and sleep-wake states.
Autapses are self-synapses formed by a single neuron. They selectively form in a subpopulation of neocortical glutamatergic pyramidal cells (PCs) where autaptic transmission provides strong feedback regulation of self-activity in individual neurons. PCs in the hippocampal formation (HPF) possess morphological and electrophysiological characteristics similar to neocortical PCs, it remains unclear, however, whether they form functional autapses. We performed whole-cell recording from HPF PCs in acute slices obtained from mice of either sex and found surprisingly that none of the recorded PCs in CA1, CA2 and CA3 show autaptic responses, only a subpopulation of PCs (∼50%) in the subiculum form functional autapses, particularly those targeting to the nucleus accumbens. Further experiments reveal that the autaptic responses in subicular PCs are mediated solely by AMPA receptors but not NMDA receptors, and occur much earlier than those of the medial prefrontal cortex (mPFC) during early development. Together, the results indicate that functional autapses selectively form in a considerable subset of subicular PCs, but are completely absent from PCs in the hippocampus proper, suggesting a key role of autapses in regulating the self-activity of subicular PCs and thus the main output signals of the hippocampus.Significance StatementNeurons of HPF wire together through synapses to form circuits critical for high-order brain functions. Unlike conventional synapses formed by two neurons, autapses are self-synapses providing feedback regulation of a neuron’s own activity. We find that autapses selectively form in a subpopulation of subicular PCs, but are entirely absent from other HPF PCs, suggesting a key role of autapses in regulating the self-activity of individual subicular PCs and thereby the primary output of HPF. Additionally, autapses of subicular PCs emerge earlier than those in mPFC, and their time course correlates well with developmental changes in neuronal morphology. Therefore, the selective and early formation of autapses in subicular PCs may play a vital role in early-life cognitive functions.
We often mistake visual noise for meaningful images, which sometimes appear as convincing as veridical percepts. This suggests considerable overlap between the mechanisms that underlie false and veridical perception. Yet, false percepts must arise at least in part from internally generated signals. Here, we apply multivariate analyses to human MEG data to study the overlap between veridical and false perception across two aspects of perceptual inference: discrimination of content (what did I see?) and detection (did I see something?). Male and female participants performed a visual discrimination task requiring them to indicate the orientation of a noisy grating, as well as their confidence in having seen a grating. Importantly, on 50% of trials only a noise patch was presented. To exclude external signals driving false percepts, noise patches were carefully designed not to contain orientation signal. Still, participants occasionally confidently reported seeing a grating on noise-only trials, dubbed here false percepts. Decoding analyses revealed a sensory signal reflecting the content of these false percepts, despite no such grating being physically presented. Uniquely, high confidence false, but not veridical, percepts were associated with increased pre-stimulus high alpha/low beta [11-14Hz] power, potentially reflecting enhanced reliance on top-down signalling on false percept trials. Later on, a shared neural code reflecting confidence in stimulus presence emerged for both false and veridical percepts. These findings suggest that false percepts arise through neural signals reflecting both sensory content and detection, similar to veridical percepts, with an increase in pre-stimulus alpha/beta power uniquely contributing to false percepts.Significance statementThe neural mechanisms underlying false percepts are likely different from those that underlie veridical perception, as the former are generated endogenously, whereas the latter are the result of an external stimulus. Yet, false percepts often get confused for veridical perception, suggesting a converging mechanism. This study explores the extent to which the mechanisms diverge and converge. We found that both high confidence false and veridical percepts were accompanied by content-specific stimulus-like orientation signals, as well as a shared signal reflecting perceptual confidence. In contrast, we found that false, but not veridical, percepts were preceded by increased high alpha/low beta [11-14 Hz] power, possibly reflecting a reliance on endogenous signals.
The circadian rhythm shapes behavioral processes by providing temporal cues for molecular regulation and adaptation in the hypothalamus of the brain. Deeper yet in the striatum of the brain, circadian rhythm also exerts an impact, conditioning diurnal patterns in neurodegenerative-related motor dysfunction. While motor properties are clearly linked to striatal dopamine, the interplay between the circadian rhythm with the key circadian transcription factor Bmal1 and dopamine signal decoding remains unknown. Here, we utilized both sexes of global and local striatal Bmal1 knockout mice to investigate changes in dopamine-mediated cAMP signaling and motor behavior. By conducting a 24-hour time-course study, we first established Bmal1-dependent molecular signatures in striatal dopamine signaling machinery that correlated with cAMP levels. Next, recording real-time signal transduction with a 2-photon FRET biosensor in brain slices revealed diminished efficacy of dopamine signaling in the absence of Bmal1. As a final functional outcome, we then found that striatal Bmal1 was necessary for motor learning in mice. Altogether, our data support a strong connection between striatal Bmal1 and dopamine signaling with potential impact in brain-related motor function.Significance StatementHuman physiology is intertwined with the circadian rhythm to orchestrates neuronal activity over a 24-hour period. Interruptions to the circadian rhythm are often met with anomalies in motor behavior, which are processes shaped by dopaminergic signaling. Understanding how dopamine transfers information between neurons remains one of the most important areas of neuroscience research. Yet it remains unclear how regulatory proteins that shape circadian rhythm coordinate decoding of dopamine neurotransmission. By examining the dopamine signaling cascade throughout the day in mice, we found that oscillations in the second messenger cAMP depend on the circadian transcription factor Bmal1. Additionally, disruptions to Bmal1 modulate motor learning. This work provides a strong case that Bmal1 greatly influences encoding of dopamine signals in the striatum.
To build an understanding of our world, we make inferences about the connections between our actions, experiences, and the environment. This process,state inference, requires an agent to guess the current state of the world given a set of observations. During value-based decision-making, a growing body of evidence implicates the orbitofrontal cortex (OFC) and the hippocampus (HPC) in the process of contextualizing information and identifying links between stimuli, actions, and outcomes. However, the neural mechanisms driving these processes in primates remain unknown. To investigate how OFC and HPC contribute to state inference, we recorded simultaneously from both regions while two male monkeys (Macaca mulatta) performed a probabilistic reversal learning task, where reward contingencies could be captured by two task states. Using population-level decoding, we found neural representations of task state in both OFC and HPC that remained stable within each trial but strengthened with learning as monkeys adapted to reversals. Subjects also appeared to use their understanding of task structure to anticipate reversals, evidenced by anticipatory neural representations of the upcoming task state.Significance StatementDuring value-based decision-making, a growing body of evidence implicates the orbitofrontal cortex (OFC) and the hippocampus (HPC) in the process of contextualizing information and identifying links between stimuli, actions, and outcomes. However, limited work has been done in nonhuman primates to bridge the gap between rodent and human models. In this study, we show that task state is represented in both OFC and HPC in nonhuman primates. These representations remain stable within each trial, but evolve with learning and anticipate upcoming task changes, equipping subjects to adapt their choice preferences to reversals in reward contingencies. Our results support the theory that OFC-HPC interactions are important for flexible, goal-directed decision making, and provide insight into how the OFC and HPC participate in decision making when information is not explicitly provided, but must instead be inferred.
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Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of these neurons co-transmit glutamate and GABA (VGluT2+VGaT+ neurons), transmit glutamate without GABA (VGluT2+VGaT- neurons), or co-transmit glutamate and dopamine (VGluT2+TH+ neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified in male and female mice that VGluT2+ subpopulations are sensitive to reward value in unique ways. VGluT2+VGaT+ neurons increased activity magnitude with increased sucrose concentration, whereas VGluT2+VGaT- neurons increased magnitude and sustained activity with increased sucrose concentration, and VGluT2+TH+ neurons increased sustained but not maximum activity with increased sucrose concentration. VGluT2+ subpopulations also uniquely signaled signaled consumption of sweet/non-caloric (saccharine) and non-sweet/high calorie rewards (fat). VGluT2+VGaT+ neurons uniquely signaled lower-calorie sucrose over fat whereas both VGluT2+VGaT- neurons and VGluT2+TH+ neurons showed a signaling preference for higher-calorie fat over sucrose, but in temporally distinct ways. Further experiments suggested that VGluT2+VGaT+ consummatory reward-related activity was related to sweetness, partially modulated by pre-feeding, and not dependent on caloric content. Additionally, aversive stimuli increased activity for each VGluT2+ subpopulation but VGluT2+VGaT+ neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2+VGaT+ neurons during low intensity footshock enhanced fear-related behavior without inducing place preference or aversion. About half of VGluT2+VGaT+ sucrose-sensitive neurons were transcriptionally activated by footshock. We interpret these data such that VTA glutamatergic subpopulations signal different elements of rewarding and aversive experiences and highlight the unique role of VTA VGluT2+VGaT+ neurons in enhancing salience.Significance StatementVentral tegmental area glutamate neurons play a role in reward and aversion-based motivated behaviors. We identify that genetically-distinct ventral tegmental area glutamatergic subpopulations show differences in their signaling of consummatory rewards and aversive experiences. While all glutamatergic subpopulations signaled rewarding and aversive experiences, glutamatergic subtypes differed in their phasic magnitude and sustained activity profiles in response to the value of consummatory rewards, comparisons between multiple present rewards, and the value of aversive stimuli. VGluT2+VGaT+ neurons showed unique profiles related to both rewarding and aversive events. Based on these results we hypothesize that VTA VGluT2+VGaT+ neurons have a role in signaling the general salience of positive and negatively valenced behavioral experiences.
Previous studies on animal models suggested that visual areas involved in motion processing could undergo important cortical reorganizations following retinal damages. This could have major implications for patients suffering from macular degeneration (MD), one leading cause of vision loss. Here, we performed fMRI recordings in a group of maculopathy patients (N=7, 3 women, including individuals suffering from age-related macular degeneration or from Stargardt’s Disease) and a control group to characterize the motion processing cortical network in MD patients and determine whether this network is modified following the onset of the scotoma. We used an experimental protocol based on random-dot kinematograms (RDKs) classically employed to characterize motion-selective areas in the brain. To ensure that the visual information processed by the two groups was equivalent, the visual field in each control participant was masked using an artificial scotoma directly derived from clinical measurements in their paired patient. We found that in MD patients, translational motion elicited significant and robust activations in a restricted cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas (V1, V2 and V3) connected to peripheral vision. Importantly, the same patterns of responses were also observed in control participants. Moreover, the extent and strength of activation within these motion-selective areas did not differ significantly between the two groups. Altogether, these results suggest that in humans, the motion-selective network does not undergo significant large-scale cortical reorganizations following the onset of MD.Significance statementMotion processing in the visual cortex of patients with macular degeneration has never been characterized. Here, we performed fMRI recordings in 7 maculopathy patients and found robust motion-selective activations in a cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas connected to peripheral vision. These activations closely align with those reported in participants with normal vision in the literature and do not significantly differ from those measured in a group of age and gender-matched control participants who viewed the motion stimuli with a matched artificial scotoma. Altogether, our results suggest that the motion-selective network does not undergo significant large-scale reorganizations in maculopathy patients following the onset of the scotoma.
Altered function of peripheral sensory neurons is an emerging mechanism for symptoms of autism spectrum disorders. Visual sensitivities are common in autism, but whether differences in the retina might underlie these sensitivities is not well understood. This includes Fragile X syndrome, which is the most common syndromic cause of autism. We explored retinal function in the Fmr1 knockout mouse model of Fragile X syndrome. We focused on a specific type of retinal neuron homologous with primate ganglion cells, the “sustained On alpha” retinal ganglion cell, which plays roles in contrast sensing and binocular vision in mice. We found that these cells exhibit changes in dendritic structure and dampened responses to light in male Fmr1 knockout mice. We show that decreased light sensitivity is due to increased inhibitory input and reduced E-I balance. The change in E-I balance supports maintenance of circuit excitability similar to what has been observed in cortex. However, this maintenance also reshapes the tuning of this retinal ganglion cell type. These results show that loss of Fmr1 in the mouse retina affects sensory function of one retinal neuron type. As other retinal cell types also express Fmr1, Fragile X syndrome may affect the tuning of retinal cells more broadly. Our findings suggest that the retina may be relevant for understanding visual function in Fragile X syndrome.Significance statementAtypical sensory processing underlies some symptoms and experiences of people with autism spectrum disorders. These symptoms may include differences in vision, audition and sense of touch. In recent years, evidence has emerged that these differences start with atypical function of neurons in the periphery. However, not much is known about how ASD affects the function of the retina. Here, we explored retinal function in a mouse model of a disease strongly linked to ASD, Fragile X syndrome. Our experiments demonstrate that a cell type in the retina has dampened responses to light in the mouse model of Fragile X syndrome. Our work suggests that atypical processing in the retina may contribute to sensory symptoms in Fragile X syndrome.
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Accumulating evidence suggests that, in addition to dopamine, the neurotransmitter norepinephrine may play an important role in Parkinson disease (PD). The norepinephrine transporter (NET) regulates noradrenergic signaling and can serve as an index of noradrenergic innervation in neuroimaging studies. ThePink1-/-rat model, which exhibits many signs similar to PD, notably in the non-motor domain, has exhibited abnormal noradrenergic markers. In this work, we sought to (1) implement reference region pharmacokinetic modeling of positron emission tomography (PET) imaging with the novel NET ligand [18F]NS12137, (2) validate the resulting indices of NET concentration, and (3) characterize NET in thePink1-/-model. Long-EvansPink1-/-male rats were imaged by PET with [18F]NS12137 at 9 and 11 months and compared to wildtype (WT) controls. An additional group of WT rats of both sexes were imaged with [18F]NS12137 PET after pretreatment with the specific and selective NET ligand nisoxetine. Binding in locus coeruleus (LC), thalamus (Thal), and prelimbic area (PrL), regions rich in NET, were analyzed by a two-tissue compartment reversible binding model using a cerebellar reference region. [18F]NS12137 binding exhibited moderate test-retest reproducibility in LC, Thal, and PrL. Nisoxetine blockade yielded substantial reductions of [18F]NS12137 binding in LC. Compared to WT controls,Pink1-/-rats exhibited reduced binding in Thal and PrL. In conclusion, pharmacokinetic analysis of [18F]NS12137 PET provides a reproducible and specific measure of NET binding and indicates reduced NET in important brain regions inPink1-/-rats. Non-invasive in vivo [18F]NS12137 PET imaging is therefore a promising method for the study of potential therapies in thePink1-/-rat model of PD with translational potential for human PD studies.Significance StatementMany signs of Parkinson disease (PD), particularly non-motor ones, are associated with dysfunction of the noradrenergic system. However, pharmacological and behavioral therapies that target norepinephrine are not well developed for PD. It is important therefore to apply new tools for evaluating the noradrenergic effects of interventions in animal models of PD. In this work, we validated positron emission tomography (PET) neuroimaging in rats with the novel norepinephrine transporter (NET) radiotracer [18F]NS12137. We also found reduced NET expression in important brain regions (thalamus and prelimbic area) in thePink1-/-rat model of PD. [18F]NS12137 PET is therefore a promising tool for trials of interventions in thePink1-/-rat, and such work may lead to improved treatments for PD.
Early dorsal telencephalon development is coordinated by an interplay of transcription factors that exhibit a graded expression pattern in neural progenitors. How they function together to orchestrate cortical development remains largely unknown. TheEmx2andDmrta2genes encode TFs that are expressed in a similar caudomedialhigh/ rostrolaterallowgradient in the ventricular zone of the developing dorsal telencephalon with, in the medial pallium,Dmrta2but notEmx2expressed in the developing choroid plexus. Their constitutive loss has been shown to impart similar cortical abnormalities, and their combined deletion exacerbates the phenotypes, suggesting possible cooperation during cortex development. In this study, using embryos of both sexes, we utilized molecular and genetic approaches to dissect how Emx2 functions with Dmrta2 during mouse cortical development. Our results show that while they regulate a similar set of genes, their common direct targets are limited but include key regulators of cortical development. The identification of the interaction partners of Emx2 suggests that it coordinates with the LIM-domain binding protein Ldb1 to execute the activation and repression of some of its downstream targets. Finally, whileEmx2is known to suppress choroid plexus development, we also provide evidence thatDmrta2is, in contrast, required for choroid plexus since in its absence in medial telencephalic progenitors, mice develop hydrocephalus postnatally, a phenotype that appears to be due to a compromised cytoarchitecture. Together, these data indicate that Emx2 and Dmrta2 have similar but also distinct functions in telencephalon development and provide the first insights into Emx2 mechanism of action.Significance statementEmx2andDmrta2encode transcription factors that generate similar phenotypes upon their loss in the developing cortex suggesting possible cooperation. Here we explored how Emx2 functions with Dmrta2 during cortical development. Results obtained indicate that Emx2 directly regulates with Dmrta2 only a few genes, some coding for key cortical determinants and that Emx2 utilizes the Ldb1 cofactor for the regulation of some of its targets. Results also suggest that, unlike Emx2 which suppresses choroid plexus development, Dmrta2 is required for choroid plexus as its loss in medial telencephalic progenitors leads to hydrocephalus. Together, our results reveal that Emx2 and Dmrta2 have similar but also distinct functions during telencephalon development and provide novel insights into the mechanism of action of Emx2.
Cocaine is an addictive psychostimulant, and the risk of developing cocaine use disorder (CUD) is highly heritable. Little is known about the specific genes and mechanisms that lead to the development of CUD, and there are currently no FDA-approved pharmacotherapies that can treat it.Drosophilahas proven an effective model organism to identify genes and mechanisms underlying addiction, especially alcohol use disorder. While flies exposed to cocaine display features of acute intoxication like those observed in mammals, including hyperactivity and reduced sleep, to date, there is no model of preferential cocaine self-administration in flies. Here, we assayed cocaine consumption inDrosophilamales, as well as preference in a two-choice paradigm. We also investigated mechanisms involved in cocaine taste sensing using genetic and imaging tools. We show that cocaine is innately aversive to flies and that this avoidance depends on bitter sensing. Gustatory sensory neurons expressing the Gr66a bitter receptor are activated upon exposure to cocaine. Silencing of these bitter-sensing neurons or mutation ofGr66areduces cocaine avoidance. In a longitudinal choice assay, these flies develop preference for cocaine-containing solutions within 12-18 h, whereas control flies do not. Our findings show that bitter sensation protects flies from developing cocaine self-administration preference. Conversely, silencing bitter perception enables us to useDrosophilaas a model for experience-dependent cocaine self-administration preference. This opens the door to testing human variants associated with CUD for their causative role in cocaine self-administration in this highly tractable model organism.Significance statementCocaine use disorder (CUD) is a highly heritable condition for which there are no effective treatments. Testing the many human genetic variants linked to CUD requires a cost-effective, genetically tractable model. Here, we show that bitter-sensing neurons prevent cocaine self-administration inDrosophila. Furthermore, we demonstrate that disruptingDrosophilabitter perception enables a model for experience-dependent cocaine preference. Our findings underscore the potential ofDrosophilaas a crucial tool for identifying the genetic mechanisms underlying CUD, aiding in the discovery of new therapeutic targets, and contributing to the development of effective treatments for this highly heritable disease.
Visual information consists of static and dynamic properties. How is their representation organized in the visual system? Static information has been associated with ventral temporal regions and dynamic information with lateral and dorsal regions. Investigating the representation of static and dynamic information is complicated by the correlation between static and dynamic information within continuous visual input. Here, we used two-stream deep convolutional neural networks (DCNNs) to separate static and dynamic features in quasi-naturalistic videos and to investigate their neural representations. One DCNN stream was trained to represent static features by recognizing action labels using individual video frames. The second DCNN stream was trained to encode dynamic features by recognizing actions from optic flow information that describes changes across different frames. To investigate the representation of these different types of features in the visual system, we used representational similarity analysis (RSA) to compare the neural network models to the neural responses in different visual pathways of 14 human participants (6 females). First, we found that both static and dynamic features are encoded across all visual pathways. Second, we found that distinct visual pathways represent overlapping as well as unique static and dynamic visual information. Finally, multivariate analysis revealed that ventral and dorsal visual pathways share a similar posterior-to-anterior gradient in the representation of static and dynamic visual features.Significance statementHow does the human cortex represent static and dynamic visual features? Investigating the representation of static and dynamic information in realistic stimuli is difficult: separating static and dynamic features requires specially designed artificial stimuli. We tackled this challenge by using neural networks and investigated separately the representation of static and dynamic information in quasi-naturalistic videos. Our results challenge the common belief that associates static features with the ventral visual pathway and dynamic features with the dorsal pathway. We found that different visual pathways represent unique as well as overlapping static and dynamic features. We also identified a gradient in the representational pattern of static and dynamic visual features from posterior to anterior regions, spanning both ventral and dorsal visual pathways.
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AbstractWhile bacterial motility has been well characterized in uniform liquids, only little is known about how bacteria propagate through complex environments, such as gel-like materials or porous media that are typically encountered in tissue or soil. Here, we study bacterial swimming in polysaccharide matrices formed by different concentrations of agar. We focus on the soil bacteriumPseudomonas putida(P. putida) that is known for its multimode swimming pattern, where a polar bundle of flagella may push, pull, or wrap around the cell body. In the gel matrix,P. putidacells display run-and-turn motility with exponentially distributed run times and intermittent turning phases that follow a dwell time distribution with power-law decay. An analysis of the turn angle distribution suggests that both, flagella mediated turning as well as mechanical trapping in the agar matrix are part of the overall swimming pattern. We compare these results to knockout mutants which differ from the wild-type in their swimming speed and show altered probabilities for the occurrence of the three swimming modes. Their run length distributions in the agar matrix are, however, identical demonstrating that run episodes of bacterial swimmers in a gel matrix are primarily determined by the surrounding geometry. We propose a minimal active particle model providing analytical solutions that quantitatively explain the observed time dependence of the mean squared displacement in the gel based on the experimentally observed motility pattern and the measured waiting-time distributions.
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AbstractIn this study, the integration of PbO2into a borosilicate glass system was investigated for enhanced radiation shielding performance. Several glasses with varying PbO2concentrations (31, 33, 35 and 37 mol%) were prepared using the melt-quenching method. The density of the glasses increases from 4.579 to 5.044 g/cm3as a result of increase the PbO2content. The radiation attenuation factors were experimentally determined at 0.059, 0.662, 1.173 and 1.333 MeV, using HPGe detector. The results indicate that increasing PbO2content notably influences the mass attenuation coefficient and the effective atomic number. The tenth value layer (TVL) increased significantly with rising energy levels. For the glass sample containing 31 mol% PbO₂, the TVL increased from 0.177 cm at 0.059 MeV to 5.325 cm at 0.662 MeV, and to 9.094 cm at 1.333 MeV. Similarly, for the glass with 37 mol% PbO₂, the TVL increased from 0.146 cm at 0.059 MeV to 4.733 cm at 0.662 MeV, and to 8.231 cm at 1.333 MeV. The results also showed that PbO₂ has an inverse effect on the TVL, where adding more PbO₂ leads to a decrease in the TVL. At 0.662 MeV, increasing the PbO₂ content from 31 to 37 mol% reduces the TVL by approximately 11.12%. The transmission factor (TF) for the glass with a thickness of 2 cm was investigated, and results showed that the TF is nearly 0 at 0.059 MeV, indicating that the glass provides complete shielding at this low energy. The TF increases with rising energy, reaching 37.8–42.11% at 0.662 MeV, indicating that more photons penetrate the glass as the energy increases.
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AbstractThe Red Sea’s near-shore zones are considered nurseries and grazing grounds for the various economic fish species. To illustrate the relation between human health and seafloor sediments, the geological and geochemical properties of seafloor sediments were investigated in near-shore zones at Marsa Alam and Hurghada cities along the Red Sea. The obtained data illustrated that the sediment nature at Hurghada is primarily of biogenic origin, as indicated by the high carbonate contents; however, the sediment nature at Marsa Alam is attributed mainly to the terrigenous origin. Accordingly, the studied heavy metals at both localities showed different feeding sources; Marsa Alam sites showed high levels of Fe, Mn, Zn, Ni, and Cu attributed to terrigenous inputs; however, the high averages of Cd and Pb at Hurghada indicating influence from land-based and anthropogenic activities. The calculated risk assessment parameters and carcinogenic risk (ILCR) do not indicate any significant risk. Geochemically and as indicated by the statistical parameters: correlation coefficient, PCA, and Geo-accumulation (Igeo); Mn, Zn, Cu, and Ni were found to be mainly associated with Fe in the same source of accumulation and similar geochemical forms. However, the adsorption over sediment particles and/or assimilation inside the carbonate lattices are possible occurrences of Cd, Pb, and partially Ni. The calculated risk assessment parameters and carcinogenic risk (ILCR) do not indicate any significant risk to marine organisms and human consumption.
AbstractAromatic plants produce essential oils (EOs) with diverse phytochemicals and biological applications. This study investigated three eco-friendly nanoemulsions of Lemon peel (LPO), Turmeric (TO), and Black seed (BSO) oils loaded into nanochitosan (NCh) for their antifungal activity against resistant fungal strains. Phytochemical analysis identified oxygenated/non-oxygenated hydrocarbons and saturated/unsaturated fatty acids in the EOs. Physicochemical characterization using FTIR, DLS, and HR-TEM showed stable nanoemulsions and nanochitosan with homogeneous particle size distributions in the nanoscale range. Notably, the essential oil nanoemulsions exhibited potent antifungal activity againstMucor racemosus,Rhizopus microsporus, andLichtheimia corymbifera, resistant to commercial antifungal drugs. The nanoemulsions loaded with 1–3% chitosan showed inhibition zones ranging from 17 to 23 mm, outperforming the synthetic antifungal treatments. These findings highlight the potential of plant-derived essential oil nanoemulsions loaded into biocompatible nanochitosan as a promising, sustainable alternative to combat the growing threat of invasive fungal infections and drug resistance. Incorporating natural, eco-friendly materials enhances the stability, bioavailability, and targeted delivery of the active phytochemicals, contributing to the antifungal solution’s overall efficacy and safety profile.
AbstractThe insecticidal furan-2-carbaldehyde thiosemicarbazone(1)as staring compound underwent a nucleophilic substitution reaction with different reagents, chloroacetyl chloride, chloroacetic acid. 1,4-dibromobutane-2,3-dione and also, with different activated reagents 2-cyanoacetohydrazide, phthalic anhydride, and 2-chloroquinoline-3-carbaldehyde as good yields. The structures of these compounds were confirmed by elemental and spectral analyses. The majority of the synthesized compounds were assessed for their insecticidal activity towards three insects,Cryptoblabes gnidiella,Retithrips syriacusandSpodoptera frugiperdaunder laboratory conditions and promising results were obtained, with encouraging outcomes observed. Compounds5, 7, 9, 11and15were found to the most effective than other compounds on all insects. Also,R. syriacusinsects are more affected thanC. gnidiellaandS. frugiperdaafter one day of treatment with LC50values 15.68, 18.90, 58.04, 17.81, and 42.21 μg/mL respectively, comparing with positive control LC50, 8.90 μg/mL. Furthermore, biochemical parameters of five enzymes ofS. frugiperda; Acid Phosphatase, alkaline phosphatase, aspartate transferase, alanine transaminase, and acetylcholinesterase enzymes were conducted at LC50value of the highly toxic compounds. Density functional theory calculations were employed to optimize the molecular geometry and compute the electrostatic potential, complemented by molecular docking to predict the most acceptable score and root mean square deviation and affinities of the synthesized compounds.
AbstractPatients with virus encephalitis, such as herpes simplex encephalitis and Japanese encephalitis frequently relapse with autoimmune encephalitides associated with neural autoantibodies. It has been hypothesized that the infection-induced damage to the central nervous system results in shedding of neural autoantigens, their presentation to the peripheral immune system, and initiation of a secondary autoimmune encephalitis that targets these autoantigens. To test this hypothesis, we utilized a transgenic mouse model of virus-like but sterile encephalitis. After induction of acute neuronal death in the hippocampus, we monitored the mice for encephalitis-like symptoms for up to 10 months, evaluated the degree of neuroinflammation at several time points and screened their plasma for autoantibodies against 49 different autoimmune disease-associated brain autoantibodies. Throughout the study period, we did not detect any symptoms of severe autoimmune encephalitis, like hyperactivity, circling, seizures, lethargy. Evaluation of microglia numbers and morphology revealed pronounced microgliosis 1-week after initial encephalitis induction, which decreased over time. Scattered lymphocyte infiltration was present at all times in hippocampi of encephalitis mice, and did not increase over time. Perivascular cuffs were not detected. Infiltrating lymphocytes mainly consisted of CD8+ T cells. B cell infiltration was rare and did not differ from healthy control mice. High-parameter immunophenotyping of peripheral blood leukocytes did not reveal any changes associated with an autoimmune response. Testing all plasma samples (n = 30/group) at a dilution of 1:100 for autoantibodies against 49 neural autoantigens gave only two positive results, namely one healthy control with anti-CASPR2 autoantibodies (IgG) and one post-encephalitis mouse with anti-homer-3 autoantibodies (IgM). Overall, these findings suggest that acute neuronal cell death and neuroinflammation per se are not sufficient to trigger downstream autoimmune encephalitis relapses in mice.
AbstractBiallelic variants in the adenosine deaminase tRNA specific 3(ADAT3)gene are associated with a distinct neurodevelopmental disorder characterized by dysmorphic facies, poor growth, cognitive impairment, and variable brain anomalies. We describe 24 patients from 16 unrelated Egyptian families withADAT3-related neurodevelopmental disorder. All patients presented with developmental delay, growth retardation, cognitive impairment, and the characteristic facial features of the disorder, which appears to be more recognizable in older patients. Seizures were noted in 20% of patients and showed favorable responses to treatment. Brain imaging showed corpus callosum abnormalities in most patients (91.6%), followed by delayed myelination and cortical atrophy. Exome sequencing identified threeADAT3variants, including the Saudi founder variant c.430G > A (p.Val144Met), which was detected in 17 patients (70%). In addition, two novel variants were identified, c.319G > A (p.Glu107Lys) and c.1013_1018dup (p.Arg338_Ile339dup). The c.319G > A (p.Glu107Lys) was recurrent in 6 patients (25%) who shared a similar haplotype, suggesting a likely founder effect in our population. On the other hand, the c.1013_1018dup (p.Arg338_Ile339dup) was identified in a single patient. Our study reports a large cohort of patients withADAT3-related neurodevelopmental disorder from Egypt and reinforces the clinical and brain imaging characteristics of the disorder. The high prevalence of the c.430G > A (p.Val144Met) in our population strongly suggests the existence of a founder effect of this variant in the Middle East and Arab region. In addition, we report a new founder variant expanding the mutational spectrum of this rare disorder.
AbstractThis study is focused on the Menes oil field, located on the western flank of Shushan Basin in Egypt’s northern Western Desert (NWD). The primary oil-bearing reservoir in this area is the Lower Cretaceous Alam El Bueib (AEB) Formation (Fm), that extends through the Barremian to Aptian stages. This formation is characterized by thick, massive, argillaceous, and calcareous sandstones interbedded with shale and carbonate layers. 2D seismic profiles are interpreted to delineate the structural features of the subsurface. The well to seismic tie via synthetic seismograms and check-shot data are utilized for mapping the formation tops of Alamein dolomite, as well as the AEB units (1, 3 A, 3 C, and 3D), and the Paleozoic strata. Electrical wireline logs from four wells in Menes oil field were analyzed to estimate key petrophysical parameters, including porosity and hydrocarbon saturation for reservoir characterization. Finally 3D structural model was developed to enhance subsurface visualization, enabling a more precise characterization of the AEB reservoirs. This model also aims to reduce exploration risks and improve field development strategies in the study area. These findings provide crucial insights into the subsurface characteristics and hydrocarbon prospects of this formation, offering valuable information that can inform strategic decision-making in both exploration and production activities within Shushan basin. The comprehensive understanding gained from these results serves as a key contribution to optimizing future exploration efforts and enhancing the development of hydrocarbon resources in the near by regions.
AbstractThe adoption of advanced and practical technologies to boost plant productivity and improve quality under challenging environmental conditions, such as salinity, has become an essential need in modern agriculture. Plasma technology can significantly improve the seed’s resistance to stress factors like high salinity and dry environments. Thus, the current work aimed to improve the yield and quality of cowpea as an important forage crop grown in saline soil using a plasma coating approach. The seeds of cowpea were treated with three plasma doses expressed in different times of exposure (0.0, 1.0 and 2.0 min) and planted (for two seasons of 2022 and 2023) in three soil salinity levels expressed in electrical conductivity, EC (normal, 0.3 dS m−1, moderate salinity 5.5 dS m−1, and high salinity, 7.0 dS m−1, abbreviated as EC3.0, EC5.5 and EC7.0, respectively). The electron micrographs and elemental detection revealed that 2.0 min treatment resulted in deep cracking and topographical modulation with the best enhancements in cowpea seed surface nutrients. The agronomic findings revealed that compared to the corresponding check treatment (without plasma, 0.0 min), the exposure to plasma for 2.0 min in the first season was the efficient for enhancing forage yield under normal (1.37-fold increase) and medium salinity (1.79-fold increase). The in vitro data showed plasma-treated seeds for 2.0 min displayed higher acid detergent fiber content under EC3.0 or EC5.5 compared to the other treatments. Plants grown from seeds treated with plasma for 1.0 min showed higher dry matter degradability levels at EC7.0 compared to the other treatments. At EC7.0 the highest ammonia concentration was recorded in plants grown plasma-treated seeds for 1.0 min, while the lowest value was observed in 2.0-min. 2.0-min plasma-treated seeds produced the highest total volatile fatty acids across different salinity conditions, particularly at EC7.0. Plasma treatment, as a safe and innovative seed priming method, validates substantial potential in improving cowpea productivity under saline conditions. This study revealed that exposing cowpea seeds to a 2-min plasma treatment before sowing enhanced seed germination rate, and overall yield, even under challenging saline environments. Moreover, enhanced feed quality resulting from plasma-treated seeds offers direct benefits to livestock nutrition, supporting both human and animal food chains.
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AbstractGregarious desert locusts produce stage-specific pheromones that facilitate cohesive behavior in juveniles and synchronize maturation and mating in sexually mature adults. During locust outbreaks, merging populations result in cross-stage interactions, yet their impact on locust biology remains poorly understood. This study tested the hypothesis that cross-stage interactions influence juvenile cohesion and physiological traits. Using behavioral assays and gas chromatography-mass spectrometry, we examined short- and long-term interactions between juvenile and adult desert locusts. In short-term (24 h) cage assays, the presence of adults did not significantly affect grouping behavior in gregarious 3rd instar nymphs, as measured by the mean distance between individuals. Likewise, overall, juvenile pheromone emissions, based on previously identified nymphal components, showed no significant differences regardless of adult presence. Cross-stage interactions also had no measurable effect on the development time of 3rd instar nymphs. In contrast, long-term assays showed that 1st instar nymphs grouped with adults matured faster and grew heavier than older nymphal instars and fledglings, and, as mature males, released higher levels of phenylacetonitrile (PAN). Additionally, adult females emerging from these interactions oviposited earlier and laid more eggs than those not exposed to adults as juveniles. These findings indicate that cross-stage interactions impact development uniquely across different gregarious locust stages. Additionally, they offer important insights into desert locust behavior and chemical ecology, which could aid in developing more effective management strategies.
AbstractAntimicrobial agents produced byXenorhabdusspp. may hold the answer to novel antimicrobial agents. Antibacterial activity of some bacterial strains isolated from different Egyptian archaeological sites was evaluated. The most potent organism that reported high antibacterial activity was identified asXenorhabdus nematophila. The produced bioactive compound was identified as xenortide using LC–MS and NMR studies. Optimization of xenortide’s production was assessed using a central composite statistical design. The most effective fermentation factors were identified as carbon, nitrogen source concentrations and pH levels. Nano-xenortide was synthesized using the ball milling method, followed by its characterization and evaluation for its anticipated antibacterial and anticancer properties. Statistical analysis of the findings indicated that the produced nano-xenortide exhibited superior antibacterial efficacy. Furthermore, the assessment of its cytotoxicity revealed that nano-xenortide is a promising, safe candidate that can be used as an antibacterial and anti-colorectal-carcinoma agent.
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AbstractThe novel ligand (H2L), N’-(2-cyanoacetyl)isonicotinohydrazide, has been synthesizedviareacting the isonicotinic hydrazide with 1-cyanoacetyl-3,5-dimethylpyrazole. The keto-form of the free ligand has been evoked from its spectral data. Based on elemental analyses and mass spectra, the ligand formed 1:1 (M: L) metal complexes with the acetate salts of Cu(II), Co(II), Ni(II) and Zn(II). The complexes’ spectral analyses revealed that the ligand behaved as a mononegative bidentateviathe hydrazonyl N1and deprotonated enolized acetyl oxygen. Moreover, the DFT quantum chemical calculations revealed that the ligand had higher HOMO and lower LUMO energies than metal complexes, implying an electron donating character. Furthermore, the in vitro anticancer activity against HepG2 and HCT-116 cell lines displayed that the ligand was more potent than doxorubicin against both cell lines, although the metal complexes displayed lower efficacy.
AbstractThe present research was set out to delineate the protective and therapeutic potency of hesperidin (Hesp) versus cisplatin (Cis) against the deleterious consequences of Ehrlich ascites carcinoma (EAC) on the liver and the prospective mitigative effect of Hesp against Cis-mediated hepatotoxic side-effects. A total of 70 female mice were randomly assigned into control, Hesp, EAC, Hesp-protected, Hesp-treated, Cis-treated, and Cis + Hesp-treated groups. Mice inoculated with EAC cells exhibited significant reductions in the serum total protein and albumin levels, along with significant elevations of the serum aminotransferases, lactate dehydrogenase, amylase, and lipase activities, and alpha-fetoprotein level. A significant increment in malondialdehyde level concomitantly with significant declines in reduced glutathione concentration and catalase activity were also observed in the liver of EAC-bearing mice. Additionally, marked hepatic pathological changes as well as a strong Ki-67 expression and a weak caspase-3 expression in the neoplastic cells infiltrating hepatocytes were observed. In contrast, the administration of Hesp and/or Cis to the EAC-bearing mice reversed, to varying degrees, the cytotoxic effects of EAC. Besides, Hesp minimized the harmful hepatic chemotherapeutic side-effects of Cis. Overall, Hesp could be a promising phytochemical against EAC-induced cytotoxicity with its potential to improve the antitumor efficacy of chemotherapeutic drugs and minimize their hepatic adverse side-effects.
AbstractExcessive fibroblast proliferation and metabolic reprogramming are hallmarks of pathological cardiac remodeling, contributing significantly to impaired cardiac function. This study investigates the role of circular RNAs (circRNAs) in fibroblast metabolic reprogramming, an unexplored area with potential therapeutic implications. Through deep circRNA sequencing of cardiac tissue from heart failure (HF) patients and healthy individuals, we identified circIGF1R (hsa_circ_0005035), which exhibited dysregulation specifically in isolated cardiac fibroblasts derived from failing hearts. Silencing circIGF1R in patient-derived human cardiac fibroblasts (HCFs) led to accelerated proliferation, enhanced glycolytic activity, altered glucose trafficking, and increased glucose import. Conversely, administering recombinant circIGF1R inhibited the accelerated proliferation and enhanced glycolytic activity observed in HCFs from HF patients. Mechanistically, RNA pulldown assays and in silico analyses identified AZGP1 as a potential interaction partner facilitating the glycolysis-inhibitory and anti-proliferative functions of circIGF1R. Our findings identify circIGF1R as a pivotal regulator of fibroblast proliferation via metabolic reprogramming, particularly by glycolysis inhibition. Overexpression of circIGF1R demonstrated significant anti-fibrotic effects in cardiac fibroblasts derived from heart failure patients. These results underscore the therapeutic potential of circIGF1R in attenuating cardiac fibrosis by directly targeting fibroblast metabolism in the context of pathological cardiac remodeling.
AbstractAcute dyspnoea is one of the most common presenting symptoms in the emergency department (ED) and has a variety of underlying causes. Calprotectin is a neutrophil activation marker associated with adverse outcomes in acute cardiovascular and infectious diseases. However, the usefulness of calprotectin in the risk stratification of patients with acute dyspnoea is unknown. The objectives were to, in unselected patients presenting to the ED with acute dyspnoea, investigate the association between (1) calprotectin and 90-day mortality, (2) calprotectin and 90-mortality in subgroups of patients with cardiovascular disease or pneumonia, and (3) calprotectin and illness severity. Single-centre observational cohort study from a university hospital in southern Sweden. A total of 1186 patients from the original Acute Dyspnoea Study, were included. Patients were followed for discharge diagnosis and mortality. Calprotectin concentration was measured in plasma samples collected at the ED. Mean age was 72 years and 56% were women. During follow-up, 143 patients died. In multivariate Cox regression for 90-day mortality, calprotectin in the highest quartile (> 0.96 mg/L) compared to the lowest quartile (< 0.27 mg/L) was associated with a hazard ratio of 2.71 (95% confidence interval 1.39–5.26,p< 0.01). The association with mortality remained significant in the subgroup of patients with acute cardiovascular disease (N= 205,p< 0.01). There was no statistically significant difference in median calprotectin values between survivors and non-survivors with pneumonia (1.62 vs. 1.31,p= 0.155). Multivariate linear regression showed a strong positive correlation between calprotectin and illness severity (respiratory rate ≥ 29 or oxygen saturation ≤ 90%,p< 0.001). In conclusion, calprotectin was associated with 90-day mortality and correlated strongly with illness severity. This indicates that measurement of calprotectin at admission could improve clinical risk stratification of the acute dyspnoeic ED patient.Clinical trial number: Not applicable.
AbstractWe studied the characteristics and survival of patients with sorafenib-treated HCC and impact of underlying etiology on outcomes. This retrospective multicenter study recruited patients with sorafenib-treated advanced HCC (12/2016 to 4/2023) till death or the study end (2/2024). Time to progression (TTP) and overall survival (OS) were recorded. We evaluated; Clinico-laboratory and imaging predictors of OS, The impact of underlying etiology on tumor variables, outcomes and tolerance for sorafenib > 6 months. This study included 706 patients. Median duration of Sorafenib therapy was 240.00 (90.00–360.00) days. Median OS was 314.00(146.00–601.00) days. Median TTP was 180.00(90.00–330.00) days. COX regression revealed that the independent factors of mortality were baseline AST, Tumor size, hepatic vein thrombosis (HVT), development of jaundice and shifting to Regorafenib. Advanced HCCs were more common on top of non-cirrhotic non-viral and HBV-related liver disease. Adverse events, TTP and tumor response didn’t differ with the underlying etiology. Median OS was lower in non-viral-related HCC than HCV-related HCC (218.00 versus 326.50 days,P-value = 0.048). Patients who continued sorafenib > 6 months had lower AFP, HVT, adverse effects and better tumor response after 3 months. OS is lower in non-viral Sorafenib-treated HCC compared with viral-related HCC and Sorafenib was well-tolerated among different HCC etiologies.
AbstractSleep inertia is the post-awakening transitional state of lowered arousal, characterized by increased low-frequency activity in the electroencephalogram (EEG) and impaired cognition. While some theories consider arousal holistically, recent research questions whether these findings apply to situations requiring immediate critical action post-awakening, such as for pilots, emergency responders, or future drivers of automated vehicles. This study compared self-reported, cortical, and physiological arousal in such a scenario. Twenty-four participants completed four drives in a driving simulator. In three drives, participants were instructed to sleep for 20, 40, and 60 min during automated driving before being prompted to resume control. The sleep stage prior to the takeover request served as a quasi-experimental independent variable. Regression analyses showed that cortical arousal was low following awakenings from N2 or N3, indicated by increased delta, theta, and alpha activity. However, beta activity and heart rate also increased, suggesting elevated physiological arousal. Significant positive correlations were found between delta activity, heart rate and self-reported sleepiness. This “arousal paradox” is not in line with the idea of arousal as a holistic concept. We hypothesize that the heightened physiological response under sleep inertia may be attributed to stress in demanding situations under sleep inertia. We conclude that forced awakenings from N2 or N3 should be avoided. If someone is nevertheless awakened from N2 or N3, they should be given sufficient time between awakening and taking over duties for arousal to normalize.
AbstractSoil-transmitted helminths primarily compriseAscaris lumbricoides,Trichuris trichiura, and hookworms, infecting more than 600 million people globally, particularly in underserved communities. Manual microscopy of Kato-Katz thick smears is a widely used diagnostic method in monitoring and control programs, but is time-consuming, requires on-site experts and has low sensitivity, especially for light intensity infections. In this study, portable whole-slide scanners and deep learning-based artificial intelligence (AI) were deployed in a primary healthcare setting in Kenya. Stool samples (n= 965) were collected from school children and Kato-Katz thick smears were digitized for AI-based detection. Light-intensity infections accounted for 96.7% of cases. Three diagnostic methods - manual microscopy, autonomous AI and human expert-verified AI - were compared to a composite reference standard, which combined expert-verified helminth eggs in physical and digital smears. Sensitivity forA. lumbricoides,T. trichiuraand hookworms was 50.0%, 31.2%, and 77.8% for manual microscopy; 50.0%, 84.4%, and 87.4% for the autonomous AI; and 100%, 93.8%, and 92.2% for expert-verified AI in smears suitable for analysis (n= 704). Specificity exceeded 97% across all methods. The expert-verified AI had higher sensitivity than the other methods while maintaining high specificity for the detection of soil-transmitted helminths in Kato-Katz thick smears, especially in light-intensity infections.
AbstractDespite the advent of advanced molecular prognostic tools, it is still difficult to predict the course of disease for cancer patients at the individual level. This lack of predictability is also reflected in many experimental cancer model systems, begging the question of whether certain biological aspects of cancer (eg. growth, evolution etc.) can ever be anticipated or if there remains an inherent unpredictability to cancer, similar to other complex biological systems. We demonstrate by a combination of agent-based mathematical modelling, analysis of patient-derived xenograft model systems from multiple cancer types, and in-vitro culture that certain conditions increase stochasticity of the clonal landscape of cancer growth. Our findings indicate that under those conditions, the cancer genome may behave as a complex dynamic system, making its long-term evolution inherently unpredictable.
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AbstractPlant-parasitic nematodes (PPNs) pose a significant problem for farmers worldwide, leading to yield losses. Several conventional strategies, such as artificial nematocides, have been used in the past to control PPNs in pepper plants. In an in vivo trial aimed at reducing root-knot nematodes, (RKNs)Meloidogyne incognitacommunities in soil and root infestation, certain plant seed cake (PSC) was evaluated for its potential use. In this study, four PSCs were used to manage PPNs: black seed, jojoba, olive, and jatropha. These PSCs relatively inhibited nematode reproduction and promoted pepper plant health. Notably, black seed and jojoba were the most effective toxic PSC against RKNs,M. incognita, especially targeting the second-stage J2s in soil. For example, treatment with black seed at both 15 and 30 g rates, as well as jojoba at 15 g rate, was consistently effective in reducing the final nematode population. Growth parameters, including shoot and root weight and length, as well as the number of leaves, were measured. The results showed that black seed at 30 g and jojoba at 15 g significantly increased shoot weight, followed by black seed at 15 g, with corresponding values of 75.89 g, 47.86 g, and 45.9 g, respectively. According to GC-MS analysis, the mode of action of these PSC may involve natural active compounds capable of killing or inhibiting nematode communities. The GC-MS analysis of jatropha seeds cake showed remarkable bioactive compounds, including D-Psicofuranose, pentakis (trimethylsilyl) ether (isomer 2); 9,12-Octadecadienoic acid; 2-((2-Methyl-1-oxa-4-azaspiro [4.4]non-4yl) carbonyl) cyclopropane carboxylic acid and 1 H-Indene, 2,3-dihydro-4-propyl. These compounds have antimicrobial, insecticidal, anti-nematodal, and antiviral activities confirming their potential as natural biopesticides.
AbstractCurrent staple crops such as rice, wheat, and maize dominate food systems but lack climate resilience, necessitating a shift toward nutrient-rich, sustainable alternatives.Chenopodium quinoa, (C. quinoa) has gained global recognition for its adaptability and nutritional value. However, while quinoa grains have been extensively studied, young green quinoa (YGQ) leaves remain underexplored despite their potential to enhance both agricultural sustainability and human health. This study investigates the anti-inflammatory properties of YGQ leaves extracts from eight quinoa accessions cultivated during the summer. Using lipopolysaccharide (LPS)-activated mouse macrophage cells (RAW264.7), we assessed the inhibition of key pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and Interleukin (IL)-6. Four types of extracts—Ethanol:Water (70:30) (ETDW), Ethanol (ET), Ethyl Acetate (EA), and Hexane (HE) were prepared, revealing significant and specific IL-6 inhibition, with ETDW exhibiting the highest suppressive effect (73–100%). LC–MS/MS analysis identified flavonoids as the likely bioactive compounds responsible for this activity. Importantly, toxicity assays confirmed the extracts’ safety. These findings position YGQ leaves as a valuable natural source of bioactive compounds with potential applications in functional foods, which offer health benefits beyond basic nutrition by targeting the prevention of noncommunicable diseases and chronic inflammatory conditions. Furthermore, integrating YGQ leaves into food systems could support sustainable agriculture, as quinoa is a climate-resilient crop, providing dual benefits for public health and food security.
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AbstractEmotions mediate a wide range of cognitive functions, including memory, attention, and decision making. Studies of emotion in non-human animals have typically focused on negative emotions—like fear—that have clear behavioral correlates (e.g., freezing or retreating). To address this one-sided treatment of affect, we used a cognitive bias test to ask whether vocalizations associated with positive affect lead apes to expect positive future outcomes. All great apes produce laughter-like vocalizations during play that likely evolved from a shared ancestral form of laughter. We primed bonobos with conspecific laughter and then asked whether they were more likely to treat an ambiguous stimulus as if it were positive. Subjects (n= 4) were first trained to approach rewarded (black) stimuli and skip unrewarded (white) stimuli. We then presented occasional ambiguous (grey) stimuli. Bonobos approached ambiguous stimuli to search for rewards more often after hearing laughter. Our results suggest that hearing laughter induces positive emotions and may thus bias bonobos’ decision making, including foraging or search behavior. While only apes produce human-like laughter, several other non-human animals have contagious play vocalizations. These vocalizations may lead other animals to anticipate positive outcomes, revealing commonalities in the role of positive emotion in behavior and cognition across species.
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AbstractUltra-high-performance fiber-reinforced concrete (UHPFRC) is an exceptional type of cementitious composite with superior mechanical and durability performances. Achieving these properties involves maintaining a low water-to-cement ratio, optimizing aggregate size distribution, and integrating fiber reinforcement. Recently, there has been a notable trend in the development and application of UHPFRCs. However, there is still a requirement for artificial intelligence (AI) methods to predict the early-age compressive strength (CS) of UHPFRC and to define the key input factors for optimal mix design with appropriate proportions. Therefore, five AI models were chosen to assess the predictive accuracy of early-age CS in the current study. These models include support vector regression (SVR), random forest (RF), artificial neural network (ANN), gradient boosting (GB), and Gaussian Process Regression (GPR). As part of evaluating model performance and conducting error analysis, this study investigated differences in prediction accuracy among five models across training and testing datasets. Additionally, feature importance analysis was implemented to explore the influence of the input variables on the early-age CS. Results indicate that GPR and SVR models with high predictive accuracy (R2> 0.90) outperformed ANN, RF, and GB models. Water, superplasticizer, curing temperature, and fiber content emerged as the most significant controlling parameters affecting early-age CS. The analysis of the interaction among the significant input variables and early-age CS suggests recommended inclusion levels for optimal performance. Specifically, it is recommended that the water content be maintained between 145 and 155 kg/m2, the superplasticizer content between 30 and 40 kg/m2, and the fiber content exceed 200 kg/m2. These recommendations are aimed at achieving desirable early-age CS characteristics. The overall findings reveal that the AI models can effectively improve the monitoring of early-age CS of UHPFRC.
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AbstractThere is strong evidence that ceramides play a significant role in the pathology of inflammatory bowel disease (IBD) and chronic liver injury. Long-chain (LC) and very long-chain (VLC) ceramides have opposing functions, yet the associations of circulating levels of ceramide species in patients with IBD and primary sclerosing cholangitis (PSC)—as inflammatory biliary-hepatic disease closely linked to IBD— with disease severity remain poorly studied. This study investigates whether serum levels of ceramide (Cer) and hexosylceramide, a glycated ceramide derivative, are associated with disease severity in these conditions. Serum levels of eight ceramide and five hexosylceramide species were measured in 16 healthy controls, 57 patients with IBD, 7 patients with PSC, and 13 patients with PSC-IBD. Lipid levels were determined using direct flow injection analysis with a triple quadrupole mass spectrometer. Patients with IBD exhibited higher levels of Cer 18:1;O2/16:0 and Cer 18:1;O2/18:0 compared to controls. Their LC/VLC ceramide ratio was elevated and positively correlated with C-reactive protein and fecal calprotectin. However, ceramide and hexosylceramide levels were not associated with stool consistency, disease localization, or extra-intestinal manifestations. Patients with PSC and PSC-IBD also had increased LC/VLC ceramide ratios, primarily due to a decline in VLC ceramide species. In PSC-IBD, this ratio correlated positively with cholestasis markers. Additionally, serum hexosylceramide 18:1;O2/16:0 and 24:1 levels were specifically elevated in PSC. This study demonstrates that an altered LC/VLC ceramide balance is associated with disease severity in IBD, PSC-IBD, and PSC, highlighting its potential as a biomarker for IBD, PSC-IBD, and PSC. As our PSC cohorts were small, a confirmatory study is required.
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AbstractPristine PEDOT: PSS is a p-type material with salient features. However, studies have revealed that the electrical property of pristine PEDOT: PSS can be switched to n-type by solvent treatment. Notwithstanding that this method is simple, it performs inconsistently and primarily affects the samples’ surfaces due to the migration of the solvent molecules into the polymer network. These solvents are also hazardous and unfavourable to the environment. In this work, we report solvent-free switching electrical characteristics of pristine PEDOT: PSS to n-type using a spray coating technique. The obtained n-PEDOT: PSS exhibits excellent optical and electrical characteristics. In addition, high Seebeck coefficient of – 1320.06 ± 38.42 µVK−1and power factor of 4.32 ± 0.25 µWm−1K−2were found. The obtained n-PEDOT: PSS was used in the fabrication of a homojunction diode. The I-V curve showed rectification characteristics with rectification ratio and barrier height of 17.2 and 0.047 eV, respectively, which is one of the best reported values in the literature for all PEDOT: PSS-based diode.
AbstractSepsis is associated with substantial mortality rates. Traditional treatment strategies often fail to address the underlying dysregulation in immune response, necessitating novel therapeutic approaches. Ozone (O3) is an inorganic molecule with no evident function in the body. We investigated the properties of ozone, using a system of extracorporeal ozone blood treatment inPseudomonas aeruginosaseptic shock. We hypothesized that extracorporeal ozonation would decrease bacteria in blood, have immunomodulating properties, and improve organ function. In this 4-h sepsis model swine were allocated toP. aeruginosa(PA-103, ATCC 29260, CCUG31589) infusion and ozone treatment (n = 7) orP. aeruginosainfusion and no ozone treatment (n = 6). Bacteria were infused in a peripheral vein. Mean (SD) duration of ozone treatment was 134 (67) min. A single pass through the system decreased viableP. aeruginosaby 53%, mean 2193 to 1023 colony forming units/mL, mean of differences -1170 (95% CI − 1689 to − 651,P< 0.0001). No difference in viable bacterial concentration was detected in peripheral venous blood between groups (P= 0.68). IL-1β, IL-4, IL-6, IL-8 and IFN-γ decreased by ozonation. Classical and alternative complement pathways were not affected. Blood hemoglobin, hematocrit and noradrenaline doses decreased in the treatment group. Breathing frequency and pulmonary peak airway pressure decreased in the ozone treatment group. Median survival in ozone treatment was 134 min and no treatment 159 min, with no statistical difference. Extracorporeal ozone blood treatment modulated the immune response inP. aeruginosaseptic shock, which decreased mostly proinflammatory cytokines and was associated with indications of decreased vascular permeability and improved lung function and warrants further investigation for potential use in clinical settings.
AbstractDiabetes mellitus (DM) represents a multifactorial condition linked to hyperglycemia, which, can lead to damage across multiple organs, including the lungs. Nod-like receptor protein-3 (NLRP3)- mediated pyroptosis could contribute to the onset of DM consequences. Several approaches have been established aimed to minimizing the complications associated with DM. Among these, linagliptin and vildagliptin, di-peptidyl peptidase-4 (DPP-4) inhibitors, are known to exert not only antihyperglycemic effects but also additional beneficial biological activities. The current study investigated the impact of linagliptin and vildagliptin on pulmonary function, oxidative stress, and NLRP3-induced pyroptosis in rats. Thirty-two male Sprague Dawley rats were given a 7-day acclimatization period. A single intraperitoneal injection of freshly produced STZ (60 mg/kg) was utilized to develop DM type-1 in rats. Following STZ treatment, all rats were given a 5% glucose solution overnight. Blood glucose levels were monitored in overnight fasted rats 72 h later, with a threshold of 250 mg/dL or higher confirming the onset of DM. The diabetic rats were randomly allocated to treated daily with either vildagliptin (5 mg/kg/p.o.) or linagliptin (5 mg/kg/p.o.) for 30 days. Additionally, the typical control group received merely the vehicle. The findings revealed that vildagliptin improves pulmonary dysfunctions associated with DM by restoring glucose homeostasis, insulin, redox marker levels, and inflammatory indices. Additionally, the NLRP3-pyroptosis-mediated IL-1β was suppressed. Vildagliptin has been shown to mitigate the detrimental effects of diabetes mellitus (DM) on the lungs, as evidenced by a reduction in pathological lung alterations and a decrease in Caspase 3 expression, which is indicative of immunohistochemical changes. In conclusion, pyroptosis triggered by the NLRP3 inflammasome possibly exacerbate diabetic pulmonary injury in rats. Vildagliptin is superior to linagliptin in ameliorating diabetes-induced lung injury primarily via targeting the NLRP3 inflammasome pathway.
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AbstractHybrid fiber-reinforced polymer (FRP) and steel reinforced concrete (hybrid FRP-steel RC) beams have gained recognition for their exceptional flexural performance, surpassing that of beams reinforced exclusively with FRP bars (FRP-RC). However, current design guidelines, such as ACI 440.11–22, fail to accurately predict the flexural strength of these hybrid systems. This study aims to enhance the predictive accuracy and interpretability of flexural strength models by applying advanced computational approaches—specifically, machine learning (ML) techniques and symbolic regression. A robust dataset of 134 experimental data points was utilized to develop predictive models. The prediction results showed that both ML and symbolic regression models significantly outperformed the ACI 440.11–22 equations, achieving lower errors (MAE, MAPE, RMSE) and higher accuracy (R2). The results demonstrate that the ML models—Gaussian process regression (GPR), NGBoost, and CatBoost—achieved high predictive accuracy, with mean R2values approaching 1.0 and MAPE% as low as 5.19 (training) and 11.51 (testing) for GPR. Furthermore, symbolic regression yielded a transparent mathematical expression with a mean prediction ratio (µ) of 1.003, a CoV of 0.139, and a MAPE% of 11.08. These findings highlight the practical and technical advantages of symbolic regression in developing reliable, interpretable, and efficient design equations for hybrid FRP-steel RC beams.
AbstractAcute and chronic alcohol abuse are common among burn patients and may be associated with chronic liver injury, a potential factor influencing outcomes. This study evaluates the predictive power of the blood alcohol concentration (BAC) and non-invasive liver fibrosis scores and their applicability in burn patients. A retrospective analysis was conducted on patients admitted to a high-volume supraregional burn center in Northern Germany between 2007 and 2024. Patients were categorized based on their BAC at admission: low (< 100 mg/dL) vs. high (≥ 100 mg/dL). Data collected included demographics, comorbidities, and outcomes. Non-invasive liver fibrosis markers such as the Fibrosis-4 (FIB-4) score, aspartate transaminase-to-platelet ratio index (APRI) and non-alcoholic fatty liver disease (NAFLD) fibrosis score were applied to both groups. Among 121 large-surface burn patients (mean total body surface area: 16.4%), no significant differences were observed between BAC groups in demographics, comorbidities, or ICU admission rates. The serum ethanol concentration showed no significant predictive value for mortality (AUC = 0.515). In contrast, the FIB-4 score (AUC = 0.781) and APRI (AUC = 0.736) demonstrated strong prognostic accuracy. In multivariate analysis, the Abbreviated Burn Severity Index (OR = 2.42;p= 0.001), serum albumin (OR = 0.29;p= 0.016), and FIB-4 score (OR = 1.50;p= 0.033) emerged as independent predictors of mortality. Propensity score matching analysis confirmed that BAC was not associated with increased mortality after adjustment for burn depth and extent. Non-invasive liver fibrosis markers, such as FIB-4 score, provide valuable prognostic insights in burn patients, independent of acute alcohol intoxication and should be considered a routine screening tool for large surface burn patients. Incorporating chronic liver dysfunction into existing burn severity models may enhance risk stratification and outcome prediction.
AbstractEmerging tick-borne infections pose public health challenges and may complicate treatment decisions. The EMBio study, a multicenter observational study, aims to describe erythema migrans (EM), an early localized manifestation ofBorrelia burgdorferi sensu lato(s.l.) infection, and investigate the occurrence of tick-borne co-infections among patients presenting with this skin lesion. Additionally, the study seeks to determine relations between EM morphology, other clinical manifestations, specific pathogens, and disease prognosis. Clinical characteristics, skin biopsies, and blood samples were analyzed from 26 patients to assess co-infections, quantity,Borreliaspecies, and spirochete load.BorreliaDNA was detected in 88% of EM skin lesions, withBorrelia afzeliias the predominant species. Two cases of co-infections were identified, one involving twoBorreliaspecies and one involvingBorrelia afzelii andthe intracellular bacteriumNeoehrlichia mikurensis. Notably, homogeneous EM lesions harbored significantly higher spirochete quantities in the central zone compared to annular lesions, suggesting that lesion morphology reflects local bacterial density. This supports the value of molecular diagnostics in detecting mixed infections and supports morphology-guided biopsy strategies in the clinical assessment of cutaneous infections. This study contributes to a better understanding of co-infection dynamics and may improve diagnostic accuracy and patient management in endemic settings.
AbstractA novel application of light rare earth elements (LREEs) was explored for their biological activity as potential eco-friendly molluscicides and antimicrobials onTheba pisana(Müller, 1774) and their feeding behavior, and microorganisms likeCandida albicans,Bacillus cereus,Aspergillus niger,Staphylococcus aureus, andEscherichia coli. Our data showed increased snail mortality with higher element concentrations till 500 mg/L. LC25and LC50values after ten days of exposure were 513.70 and 3012.72 mg/L, respectively, lower survival rates than the control. As treatment concentration and exposure duration increased, the ingested leaf area and daily consumption rates of treated lettuce leaves declined. On day one, consumption dropped from 60.00 ± 0.00 cm² (control) to 30.25 ± 6.13 cm² at 500 mg/L, further decreasing to 31.25 ± 0.76 cm² and 14.00 ± 1.46 cm² by day four at the same concentrations. Low concentrations had minimal impact on snail feeding, while higher levels significantly reduced appetite, consumption and freshness of leaves. LREEs-based formulations exhibited marked antimicrobial activity against all tested pathogens by the measured inhibition zones. Results highlight the promising application of LREEs in integrated pest and microbial disease management. However, these findings warrant further investigation to optimize their safe and practical use in the field.
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AbstractProstate cancer (PCa) incidence has steadily increased in Sweden, more steeply in the mid-1990s caused by increased opportunistic prostate-specific antigen (PSA) testing. Tallness, normal weight, and non-smoking are associated with more PSA testing, which increases detection of low-risk and localised PCa. We investigated time trends of height, body mass index (BMI), and smoking with PCa risk in 171,889 men in Sweden aged 50–64 years at baseline, who were linked to nationwide cancer registers during follow-up. Cox regression determined the association of these factors assessed before 1980, 1980–1994, and 1995–2004 with PCa risk. During 15 follow-up years, 8,049 men were diagnosed with PCa. The association of height with PCa was weakly positive across all calendar periods. For obesity (BMI ≥30 kg/m2) vs. normal weight (BMI 18.5–24.9 kg/m2) and current vs. never smoking, the associations changed from null before 1980 (HR 1.03, 95% CI 0.86–1.23, and 1.11, 95% CI 0.97–1.27) to negative in 1995–2004 (HR 0.83, 95% CI 0.74–0.93, and 0.86, 95% CI 0.79–0.93; pinteractionbetween periods = 0.05 and 0.001). In men with clinical characteristics available, height was positively associated with both aggressive and non-aggressive PCa whilst obesity and smoking showed negative associations only with non-aggressive PCa. These findings likely reflect differences in PSA testing by BMI and smoking habits and contribute important knowledge for etiological studies of PCa.
AbstractThis study aimed to explore the development of eco-friendly antimicrobial coatings by combining antimicrobial nanocomposites with waterborne resins. Novel nanocomposites, such as nano-ZnO/silica fume and nano-CuO/silica fume, were synthesized using the solution combustion method, along with pure nano-ZnO and nano-CuO. The nanocomposites consist of a thin layer of nanometal oxide on silica fume, aiming to enhance antimicrobial activity. These nanocomposites were incorporated into acrylic waterborne resin at two concentrations (0.4 and 0.8 wt%) to provide cost-effective alternatives to imported and expensive antimicrobial agents. Antimicrobial effectiveness was evaluated againstStaphylococcus aureus,Micrococcus luteus,and Candida albicansusing disc diffusion and shake flask methods. Besides, the mechanical and physical properties of the coatings were compared to the properties of a commercial coating. The findings showed that the commercial coating offered inhibition zones ranging from 16 to 21 mm. While the disc containing 0.8% nano-ZnO/silica fume offered the greatest antimicrobial activity, with inhibitory zones ranging from 17 to 26.6 mm. Additionally, the results demonstrated that discs containing nano-ZnO were better than discs containing nano-CuO. The mechanical properties indicated that the hardness of coatings with either nano-ZnO or nano-CuO is similar to the commercial coatings in group I. However, coatings with nano-ZnO/silica fume and nano-CuO/silica fume exhibited slightly higher hardness. In group II, higher ratios of nano-ZnO, nano-CuO, and their silica fume composites significantly increase hardness compared to the commercial coatings, attributed to the formation of a more compact film. Moreover, the results showed that coatings with a high ratio of pigments (0.8%) adhered better than those with 0.4% of pigments.
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AbstractMethicillin-resistantStaphylococcus aureus(MRSA) represents a significant global health challenge due to acquired resistance mechanisms, primarily involving penicillin-binding protein 2a (PBP2a), necessitating novel therapeutic strategies. This study explores the potential of amoxicillin-conjugated magnetic nanoparticles (Amox-MNPs) as a means to overcome resistance by targeting the alternative essential protein, PBP1a. Fe₃O₄@SiO₂ core-shell MNPs were synthesized via controlled co-precipitation followed by a silica coating using the Stöber method, and subsequently conjugated with amoxicillin. Physicochemical characterization confirmed nanoparticle formation and successful conjugation. In vitro antibacterial assays againstS. aureusATCC 43,300 (MRSA) revealed that Amox-MNPs exhibited a mean inhibition zone diameter of 26.0 ± 0.82 mm, approximately double that of free amoxicillin (13.5 ± 1.12 mm) at equivalent concentrations (p< 0.05), indicating significantly enhanced antibacterial efficacy. Integrated computational modeling, including molecular docking and dynamics simulations, elucidated the favorable binding (−8.64 kcal/mol docking score;−32.65 kcal/mol MM-PBSA energy) and stable interaction dynamics between amoxicillin and PBP1a, identifying key stabilizing residues. These findings highlight the potential of MNP-mediated delivery to enhance amoxicillin’s efficacy against MRSA by targeting PBP1a, offering a promising preclinical strategy requiring further validation in animal models for combating resistant bacterial infections.
AbstractIn inflammatory bowel disease (IBD) the pathogenetic process is characterized by dysbiosis, increased permeability, translocation, and immune activation. The aim of the present study was to assess the presence of viable bacteria in the blood of patients with IBD and to correlate the findings with clinical characteristics. The study included 28 patients with Crohn’s disease (CD) (median age 38 years, 50% female, biological treatment in 71%) and 19 patients with ulcerative colitis (UC) (median age 45 years, 33% female, biological treatment in 84%). Identification of viable bacteria in the blood was evaluated by optimized cultivation and Sanger sequencing and for quantification real-time PCR was performed. Viable Gram-positive bacteria were detected in 34 IBD patients (72.3%). There were no associations between the presence of bacteria and gender, antibiotic treatment, intake of alcohol, use of PPI, steroids, or biological treatment. The number of bacterial copies was correlated with higher C-reactive protein (CRP) (p= 0.013). In ¾ of the patients, viable bacteria were identified in the blood despite treatment with biologicals, which indicates a vast barrier defect. This observation also indicates that the disease is still active. To obtain a true deep mucosal healing an intact barrier function is required.
AbstractAdverting biodiversity loss is one of the most urgent challenges of our time. The ongoing amphibian extinction crisis is the result of a multitude of factors, with emerging infectious diseases having played a key role. While extensive contributions have been made to study chytrid fungi and ranaviruses in the last two decades, other amphibian pathogens have remained largely unstudied. Here, we evaluated the spatiotemporal distribution of Bufonid herpesvirus 1 (BfHV1) in Europe, a pathogen capable infecting true toads (family Bufonidae). Using molecular detection and histology, we identified seven new BfHV1 positive sites in Germany and a first record for Luxembourg. Phylogenetic analysis of samples from these sites revealed a monophyletic cluster with the known BfHV1 reference sequences. Through additional systematic examination of photographic records from citizen scientists, we identified 229 BfHV1 cases (62 positive, 167 suspicious) in the genusBufo(B. bufo,B. spinosus), with suspicious cases being widespread across Europe and dating back until at least 2007. As such, this first continental assessment suggests that BfHV1 has been rather overlooked than being recently emerging. Yet, in view of increasing observations of population declines in bufonids across Europe, additional research is warranted to assess its effects on amphibian populations.
AbstractTheodolites and drones are key instruments for observing small whales in coastal areas. This study compared their performance while observing the harbour porpoise (Phocoena phocoena) in the western Baltic Sea. The methods were used simultaneously providing information on location, behaviour and group size during a field campaign in 2022. Theodolite observers were able to detect surfacing positions during 80.5% of porpoise sightings while a drone collected data during 50.7% of total sightings detected by plain eye. The drone footage quality was poor during 47.3% of these sightings. An in-depth analysis of 75:36 h of good quality footage resulted in 16:55 h (22.4%) of cetacean appearance. The determination of group size was significantly more precise using drone footage while the theodolite was more accurate in determining the start/end of a sighting. The accuracy of locations was modelled using the distance (Dt-d) between recorded theodolite and drone coordinates of the same surfacing porpoise. Dt-dvaried significantly based on the point quality. Sea state and porpoise to theodolite observer distance did not influence Dt-d. Both methods complement each other and should ideally be used simultaneously to obtain both accurate and detailed information on harbour porpoises and other marine mammals during land-based observation studies.
AbstractCardiovascular failure has been recognized as the predominant cause of perioperative mortality in small animals, particularly dogs. This study was designed to evaluate the effectiveness of adding intravenous atracurium to a ketofol infusion during anesthesia in dogs. Thirty male mongrel dogs were premedicated with an intramuscular injection containing 0.02 mg/kg of acepromazine and 0.2 mg/kg of methadone. Thirty minutes later, the dogs were equally and randomly divided into two groups (n = 15): the Ketofol Group (KFG), in which anesthesia was induced using IV administration of 0.5 ml/kg of ketofol, and the atracurium/ketofol Group (AKFG), in which anesthesia was induced using IV administration of 0.25 mg/kg of atracurium with 0.5 ml/kg of ketofol. Following intubation, anesthesia was maintained by a variable intravenous infusion at 0.2 ml/kg/min in KFG or a combination of 0.01 mg/kg/min atracurium and 0.2 ml/kg/min ketofol in AKFG. Respiratory frequency (fR), mean arterial pressure (MAP), heart rate (HR), oxygen saturation of hemoglobin (SpO2), end-tidal carbon dioxide concentration (EtCO2), rectal temperature (RT), the quality of induction, intubation, recovery period, ejection fraction percentage (EF%), fractional shortening percentage (FS%), and stroke volume (SV) were recorded. The ketofol doses were significantly lower,P≤ 0.01, in the AKFG group (4.2 ± 0.44 mg/kg) than in the KFG group (2.27 ± 0.6 mg/kg). There were statistically significant increases in RR, HR, MAP, EtCO2, and echocardiography parameters in the AKFG group compared to the KFG group. Additionally, the AKFG group exhibited a significant reduction in induction, intubation, and recovery scores compared to the KFG group. Adding atracurium to ketofol during dog anesthesia positively impacts the hemodynamic and cardiac parameters and improves the quality of induction, intubation, and recovery.
AbstractThis study explores the influence of the polarization angle on the formation of Laser-Induced Periodic Surface Structures (LIPSS) during Direct Laser Interference Patterning (DLIP) and its impact on ablation efficiency in stainless steel and aluminum 2024 substrates. Two pulse durations, 12 ps and 70 ps, with a laser wavelength of 1064 nm, are employed at varying accumulated fluences to evaluate their effects on the surface structuring process. The results demonstrate that the Low Spatial Frequency LIPSS (LSFL) orientation with respect to the line-like structures produced by two-beam DLIP is strongly influenced by the polarization angle and the alignment of DLIP features. In addition, the spatial period of LSFL in stainless steel remained relatively stable regardless of the polarization angle (~ 900–1000 nm), whereas in aluminum 2024, it exhibited significant variation, decreasing from approximately 920 nm to 506 nm as the LSFL rotated. The polarization angle also affected the reached structure depth at constant irradiation conditions, particularly in stainless steel, where greater depths were achieved when the LSFL aligned perpendicularly to DLIP lines (over 50% variation). These findings provide valuable insights for optimizing laser-based surface processing techniques for metallic substrates.
AbstractThe exact cause for no pain, local pain and referred pain groups according to the upper cervical palpation test (UPT) and whether neck pain in migraine patients is caused due to pain sensitization or influenced by perceived neck-related disability, is not fully understood. The aim was to determine whether upper cervical spine sensitivity tested by the UPT is associated with neck-related disability or increased pain sensitization in patients with migraine. Forty-two patients with episodic migraine were examined regarding mechanical and pressure pain thresholds, central sensitization (CSI), allodynia (ASC-12) and neck-related disability (NDI), and sub-grouped according to the UPT. An ANOVA analysis was performed for group differences. Exploratory regression and correlation analyses were performed with NDI and CSI as dependent variables to understand which factors are related and contribute to either subgroup allocation. No significant differences were found in UPT subgroups regarding CSI and NDI. The UPT subgroups could not be determined by any evaluated variable. The NDI was explained in 43.6% by the CSI and neck pain intensity. CSI results were explained to 49.4% by a model including ASC-12 and NDI. In conclusion, UPT subgroups were neither explained by differences in CSI, mechanical or pressure threshold testing or NDI.
AbstractNeem is a plant used both as food and in traditional medicine. Its many active components, such as Carotenoids, Saponins, Triterpenoids and Nimbidin, may render it a beneficial feed additive for rabbits. Healthy weaned rabbits from breed V-line (VL) were selected to examine the effect of neem (Azadirachta indica) on growth performance, carcass traits, morphology, and blood parameters responses. Thirty-two V-line rabbits (45 days old) were randomly assigned to four groups (n= 8 per group): a control group (G1) receiving a basal diet, and three treatment groups (G2, G3, G4) receiving the basal diet supplemented with 5%, 10%, and 15% neem leaf powder, respectively. Neem leaf supplementation had no significant effect on the rabbits’ growth performance, live body weight, carcass weight, lungs and abdominal fat, dressing percentage and liver. There was a significant (P< 0.05) increase in intestine length in G4. Nevertheless, the cecum considerably shrank (P< 0.05) in G3 and G4, which might have a more negative impact on growth performance. Certain biochemical measures (albumin, globulin, triglycerides, LDL, total protein, cholesterol, glucose, AST, and ALT) did not exhibit significant variations. However, a significant (P< 0.01) drop in blood urea occurred after the higher concentration. A significant (P< 0.05) rise in HDL after neem supplementation. Histologically, the liver showed signs of hepatotoxicity in the group supplemented with neem leaves, such as abnormal hepatocytes’ nuclear membranes, pyknotic nuclei, karyorrhexis and karyolysis. Additionally, the portal and central veins were congested, and a greater number of Kupffer cells were seen. In conclusion, the findings suggest that dietary neem leaf supplementation may have adverse effects on rabbit health and performance, particularly at higher concentrations.
AbstractInstructional videos need to maintain learners’ attention to foster learning, therefore, a fine-grained measurement of attention is required. Existing gaze measures like inter-subject correlation (ISC) assume a singular focal point deemed meaningful for indicating attention. We argue that multiple meaningful foci can exist and propose an automatically generated gaze measure labeled gaze cluster membership (GCM). By applying the density-based clustering in spatial databases (DBSCAN) algorithm to gaze position data from over 100 participants, we categorize viewers as attentive when they are part of a cluster and as inattentive when they are not. Using two videos, we demonstrate that our settings of DBSCAN generate meaningful clusters. We show that low ISC values (neuronal and eye tracking data) during multiple meaningful foci do not necessarily indicate a lack of attention. Additionally, GCM predicts participants’ self-reported mental effort and their tested knowledge. Our innovative approach is of high value for assessing learner attention and designing instructional videos.
AbstractCisplatin is a well-established drug for the treatment of solid tumors. One of the most common side effects is neurotoxicity and peripheral neuropathy, which affects patients’ quality of life. In previous studies, a protective effect of nimodipine on neuronal cell stress was demonstrated. Therefore, the objective of this study was to examine the impact of nimodipine on cisplatin-treated Schwann cells, neuronal cells, and tumor cells. Schwann and neuronal cells were used to investigate the neuroprotective effect of nimodipine, as well as the cancer cell lines A549, SAS and SKOV-3 to determine the effect on tumor cells. Cell death was measured using extracellular lactate dehydrogenase activity and propidium iodide staining. In addition, the protein level of the LIM-domain only four protein and the activation of known interacting anti-apoptotic pathways were analyzed. The cytotoxic effect of cisplatin was reduced by up to 23.6% in neuronal cells (p≤ 0.0001) and up to 30.6% in Schwann cells (p≤ 0.05) by nimodipine pre-treatment. However, no decrease in apoptosis could be shown in the cancer cells. Nimodipine-dependent activation of anti-apoptotic signaling pathways was detectable in Schwann cells and neuronal cells, whereas the opposite effect could be demonstrated in the cancer cells. In conclusion, the treatment with nimodipine may represent a new approach against neurotoxically side effects in cisplatin chemotherapy.
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AbstractLorazepam is extensively used to treat anxiety disorders and anxiety associated with depression. This study evaluates the safety of lorazepam based on real-world data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Data were collected from January 2004 to June 2024. After standardizing the data, we quantified signals using four algorithms, including the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Multi-Item Gamma Poisson Shrinker (MGPS) to quantize the signal by Bayesian analysis and disproportionation analysis. AE signals were predominantly involved psychiatric disorders, nervous system disorders, injury, poisoning and procedural complications, and cardiac disorders. Notably, new potential AE signals of clinical value were identified in this study, including tachycardia, rhabdomyolysis, neologism, phagophobia, pancreatic fibrosis, and pneumonia. Sex-stratified analysis showed that the risk of poisoning was more pronounced in females and the AEs of sedation were more pronounced in males. Age-stratified analysis demonstrated variations in AEs across different age groups.The findings of this study were consistent with clinical trials, and identified several new potential AE signals. In addition, there are gender and age differences in some AEs. These findings provide valuable insights into lorazepam in clinical practice.
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AbstractThe biomass filtrate of marine actinobacterium,Streptomyces vinaceusdrappusAMG31, was utilized as a biocompatible and biocatalyst for titanium dioxide nanoparticles (TiO₂-NPs) synthesis. Characterization revealed well-dispersed, spherical structures with high crystallinity in the anatase phase, with sizes from 10 to 50 nm. The biosynthesized TiO₂-NPs demonstrated potent antioxidant activity with maximum DPPH and ABTS radical scavenging percentages of 94.6% and 88.2% at 1000 µg/ml, with IC₅₀ values of 11.1 and 14.36 µg/ml, respectively. TiO₂-NPs exhibited moderate wound healing activity with 66.6% wound closure compared to controls (62.6%) after 48 h. The hemocompatibility assessment revealed minimal hemolytic activity (1.9% at 1000 µg/ml) and modest anticoagulant effects in PT (14.2 s) and PTT (43 s) at 75 µg/ml. Moreover, TiO₂-NPs displayed selective cytotoxicity towards cancer cells (Caco-2 and PANC-1) with IC₅₀ values of 74.1 ± 0.7 and 71.04 ± 1.2 µg/ml, respectively, while showing lower toxicity towards normal WI38 cells (IC₅₀ 153.1 ± 1.01 µg/ml). The nanoparticles demonstrated significant antidiabetic potential through α-amylase and α-glucosidase inhibition (IC₅₀ 69.3 and 40.81 µg/ml, respectively). Notably, TiO₂-NPs exhibited potent antibacterial activity against Gram-positive bacteria, particularlyEnterococcus faecalis(37 ± 0.1 mm inhibition zone vs. 28 ± 0.1 mm for gentamicin) and Gram-negative bacteria, especiallyE. coli(29 ± 0.1 mm vs. 22 ± 0.2 mm for gentamicin), with low MIC/MBC values (12.5/25 µg/ml for Gram-positive and 6.25/12.5 µg/ml forE. coli). The nanoparticles demonstrated superior antifungal activity compared to fluconazole againstPenicillium glabrum(45 ± 0.1 mm vs. 38 ± 0.1 mm),Aspergillusniger(37 ± 0.2 mm vs. 36 ± 0.1 mm), andCandida albicans(30 ± 0.3 mm vs. 26 ± 0.3 mm). Furthermore, TiO₂-NPs showed remarkable antibiofilm activity against bacterial (90.8–98.2% inhibition) and fungal (97.3% inhibition forC. albicans) biofilms at 75% MBC/MFC concentrations. The actinobacterial TiO₂-NPs’ biological activity profile, in conjunction with their biocompatibility, selective cytotoxicity, and minimal hemolytic activity, positions the actinobacterial TiO₂-NPs as promising candidates for various biomedical applications.
AbstractThroughout every day, we perform actions, and action information has been suggested to inform scene categorization. Here we hypothesise that actions also drive the hierarchical structure of many scenes, where anchor objects (e.g., stoves) predict the presence and position of local objects (e.g., pots) by dividing a scene in functionally distinct ‘phrases’. Specifically, we test whether the presence of anchor objects informs scene function understanding. In Experiment 1, participants matched an action word and a scene from which we either removed an action-related anchor object (REL), an action-unrelated anchor (UNREL) or a non-anchor object (RAND). Matching performance was impaired in REL compared to UNREL and RAND. Experiment 2 measured scene function activation more implicitly by priming a lexical decision task (LDT) on action words with the same stimuli (including an inconsistent condition: INCON, e.g., “cooking” in a bathroom). LDT performance was impaired after INCON and REL compared to RAND and UNREL primes. A control experiment showed that this effect was partly but not solely due to scene categorization. The results imply that understanding scene function is most closely tied to anchor objects directly relevant for actions whereas contextual scene information is not always sufficient to give rise to this understanding.
AbstractThe impact of orthostatic regulation during exercise, particularly resistance training, is not fully understood. This study investigates the acute cardiopulmonary responses of intensity-matched resistance exercises, targeting similar muscle groups but performed in different body positions in young trained females. Fourteen healthy females (21.6 ± 2.0 years) performed a 3-repetition Maximum test (3-RM) for the squat movement in the Smith machine (SM) and the leg press (LP). During two subsequent visits, they randomly completed two training sessions in SM and LP (two sets of ten repetitions at 50% 3-RM). Blood pressure (vascular unloading technique) and cardiopulmonary parameters (impedance cardiography, spirometry) were measured continuously. At baseline, there was a significant difference in heart rate and stroke volume between the SM and LP conditions. During training sessions, the SM condition showed higher ground reaction force (986.9 ± 93.3 vs. 811.2 ± 71.6 N;p< .01), systolic blood pressure (156 ± 15 vs. 141 ± 10 mmHg;p< .01), diastolic blood pressure (111 ± 11 vs. 96 ± 8 mmHg;p< .01), HR (123 ± 11 vs. 97 ± 7 bpm;p< .01), and oxygen uptake (901 ± 104 vs. 623 ± 65 ml/min;p< .01) compared to the LP condition. Total peripheral resistance (TPR) was similar. Significant different post-exercise changes could be detected in mean arterial pressure (-20.9 ± 9.9 vs. 3.3 ± 11.0 mmHg;p< .01) and TPR (-2.3 ± 1.7 vs. 0.7 ± 1.7 mmHg⋅ l⋅min-1;p< .01). Squats in the SM require greater cardiovascular and pulmonary effort than matched exercising in LP due to orthostatic stress and higher muscle activation. Conversely, the risk of blood pressure peaks is much lower with LP. Future analysis should focus on the effects of body position on patient responses.
Abstract30/70 wt.% poly (vinyl chloride-co-vinyl acetate-co-2-hydroxypropyl acrylate) (PVVH) / poly (vinylidene fluoride-co-trifluoroethylene) P(VDF-TrFE) polymer blend (PB) are prepared and doped with various content of Zinc oxide nanoparticle (ZnO NPs) using casting technique. X-ray diffraction (XRD), Fourier transform infrared (FT-IR), Transmission electron microscopy (TEM), UV–Vis and Thermogravimetric analysis (TGA) are used for structural, optical and thermal properties investigation. XRD results revealed that the crystallinity degree of PB is enhanced from 83.8 to 92.3% upon increasing the ZnO NPs. FTIR analysis showed a shift in position of some characteristic bands, confirming the complexation between ZnO NPs and functional groups of PB. UV–Vis analysis showed that both direct and indirect energy gaps (Edg/Eig) are reduced from (4.08/2.34) for PB to (3.65/1.99) eV for 1.25 wt% ZnO/PB nanocomposite. Thermally stimulated depolarization current (TSDC) measurements demonstrated that the phase transition from ferroelectric to paraelectric phase occurred at 343 K for PB and increased to 350 K after embedding ZnO NPs. Thermal sampling (TS) technique is applied and thermodynamic parameters are estimated. Piezoelectric coefficient (d33) is optimized from 12.8 pC/N for PB sample to 23.7 pC/N for 1wt.% ZnO/PB nanocomposite at 6.24 × 105Pa. Our results give a prediction for new piezoelectric material design capable for various energy harvesting applications.
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AbstractPerceived stress is prevalent in industrial societies, negatively impacting mental health. Smartphone-based stress management interventions provide accessible alternatives to traditional methods, but their efficacy remains modest, potentially due to limited integration of smartphone sensor technology. The primary aim of this study was to evaluate the efficacy of an 18-day smartphone-based stress management intervention,MT-StressLesswith integrated heart rate (HR)-based biofeedback using built-in accelerometer sensors, compared to a waitlist control (WLC) condition. Secondary outcomes included emotion regulation skills, depressive symptoms, overall well-being, usbiality and usage data. As exploratory aims, we investigated whether theMT-StressLessversion without HR-based biofeedback was also superior to the WLC condition, and whether the version with HR-based biofeedback provided additional benefits compared to the version without. In a three-arm randomized controlled trial, 166 participants were assigned toMT-StressLesswith HR-based biofeedback,MT-StressLess, or the WLC condition. Linear mixed-effects models were used to analyze intervention effects over time (baseline, postintervention, and 1-month follow-up). At postintervention,MT-StressLesswith HR-based biofeedback showed significantly greater reductions in perceived stress compared to the WLC condition (d= 0.41, 95% CI [0.03, 0.79]), whereas the version without biofeedback did not differ significantly (d= 0.14, 95% CI [−0.24, 0.51]). No significant differences were observed between the two active conditions (d= 0.29, 95% CI [−0.08, 0.66]). Both active conditions, however, led to significant improvements in the secondary outcomes of emotion regulation skills and well-being compared to the WLC (allds= −0.58 to −0.27). These patterns persisted at the 1-month follow-up. Usability ratings were high, but overall adherence was moderate. The findings in the main comparison may reflect increased interoceptive awareness and self-regulation. Yet, the limited effects of the core intervention and the biofeedback component also suggest the influence of non-specific factors, such as placebo effects, outcome expectancy and user engagement, which highlights the need to better understand optimal intervention duration, motivation, reinforcement, and more individualized approaches to stress reactivity. Overall, the findings provide preliminary support for the potential of a smartphone-based intervention that includes HR-based biofeedback to reduce perceived stress compared to no intervention. As these interventions are still in their early stages, future research should explore how personalization driven by artificial intelligence and real-time physiological tracking can enhance engagement and efficacy.
AbstractSea cucumber represents a potential marine source of high value compounds with medicinal properties especially its anti-cancer activity. Sea cucumbers contain numerous biomolecules, including sulfated polysaccharides (Ps) which have enormous therapeutic and nutraceutical potential. This study aimed to investigate anticancer effect of Ps extracted from sea cucumbers on hepatocellular carcinoma. This study was in vitro study conducted on HepG-2 cells and normal wish cells that were divided into four groups: Group I including untreated cells, Group II including cells treated with different concentrations of 5-FU, Group III including cells treated with various concentrations of Ps extract. Group IV including cells treated with different concentrations of combined 5-FU and Ps extract. The extracted Ps were characterized using FT-IR, HPLC, and GC–MS. The anticancer effect of Ps extract was determined using cytotoxicity MTT assay, DNA fragmentation assay, wound healing assay, colony formation and soft agar assay. Also, the effect of Ps extract onVEGF,survivin,BAXandBIDgene expression was determined by qRT-PCR and its effect on Bcl2 and BAK protein level was determined by western blotting technique. The results indicated that sea cucumber Ps extract either alone or in combination with 5-FU reduced HepG-2 and wish cell viability with higher selectivity index. Also, it inhibited both adherent and non-adherent colony forming ability and cell migration of HepG-2 cells. Moreover, it was significantly downregulatedVEGF,survivinand Bcl2 while, it was significantly upregulatedBAX, BAK andBID. In conclusion, sea cucumber Ps extract may be an effective chemotherapeutic agent against HCC.
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AbstractHigh salinity impairs offspring production in Florida red tilapia (FRT)Oreochromissp. A total of 624 FRT broodstock (1:1 ratio of ♂: ♀) were divided into 16 groups, with 4 males and 4 females housed separately at two salinity levels (18 ppt and 32 ppt). Fish were fed four different levels ofMoringa oleiferaleaf extract (MOLE) supplementation (0, 5, 10, and 15 g MOLE kg−1diet) for two months. Following the initial feeding period, males and females receiving the same MOLE level under the same salinity conditions were transferred to 24 spawning concrete tanks. The experiment consisted of eight groups, each containing 3♂ and 6♀, with triplicate setups (four groups at 18 ppt and four groups at 32 ppt). Fish were fed at 1% of their body weight for four months. The results revealed significant (p< 0.05) improvements in water quality (lower ammonium and nitrite), growth parameters, feed conversion ratio, carcass protein content, digestive enzymes, liver enzymes, cortisol level, innate immunity, antioxidants, testosterone and progesterone hormones, and reproductive function (♂ and ♀) with MOLE-fed broodstock in both salinities. MOLE at 10–15 g/kg can improve FRT performance, welfare, fertility (♀), and reproduction under high salinity conditions (32 ppt).
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AbstractGesture recognition plays a vital role in computer vision, especially for interpreting sign language and enabling human–computer interaction. Many existing methods struggle with challenges like heavy computational demands, difficulty in understanding long-range relationships, sensitivity to background noise, and poor performance in varied environments. While CNNs excel at capturing local details, they often miss the bigger picture. Vision Transformers, on the other hand, are better at modeling global context but usually require significantly more computational resources, limiting their use in real-time systems. To tackle these issues, we propose a Hybrid Transformer-CNN model that combines the strengths of both architectures. Our approach begins with CNN layers that extract detailed local features from both the overall hand and specific hand regions. These CNN features are then refined by a Vision Transformer module, which captures long-range dependencies and global contextual information within the gesture. This integration allows the model to effectively recognize subtle hand movements while maintaining computational efficiency. Tested on the ASL Alphabet dataset, our model achieves a high accuracy of 99.97%, runs at 110 frames per second, and requires only 5.0 GFLOPs—much less than traditional Vision Transformer models, which need over twice the computational power. Central to this success is our feature fusion strategy using element-wise multiplication, which helps the model focus on important gesture details while suppressing background noise. Additionally, we employ advanced data augmentation techniques and a training approach incorporating contrastive learning and domain adaptation to boost robustness. Overall, this work offers a practical and powerful solution for gesture recognition, striking an optimal balance between accuracy, speed, and efficiency—an important step toward real-world applications.
AbstractBackground and aim: The Albumin Platelet Product (APP) has emerged as a promising non-invasive biomarker for fibrosis staging in chronic liver disease (CLD). This cross-sectional study aims to evaluate the effectiveness of APP compared to established non-invasive markers of fibrosis in an Egyptian cohort with HCV-related CLD. Methods: 580 participants were assessed across different fibrosis stages (F0-F4) to analyze the relationship between APP and liver fibrosis. APP was compared with FIB-4 and APRI scores for diagnostic performance. Results: The study included 580 patients with HCV-related CLD (mean age: 37.6 ± 9.66 years; 74.3% males). APP proved superiority in identifying liver cirrhosis (F4) at Cut-off values ≤ 0.59 with 81% sensitivity, 63.6% specificity (p< 0.001). APP showed a significant correlation with fibrosis stages, with an AUC of 0.920 (95% CI: 0.888–0.953) for distinguishing F4 from F0-F3 surpassing both FIB4 and APRI scores. However, FIB-4 proved superiority in distinguishing advanced fibrosis (F ≥ 3) with AUC of 0.899 (95% CI: 0.871–0.927) compared to APP with AUC of 0.87 (95% CI: 0.84–0.90), respectively. Multivariate analysis confirmed APP as an independent predictor of fibrosis (OR: 0.997, 95% CI: 0.995–0.998;p< 0.001). Conclusion: APP showed the highest performance in predicting cirrhosis, suggesting its potential as a simple, non-invasive marker for identifying patients with advanced liver disease. Its integration into clinical practice may enhance early detection and risk stratification in chronic HCV-related fibrosis. However, further multicenter, longitudinal studies are required to validate its efficacy across diverse populations and other liver disease etiologies.
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AbstractThe classical approach of using adjacent pieces of fresh-frozen tissue for various omics analysis from the same sample possesses a risk of biological mismatch between arising from intrinsic tissue heterogeneity. We propose an alternative approach of tissue cryogenic pulverization and lyophilization before distribution for omics studies for a more reliable analysis. Here, we compare individual omics layer readouts from fresh-frozen adjacent tissue pieces and homogenized powder in mouse brain, kidney, and liver. Genomics, transcriptomics, proteomics, and metabolomics analyses showed comparable RNA integrity, DNA methylation, and coverage of transcripts, proteins, and metabolites across both methods. Moreover, the homogenized-lyophilized powder usage led to reduced heterogeneity between biological replicates. We conclude that the cryogenically pulverized-lyophilized tissue approach not only maintains a critical molecular feature coverage and quality but also provides a homogenous basis for various omics analysis enhancing reproducibility, sample transport, storage and enabling multi omics base on one and the same tissue aliquot.
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AbstractThe global pandemic caused by SARS-CoV-2 has underscored the critical necessity for effective antiviral therapies. The viral main protease (Mpro), crucial for viral replication, has emerged as a promising therapeutic target. In the present study, the inhibitory potential of ten drug-like compounds (KL1-KL10), designed as derivatives of the parent inhibitor K36, against Mpro, has been computationally investigated. To elucidate the binding affinities and interactions of the suggested drugs with the Mpro active site, molecular docking and molecular dynamics (MD) simulations till 500 nanoseconds have been applied. Our results revealed that many suggested inhibitors exhibited enhanced binding affinities compared to the parent inhibitor K36. Among these, KL7 displayed the most favourable binding characteristics, with a docking score of -13.54 and MM-PBSA binding energy of -34.57 kJ/mol, surpassing that of K36. Molecular dynamics simulations demonstrated persistent binding of these compounds to Mpro, with RMSD values ranging from 0.5 to 2.0 nm, suggesting their potential as effective inhibitors. These findings suggest that the proposed ligands hold promise as potential scaffolds for developing potent antiviral drugs against COVID-19.
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AbstractThe existence of transgenerational effects of radiation exposure on the human germline remains controversial. Evidence for transgenerational biomarkers are of particular interest for populations, who have been exposed to higher than average levels of ionizing radiation (IR). This study investigated signatures of parental exposure to IR in offspring of former German radar operators and Chernobyl cleanup workers, focusing on clustered de novo mutations (cDNMs), defined as multiple de novo mutations (DNMs) within 20 bp. We recruited 110 offspring of former German radar operators, who were likely to have been exposed to IR (Radar cohort, exposure = 0–353 mGy), and reanalyzed sequencing data of 130 offspring of Chernobyl cleanup workers (CRU, exposure = 0–4080 mGy) from Yeager, et al. In addition, we analyzed whole genome trio data of 1275 offspring from unexposed families (Inova cohort). We observed on average 2.65 cDNMs (0.61 adjusted for the positive predictive value (PPV)) per offspring in the CRU cohort, 1.48 (0.34 PPV) in the Radar cohort and 0.88 (0.20 PPV) in the Inova cohort. Although under the condition that the proportion of true mutations is low in this analysis, this represented a significant increase ($$\:p<0.005$$) of cDNMs counts, that scaled with paternal exposure to IR ($$\:p<0.001$$). Our findings corroborate that cDNMs are a potential transgenerational biomarker of paternal IR exposure.
AbstractRecently, men with overactive bladder have been prescribed mirabegron and tamsulosin for the treatment of benign prostatic hyperplasia. Highly efficient and environmentally sustainable spectrophotometric methods have been developed for the accurate determination of mirabegron and tamsulosin in their pure forms as well as within pharmaceutical formulations. This study presents three effective and simple spectrophotometric methods for the simultaneous quantification of mirabegron and tamsulosin. The current protocols have demonstrated validation for linearity across concentration ranges of 3–20 µg/mL for mirabegron and 2–40 µg/mL for tamsulosin, utilizing dual wavelength, ratio difference, and derivative ratio techniques. The coefficients of determination exceeded 0.999. The validation of these methodologies was conducted in accordance with the guidelines set forth by the International council for Harmonization (ICH). Quality control laboratories may utilize existing techniques to identify the binary combination because of their high accuracy and cheap cost. The evaluation of the environmental sustainability of the established approaches was conducted using AGREE, GAPI, MOGAPI and whiteness revealing their notable eco-friendliness. The proposed method was deemed practical after the evaluation carried out with the Blue Applicability Grade Index (BAGI) assessment.
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AbstractChronic low back pain (cLBP) is a leading cause of disability worldwide, however, the influence of age on electromyography (EMG) during lifting tasks is not well understood. This study examined the effects of age and pain on EMG and kinematics in 102 participants. They were divided into no low back pain (no-BP) (n= 42; mean age: 41.86) and cLBP groups (n= 60; mean age: 43.41) and further categorized by age: 44 under 40 years (mean age: 31.14) and 58 over 40 years (mean age: 51.38). Two lifting tasks from the ground to the hip height were performed: lifting a 10 kg box in front of the body (Task 1) and two 5 kg dumbbells beside the body (Task 2), with EMG and flexion angles recorded. Older participants showed significantly higher EMG amplitudes (p< 0.05), particularly in Task 1 while holding the weight at hip height. No significant EMG differences were found between cLBP and no-BP groups after adjusting for age, sex, and body mass index (BMI) (p> 0.05). Task 1 showed higher back muscle activation than Task 2 (p< 0.05). These findings suggest that age, rather than pain, may play a more critical role in muscle activation, highlighting the need for age-specific interventions in cLBP rehabilitation.
AbstractRecently, meta-heuristic optimization algorithms have enhanced resource efficiency, facilitated informed decision-making, and addressed complex problems involving multiple variables and constraints in engineering and science fields. However, numerous handicaps are reported on the performance of a quite number of these optimizers, such as local solution trapping, slow convergence and the requirements for elevated storage and computation capability. This article proposes a novel, simple, and elaborate remedy for the reported deficiencies of meta-heuristic optimizers. This deficiency is accomplished by proposing a hybrid optimizer composed of an ambiguous optimizer and Artificial Intelligence (AI). The performance of the proposed technique is evaluated using four different meta-heuristic optimizers: Genetic Algorithm (GA), Particle Swarm Optimization (PSO), Teaching–Learning-Based Optimization (TLBO), and Artificial Gorilla Troops Optimization (AGTO). These optimizers range from the mature to the recently evolved. These meta-heuristic optimizers validate the proposed solver and confirm its applicability to any meta-heuristic optimization algorithm. Economic Dispatch (ED) of the IEEE 30-bus system is utilized to evaluate the performance of the proposed solver. The comprehensive results demonstrate the superiority, reliability, and adequacy of the proposed technique. It consistently converges to the global optimum solution, achieving the minimum energy cost of the system under concern while requiring the fewest iterations and minimal computational requirements.
AbstractLittle documented studies regarding analysis of macular telangiectasia type 2 in Egyptian patients. This prospective study included 24 eyes with MacTel-2, and 24 control eyes. Spectral-domain optical coherence tomography Angiography (OCT-A) was performed. Staging of eyes with MacTel-2, quantification of Foveal and parafoveal vascular density and full retinal thickness were performed. In MacTel-2 eyes, the superficial capillary vessel density was significantly decreased in the temporal, superior and inferior para-foveal area (p-value = 0.004, < 0.001 and 0.002 respectively). Only temporal parafoveal deep vessel density showed significant decrease in the MacTel-2 group as compared with the normal control group (49.6% versus 54.01%, p value = 0.010). There was a statistically significant decrease in the foveal and all the para-foveal thickness as compared with normal control group (P< 0.001). One-fourth of cases were classified as stage 4 MacTel-2. The patterns of neovessels were sea-fan, tangled or dead tree network, equally distributed among the six affected eyes. A significant reduction in both foveal density and visual acuity was documented with disease progression. This study emphasizes the role of OCT-A in diagnosis, staging and identification of neovascular pattern of MacTel-2. Furethermore, this study is considered one of the few Egyptian studies in staging the disease providing correlation to visual acuity, macular thickness and vessel density affection.
AbstractThe global outbreak of the novel coronavirus (COVID-19) has highlighted the urgent need for innovative therapeutic solutions. Remdesivir (REM) was the first drug granted approval by the US FDA for treating hospitalized COVID-19 patients. A selective and sensitive derivative spectrofluorimetric method has been developed and validated for the determination of Remdesivir (REM) in presence of its Alkaline-induced degradation product (AKDP), which is also known to be its metabolite (GS-441524). The method utilized the intrinsic fluorescence properties of REM, achieving a linear response within the range of 3.0–120.0 ng/mL at 428.3 nm using first-order derivative. Methodological parameters were optimized to ensure high sensitivity, with detection and quantification limits of 1.12 and 3.67 ng/mL, respectively. This approach successfully quantified REM in pure form, intravenous infusions, and spiked human plasma. Recovery rates in plasma were satisfactory at 97.64 ± 1.87, confirming the method’s suitability for therapeutic drug monitoring (TDM) in COVID-19 patients. Additionally, the environmental sustainability of the method was evaluated using GAPI, AGREE, and RGB12 metrics, underscoring its green and eco-friendly characteristics.
AbstractPhytogenic feed additives are increasingly used to improve animal health and productivity. This study compared the effect of supplementation with tannin to an herbal mixture consisting of ginger, garlic, artemisia, and turmeric on the performance, intestinal parasites, blood metabolites, carcass characteristics, and histology of muscles and intestine of goats. Twenty-seven Shami male goats were assigned to three treatments (n = 9): non-supplemented goats fed a control diet (CC); goats supplemented with 10g /animal/day of quebracho tannins as a source of condensed tannin (TT); and goats supplemented with 10g/animal/day of an herbal mixture (HM). All the animals received a basal diet consisted of concentrate feed mixture and alfalfa hay. The supplementation improved growth performance, nutrients digestibility, and serum immunoglobulins concentration (P< 0.05). The supplementation decreased fecal parasite counts, blood cholesterol, and glutamic-pyruvic transaminase (GPT) enzyme and improved blood glucose (P< 0.05). The supplementation decreased renal and meat fat, and group HM revealed higher polyunsaturated fatty acids and α-Linolenic acid in meat (P< 0.05). Tannin supplementation (TT group) negatively affected the histology of muscles and intestines. The results provide evidence for the beneficial use of an herbal mixture in the diet to improve animal performance, health status, and meat quality in goats.
AbstractTemporal contiguity between conditioned (CS) and unconditioned stimuli (US) is a crucial factor in Pavlovian learning, yet little is known about its role in appetitive conditioning and extinction. In a within-subject design, 60 participants underwent both a delay (DC) and trace conditioning (TC) session with partial reinforcement (75%) by monetary rewards (US) and varying interval between CS offset and US onset (DC: 0s; TC: 4s). In addition to self-report indices (reward expectancy, arousal, valence), psychophysiological markers (pupil dilation, heart-period and startle reflex modulation) were recorded during acquisition and extinction training. For most measures, significant differential conditioned responses emerged, irrespective of temporal contiguity, with no major differences observed between TC and DC during acquisition (except for potentially diminished startle attenuation in TC). Despite overall similar patterns in conditioned responding (with small to moderate effects on physiological measures), there was no intraindividual concordance between sessions, yet evidence for differential TC effects on extinction learning. Specifically, smaller reductions in differential reward expectancy, heart-period deceleration and startle modulation after extinction in TC suggested relatively diminished extinction learning. Conditioned pupil dilation (0–2 s after CS onset) remained comparatively stable. Taken together, our findings extend evidence of differences in underlying learning mechanisms between TC and DC to the context of reward learning.
AbstractEvaporation represents a fundamental hydrological cycle process that demands dependable methods to quantify its fluctuation to ascertain sustainable agriculture, irrigation systems, and overall water resource management. Meteorological variables such as relative humidity, temperature, wind speed, and sunshine hours affect evaporation non-linearly, resulting in challenges while developing prediction models. To combat this, the study aimed to develop robust models for estimating evaporation in semi-arid environments by applying machine learning techniques. Daily meteorological datasets (from January 2000 to December 2010) for the above variables (input) were collected from the Sidi Yakoub meteorological station in the Wadi Sly basin, Algeria. Conventional deep neural network (DNN) coupled with support vector machine (SVM), Bayesian additive regression trees (BART), random subspace (RSS), M5 pruned, and random forest (RF) were used for developing prediction models using various input variable combinations. Model performances were compared using mean absolute error (MAE), root mean square error (RMSE), determination coefficient (R2), Nash–Sutcliffe efficiency (NSE) coefficient, and percentage bias (PBIAS). Results indicated comparatively better performance for hybrid models (DNN-SVM, DNN-BART, DNN-RSS, DNN-M5 pruned, and DNN-RF) than conventional models (standalone DNN). Among hybrid models, the DNN-SVM model outperformed others with high accuracy and performance and fewer statistical errors in the daily pan evaporation prediction during the testing phase (R²=0.65, RMSE = 3.00 mm, MAE = 2.13, NSE = 0.65, and PBIAS = 3.54). DNN-RF was in the second rank for the prediction with R2of 0.64, RMSE of 3.00 mm, MAE of 2.16, NSE of 0.64, and PBIAS = 0.41. While the standalone DNN model gave the lowest results with MAE of 4.87, RMSE of 5.00 mm, and NRMSE of 0.65. The present framework’s success in Algeria’s Wadi Sly basin highlights its potential for scalable adoption in irrigation scheduling and drought resilience strategies, yielding implementable steps for policymakers, addressing climate-driven water scarcity. Future research should explore integrating real-time climate projections and socio-hydrological variables to improve predictive adaptability across diverse agroecological zones.
AbstractRewetting of peatlands requires the development of new biomass utilization pathways. The supply of strategic elements with key importance for the development of priority technologies, such as germanium (Ge), silicon (Si) and rare earth elements, from fenland plants is one option. To provide a first estimation of the potential, concentrations of strategic elements were determined in nine biomass samples covering typical fenland vegetation in northeast Germany. Subsequently, a simplified estimation of potential revenue from strategic element recovery was made. The analysed plant species can be classified as high or intermediate Si plant accumulators with highest contents of more than 16.0 g Si kg−1dry mass (DM) in sedges and common reeds. Ge concentrations were lower with reed canary grass containing the highest amounts of 465.3 µg Ge kg−1DM. Simultaneous acquisition of Ge and Si could provide higher total element yields and revenues of up to 500 $ ha−1. In contrast, the potentials for supplying rare earth elements appeared to be very low, with common reed containing the highest sum of rare earth elements of 437.4 µg kg−1DM. Biomass from rewetted fenlands is capable of accumulating strategic elements. More knowledge is required to understand the factors affecting their accumulation.
AbstractThis was a retrospective cross-sectional study evaluating the aetiology and antibiotic susceptibility in patients treated for suspected bacterial keratitis at Skåne University Hospital during 2019. Inclusion criteria: eyes with bacterial keratitis. Exclusion criteria: co-infection with other microbes. Primary outcome parameters: predisposing factors, causative pathogens and antibiotic susceptibility. Secondary outcome parameter: antibiotic treatment. A total of 255 cases met the inclusion criteria. Of these, 149 (58%) occurred in contact lens wearers. Corneal cultures, when performed, were positive in 51% of cases. For eyes which had received antibiotic treatment prior to corneal culture (n = 36), the proportion of positive cultures was 50%. Ulcers < 1 mm were less likely to yield a positive culture than those ≥ 1 mm. The most frequently isolated bacteria were coagulase-negative staphylococci (48%). Antibiotic resistance rates were lowest to levofloxacin (0%), ciprofloxacin (2%) and chloramphenicol (4%), and highest to fusidic acid (47%) and clindamycin (19%). The low proportion of positive cultures from small ulcers suggests that these warrant a different diagnostic approach. Furthermore, corneal cultures from eyes with ongoing antibiotic treatment were positive to the same extent as those from untreated eyes, suggesting that discontinuation of antibiotic treatment before re-culturing might not be necessary.
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AbstractGentamicin (GET), a widely utilized aminoglycoside antibiotic for severe bacterial infections, is associated with significant hepatorenal toxicity. These adverse effects are frequently exacerbated by GET-induced oxidative stress and inflammation. This study aimed to evaluate the potential protective efficacy of vincamine (VIN) against GET-induced hepatic and renal damage. 4 groups of adult male rats were assigned: normal control (received CMC), GET (100 mg/kg, i.p.), VIN (40 mg/kg, p.o.), and GET/VIN (received both VIN and GET) for 7 days. Liver and kidney function tests were performed. Serum total antioxidant capacity (TAC) and tissue malondialdehyde (MDA) were quantified. To assess apoptosis,BaxandBcl-2mRNA levels were quantified using real-time polymerase chain reaction (RT-PCR), while cleaved caspase-3 protein levels were measured using ELISA. Histopathological alterations were also examined. The implication of autophagy was assessed by detecting AMPK, beclin-1, LC3 and mTOR proteins. Our results indicated that VIN significantly attenuated GET-induced hepatotoxicity and nephrotoxicity by mitigating oxidative stress and apoptosis. Mechanistically, VIN modulated apoptotic pathways by upregulating the anti-apoptoticBcl-2gene and downregulating the pro-apoptoticBaxgene. Notably, VIN potently enhanced autophagy through modulation of the AMPK/mTOR signaling pathway, evidenced by the upregulation of beclin1 and LC3 levels. Histopathological analysis further corroborated these findings, demonstrating that VIN markedly reduced the tissue damage associated with GET administration. VIN demonstrates potential as a cytoprotective agent against GET-induced hepatorenal toxicity. The protective effect of VIN may be attributed to its capacity to modulate the Bax/Bcl-2/Caspase-3-dependent apoptotic pathway and the AMPK/mTOR-mediated autophagy pathway.
AbstractGene doping is known as the manipulation of congenital traits by gene therapeutic approaches with the intent of illicit athletic performance enhancement. A panel prototype suitable for multiplex gene doping detection by combining multiplex Polymerase Chain Reaction (PCR)-amplification with Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) analysis was developed and examined for its specificity and sensitivity, and its applicability in human sports drug testing programs was assessed. The panel comprises 20 assays for exon-exon-junction detection of seven human transgenes (EPO, FST, GH1, IGF1, MSTN(propeptide),VEGFA, VEGFD), which have been considered as material to routine doping controls, in one reaction. Alongside, a suitable reference material (RM) was designed and tested for its utility. An estimated LOD95of 1,500 cp / mL or 30 copies (cp) per reaction of the panel and 500 cp / mL or 10 cp per reaction of the RM was determined in plasmid-spiked human whole blood samples. The specificity and applicability of the panel and the RM was further determined by testing equine plasma samples obtained from an animal that received rAAV-delivered human transgenicEPOas well as 111 native human doping control samples.
AbstractIdentifying the direction of fault is an essential mission of the transmission line protective scheme. This paper discusses a direction protective technique based on a positive impedance approach. The samples of the instantaneous positive sequence voltage component and the instantaneous positive sequence current component are used to determine the impedance approach and complete the Z matrix values. The fault direction can be determine using Z matrix values. Different configurations of the power system are utilized to examine the proposed protective scheme. Software ATP-EMTP (Simulation experiments) verified the feasibility of the presented scheme. To verify the capability and accuracy of presented scheme, it is examined by many fault scenarios such as high fault resistance, far end fault, cross-country fault, power flow change, single pole tripping, CT saturation and noise impact. In addition, the validity of the presented scheme is compared with other protection directional schemes.
AbstractThe increase in infections caused by multi-resistant Gram-negative bacteria, likeStenotrophomonas maltophilia, has become a growing health crisis worldwide.S. maltophiliaposes a risk because of its tendency to opportunistically infecting patience for example through colonization of catheters in hospital environments using its intrinsic resistance against multiple antibiotics. Through the COVID-19 pandemic it gained more prominence by being a key pathogen in respiratory co-infections. This study will present a structural analysis of StmPr1,S. maltophilia’s main virulence factor, an excreted serine protease. Our study outline structure and functional aspects of StmPr1, revealing a unique autoproteolytic activity resulting in a shortened version of the active enzyme. We also investigated the potential of two groups of peptide-based inhibitors, one being acetyl- and the other being boron-based inhibitors. The focus here lies on Bortezomib, a boron-based serine protease inhibitor, and its potential therapeutic use againstS. maltophilia.We provide a structure-function analysis which includes X-ray crystallography data with resolutions ranging from 1.64 to 2.08 Å, molecular dynamic simulations and small-angle X-ray scattering (SAXS) experiments. These data provide a deeper understanding of StmPr1’s resilience and mechanisms, while highlighting the relevance of StmPr1’s C-terminal extension for correct folding and its stability. Moreover, it also shows that StmPr1 is promising target for further drug discovery investigations to identify compounds and drugs to treatS. maltophiliainfections.
AbstractThe aim of this study is to explore the association between grandparental socioeconomic disadvantages and grandchild psychiatric disorders, the role of parental socioeconomic and psychosocial factors in this association, as well as potential gender differences. We utilized a cohort study design using data from the Stockholm Birth Cohort Multigenerational Study, including 11,299 individuals born in 1953 (parental generation), their 22,598 parents (grandparental generation), and 24,707 adult children (grandchild generation). Grandparental and parental socioeconomic disadvantages, respectively, included low income, non-employment, and overcrowding. Parental psychosocial disadvantages included single parenthood, psychiatric disorders, and criminality. Psychiatric disorders in the grandchildren were reflected by hospitalizations due to mental and behavioral disorders from age 18 to 30 (1986–2019). Analyses were performed within the Structural Equation Modeling framework. We found an association between grandparental socioeconomic disadvantages and grandchild psychiatric disorders (standardized total effect 0.155, 95% confidence interval [CI] 0.099–0.211), which was mediated through parental psychosocial disadvantages (standardized mediating effect 0.101, 95% CI 0.073–0.130). The mediation was more pronounced via psychosocial disadvantages among mothers than fathers. These findings indicate that psychosocial disadvantages among parents, especially mothers, reflect an important mediating mechanism, and addressing such disadvantages may help mitigate social inequalities in mental health across generations.
AbstractThis study explores the potential of six novel thiophene derivative thin films (THIOs) for reducing cancer cell adhesion and enhancing controlled drug release on inert glass substrates. Thiophene derivatives3a–cand5a–cwere synthesized and characterized using IR,1H NMR,13C NMR, and elemental analysis before being spin-coated onto glass to form thin films. SEM analysis and roughness measurements were used to assess their structural and functional properties. Biological evaluations demonstrated that the films significantly reduced HepG2 liver cancer cell adhesion (~ 78% decrease vs. control) and enabled controlled drug release, validated through the Korsmeyer-Peppas model (R2> 0.99). Theoretical studies, including in-silico target prediction, molecular docking with JAK1 (PDB: 4E4L), and DFT calculations, provided insights into the electronic properties and chemical reactivity of these compounds. Notably, compound5bexhibited the best binding energy (-7.59 kcal/mol) within the JAK1 pocket, aligning with its observed apoptotic behavior in cell culture. DFT calculations further revealed that5bhad the lowest calculated energy values; -4.89 eV (HOMO) and − 3.22 eV (LUMO), and the energy gap was found to be 1.66 eV, supporting its role in JAK1 inhibition and cancer cell adhesion reduction. These findings underscore the promise of thiophene derivatives in biomedical applications, potentially leading to safer surgical procedures and more effective localized drug delivery systems.
AbstractDuring the breeding season, the male stickleback proximal tubule of the kidney undergoes hypertrophy. This is due to the synthesis of the nest building protein spiggin, in response to increased levels of 11-ketotestosterone. The increased protein synthesis that is initiated during breeding alters the kidney function and the ability to secrete excess water, to osmoregulate, in fresh water. It has earlier been shown that there exist organ specific differences in transport proteins between mature and non-mature three-spined stickleback. To understand the molecular mechanisms compensating for kidney functions, this study examined transport genes responsible for functional changes between the kidney and intestine. RNA sequencing was performed on castrated and 11-ketoandrostenedione (11KA)-treated male stickleback. Results showed organ-specific responses: 2,549 differentially expressed genes (DEGs) in the kidney and 885 in the posterior intestine, with 210 shared between the organs. Solute transporters, aquaporin 10a and cadherin-17, were upregulated in the posterior intestine but downregulated in the kidney in 11KA treated males. Enrichment analysis revealed distinct biological processes, primarily involving solute transporters, indicating functional adaptation. While amino acid and ion transport were downregulated in the kidney, compensatory transport was observed in the posterior intestine. However, cellular hexose transporters were downregulated in both organs, suggesting a reduction in glucose absorption and passive water diffusion. The present study shows that androgens alter the expression of cellular transporters and redirect functions of the kidney to the posterior intestine. The results also indicate reduced glucose absorption in breeding, male three-spined stickleback.
AbstractStudies investigating psychological safety in sports and non-sports contexts have mostly utilized the universal Team Psychological Safety Scale (TPSS) aimed for performance development in professional teams. The Sport Psychological Safety Inventory (SPSI) has recently been introduced for psychological safety measurement specifically in sports. The aim of this study was to compare the psychometric properties of the TPSS and the SPSI within an elite sport context. A cross-sectional survey was used to collect data for assessment of the internal consistency, factorial validity, construct validity and measurement invariance of the TPSS and the SPSI. Complete data sets were provided by 371 elite Athletics athletes (track and field) and orienteers. Both the TPSS (ω = 0.72) and the SPSI subscales (range: ω = 0.81-0.88) showed acceptable internal consistency. Confirmatory factor analyses indicated a mediocre to good model fit for the TPSS and the SPSI three-factor correlated structure. The TPSS and the SPSI subscale ‘mentally healthy environment’ showed a moderate correlation. Measurement invariance tests suggested the TPSS to be fully invariant across genders, while the SPSI was found non-invariant. The study shows that the TPSS appears sound for assessing psychological safety in elite sports, while caution is needed when using the SPSI.
AbstractManganese, an essential nutrient for male reproductive health, exerts dose-dependent effects, with excessive exposure—particularly to manganese dioxide nanoparticles (MnO2-NPs) from environmental or industrial sources inducing gonadal damage via oxidative stress, hormonal disruption, and impaired steroidogenesis. This study evaluated rosemary essential oil (REO) againstMnO2-NP-induced reproductive dysfunction in male rats. Seventy-two Sprague–Dawley rats (130 ± 10 g) were divided into six groups (n= 12): Group I (deionized water), Group II (saline), Group III (MnO2-NP, 100 mg/kg bw/day), Group IV (REO, 250 mg/kg/day), Protective Group V (REOpre-treatment +MnO2-NPs), and Therapeutic Group VI (MnO2-NPs + REOco-treatment) for 56 days.MnO2-NPexposure caused testicular injury, marked by elevated lipid peroxidation (↑malondialdehyde, ↑nitric oxide), suppressed antioxidants (↓total antioxidant capacity, ↓catalase, ↓glutathione), impaired sperm parameters (motility, count, morphology), and altered serum hormone levels (follicle-stimulating hormone, luteinizing hormone, testosterone). These effects correlated with downregulated steroidogenesis genes (StAR,HSD-3β,CYP11A1). Both Protective and Therapeutic REO treatment mitigatedMnO2-NPsoxidative stress, restored hormonal balance, and normalized gene expression. Histopathology revealed reduced seminiferous tubule degeneration and enhanced spermatogenesis inREOgroups. Findings demonstrateREO’sefficacy in alleviatingMnO2-NPsinduced reproductive toxicity via antioxidant and steroidogenic modulation, positioningREOas a promising therapeutic against nanomaterial-induced gonadotoxicity.
AbstractThe Nile Delta coastal area surface sediments were evaluated for twenty-five elements. Inductively coupled plasma-mass spectroscopy (ICP-MS method) was used to analyze the digested solutions, previously filtered using discrete 0.2 μm PTFE syringe filters according to USEPA protocols. Potentially toxic elements (PTEs) and pollution levels were estimated using several indices. Pollution guides such as the enrichment factor (EF), contamination degree (Cd), geoaccumulation index (Igeo), and pollution load index (PLI) are mainly determined by actually toxic elements such as Cr, Co, Cd, Hg and Pb, while Principal component analysis (PCA), concerned with the distribution of all elements in sediment to determine the sources of elements. The following is the order of the EF values: Mn < Cu < Zn < Ni < Pb < Cr. The areas under investigation showed no pollution with Cr, Cu, Mn, Ni, Pb, or Zn, as indicated by their (Igeo≤0) values andCd(< 1.5). Significant connections between Mn, Fe, Cr, Co, and Ni values were observed, indicating comparable origins. In the current study, the children’s Hazard Quotient (HQ) results for the dermal exposure pathway are low, but adult values are 3–4 times higher. The chronic daily intake(CDIDermal) and carcinogenic risk (CRDermal) through dermal absorption were also investigated.
AbstractTherd10mouse is a widely used model for degenerative retinal diseases such as retinitis pigmentosa (RP). Its retina shows rhythmic spontaneous activity at a frequency of three to seven Hz, and the retinal ganglion cells (RGCs) are less electrically excitable. We hypothesize that the electrical excitability can be improved by suppressing the oscillations using the neuroprotective drugs 2-aminoethanesulphonic acid (taurine), brimonidine and betaxolol. These are involved in calcium homeostasis and may play a crucial role in neuroprotection and excitotoxicity by preventing Ca2+overload. Spontaneous activity and responses to electrical stimulation of isolated retinas from 3- to 4-month-oldrd10mice were recorded using multielectrode arrays. At defined times, the neuroprotectants were repeatedly added to the medium according to a standardized protocol to analyze the reproducibility and reversibility of their effects. Taurine and betaxolol significantly reduced oscillations and bursting behavior and ameliorated electrical efficiency. Brimonidine only reduced the frequency of oscillations. The effects on oscillation, spontaneous firing frequency, bursting behavior and stimulation efficiency were reproducible and reversible. The drugs tested appear to be promising therapeutic candidates for improving the residual function of RGCs. They will be further investigated and combined with other RP treatments, such as retinal prostheses, in the future.
AbstractData Harmonization is an important yet time-consuming process. With the recent popularity of applications using Language Models (LMs) due to their high capabilities in text understanding, we investigated whether LMs could facilitate data harmonization for clinical use cases. To evaluate this, we created PASSIONATE, a novel Parkinson’s disease (PD) variable mapping schema as a ground truth source for pairwise cohort harmonization using LLMs. Additionally, we extended our investigation using an existing Alzheimer’s disease (AD) CDM. We computed text embeddings based on two language models to perform automated cohort harmonization for both AD and PD. We additionally compared the results to a baseline method using fuzzy string matching to determine the degree to which the semantic capabilities of language models can be utilized for automated cohort harmonization. We found that mappings based on text embeddings performed significantly better than those generated by fuzzy string matching, reaching an average accuracy of over 80% for almost all tested PD cohorts. When extended to a further neighborhood of possible matches, the accuracy could be improved to up to 96%. Our results suggest that language models can be used for automated harmonization with a high accuracy that can potentially be improved in the future by applying domain-trained models.
AbstractCOVID-19 has been linked to acute and long-term cognitive impairments, including memory and concentration deficits, as well as neuropsychiatric symptoms such as anxiety and depression. However, the neuropathophysiological mechanisms underlying these cognitive and affective changes remain poorly understood. Accumulating evidence points towards neuroinflammation as a potential driver of most acute and post-acute neurofunctional symptoms. In this study, we aimed to comprehensively characterize cognitive impairment associated with COVID-19 using a large online cohort of over 1400 participants, including individuals reporting a previous SARS-CoV-2 infection and individuals who had never been tested positive. Our cognitive test battery covered alertness, executive functions, and episodic long-term memory. Our results demonstrate a pronounced and selective impairment of individuals previously infected in a mnemonic discrimination task known to engage hippocampus-dependent pattern separation. This impairment remained statistically significant after controlling for potential confounding factors (i.e., age, gender, education, depressiveness, anxiety, and stress). This finding, derived indirectly from behavioral performance, suggests compromised hippocampal neurogenesis following infection, which may contribute to COVID-related memory deficits. Our study has important implications for understanding the neurofunctional consequences of COVID-19 and highlights the potential significance of neuroinflammation in the manifestation of cognitive impairments.
AbstractRunning performance from sprint to long distance is largely determined by the interplay between basic speed and endurance. Existing power-law, physiological, and theoretical models describe and explain the characteristic decline in pace with increasing distance. However, normative and statistically validated measures that capture both the average and variability of pace decline across standard track distances remain incomplete. To address this gap, we analysed over 14,000 race times from competitive male runners and introduce the coefficient of special endurance (KsA), a novel metric that quantifies relative pace loss between adjacent race distances, from 100/200 to 5000/10,000 m. The KsA values obtained for seven distance pairs are nearly constant over decades in national runners, show low variability, and predict race times with less than one percent. The KsA-based reference ranges allow performance to be evaluated from the international to the regional level. This provides specific insight into runners’ strengths, weaknesses and progression for individualizing training, selecting the most promising race distance, and identifying and developing talent. Overall, we provide empirically derived KsA values that serve as statistical norms for pace loss from 100 m to 10,000 m to evaluate running performance of males. The current approach should also be applicable to women, juniors, and road runners.
AbstractLyme neuroborreliosis (LNB) is the most common form of disseminated Lyme borreliosis in Europe and North America. There are limitations in existing LNB diagnostics and a lack of reliable objective markers for disease-course. Here, extensive protein profiling with two panels of 184 proteins, was done in the search for new clinically useful diagnostic and prognostic candidate biomarkers. Cerebrospinal fluid (CSF) was collected from patients with definite LNB (n= 13) at the time of diagnosis before initiating antibiotic treatment, and at a follow-up one month later. When symptoms were evaluated at a six-month follow-up, six patients had recovered with no persistent symptoms (NPS), and seven experienced delayed recovery with persistent post-treatment symptoms (PS). Orthopedic patients (n= 60) served as controls. With the panels used, no protein biomarkers able to differentiate between PS and NPS were identified. However, from a diagnostic perspective, we identified multiple proteins that were differentially expressed between LNB and controls. The majority of them were downregulated following antibiotic treatment, at the one-month follow-up. IL10, TNF, and CCL8 were considered examples of potentially useful candidate biomarkers in both the early diagnostics and in monitoring of treatment response. These markers merit further investigation to understand their utility in relation to other neurological manifestations.
AbstractThe current research discuss in detail the tourmaline distribution in Sikait leucogranites in order to deduce its genesis and type. We conduct new detailed geological, petrographical, mineralogical, and geochemical examinations to understand the Arabian Nubian Shield development by investigation of such the examined leucogranites. Tourmaline occurs as disseminated or cluster nodular within coarse-grained leucogranites. Geochemically, the examined leucogranites have high contents of SiO2(69.44–75.87 wt%), and total alkalis (mean > 7) with low mean CaO (0.4 wt%), Fe2O3(1.93 wt%), and Mg# (14.59) values. They share features of calc-alkaline, strongly peraluminous (A/CNK > 1.1), with high contents of Zn (av. 266.68 ppm), Pb (av. 29.13 ppm), Rb/Sr (av. 22), Al2O3/TiO2(av. 832.6), FeO/MgO (av. 12.24). They are remarkably enriched in semi-volatile elements (Pb = 12–235 ppm), and LILEs (Rb = 192–679 ppm) relative to HFSEs (e.g. Zr, U and Nb) with notable strong Ba, Sr and Ti negative anomalies. They are depleted in ∑REEs (av. 19.1 ppm) and reveal parallel, uniform patterns slightly notable depletion of HREEs in comparison with LREEs. They reveal extreme pronounced Eu (av. Eu/Eu*= 0.02) negative and Ce/Ce* (0.76–1.12) positive anomalies. The examined rocks have prominent tetrad effect (M-type) as indicated by Irber and Lambda methods. Based up on conventional geochemical diagrams, the examined rocks are post-collisional S-type granites derived by partial degree of the clay-rich pelite rocks melting followed by extreme fractional crystallization processes during post-collisional extension episode at temperatures (663 –786 °C) based on saturation temperature of zircon. The investigated tourmaline nodules are of alkali group and foitite end-member.
AbstractAttenuated interpersonal synchrony (IPS) has been shown between autistic individuals and their interaction partners; however, the mechanisms of this attenuation remain unclear. One possibility could lie in perceiving the timing of others’ behaviors. The present study aimed to relate the behavioral production of IPS with the perception of temporal dynamics of social interactions and event timing perception in autistic and non-autistic adults. Autistic and non-autistic participants engaged in naturalistic conversations with a non-autistic stranger, who was naïve to the participant’s diagnostic status. Behavioral IPS was computed using automatic video-based analysis. Participants reported their experiences of perceived IPS with the partner, as a measure of the perceived temporal dynamics of the social interaction. A perceptual simultaneity task measured the perception of event timing in a nonsocial context. Bayesian linear mixed models were used to evaluate the effects of perceived IPS ratings and simultaneity thresholds on behavioral IPS. Expectedly, behavioral IPS was reduced for dyads including an autistic adult. Neither perceived IPS ratings, nor simultaneity thresholds, were associated with reduced behavioral IPS for dyads with or without an autistic adult. These findings hint that attenuated behavioral IPS may not result from atypical perceived timing of others’ behaviors or event timing perception.
AbstractThis article presents several innovative methods to mitigate frequency deviations in hybrid renewable power grids (HRPGs) with high penetration of renewable energy sources (RESs). Two models of the HRPGs are considered: the first model is a two-area power grid that combines three conventional power plants and two RESs in each area, while the second model is the IEEE 39-bus system. The tie-line is connected in series with a unified power flow controller (UPFC). The first method introduces an approach in the secondary control loop (SCL), where a fuzzy logic controller is cascaded with an Integral-Tilt-Derivative (I-TD) controller (Fuzzy I-TD). Additionally, the performance of the Fuzzy I-TD controller is compared with other approaches, such as Fuzzy Proportional-Integral-Derivative (Fuzzy-PID) and Fuzzy Integral-Proportional-Derivative (Fuzzy I-PD). The second strategy integrates the Fuzzy I-TD controller in the SCL along with controlled energy storage systems (ESSs), such as plug-in electric vehicles (PEVs). The parameters of the strategies are optimized using a recent metaheuristic algorithm known as the Sea Horse Optimizer (SHO) under different operating conditions. A comprehensive investigation is conducted to validate the effectiveness of the Fuzzy I-TD controller and the Fuzzy I-TD controller with PEVs in HRPGs. The Fuzzy I-TD controller significantly reduces frequency and tie-line deviations in the SCL by 82.7% and 97.01%, respectively, when compared to the Fuzzy I-PD and Fuzzy-PID controllers. Moreover, the Fuzzy I-TD with PEVs reduces frequency fluctuations by 40% compared to the Fuzzy I-TD alone in the SCL. The results demonstrate that the presented strategy is efficient and effective for HRPGs.
AbstractThe current investigation evaluated the impact of the dietary addition of commercial bile acids (BAs) on growth, nutrient assimilation, immunity, antioxidant status, intestinal and hepatic histomorphometry, and gene expression of lipid metabolism in Nile tilapia (Oreochromis niloticus). In a study conducted for seventy days, 180 healthy fingerlings weighing 9 ± 0.5 g were divided into 18 hapas measuring 0.7 × 0.7 × 1.0 m. The fish were fed on six meals enriched with varied amounts of BAs: 0.0 (D1), 0.1 (D2), 0.2 (D3), 0.3 (D4), 0.4 (D5), and 0.5 (D6) g/kg diet. Nile tilapia fed the D3 diet exhibited significantly enhanced growth performance, with a specific growth rate of 1.89%/day and had the greatest feed conversion ratio (1.25), protein productive value, and energy utilization (33.28%). Fish fed the D3 exhibited significantly the highest crude protein content (64.50%). Energy content varied significantly, with D1 showing the lowest value (533.34 Kcal/100 g) and D3 the highest (604.27 Kcal/100 g). D3 improved biochemical indicators, immunological parameters, and digestive enzymes ofO. niloticus. Histological analysis revealed notable liver and intestinal integrity enhancements among fish receiving BA-enriched diets, especially D3. Additionally, gene expression related to lipid metabolism in liver, peritoneal fat, and muscle tissues was upregulated in the treatment groups, especially 0.2 g/kg BAs compared to the control group. Results illustrate significant modulation of lipid metabolism gene expression parameters (Adipose triglyceride lipase; ATGL, Hormone-sensitive lipase; HSL, Peroxisome proliferator-activated receptor α; PPARα, Fatty acid synthase; FAS) by BAs treatments and were upregulated in BA-fed groups (D2–D6). Conversely, Carnitine palmitoyl transferase 1; CPT-1and Insulin-like growth factor-II; Igf-IIexpression declined, particularly when the BAs dose was increased. Accordingly, dietary 0.2 g/kg BAs supplementation positively influences on physiological, biochemical parameters, and lipid metabolic of Nile tilapia, making it a promising feed additive for aquaculture.
AbstractAmorphous calcium carbonate (ACC) plays an important role in the crystallization pathways of calcite and its polymorphs influencing many natural and anthropogenic processes, such as carbon sequestration. Characterizing the dissolution rate of ACC in presence of additives of contaminants in favor of crystalline phases is challenging as such reactions occur readily in bulk solution. Droplet microfluidics offers a solution by confining ACC within a droplet, enabling a quantification of the transformation rate of ACC into crystalline phases. However, accurate quantification of this transformation requires analyzing more than thousands of droplets identifying the different polymorphs of calcium carbonate during an experiment, which is labor-intensive. Here we develop a visual-based machine learning method, combining cascading U-Net and K-Means clustering, to allow efficient analysis of droplet microfluidics experiment results. Using our method, we accurately inspect 11,288 droplets over 6 hours of experimental time to identify the polymorphs, using a CPU core in a laptop for only 42 minutes. This is achieved with manual labeling of 11 experimental microscopy images before augmentations. From our analyses the transformation rate of ACC into its crystalline phases can be inferred. The transformation rate indicates an increasing stability of the ACC phase in confinement. Our method is generalizable and can be applied to different setups of droplet microfluidics experiments, facilitating efficient experimentation and analysis of complex crystallization processes.
AbstractPosterior fossa (PF) tumors are the most common neoplastic entity in pediatric neurosurgery. Children suffering from PF tumors regularly present with hydrocephalus and CSF diversion is a crucial point of treatment. There is an ongoing debate about external ventricular drainage (EVD) management before surgery and its influence on ongoing hydrocephalus treatment afterwards. Beyond onco-surgical aspects, the prevention of shunt-dependency is an important goal in posterior fossa surgery. Various predictors for shunt-dependency after posterior fossa surgery in children have been suggested. Because these predictors may only apply to small subsets of children, and their reliability has been questioned, we evaluated a straightforward, potentially automated, and unbiased method for shunt prediction. In this retrospective radiomic study we analyzed 60 pediatric patients with posterior fossa tumors. Exclusion criteria were age under two years, missing MRI data, tumor location non-exclusive to the PF, traumatic brain injury and less than 6 months follow-up. Ultimately, 36 children met the inclusion criteria. We performed a volumetric assessment of various skull and brain compartments before and after surgery focused on ventricle-brain ratio (VBR). We dichotomized for potential predictors and performed ROC analyses. We evaluated the prognostic parameters for shunt dependency, including supratentorial transependymal edema and VBR, as well as pre- and postoperative radiomic measurements as early prognostic tools. The cutoff in ventricle volume for CSF diversion was 60.9 ml (AUC 0.788,p= 0.001). The radiomic-based prediction of shunt dependency with VBR-scoring showed an AUC of 0.783. Postoperative reduction in ventricle size, depicted by the deltaVBR scoring, showed an AUC of 0.719 in predicting shunt-free survival. Perioperative CSF diversion did correlate with postoperative persistent HCP, whereas the odd’s ratio for shunting was decreased, but not significantly lower, when CSF diversion was undertaken perioperatively (AUC = 0.618, OR = 0.273, CI = 0.029–2.577). Ventricle-brain ratio may be a potential predictor for the necessity of CSF diversion. In our cohort, radiomic predictors performed better than hydrocephalus categorization, modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) or transependymal edema alone. VBR pre- and deltaVBR postoperatively may be potential tools to predict the need for shunting in pediatric posterior fossa tumor patients. The decision for pre- or intraoperative CSF diversion showed no correlation and no influence on persistent hydrocephalus.
AbstractAir temperature plays a critical role in estimating agricultural water requirements, hydrological processes, and the climate change impacts. This study aims to identify the most accurate forecasting model for daily minimum (Tmin) and maximum (Tmax) temperatures in a semi-arid environment. Five machine learning models—linear regression (LR), additive regression (AR), support vector machine (SVM), random subspace (RSS), and M5 pruned (M5P)—were compared for Tmaxand Tminforecasting in Gharbia Governorate, Egypt, using data from 1979 to 2014. The dataset was divided into 75% for training and 25% for testing. Model input combinations were selected based on best subset regression analysis, result shows the best combination was Tmin(t−1), Tmin(t−3), Tmin(t−4), Tmin(t−5), Tmin(t−6), Tmin(t−7), Tmin(t−8)and Tmax (t−1), Tmax (t−2), Tmax (t−3), Tmax (t−4), Tmax (t−5), Tmax (t−6), Tmax (t−8)for daily minimum maximum air temperature forecasting, respectively. The M5P model outperformed the other models in predicting both Tmaxand Tmin. For Tmin, the M5P model achieved the lowest root mean square error (RMSE) of 2.4881 °C, mean absolute error (MAE) of 1.9515, and relative absolute error (RAE) of 40.4887, alongside the highest Nash-Sutcliffe efficiency (NSE) of 0.8048 and Pearson correlation coefficient (PCC) of 0.8971. In Tmaxforecasting, M5P showed a lower RMSE of 2.7696 °C, MAE of 1.9867, RAE of 29.5440, and higher NSE of 0.8720 and R² of 0.8720. These results suggest that M5P is a robust and precise model for temperature forecasting, significantly outperforming LR, AR, RSS, and SVM models. The findings provide valuable insights for improving decision-making in areas such as water resource management, irrigation systems, and agricultural productivity, offering a reliable tool for enhancing operational efficiency and sustainability in semi-arid regions. The Friedman ANOVA and Dunn’s test confirm significant differences among temperature forecasting models. Additive Regression overestimates, while Linear Regression and SVM align closely with actual values. Random Subspace and M5P exhibit high variability, with SVM differing significantly. For maximum temperature, Random Subspace and M5P perform similarly, while SVM remains distinct.
AbstractOptical Coherence Tomography Angiography (OCTA) has become an essential non-invasive imaging technique for high-resolution visualization of retinal microvasculature. This study evaluates the performance of a novel Swept-Source OCTA device, Intalight DREAM, compared to established systems: Heidelberg Spectralis, Topcon Triton, and Zeiss Cirrus. We assessed acquisition time and microvascular parameters in the superficial (SCP) and deep (DCP) capillary plexuses using the OCTA Vascular Analyser algorithm for standardized image analysis across devices on 30 eyes from 15 healthy participants. In the SCP, DREAM demonstrated a higher median vessel length (47 μm) and greater fractal dimension (mean: 1.999) than the other devices, indicating enhanced continuity and network complexity. In the DCP, DREAM showed a smaller foveal avascular zone (median: 0.339 mm2) compared to Spectralis (0.51 mm2), Triton (0.5935 mm2), and Cirrus (0.9145 mm2), along with a smaller vessel diameter (median: 23 μm) compared to Triton and Cirrus. With a median imaging time of 9.1 s, DREAM was significantly faster than the Spectralis system (23.3 s) while providing largely comparable image quality, enhancing patient comfort, and potentially minimizing motion artifacts. These findings suggest that DREAM OCT is a promising tool for deep retinal imaging, with strong potential for clinical application and research.
AbstractBenign prostatic hyperplasia (BPH) is a prevalent progressive age-related disorder in men, yet its etiopathophysiology remains poorly understood. Current treatments like finasteride (Fin) have limited long-term efficacy, necessitating alternative therapies. Hydroxychloroquine (HCQ), a safe antimalarial agent, possesses anti-inflammatory, immunomodulatory, and antiproliferative activities, however, its therapeutic effect in BPH has not been investigated. Accordingly, we examined its therapeutic potential and underlying mechanisms, alone or combined with Fin, in testosterone-induced BPH in rats. In BPH-induced rats, HCQ markedly reduced prostate weight and index, and PSA, testosterone, dihydrotestosterone, pro-inflammatory cytokines (TNF-α, κ and IL-6), and the transcription factor “NF-κB” levels, while improving histological abnormalities in epithelial and stromal tissues. HCQ reduced the mRNA expression of AR and ERK1/2, and decreased the protein levels of EGFR and STAT3. Additionally, HCQ increased the mRNA expression of FOXO1 and promoted apoptosis through both intrinsic and TRAIL-mediated pathways. This was evidenced by the upregulation of pro-apoptotic Bax and the downregulation of anti-apoptotic Bcl-2 and Bcl-XL levels in the intrinsic pathway, as well as the reduction in mRNA expression of DR4 and DR5 in the TRAIL-mediated pathway. Notably, combining HCQ with Fin enhanced these effects. Molecular docking revealed HCQ’s strong interactions with androgen receptor (AR), EGFR, ERK1/2, FOXO, and TRAIL death receptors (DR4/DR5), comparable to Fin except for STAT3. Our findings suggest that HCQ modulates BPH progression by targeting STAT3/FOXO1/TRAIL and EGFR/ERK/AR pathways, offering a promising therapeutic strategy for BPH, either alone or in combination with Fin.
AbstractThe aim of this study was monitoring health status of mastitic Barki ewes using candidate gene approach, gene expression and serum profile of inflammatory and antioxidant markers. A total of 70 ewes were allocated into two equal-sized groups: healthy and ewes have a history of mastitis. DNA sequencing ofIFN-γ(365-bp),IL-4(285-bp),TNF-α(273-bp),MYD88(660-bp),CCL5(360-bp),TLR4(256-bp),TLR9(414-bp),LTF(299-bp),PRLR(891-bp),CAT(300-bp),GPX1(221-bp),Keap1(360-bp),OXSR1(357-bp),ATOX1(433-bp),GST(480-bp) andNrf2(340-bp) revealed single nucleotide polymorphisms (SNPs) between healthy and mastitic ewes. Levels ofIFN-γ,IL-4,TNF-α,MYD88,CCL5,TLR4,TLR9,LTF,PRLR,Keap1andOXSR1genes expression were significantly up-regulated in ewes affected with mastitis than resistant ones. MeanwhileCAT,GPX1,ATOX1,GST, andNrf2genes elicited an opposite trend. There is a significant elevation of activity of AST, LDH, Hp, CP, SAA, IgG, MDA, and NO levels (P< 0.05), along with reduction of total protein, albumin, GSH, GPx, catalase and SOD (P< 0.05) in mastitic ewes. The findings of this study supported the hypothesis that SNPs in immune and antioxidant genes could be important genetic markers for mastitis susceptibility or resistance in Barki ewes. The examined genes’ gene expression profiles may also be utilized as surrogate biomarkers to establish an efficient management regimen and forecast the period of time at which a disease is most likely to manifest.
AbstractUltrasound shear wave elastography (SWE) is broadly used to quantify muscle stiffness. Currently, most stiffness measures are retrieved from manually placed small measurement zones, which is an operator-dependent and laborious procedure of questionable reliability. Automated time-series measurements over the full visible muscle are expected to improve measurement validity, robustness, and efficiency in larger studies. This study aimed to develop and validate a semi-automated algorithm for analyzing SWE clips of muscle tissue using the single-image, manufacturer-provided manual measurements in every image of the corresponding clips as reference. SWE clips of the relaxed and activated upper trapezius muscle of 52 healthy participants were analyzed manually and with the algorithm for the muscle’s Young’s modulus (kPa) and shear wave velocity (SWV). Results demonstrated excellent correlation between manual and algorithm measurements, Spearman’sρ> 0.99,p< 0.001. Bland–Altman analyses indicated good method agreement with proportional biases of + 0.747 kPa and − 0.068 m/s for Young’s modulus and SWV, respectively, and widths of the limits of agreement of 8.653 kPa and 0.500 m/s, respectively. The proportional bias is within the minimal detectable change and therefore clinically negligible. These results support the algorithm as a tool enabling valid SWE time-series measurements in muscle tissue and an improved workflow.
AbstractBalance control requires the continuous integration of feedback signals from several sensory organs with feedforward estimates about the state of the body. Such feedback signals are important for standing upright, as shown in increased and more variable sway patterns when sensory feedback is compromised, for instance when standing with eyes closed or on unstable surfaces that make cutaneous signals from the foot less reliable. Poorer sensory processing is also considered to arise during healthy aging due to a decrease of the reliability and transmission rate of feedback signals. Here, we are interested in how processing of tactile signals from the lower leg is modulated when balance control is challenged and how this interacts with age-related sensorimotor changes. We examined tactile sensitivity on the lower leg during sitting, standing on stable ground, and standing on unstable ground (foam). We quantified the center of pressure during the two standing conditions by determining the area of a 95% confidence interval ellipse as well as the total displacement of the center of pressure. Tactile sensitivity was assessed by asking participants to detect brief vibrotactile probes of various intensities to the lower leg. As expected, postural sway increased when standing on foam than stable ground for both age groups. When postural demands were minimal (sitting), tactile sensitivity was overall poorer in older than younger adults. Tactile perception was also poorer when standing on foam than on the stable ground, for both age groups. We conclude that increased postural demands reduce reliance on tactile signals from the lower limb in both young and older adults.
AbstractRecent research has shown that cognitive reserve is associated with better cognitive abilities in ALS/MND, and that a slow brain ageing speed is associated with intact cognition in ALS. This study compares the effects of cognitive reserve and the predicted brain age difference (PAD) on the risk of being diagnosed with ALS, the risk of having cognitive or behavioral impairment, or even fronto-temporal dementia, and on disease duration.Our results indicated that neither PAD nor cognitive reserve was associated with an increased risk of ALS, but that higher PAD was associated with an increased risk of cognitive impairments and FTD, as well as a shortened disease duration. Higher cognitive reserve on the other hand was associated with a lower risk of cognitive impairment and a longer disease duration.Brain age as a proxy of brain reserve influences disease progression and presentation more strongly than cognitive reserve.
AbstractMagnetomyography (MMG) can be used as a contactless modality to study the neuromuscular system. On the one hand, being contactless is a practical advantage as there is no need to prepare skin or attach electrodes as in electromyography (EMG). On the other hand, it is also a disadvantage because the magnetic field decays with increasing distance. However, the effect of sensor-to-source distance in MMG has not been systematically studied. Comparative in vivo and in silico experiments of the effect of sensor-to-source distance were performed. In vivo, muscle activity was recorded using simultaneous surface EMG and one triaxial optically pumped magnetometer (OPM). For the simulations, an established multiscale muscle model was used to predict how distance affects the signal-to-noise ratio (SNR) and the signal’s spectral content. Given an environmental noise level of 0.5–1 pT root-mean-square (RMS) from 10 to 350 Hz, it was impossible to robustly detect muscle activity of one finger flexor muscle beyond a distance of two centimeters using OPM technology. In silico experiments showed a high SNR between 8 and 29 for MMG at 0.5 cm distance. Increasing the distance increases the MMG’s median frequency content. The simulations uncovered that this is due to the effect of noise. For distances greater than two centimeters, measuring MMG of voluntary contractions in medium-sized muscles with current OPM technology and conventional magnetic shielding cannot be recommended.
AbstractGlobal warming affects the Earth system in complex ways, often preventing a functional understanding of the underlying processes. Disentangling these processes between abiotic drivers and single species or entire communities is, however, essential for an in-depth understanding of the impacts of climate change on the ecosystem. Using a high-resolution time series on heat waves and cold spells in an Arctic fjord system, we demonstrate that AI-supported digital data processing, which is based on state-of-the-art observatory technology, has the potential to provide new insights into the effects of abiotic factors on biotic communities, which would not be possible with traditional expedition-based sampling methods. Furthermore, our study shows that short-term, event-driven anomalies in key ocean variables not only alter a system’s hydrography but also have the potential to impact the entire community across the trophic chain from benthos and zooplankton to fish. We found a significant positive correlation between hydrographic temperature anomalies and biota abundance, with high biota abundances linked to ‘Atlantic’ phases with frequent heat waves and low biota abundances correlated with ‘Arctic’ phases dominated by cold spells. The study also revealed that hydrographic anomalies can not only influence overall biota abundance in an area but also trigger complex shifts in species composition. This leads to fluctuating interannual abundance peaks in specific biotic groups, such as jellyfish, fish, or chaetognaths, depending on trigger factors that are not yet fully understood.
AbstractEye tracking is a widely used tool to study infant development, but creating diverse stimuli while maintaining high control over confounding variables can be challenging. In this proof-of-concept study, we examined an innovative way to generate ecologically valid stimuli using AI technology, in order to create videos that can be used in culturally diverse settings. Using the eye-mouth-index (EMI), a commonly used paradigm in infant eye tracking, we examined the consistency of eye tracking measures across original videos and two types of AI-manipulated videos in a sample of 46 infants aged 12–14 months. We found a very strong correlation of the EMI across original and AI videos (r= 0.873–0.874), and there were no statistically significant differences between mean EMI in the original and AI conditions. Additionally, we created culturally diverse videos to measure gaze following, and found that children followed the gaze of the people in the AI-manipulated videos in an expected manner. In conclusion, AI technology provides promising tools to create ecologically valid and culturally diverse stimuli, that can be used to conduct studies in a wide range of settings and to examine the generalizability of earlier findings in the field of developmental psychology.
AbstractThis study presents a novel hardware and software architecture combining capacitive sensors, quantum-inspired algorithms, and deep learning applied to the detection of Essential Tremor. At the core of this architecture are graphene-printed capacitive sensors, which provide a cost-effective and efficient solution for tremor data acquisition. These sensors, known for their flexibility and precision, are specifically calibrated to monitor tremor movements across various fingers. A distinctive feature of this study is the incorporation of quantum-inspired computational filters—namely,QuantvolutionandQuantClass—into the deep learning framework. This integration offers improved processing capabilities, facilitating a more nuanced analysis of tremor patterns. Initial findings indicate greater stability in loss variability; however, further research is necessary to confirm these effects across broader datasets and clinical environments. The approach highlights a promising application of quantum-inspired methods within healthcare diagnostics.
AbstractCirculating cell-free (cf) DNA in blood plasma is considered a diagnostic and prognostic biomarker of tissue damage and could be a driver of chronic inflammation by stimulating the innate immune response via activation of inflammasomes. Increased AIM2-inflammasome activity in the aortic wall is associated with abdominal aortic aneurysm (AAA). We here hypothesized that cfDNAs are elevated in the plasma of AAA patients and are associated with chronic inflammation. Single strand (ss)DNA, double strand (ds)DNA and mitochondrial (mt)DNA levels were explored in plasma and leucocytes from 93 AAA patients, 89 controls (non-AAA patients) and 10 healthy subjects, using fluorescence-based quantification and real-time qPCR, respectively. To analyse inflammasome activation by cfDNA, differentiated THP-1 macrophages were primed with lipopolysaccharide (LPS) and then stimulated for one, six or 24 h with DNA extracted from peripheral blood mononuclear cells (PBMC) of AAA patients. Our analysis revealed significantly increased levels of ssDNA, dsDNA and mtDNA levels in plasma from AAA patients compared with non-AAA patients and healthy subjects. In addition, the mtDNA copy number was significantly higher in PBMC from AAA patients. Stimulation of THP-1 cells with PBMC-DNA resulted in increased expression of inflammasome genes, especially the DNA sensorsAIM2andIFI16. At early time points, PBMC-DNA stimulated THP-1 showed significantly increased apoptosis-associated speck-like protein with a CARD (ASC) and Pro-Interleukin-1β protein levels compared to untreated or only LPS-primed cells, resulting in the formation of significantly more ASC specks after 24 h, a sign of inflammasome activation. We conclude from our data that cfDNA of AAA patients triggers a proinflammatory response in macrophages by activating the AIM2 inflammasome and thus could be a driving force for the chronic inflammation observed in these patients.
AbstractEven though non-invasive prediction of endometriosis may seem technically feasible using sophisticated machine learning algorithms, a standard clinical use case for non-surgical diagnosis of endometriosis has not yet been established. In the present paper, we assess the potential of the inflammatory serum markers hepcidin, soluble urokinase-type plasminogen activator receptor (suPar), and interleukin-6 (IL-6) in a cohort of 87 patients. Hereby, 59 patients were histologically diagnosed with endometriosis, whereas other 28 patients served as our non-endometriosis control group. An initial exploratory univariate statistical analysis (Mann-Whitney test) revealed the diagnostic potential of different serum levels of suPar (p= 0.024) and IL-6 (p< 0.001) between both groups; the formation of a distinct training data set (n= 77) subsequently allowed to train a supervised machine learning analysis (tree classifier) employing serum levels of suPar, hepcidin, and IL-6 as predictor variables. Based on an internal 5-fold cross validation, the classifier performance was initially assessed using standard metrics such as sensitivity, positive predictive value, and AUROC curve. Additionally, the algorithm was tested on an external validation (holdout) data set (n= 10), showing sufficient overall accuracy of 80% without tendencies of overfitting. In conclusion, our data demonstrates the diagnostic potential of IL-6 and suPar as pro-inflammatory serum biomarkers in endometriosis. Using a decision tree-based supervised learning approach, we additionally present a straight-forward way of a potential clinical employment, aiming at less invasive (non-surgical) diagnosis.
AbstractIn this study, polypyrrole/carbon black (PPy/C) filler with different amounts (5, 10, 15, and 20 wt%) was immobilized in a polymer blend consisting of chitosan/polyethylene glycol (CS/PEG) to produce conductive and dye adsorbent films. The study employed various distinctive techniques, including X-ray diffraction, Fourier transform infrared, and high-resolution scanning electron microscope, indicating that composites have high complexity and good interaction. Through the implementation of the UV-Vis technique, it has been observed that the reflectance of composites experiences enhancement with an increase in PPy/C content. The discussion covers the optical constants, such as the composites’ refractive index and optical conductivity. Notably, the uniform dispersion of PPy/C has caused a significant rise in the electrical conductivity of the pristine blend from 1.182 × 10−8(Ω.cm)−1to 1.42 × 10−5(Ω.cm)−1when 15% PPy/C was added. This increased conductivity is attributable to correlated barrier-hopping mechanisms. The effects of increasing PPy/C quantity, contact time (0–260 min), initial MO dye concentration (20–120 mg/L), adsorbent film dosage (0.1, 0.25, 0.5, 0.75, and 1 g/L), and the initial pH (4–10) were examined. Incorporating PPy/C up to 10% improved the removal effectiveness of the composite film. The 10% PPy/C film exhibited the maximum removal effectiveness relative to other films. Langmuir showed better conventionality than the Freundlich isotherm model with R2of 0.999. The maximal adsorption capacity observed in monolayer adsorption was determined to be 217 mg/g. The adsorption of MO by the 10% PPy/C film is a chemisorption process, according to the parameters of the kinetic studies. (CS/PEG)- (PPy/C) films could be assigned to the synergistic dye adsorption effect of PPy/C filler and CS/PEG polymer-making material, ensuring excellent adsorption efficiency. Because of these appealing characteristics, PPy/C has the potential to be an environmentally friendly adsorbent in the treatment of dye wastewater.
AbstractHeavy metals in wastewater represent a main source of environmental contamination for the ecosystem and aquatic system. Herein, the in situ polymerization method was used to prepare a novel nanocomposite polyaniline/muscovite (PANI/Msc) using ammonium persulphate as an oxidizing agent and HCl as a catalyst. The combination of muscovite with polyaniline (PANI) creates a hybrid material that leverages the strengths of both components. PANI/Msc nanocomposite was characterized using XRD, TEM, FT-IR, SEM, and surface area analyzer. Crystalline size of the prepared nanocomposite found in the range 15.6 – 45 nm , while its surface area was 208.6 m2/g. The resulting nanocomposite was used for Cd2+and Pb2+adsorption from their solution. Up to 75.6 and 72.6% of Cd2+and Pb2+, respectively, were removed in the optimized conditions of metal concentration 75 ppm, pH 6 and 7 for Pb2+and Cd2+, adsorbent dose 0.1 g, 25 °C solution temperature, and 60 min contact time. Kinetic and adsorption studies clearly demonstrated that the results of the adsorption process followed the pseudo-second order (qe32.8 and 33.1 mg g−1) and Langmuir models (Q036.1 and 61 mg g−1) for Cd2+and Pb2+, respectively. The thermodynamic indicated favorable, spontaneous and exothermic process. Electrostatic interaction and ion exchange mechanisms were responsible for the adsorption of Cd2+and Pb2+by PANI/Msc as demonstrated by FTIR spectroscopy and pH studies. This study ended with the cost- effective preparation of PANI/Msc nanocomposite that offers a promising solution for the removal of heavy metals from contaminated water source. In addition, the capability study regarding Pb2+and Cd2+ion adsorption over the PANI/Msc nanocomposite clearly revealed that our method is suitable for large- scale application.
AbstractAlternate bearing (AB) is a major challenge for citrus orchards. Increasing yield in one season (On year) leads to more seeds (fruits) as a supplier of gibberellins, which delay harvesting with low fruit quality and also decreases flowering and fruiting in the next season (Off year). So, the aim of this study is improving Balady mandarin fruit quality as well as accelerating fruit harvesting during the On year via foliar nourishments with potassium citrate (KC) or nitrate (KN) at 0.5% incorporated with either methionine (M) at 0.2% or sulphur (S) at 0.3%, twice two months before harvest (at flower bud induction time). The results indicated that, during On year, all treatments accelerate harvesting date, improve fruit weight, yield, fruit quality with a highly significant effect for KC + M treatment compared to the control. Moreover, this treatment increased fruit yield by 20.72% and 33.74%, for the first and the second On years, respectively. The most promising effect for KC + M is decreasing gibberellins levels during December (flower bud induction) in On year by 7& 19.4% and during January (before flowering) in Off year by 19.4% and 17.44%. Moreover, it increased both salicylic acid and auxin in the following Off year (before flowering) by 17.44%, 42.9 and 40%, respectively. This findings led to increase fruit number by 272.64% and 267.94%, and fruit yield by 251.3% and 289.65% for the following two off-year as well as decreasing AB by 61.7% and 61.67%. This study highlights the efficiency role of KC as a key for improving fruit quality during On year where heavy fruit load, as well as M application for overcoming AB as anti-gibberellins agent via accelerating harvesting in On year and enhances flowering in the following Off year via hormonal control.
AbstractThe reservoir compartment is a major uncertainty at South Abu El Naga gas field, onshore Nile Delta, Egypt. The objective of this study is to detect Abu Madi gas sand reservoir using different pre-stack inversion techniques such as AVO reflectivity attributes, impedance methods, and lambda-mu-rho (LMR) analysis. The Messinian sandstone gas reservoir at the study area was effectively characterized using these three techniques. Well logs, 2D partial angle stack, and full angle stack seismic sections are the available dataset used to derive several seismic pre-stack inversion attributes. The results of these attributes show that the gas sand bodies are clearly separated from shale and detect the gas channel lateral edges from the cutting mud filled channel. These findings determine the utility of integrating AVO reflectivity attributes and impedance methods in enhancing geophysical interpretation, reducing uncertainty, aiding exploration and support more accurate compartment delineation in data-limited settings and provide a convenient workflow applicable to other areas facing similar exploration and challenges.
AbstractMetal–organic frameworks (MOFs) have recently garnered attention as promising candidates for the effective removal of sulfur-containing compounds from liquid fuels. In this study, the potential of employing Al-MIL-53 as an adsorbent for liquid fuel desulfurization is demonstrated. Material analysis through SEM, XRD, and FTIR studies was conducted. Equilibrium between in the solution and on the adsorbent surface was successfully achieved within 1 h. Optimal operational parameters for 99% Sulfur removal were identified as a 60-min adsorption time, 50 ppm initial thiophene concentration, and 2 g adsorbent dosage. The equilibrium adsorption data is adequately represented by Freundlich isotherm (R2= 0.97). The adsorption kinetics of DBT by Al-MOF followed pseudo first-order model (R2= 0.99). The equilibrium (qm) of the prepared Al-MOF = 11 (mg/g).
AbstractThis paper aims to evaluate the bond performance of basalt FRP bars under severe conditions such as salts, alkaline, and water. Specimens were tested under direct pull-out tensile load. The specimens were exposed to aggressive solutions at an elevated temperature of 60 °C to accelerate the degradation process. The parameters were the concrete compressive strength (CCS) (25, 45, and 60 MPa), the exposure condition (water, salts, and alkaline), and the exposure duration (30, 60, and 90 days). Seventy-two specimens were investigated in terms of bond strength, failure mechanism, and stress-slippage response. The most detrimental environment was the alkaline environment, while the salt environment had an insignificant effect on the bond strength. After 90 days of conditioning in the alkaline solution, the normalized bond strength had reduced by 17.29%, 12.74%, and 8.72% for specimens of concrete compressive strength (CCS) of 25 MPa, 45 MPa, and 60 MPa, respectively.
AbstractThe textile industry exposes people to various harmful and allergenic compounds, with dye wastewater being a significant source of persistent organic pollutants (chemical substances accumulate in living organisms and pose risks to human health and ecosystems) in the environment. This study aimed to measure the activity concentrations of radionuclides, specifically238U,226Ra,232Th, and40K, in different types of textile dyes (disperse, direct, and reactive) and dye wastewater from the cities of Abour and Badr, using gamma spectrometry with a Hyper Pure Germanium detector. Additionally, heavy metal concentrations (Zn, Cd, Fe, Pb, Co, and K) were analyzed through Atomic Absorption Spectroscopy. The results indicated that the average specific activities of238U,226Ra,232Th, and40K were higher in disperse dyes compared to direct and reactive dyes. Potential radiation hazards were evaluated, revealing detectable levels of radioactivity in some textile dyes. This underscores the need for safety protocols and preventive measures for workers in the textile industry and those handling these dyes.
AbstractStability indicating RP-HPLC method was developed and validated for the estimation of finerenone (FIN) in pure and in new tablet dosage form. The proposed approach was applied and validated for determination of (FIN) related substances. Stability studies of (FIN) was carried out using five stress conditions; acid, alkali, oxidation, photodegradation and heat degradation. The chromatographic analysis of (FIN) was based on using mobile phase consist of filtered and degassed mixture of 450mL water, 550mL acetonitrile and 10mL triethylamine with pH adjusted to 7. Phenomenex (C18, 4.6 × 250 mm, 5 μm) column was used with 0.8 mL/min flow rate and 40 °C column temperature. The UV detection was set at 252 nm with injection volume (10µL). The (FIN) retention time was 4.437 ± 0.05 min. The proposed technique was validated according to ICH guidelines with good linearity in ranges (8–30 µg/mL) for assay of (FIN) and (0.2–1.4 µg/mL) for determination of (FIN) unspecified impurities. The found mean percentage recoveries were 99.74% for (FIN) assay and 99.11% for (FIN) related substance determination which indicate good trueness. The developed approach was successfully applied for the determination of (FIN) in Nexifinerenone®film coated tablet dosage form. Good agreement was established when assay results using the validated RP-HPLC method were compared statistically to those obtained using the reported method. For the greenness assessment Complex GAPI, Complex MoGAPI and AGREE methods were applied.
AbstractHigh-power, short-duration (HP-SD) ablation is a well-established radiofrequency (RF) ablation protocol in cardiac electrophysiology. Recently, very high-power, short-duration (vHP-SD) ablation has emerged as an alternative. This study compares lesion metrics between vHP-SD and HP-SD ablation protocols using the latest irrigated RF catheter with temperature-based power regulation, considering the impact of contact force (CF). RF ablations were performed in a porcine ex vivo model using myocardial preparations in a circulating saline bath. Three protocols were applied: vHP-SD (90 W for 4s), HP-SD-4 (50 W for 4s) and HP-SD-15 (50 W for 15s). A total of 360 lesions in 12 hearts were analyzed (vHP-SD: 120; HP-SD-4: 120, HP-SD-15: 120). The HP-SD-4 protocol produced the lowest mean lesion depth (2.42 ± 0.61 mm vs. 3.16 ± 0.41 mm vs. 4.49 ± 0.66 mm,p< 0.001), mean maximum lesion diameter (6.02 ± 1.00 mm vs. 7.34 ± 0.92 mm vs. 9.13 ± 1.59 mm), and mean lesion volume (52.0 ± 22.5 mm³ vs. 96.4 ± 28.8 mm³ vs. 211.4 ± 95.3 mm³,p< 0.001), followed by the vHP-SD protocol. In contrast, the HP-SD-15 protocol resulted in the highest values across all three parameters. Lesion depth, maximum lesion diameter, and lesion volume increased significantly with higher contact force (p< 0.001,p= 0.002, andp= 0.003, respectively). However, the absolute changes in these lesion dimensions were relatively small compared to those observed with power-controlled RF catheters, likely due to the effect of temperature-based power regulation.
AbstractAnimal research show that a novel exploration task performed shortly before a learning episode can strengthen hippocampal memory consolidation through behavioural tagging mechanisms. The aim of the present study was to conceptually translate behavioural tagging results to humans using a novel exploration task in virtual reality. Mimicking conditions for animal research, sixty participants underwent a context conditioning task in virtual reality to create a hippocampal-dependent fear memory. Twenty-four hours later, half of the participants performed a novel exploration task in virtual reality shortly before extinction learning the next day, and the other half performed a visual control task. Twenty-four hours after extinction learning, remaining fear responses were evaluated by a reinstatement procedure. Results showed that participants acquired context conditioning, but no effect of the novel exploration procedure on fear responses during reinstatement could be noted. Thus, the study did not conceptually translate the rodent results to humans; possible reasons for this, as well as future directions, are discussed.
AbstractThe complexity and diversity of bioscientific research laboratories, creates significant challenges for automation. Their varying workflows, personnel, and instruments, often hinder smaller research laboratories to benefit from automated processes, as existing systems seem unsuitable due to low flexibility. Therefore, we developed a versatile robotic system designed to automate a broad range of bioscience laboratory processes. Central to our system and novel, compared to all other kinds of laboratory automation concepts, is a multifunctional end effector, inspired by the Swiss-army-knife, capable of executing multiple tasks, including an operating finger, a camera system, a gripper, and a pipette. This end effector is mounted on a 6-axis robotic arm, supported by a mobile base, enabling easy transport across different bioanalytical laboratory environments. Utilizing windows manipulating scripting routines, allows the automation of diverse software programs including software-based laboratory devices. We demonstrate the capabilities of the Laboratory Automation Robotic System (LARS) by automating the pH buffer adjustments, showcasing its potential to improve efficiency and reproducibility in bioscience research. The resulting prototype allows the integration of any laboratory instrument into a desired automation routine without limitations concerning device interfaces, while using a highly flexible multifunctional end-effector as a replacement of the human hand and eye.
AbstractReinforced Concrete (RC) slabs are widely used in structural applications due to their ability to withstand heavy loads. However, under impact loading conditions such as falling objects or debris, their brittle nature makes them prone to cracking and damage. To address this, Expanded Polystyrene (EPS) has been explored as an energy-absorbing material capable of reducing the severity of impact forces. Traditionally used as an insulating material, EPS possesses favorable mechanical properties—lightweight, high deformability, and cushioning capacity—that have led to its application in civil infrastructure as geofoam and lightweight fill. Despite its growing use, the potential of EPS as a protective surface layer for RC slabs under impact loading remains underexplored. This study investigates the effectiveness of a surface-mounted EPS layer in reducing the impact response of RC slabs. Six full-scale RC slab specimens were tested under vertical impact from a 90 kg steel ball dropped from a height of 1 m. Half of the specimens were cast as control slabs, while the other half included a 5 cm thick EPS layer atop the concrete. Accelerometers were used to capture dynamic responses, and a detailed finite element model was developed in ABAQUS, incorporating experimentally measured material properties and contact interaction at the EPS–concrete interface. The model accounted for separation and frictional behavior between the two materials. Experimental and numerical results showed that the EPS layer significantly reduced the maximum acceleration, displacement, and energy dissipation within the concrete slab compared to the control specimens. While control slabs absorbed more energy through cracking and damage, the EPS slabs exhibited reduced structural deterioration, indicating more efficient impact mitigation. These findings highlight the potential of EPS as a cost-effective solution to enhance the impact resistance of RC slabs. Future work will focus on parametric studies involving EPS thickness, EPS density, steel reinforcement ratio, intensity of impact load and concrete material properties to generalize the results for broader applications.
AbstractScarring and its long-term sequelae, contribute significantly to morbidity following burn injuries. Factors associated with less favourable scar outcomes include the depth of burn, younger age, pigmented skin types and prolonged healing times. The aim of primary burn surgery is to debride non-viable tissue, to enable healing. However, international consensus regarding the optimal timing for debridement and grafting in pediatric patients with burns is lacking. Delayed wound healing is thought to increase the risk of poor scar quality, however, the evidence for this is weak with few studies investigating long-term outcomes in pediatric patients. The aim of this study, therefore, was to investigate the effect of patient and treatment factors on scar quality, one year after skin grafting in pediatric patients with burns. Patient factors included age, skin type, and site of burn, while treatment factors included timing of surgery, type of surgery, and healing times. Pediatric patients (age < 18 years) presenting to a National Burn Unit from 2011 until 2020, inclusive were considered for inclusion in the study. Burn injuries between 1% and 14.9% total body surface area (TBSA) and who required skin grafting for the primary treatment of their burn, were included. Patients who failed to attend their 12-month follow-up visit were excluded. Standardised clinical photographs were assessed using a modified version of the Patient and Observer Scar Assessment Scale, version 2.0 (POSAS). Thirty children (median age 3.9 years) were included. Factors with an independent effect on higher (worse) POSAS scores were younger age at the time of injury (p< 0.001), body site of the trunk (p< 0.002), or the lower extremity (p< 0.001) and a longer duration of healing time after skin grafting (p= 0.003). The duration of time between injury and surgery was not an independent factor for POSAS scores (p= 0.56). We had insufficient numbers to discriminate differences in scar quality for different graft types; meshed versus non-meshed. In this study, we found that long-term scar outcomes in pediatric burn patients after skin grafting were worse for those injured at a younger age, with burns on the trunk or lower extremity, or with prolonged healing time after grafting. The robustness of this conclusion is limited by the small sample size of the study cohort and by our use of photographic scar assessment .
AbstractComputed Tomography (CT)-derived body composition parameters of cardiac adipose tissue (CAT), as well as abdominal adipose and muscle tissue are surrogates for the patient’s clinical condition and have prognostic implications. However, associations between the compositions of these diverse tissue compartments remain poorly investigated. This study aimed to investigate the associations between CT-derived parameters of CAT and abdominal adipose and muscle tissues. Retrospective analysis of CT scans from 842 patients was conducted, with measurements of CAT taken at the aortic valve level and abdominal tissues assessed at the L3/L4 intervertebral disc space. Area and density were calculated for each tissue compartment using single-slice images. Strong positive correlations were found between CAT area and visceral adipose tissue (VAT) area (R= .755,P< .001), as well as moderate correlations between CAT density and VAT density (R= .521,P< .001). Additionally, skeletal muscle (SM) area exhibited modest positive correlations with VAT area (R= .370,P< .001), CAT area (R= .300,P< .001), and SM density (R= .356,P< .001). No significant differences were observed between genders in the correlation strengths of these associations. These findings indicate a systematic pattern of body composition alterations, advocating for the inclusion of comprehensive body composition analysis in future studies and emphasizing the need for a deeper understanding of the underlying systemic processes influencing body composition.
AbstractDental implant-associated infections increase the risk of implant failure, presenting significant challenges in modern dentistry. The host-microbe interaction plays a crucial role in the development of implant-associated infections. To gain a deeper understanding of the underlying mechanisms, numerous studies have been conducted using in vitro co-culture models of bacteria and human cells or in situ samples. Due to the complexity of the images generated throughout these studies, however, the analysis by means of classical image processing techniques is challenging. This study proposes a workflow—based on two custom Cellpose models—that, for the first time, allows the analysis of microbial surface coverage in microscopy images of fluorescent-stained and co-localized microorganisms and human cells with substantial background signals. The first Cellpose model demonstrated its efficacy in the analysis of individual bacteria within images derived from an 3D implant-tissue-oral biofilm in vitro co-culture model. In combination with the second custom model, which was trained to recognize microcolonies, images obtained from an in situ study could also be automatically segmented. The model’s segmentation accuracy could be further enhanced by acquiring additional training images and improving image quality, making the proposed workflow now valuable for a range of dental implant-related and other co-culture images.
AbstractDocetaxel resistance, particularly post-androgen-receptor targeted therapy (ART), undermines its clinical utility in metastatic castration-resistant prostate cancer (mCRPC). This study explores the impact of docetaxel plus carboplatin (DC) chemotherapy on serum testosterone levels in metastatic docetaxel-resistant prostate cancer (mDRPC) patients. 123 mDRPC patients were categorized into three groups: (1) no previous ART (n= 65), (2) previous ART with serum free testosterone (FT) > detection limit (DL) at baseline (n= 31), and (3) previous ART with FT < DL at baseline (n= 27). Salvage DC chemotherapy led to significant reductions in FT and total testosterone (TT) levels in groups 1 and 2 (p< 0.05). Group 1 saw FT decrease from 0.85 pg/mL to below the DL (< 0.18 pg/mL) with 54.3% achieving complete reduction (CR); group 2 showed FT decrease from 0.28 pg/mL to below the DL with 67.7% achieving CR; group 3 had baseline FT values already below the DL with 96.3% maintaining this level. TT reductions to below the DL occurred in all groups. Low FT was an independent predictor for better PFS and for improved OS in groups 1 and 2. Our data indicate that adding carboplatin may improve the therapeutic effects of docetaxel in a castration-dependent setting.
AbstractThe pulsed nature of laser-driven ion sources and their relative large emission angles result in the production of secondary, undesired, pulsed neutron (and photon) radiation. Conventional neutron monitors struggle to accurately measure in such environments, yet characterizing these fields is crucial for applications like hadron therapy. Parasitic neutron dose measurements were performed at the Petawatt beam of the Dresden Laser Acceleration Source (DRACO) employing laser energies from 4.5 to 18 J. An active extended-range neutron REM counter specifically developed for pulsed neutron fields, the LUPIN-II, was employed, as well as a passive extended-range neutron REM counter, the Passive LINUS. Neutron doses were recorded on a single-bunch level with values up to about 260 nSv per proton bunch characterized by a proton cutoff energy of about 60 MeV at about 2 m from the DRACO vacuum chamber, confirming the expected pulsed nature of the neutron field. Results of passive measurements were compared to the LUPIN-II results, integrated over the same period, and showed a reasonable agreement, confirming the presence of pulsed neutron radiation in the proximity of the DRACO ion source. These results demonstrate for the first time that this kind of radiation can be monitored, in terms of H*(10) on a single-shot basis by using the LUPIN-II neutron REM counter.
AbstractCardiovascular magnetic resonance (CMR) evaluation of valvular heart disease is an important diagnostic tool when echocardiography is inconclusive. Phase contrast flow quantification is usually performed during breath hold (BH), which can be challenging in patients suffering from dyspnea and heart failure. The purpose of the present study is to compare a free-breathing (FB) with the conventional BH approach for flow quantification in the aortic, pulmonary and tricuspid valves in 20 healthy subjects (HS) and 25 patients with tricuspid regurgitation (TR). Aortic (AoFF) and pulmonary forward flow volume (PuFF), and tricuspid inflow volume (TrIF) were evaluated. Mean, standard deviation (SD) and limits of agreement (LoA) were calculated. There were good agreements between phase contrast flow volumes obtained by FB and BH approach. Mean difference ± SD / LoA for AoFF during BH versus FB were 1 ± 6 / -10 to 13 ml. The corresponding for PuFF were 1 ± 6 / -11 to 13 ml, and for TrIF − 3 ± 6 / -15 to 9 ml, respectively. Thus, free-breathing CMR flow acquisition can be an important alternative in the assessment of stroke volume, valvular regurgitant volume and be useful in all patients with difficulties to hold their breath.
AbstractLaboratory automation has transformed bioanalytical research, yet smaller research laboratories face challenges in adopting such technologies due to limited resources, time, and technical expertise, while already facing complex bioanalytical methods. To address these barriers, we developed a robotic-arm-based camera detection system featuring two software applications designed to simplify laboratory automation. Both applications use fiducial markers (Augmented Reality University of Cordoba (ArUco)), for object detection. The first application creates a 3D digital model of the robot’s environment using ArUco markers and a Python-based Open Computer Vision (OpenCV) simulated stereo vision setup, enabling automated computer-aided design (CAD) in FreeCAD. This facilitates safe and efficient robot arm navigation. The second application integrates a deep learning neural network for automated digital display recognition, achieving an in-house error rate of 1.69%, comparable to manual readings. By leveraging low-cost hardware and open-source software available on GitHub, the system is accessible to smaller research facilities, reducing programming complexity and enabling broader adoption of laboratory automation in bioanalytical workflows. This work demonstrates an affordable and effective solution for integrating robotic arms into scientific workflows, enhancing reproducibility and efficiency in bioanalytical research.
AbstractPotential properties of astaxanthin include immunomodulation, antioxidant, and anti-inflammatory effects. In diabetic rats, we examined the potential impacts and underlying mechanisms of astaxanthin on hippocampal DNA, cognition, and glycemic status. Rats were divided into five equal groups: non-diabetic, and diabetic (non-treated, metformin treated, astaxanthin treated, and treated with a combination of metformin and astaxanthin). Both spatial and non-spatial memory and learning were assessed. IL-6, malondialdehyde, total antioxidant capacity, lipid profile, and glycemic status were assessed. Phosphorylated tau expression level was measured, and H&E section analysis was used to evaluate the hippocampal tissue. DNA fragmentation, intact DNA, and hippocampal RNA were evaluated. Induction of diabetes led to a reduction in cognitive abilities along with significant hyperglycemia, dyslipidemia, oxidative stress, hyperphosphorylation of tau, and DNA fragmentation. Astaxanthin as monotherapy or in combination with metformin improved cognitive functions with reduction of hyperglycemia, dyslipidemia, oxidative stress, hyperphosphorylation of tau, and DNA fragmentation.
AbstractBiogeochemical soil processes are closely linked to the structure of soil. In particular, nutrient transport depends on diffusivity and permeability within the soil’s pore network. A deeper understanding of the relationship between microscopic soil structure and such effective macroscopic properties can be obtained by tomographic imaging combined with a quantitative analysis of soil morphology and numerical simulations of effective macroscopic properties. In a previous work it has been shown that different parametric regression formulas can be used to predict these relations for finely sieved soils of loam and sand. In the present paper, we validate these formulas and further extend their applicability to structured soils. In particular, 3D CT data of a total of six samples, consisting of three loam and three sand samples, are used as the basis for an extensive structural analysis. As expected, the performance of most regression formulas can be improved by specifically adjusting their parameters for the considered soil structures. However, it turns out that some regression formulas based on, e.g., tortuosity which were fitted for finely sieved soils still reliably predict diffusion for structured soils without adjusting their parameters. For additional validation and improvement of the considered regression formulas, artificially generated soil structures can be utilized. Therefore, a method for the generation of such structures via samples drawn from a parametric stochastic 3D microstructure model is outlined which may serve as a basis for further work.
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AbstractMany pyridopyrimidine moieties linked to the coumarin ring were synthesized by the reaction of malononitrile with 7-hydroxy-4-methyl-2-oxo-2 H-chromene-8-carbaldehyde(2)directly in the presence of ammonium acetate and different ketones and studied the effect of other basic catalysis, ratio of reactants and the effect of the solvent. The newly synthesized compounds were evaluated for their cytotoxic activity against four cell lines namely HepG2, WI-38, VERO, and MCF-7. The cytotoxic activity showed that compounds8,9,10, and7have the highest activity against the studied cell lines. Focusing on the binding affinity and interactions between the five synthesized derivatives with the highest anticancer activity and specific amino acids of4HJOresidues over the molecular docking analysis. Derivative10recorded the highest energy score with good RMSD compared to the rest of the derivatives.
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AbstractThis study evaluated the functional relevance of relative ellipsoid zone reflectivity (rEZR) on spectral-domain optical coherence tomography as a structural biomarker for retinal integrity, focusing on its association with retinal function. Participants with age-related macular degeneration (AMD) and controls from the MACUSTAR study underwent functional testing, including mesopic fundus-controlled perimetry, best-corrected visual acuity, low-luminance visual acuity, low-luminance deficit, Moorfields Acuity Test, and Pelli-Robson contrast sensitivity, along with spectral-domain optical coherence tomography imaging. Structural and functional data were analyzed globally and spatially aligned for topographic analysis. Linear-mixed effects models, adjusted for age, sex, and eccentricity of the rEZR, assessed associations between rEZR and functional metrics. A total of 275 eyes (early AMD, n = 34; intermediate AMD, n = 152; late AMD, n = 36; controls, n = 53) from 275 participants (mean ± standard deviation age: 71.1 ± 7.2 years; 63.3% female) were included. In global analyses, rEZR was associated with the mean average threshold in mesopic fundus-controlled perimetry (coefficient estimate 0.0492, 95% confidence interval 0.0190–0.0794, p = 0.0015), low-luminance visual acuity (coefficient estimate − 0.0015, 95% confidence interval − 0.0026 to − 0.0004, p = 0.0092), Moorfields Acuity Test (coefficient estimate 0.0092, 95% confidence interval − 0.0022 to − 0.0001, p = 0.0285), and Pelli-Robson contrast sensitivity (coefficient estimate 0.0030, 95% confidence interval 0.0015–0.0045, p = 0.0001). Topographic analysis further revealed an association of rEZR with mesopic retinal sensitivity (coefficient estimate 0.0065, 95% confidence interval 0.0026–0.0104, p < 0.0001). Higher outer retinal reflectivity is linked to better retinal function in AMD and controls, supporting its potential as a biomarker for retinal integrity and function.
AbstractThe root knot nematodesMeloidogyne incognitaare the most serious threats affecting eggplant,Solanum melongenaL. Chemical nematicides are commonly used against plant-parasitic nematodes, but due to their negative impact on health and the environment, safe and environmentally friendly alternatives have become increasingly important. Biological control using rhizospheric bacteria metabolites, and plant substances have, emerged as important alternatives to the use of agrochemicals. Recently, nanotechnology has revolutionized nematode management and its effectiveness in biological control. The aim of this study is to evaluate the efficiency ofBacillus cereusNem 212 supernatant and garlic essential oil in their regular and nanoscale forms againstM. incognitainfecting eggplants CV. Baladi and investigate their impact on plant growth parameters under field conditions. All nano formulations produced higher nematicidal activities compared to their respective original extracts. Garlic oil nano emulsion and garlic oil emulsion were more effective as natural nematicides onM. incognita, and in enhancing eggplant growth parameters, followed by bio- silver nanoparticles synthesized byB. cereusNem 212 filtrate. These formulations are promising and environmentally friendly alternatives for controlling root knot nematode and have the potential to reduce reliance on hazardous agrochemicals. In addition, these techniques increase vegetative plant growth and yield production.
AbstractCocopeat is among the most frequently utilized substrates in soilless farming. Nonetheless, the extraction of Cocopeat generates a detrimental carbon footprint, highlighting the necessity for alternative, sustainable substrate options. To tackle this issue, we examined the effects of substituting Cocopeat with a blend of various Rice straw, Sawdust, and compost on cucumber growth and yield over two growing seasons, 2021–2022 and 2022–2023. The treatments included Cocopeat 100% (control), sawdust 100%, rice straw 100%, compost 100%, combinations of Cocopeat and sawdust (1:1, v/v), combinations of Cocopeat and sawdust (3:1, v/v), combinations of Cocopeat and rice straw (1:1, v/v), combinations of Cocopeat and rice straw (3:1, v/v), combinations of Cocopeat and compost (1:1, v/v), and combinations of Cocopeat and compost (3:1, v/v). The highest yield was recorded with rice straw at 100.55 ton ha− 1, followed by the Coco 50%: Compost 50% treatment yielding 74.32 ton ha-1 and 69.26 ton ha− 1, respectively, while the lowest yield was noted for sawdust at 22.23 ton ha− 1. Across both growth seasons, rice straw achieved the highest irrigation water productivity (IWP) of 51.56 and 51.91 kg m− 3, respectively, followed by Coco 50%: Rice straw 50% at 38.08 and 38.37 kg m− 3, whereas sawdust resulted in the lowest IWPs of 6.93 and 11.48 kg m− 3. In both growing seasons, the rice straw showed the greatest rate of photosynthesis, with readings of 23.34 µmol m–2s–1and 22.14 µmol m–2s–1, respectively. Conversely, the lowest photosynthesis rates during both growing seasons were observed with the Coco 75%: Compost 25% treatment, at 3.23 µmol m–2s–1and 3.03 µmol m–2s–1, respectively. The treated rice straw substrate media ranked as the most profitable and resilient option in terms of net present value (NPV) and benefit-cost (B/C) ratio metrics, followed closely by the compost treatment. It seems that treated rice straw-based media is a promising substrate in soilless culture systems as a viable alternative substrate for cucumber cultivation instead of Cocopeat substrate.
AbstractInhibition of Smoothened (SMO), a key protein in the Hedgehog signaling pathway, is effective for locally advanced basal cell carcinoma (BCC), but is not yet used for sebaceous carcinoma (SEB) or squamous cell carcinoma (SCC). This study quantified SMO expression and its relationship to proliferative activity in non-nodular periocular BCC, SEB and SCC. Tumor samples from 47 patients (17 BCC, 15 SCC, and 15 SEB) were immunostained and analyzed digitally to assess SMO optical density and Ki67 hot-spot index. SMO expression was significantly higher in all tumor types than in surrounding stroma, with no inter-tumor differences. SMO correlated with mitotic count in BCC but not in SCC or SEB, whereas higher SMO consistently paralleled a higher Ki67 index across all three carcinomas. These findings indicate that SMO expression and proliferative activity are closely linked and suggest that Hedgehog inhibitors, proven in BCC, warrant clinical evaluation as adjuvant or neoadjuvant therapy for periocular SEB and SCC.
AbstractThis research uses the third edition of the Gaia Data Release (DR3) to re-investigate the open star cluster NGC 2158. We employed the pyUPMASK Python package and HDBSCAN algorithms to identify the cluster member stars. The key focus of this investigation is our new method of evaluating membership probability based on the radius of each shell in the studied cluster, rather than applying a single probability value to the entire cluster. We calculated all astrophysical parameters of NGC 2158-including center, cluster radius, radial density distribution, color-magnitude diagram, distance, age, and reddening-using the photometric and astrometric data from Gaia DR3. The cluster’s relaxation time, total mass, luminosity, and mass functions are computed. The components of the proper motions ($$\mu$$$$_{\alpha }$$cos$$\delta$$,$$\mu$$$$_{\delta }$$), and the trigonometric parallax ($$\varpi$$) are found to be$$-$$0.196$$\pm$$0.03 ,$$-$$1.984$$\pm$$0.21 mas/yr and 0.21$$\pm$$0.044 mas, respectively. According to the King model and pyUPMASK membership, we obtained 3067$$\pm$$69.84 stars with a total mass of 3216.4$$\pm$$59.50$$M_{\odot }$$. Using the PARSEC stellar isochrones fit, the mean cluster age and its relaxation time are 1.95$$\pm$$0.28 Gyr and 89.0$$\pm$$12.54 Myr, respectively. The cluster distance modulus and reddening are estimated to be 12.86$$\pm$$0.080 , and 0.66$$\pm$$0.040 mag, resulting in a distance of 3.733$$\pm$$0.36 kpc. The mass function MF for the cluster under study has been constructed using a step function with two power lows,$$\alpha _1$$and$$\alpha _2$$, rather than the single power low suggested by Salpeter. In this cluster, the$$\alpha _1$$and$$\alpha _2$$are found to be$$-$$3.2$$\pm$$0.3 and 2.52$$\pm$$0.1 , respectively. The Gaia archive contains 17 stars flagged for variability, detecting 11 stars classified as eclipsing binaries. Additionally, we identified 62 member stars as blue stragglers. We utilized the galpy Python package to obtain the cluster’s kinematics and the Galactic orbital parameters using 126 stars which have radial velocities data in Gaia DR3 archive, with average value 26.1$$\pm$$2.3 km/s.
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AbstractHuman observers perceive natural and man-made environments differently, a distinction measurable through image statistics. However, limited evidence exists on how architectural style influences these statistics and, consequently, visual perception. Understanding this relationship is essential, as architectural design shapes both our visual and psychological experiences of built environments. The amplitude spectrum slope quantifies sharpness and detail in an image, with values closer to 1 typically found in photographs of natural scenes. Image entropy, reflecting unpredictability, also plays a role in visual attention—images with higher entropy are more likely to capture interest. In this study, we analyzed photographs of buildings designed by Antoni Gaudí, renowned for his nature-inspired architecture. Our findings reveal that Gaudí’s buildings display an amplitude spectrum slope more similar to that of natural scenes than contemporary structures from the same area, alongside higher image entropy. Effect size measures indicated that the observed differences in slope constant and entropy between images of Gaudí buildings and contemporary buildings were medium and large in magnitude. The presence of trees in front of contemporary buildings shifts their image statistics toward naturalistic values. These results suggest that incorporating naturalistic design elements into architecture can alter image statistics, potentially influencing perception and aesthetic experience. In contemporary architecture, where minimalist and geometric styles are prevalent, these insights highlight the potential benefits of reintroducing complexity and naturalistic aesthetics to create more engaging and psychologically restorative built environments.
AbstractCystic pancreatic lesions (CPL) pose a diagnostic challenge due to their morphological diversity and malignant potential. Given the limited study data, transabdominal ultrasound (TAUS) is currently not established for either primary diagnostics or CPL monitoring. This study compared the diagnostic accuracy of TAUS in the assessment of CPL to that of the reference method, endoscopic ultrasound (EUS), to identify patient subgroups suitable for TAUS monitoring. In a monocentric, retrospective analysis, patients with CPL who underwent EUS and TAUS within six months from 01/2016 to 06/2022 were included. Univariate and multiple logistic regression analyses were used to identify determinants for the detection of CPL via TAUS. Cross-method morphological assessments were analysed, and a patient-specific algorithm for selecting the appropriate monitoring method was developed. Among 105 patients, CPL were detected by both EUS and TAUS in 90 patients (86%). Patients with “TAUS negative” CPL (n= 15) exhibited greater body mass indices (BMI,p= 0.002) and smaller CPL diameters (p= 0.043). The final multivariate model (BMI, age, CPL diameter) yielded an 85% accuracy in predicting CPL detectability by TAUS. TAUS could be a cost-effective and patient-friendly imaging method for the surveillance of CPL in selected patients.
AbstractIn this work, an azo dye ligand of 2,6-dichloroaniline with nitroxoline (CPAQ), and its Zn(II), Cu(II), Cd(II), Ni(II) and Co(II) complexes have been synthesized. The structures of the synthesized compounds have been elucidated applying analytical and spectral tools. According to these results, all complexes proved to have a tetrahedral structure, except Ni(II) complex, which has an octahedral geometry. Analytical results also inferred the formation of Co(II) and Ni(II) complexes in the molar ratio 1M:1L and the remaining complexes in 1M:2L molar ratio. For further insight into the complexes’ geometry, bond lengths, bond angles, and electronic characteristics with respect to the organic ligand were assigned in addition to DFT calculations. HOMO and LOMO calculations show the Co(II) complex is more reactive. The interactions of the target compounds with theMus musculusADA enzyme structure (PDB ID: 1a4m) were estimated by applying molecular docking studies. The inhibitory effect of the synthesized compounds on adenosine deaminase enzyme (ADA) activity was tested in-vitro, showing the Co(II) to be the most active.
AbstractInduction motors (IMs) are vital in industrial applications. Although all motor faults can disrupt its operation significantly, stator turn to turn faults (ITFs) are the most challenging one due to their detection difficulties. This paper introduces an AI-based approach to detect ITFs and assess their severity. A simulation based on an accurate mathematical model of the IM under ITFs is employed to generate the training data. Recognizing that ITFs directly affect the motor’s current balance, complex current unbalance coefficient is identified and used as the key feature for detecting ITFs. Since unbalanced supply voltage (USV) can also disrupt current balance, the AI models are trained to account for USV by incorporating complex voltage unbalance coefficient that helps to distinguish between ITF-induced and voltage-induced imbalances. After feature extraction, the AI models are trained and validated with simulation data. The approach’s effectiveness is further tested using an experimental setup, where measurements from motors under various fault conditions, including USV scenarios, are considered. The results indicate that the gradient boosting model outperforms other ML models in detecting ITFs in IMs and assessing their severity. In the pursuit of achieving highest possible performance, DNN is tested and compared with ML models. The study reveals that DNN demonstrates superior performance in all tested scenarios including USV making DNN the top performer that to be used in the proposed approach. The proposed AI-based approach based on DNN offers high accuracy in fault detection and can effectively distinguish between ITFs and USV-induced anomalies, maintaining low estimation errors and robust performance across different operational conditions.
AbstractLinear repetitive construction projects present unique challenges in optimizing both completion time and cost performance. Traditional scheduling techniques often struggle to effectively address these complexities. This paper aims to enhance project optimization by introducing a metaheuristic-based Time-Cost Trade-off (TCT) framework specifically designed for repetitive project environments. Unlike previous studies that focus solely on single-algorithm applications, this research evaluates two metaheuristic optimization strategies—Genetic Algorithm (GA) and Particle Swarm Optimization (PSO)—within a consistent problem setting. The framework employs both algorithms, which are independently assessed for their effectiveness in tackling the Linear Repetitive Project Time-Cost Trade-off (LRPTCT) problem. The methodology utilizes task decomposition alongside the Line of Balance (LOB) scheduling technique, facilitating a more detailed and adaptable planning process. Each sub-task is systematically evaluated to identify the optimal construction method based on cost-time trade-offs, with scheduling constraints integrated into the fitness functions of both GA and PSO. Results from an in-depth case study reveal significant improvements in project efficiency. Specifically, GA achieved approximately a 3.25% reduction in direct costs, a 20% reduction in indirect costs, and a 7% reduction in total construction costs. In comparison, PSO demonstrated slightly superior cost performance, with a 4% reduction in direct costs and comparable reductions in indirect costs, along with a 20% decrease in total project duration. These findings highlight practical gains in resource utilization and scheduling efficiency. This study presents a structured, comparative analysis of GA and PSO within the LOB-based TCT framework, providing a replicable methodology for optimizing schedules in linear repetitive projects. By bridging the gap between traditional scheduling techniques and advanced optimization algorithms, this research contributes valuable insights for enhancing operational efficiency and informed decision-making in construction project management.
AbstractAcute myocardial infarction (MI), a serious manifestation of ischemic heart disease, remains the culprit for mortality among coronary heart disease patients. Astaxanthin has demonstrated the ability to alleviate inflammation-induced myocardial damage while maintaining a balance between oxidants and antioxidants. This study investigates the cardioprotective potential of astaxanthin (ASX), particularly when encapsulated in nanostructured lipid carriers (NLCs), in isoprenaline (ISO)-induced myocardial infarction in rats. The study involved 48 rats separated into 6 groups. ASX and Nano-ASX (5 mg/kg) were administrated orally for 21 days before MI induction (isoprenaline, 85 mg/kg, subcutaneously). Blood and cardiac tissue samples were taken 24 h following the last isoprenaline injection for biochemical and histopathological investigation. The findings reveal that nano-formulated ASX significantly reduces oxidative stress and cardiac injury markers, including CK-MB, Troponin-I, and LDH. Additionally, it enhances antioxidant enzyme activities (GSH, GPx, and GSH-RD) and decreases inflammatory markers (COX-2 and VEGF). The study further demonstrates that nano-ASX stimulates autophagy by upregulating critical genes such as Beclin-1, ULK1, and LC3B, which are vital for cardiac protection and repair. Histological analysis confirms these biochemical outcomes, showing reduced myocardial damage and inflammation in the nano-ASX-treated groups. This study concludes the potential of ASX nano-formulations as an advanced therapeutic approach for myocardial infarction, leveraging improved bioavailability and targeting oxidative stress, inflammation, and autophagic mechanisms.
AbstractIntestinal epithelial overexpression of the Th17 cell chemoattractant CCL20 is implicated in inflammatory bowel disease and influenced byNOD2mutations in Crohn’s disease. Vitamin D metabolites have been shown to ameliorate inflammatory bowel disease. ConsideringNOD2mutations in Crohn’s disease, we investigated whether Vitamin D deficiency (serum 25-hydroxyvitamin D concentration < 20 ng/mL) increases circulating CCL20 levels in inflammatory bowel disease patients and healthy controls and whether active 1,25-dihydroxyvitamin D (calcitriol) downregulates systemic and intestinal CCL20 expression. In a cross-sectional study, serum concentrations of CCL20, 25-hydroxyvitamin D, and calcitriol were measured in 170NOD2-genotyped Crohn’s disease patients, 80 ulcerative colitis patients, and 60 healthy controls. Additionally, the effect of calcitriol on experimentally induced CCL20 expression was examined using human intestinal epithelial HT-29 cells. Multivariable linear regression analyses revealed that both the diagnosis of inflammatory bowel disease and vitamin D deficiency were independently associated with elevated CCL20 levels. Compared to healthy controls, Crohn’s disease patients and ulcerative colitis patients exhibited significantly higher circulating CCL20 levels. Unlike in Crohn’s disease patients, vitamin D deficiency was associated with higher CCL20 levels in healthy controls and ulcerative colitis patients, whereas the calcitriol/25-hydroxyvitamin D activation ratios were negatively correlated with serum CCL20 levels in healthy controls and ulcerative colitis patients with sufficient serum 25-hydroxyvitamin D status. Furthermore, calcitriol markedly inhibited intestinal epithelial induction of CCL20. In Crohn’s disease patients, cholecalciferol supplementation was associated with lower serum CCL20 levels, which were unaffected byNOD2mutations. These findings suggest that although vitamin D metabolites may downregulate CCL20 expression in healthy controls and ulcerative colitis patients, this regulatory effect appears to be impaired in Crohn’s disease patients.
AbstractThis research explores the use of kraft lignin (KL), derived from pulping black liquor waste, as a supportive medium for Ag3PO4@ZnO (AZ-NC) p-n heterojunction and design a new cost-effective ternary KL-Ag3PO4@ZnO nanocomposite (AZKL). The aim is to improve its photocatalytic efficiency in treating textile wastewater while tackling environmental issues such as chemical stability, charge carrier separation, and the production of secondary waste during the photocatalytic process. The response surface methodology (RSM) analysis shows that AZKL is highly effective catalyst for methylene blue (MB: 10 - 25 mg/L) dye mineralization, achieving a rapid decolorization (> 98.2% within 40 min) under visible light at a near-neutral pH (7.48) with maintained high catalytic activity across four consecutive cycles. This outstanding performance is driven by the synergistic interplay of AZKL-based photocatalysis and advanced oxidation process using 0.03% H2O2co-catalyst. Gas chromatography-mass spectrometry analysis reveals that MB dye degrades stepwise into intermediates such as N, N-dimethyl-p-phenylenediamine, hydroquinone, and formic acid, ultimately mineralizing completely into CO₂ and H₂O. The dominant reactive oxygen species driven this multi-step process are identified as hydroxyl radicals (•OH) and photogenerated holes (h⁺), with H₂O₂ and superoxide radicals (•O₂⁻) playing secondary roles. The data also highlights the multifunctional role of KL support, which enhances charge carrier separation, captures dye molecules, and prevents Zn2+/Ag+ion leaching (less than 0.2 ppm) into the treated water during photocatalysis. This is facilitated by the electron-donating polyphenolic hydroxyl groups on the KL surface, which reduce Ag⁺ to metallic silver and stabilize AZ-NC heterojunction under light irradiation, creating Schottky junctions that improve charge transfer efficiency while reducing secondary contamination risks. A practical case study further illustrates the effectiveness of AZKL in treating real textile effluents, as evidenced by the improved biodegradability of residual organic matter, indicated by changes in chemical/biological oxygen demands (COD/BOD) ratios from 2.62 to 1.47 and inhibition tests against E. coli, meeting wastewater discharge standards. The findings emphasize that the AZKL composite could serve as an effective and adaptable photocatalyst for breaking down organic pollutants and treating intricate wastewater systems.
AbstractDespite extensive research on reinforced concrete (RC) pile caps, the influence of column and pile configuration and dimensions on their shear performance remains unexplored. This study investigates the structural behavior of RC pile caps through experimental and numerical analyses, focusing on how variations in column and pile geometry affect shear capacity. Two pile cap specimens (700 mm long × 300 mm wide) with heights of 250 mm (SB1) and 350 mm (SB2) were tested under shear-dominated conditions. Both were supported by two square piles (200 × 200 mm) and loaded centrally via a square column (200 × 200 mm). The study reports crack patterns, ultimate shear load, load-displacement behavior, elastic stiffness, and energy absorption capacity. A validated 3D finite element model was developed to parametrically analyze rectangular/circular columns and piles with dimensions ranging from 0.2d to d (where d = pile cap width). The findings indicate that failure modes were consistently shear-dominated and remained unaffected by variations in column or pile configuration and size. Increasing the rectangular column length from 0.2d to d enhanced the ultimate load capacity by 108% and energy absorption by 100%. Similarly, increasing the circular column diameter from 0.2d to d improved these metrics by 348% and 373%, respectively. Widening the rectangular pile from 0.2d to d resulted in a 34% increase in ultimate load capacity. Overall, the study demonstrates that larger column and pile dimensions significantly enhance shear performance, with circular configurations yielding superior improvements. These insights offer practical guidance for optimizing pile cap design.
AbstractThe challenge of optimizing battery operating revenue while mitigating aging costs remains inadequately addressed in current literature. This paper introduces a novel cost–benefit approach for scheduling battery energy storage systems (BESS) within microgrids (MGs) that features smart grid attributes. The proposed comprehensive approach accounts for fluctuations of real-time pricing, demand charge tariffs, and battery degradation cost. Using the dynamic programming technique, a novel high-speed BESS scheduling optimization algorithm that incorporates a LiFePO4 battery degradation cost model is developed, achieving substantial monthly operational cost savings for the MG with a fine-grained sampling interval of nine minutes and execution time under one minute. The algorithm utilizes day-ahead forecasts for MG load profiles and photovoltaic output power, enabling the prediction of BESS’s optimal power profile a day in advance. The algorithm’s rapid execution enables real-time adaptability, allowing BESS scheduling to dynamically respond to grid fluctuations. The proposed approach outperforms existing methods in the literature, delivering MG operational cost savings ranging from 33.6% to 94.8% across various scenarios. Consequently, this approach enhances MG operational efficiency and provides significant cost savings.
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AbstractIndustrial activities, especially textiles and cosmetics, release harmful wastewater, threatening the environment and human health. Photocatalysis has emerged as an effective, eco-friendly solution for these issues, particularly using metal-organic frameworks (MOFs) for water treatment. This study explores the performance, computational analysis, and mechanistic behavior of a novel magnetically responsive cellulose-based metal-organic framework (MOF) nanocomposite, DAC@PdA@FM, for the simultaneous photocatalytic degradation of Toluidine Blue O (TBO), Crystal Violet (CV), and Sunset Yellow FCF (E110) dyes. The material was synthesized using a controlled oxidation method and characterized using FTIR, XRD, EDX, SEM, TGA techniques and PPPS saturation magnetization properties. The uptake capacity of DAC@PdA@FM toward organic dyes as TBO, CV, and E110 from water, achieving reductions of 988.75, 1242.5, and 497 mg/g, respectively, within short time frames.The kinetic and isotherm studies were best fitted by PSO and the Langmuir models due to the higher correlation coefficient (R2≥ 0.999) and the lower error functions. The nanocomposite exhibited enhanced reusability and separation efficiency due to its superparamagnetic nature. Density functional theory (DFT) calculations confirmed the electronic structure and charge transfer mechanisms. Comparative analysis with previous studies confirmed superior degradation efficiency. The results also suggest that the MOF: DAC@PdA@FM nanocomposite possesses notable antimicrobial activity, particularly against gram-ve bacteria. These findings suggest that the MOF: DAC@PdA@FM nanocomposite is a promising applicant for wastewater treatment applications. The catalytic degradation mechanism for dyes on the prepared MOF:DAC@PdA@FM nanocomposite involves various interactions, including electrostatic attraction, pore-filling, π–π stacking, and hydrogen bonding. Also, The results suggest that utilizing pre-prepared MOF:DAC@PdA@FM nanocomposite could serve as a potent and efficient antimicrobial agent.
AbstractIndoor air pollution may harm child health. Indoor air pollution inequalities among children and adolescents is under-researched. We analyzed associations between equivalized disposable income, socioeconomic status, and history of migration with benzene, toluene, xylene, limonene, and formaldehyde among children and adolescents in Germany. Using pooled data from the German Environmental Survey (GerES IV, GerES V) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Baseline, KiGGS Wave 2) (N = 1117, aged 3–14 years), six out of fifteen random intercept models revealed statistically significant findings. An increase of one standard deviation in equivalized disposable income was associated with 5% lower benzene concentrations (exp(ß): 0.95, 95% confidence interval [CI] 0.91, 0.99). Higher socioeconomic status was associated with a 10% decrease in benzene (exp(ß): 0.90, 95% CI 0.87, 0.94) and a 6% decrease in toluene (exp(ß): 0.94, 95% CI 0.89, 0.99). Having a parental history of migration was associated with 24% higher concentrations of formaldehyde (exp(ß): 1.24, 95% CI 1.07, 1.43) and 102% increased limonene concentrations (exp(ß): 2.02, 95% CI 1.61, 2.55). Subgroup analysis from urban municipalities showed only slight differences. Although results varied, they highlight that indoor air pollution is unequally distributed among children and adolescents in Germany.
AbstractA growing number of studies have compared human and AI creative performance. These studies differ in AI chatbots, human populations, creativity tasks, and creativity indicators (e.g., originality, usefulness, elaboration). They mostly neglect psychological research on determinants of creative performance such as instructions or processing time. The present study contributes to the theoretical foundation and replicates a study comparing humans’ and AI’s creative output in the Alternate Uses Task. Building on established knowledge of creativity determinants, we modified the Alternate Uses Task’s instructions (call for quality AND quantity), provided more time for the human participants, and added a second task (Remote Associates Task). The Alternate Uses Task output was scored in two ways: the mean and maximum scores of each Alternate Uses Task item, both in terms of semantic distances and in terms of human rating scores. The result shows that AI’s mean scores were significantly higher in the original and modified Alternate Uses Task condition, maximum scores in the original Alternate Uses Task condition, and in the Remote Associates Task. No significant differences between humans and AI were found for the maximum scores in the modified Alternate Uses Task. We mainly replicated the original studies’ findings. Our study provides initial clues that the evaluation of creative performances depends on creativity indicators and approaches (instructions and time).
AbstractThree novel morpholinium-cationic surfactants (coded: DCSM-8, DCSM-10, and DCSM-12) with chemical structure confirmed via FT-IR, HNMR, and mass analysis were applied for carbon steel (CS) corrosion control in acidic 4 M HCl solution. The investigated compounds decreased water surface tension (72 mN.m-1) to 19.85 mN.m-1after the addition of DCSM-12. The surfactants mitigation performance was assessed via weight loss (WL), potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS). The synthesized surfactants protectedCSefficiently with higher inhibition efficiencies up to 97.029% at 1 × 10–3M for DCSM-12 using PDP which also indicated that, the prepared surfactants inhibited bothCSanodic and cathodic sites with cathodic dominant. EIS data showed higherCSresistance from 35.24 Ω.cm2to 1245.54 Ω.cm2after addition of 1 × 10–3M for DCSM-12 with mitigation potency 97.17% which can be attributed to their adsorption process overCSsurface forming a protective film layer that followed Langmuir adsorption isotherm reflecting the chemical adsorption affinity of the prepared mitigators with higher adsorption energy (ΔG*ads) values (> -40 kJ.mol-1). Also, the protection effect of the prepared inhibitor (DCSM-12) was confirmed using SEM (scanning electron microscopy) and EDX (energy-dispersive X-ray) showing improvement inCSsurface morphology. The reactivity of the prepared surfactants and their mitigation role inCSdeterioration were confirmed theoretically using DFT (density functional theory) and MCs (Monte Carlo simulations).
AbstractThis study investigated the effects of astaxanthin (ASTA) on diabetic cardiomyopathy (DCM) and nephropathy (DN) in rats. Type 2 diabetes was induced through a high-fat/high-fructose (HF/HFr) diet followed by a sub-diabetogenic dose streptozotocin injection. Diabetic rats were treated with ASTA at a dose of 100 mg/kg for four weeks. Serum markers of renal and cardiac function, oxidative stress parameters, and electrocardiographic (ECG) measurements were assessed. Diabetic control rats exhibited significant impairment in renal and cardiac functions, heightened oxidative stress, and altered ECG parameters. Treatment with ASTA (100 mg/kg) markedly improved these conditions, proven by reduction in serum urea, creatinine, cardiac creatine phosphokinase-MB (CK-MB), and LDH levels. Additionally, oxidative stress markers such as MDA, GSH, SOD, and NOX4 were restored in both heart and kidney tissues. Furthermore, ASTA was able to increase the cardiac and renal Fractalkine chemokine as well as attenuate the elevated Nrf2 and AP-1. ECG abnormalities were partially reversed, with enhancements in the QTc interval and ST segment height. The histopathological examination of cardiac and renal tissues confirmed these results. Finally, the forementioned promising observations suggest that ASTA may offer therapeutic potential in mitigating DCM and DN via modulation of NOX4, Fractalkine, Nrf2, and AP-1 Pathway, warranting further research into its mechanisms and clinical applicability.
AbstractUltrashort XUV pulses of the Free-Electron-LASer in Hamburg (FLASH) were used to investigate laser-induced fragmentation patterns of the prototypical chiral molecule 1-iodo-2-methyl-butane ($$\hbox {C}_5$$$$\hbox {H}_{11}$$I) in a pump-probe scheme. Ion velocity-map images and mass spectra of optical-laser-induced fragmentation were obtained for subsequent FEL exposure with photon energies of 63 eV and 75 eV. These energies specifically address the iodine 4d edge of neutral and singly charged iodine, respectively. The presented ion spectra for two optical pump-laser wavelengths, i.e., 800 nm and 267 nm, reveal substantially different cationic fragment yields in dependence on the wavelength and intensity. For the case of 800-nm-initiated fragmentation, the molecule dissociates notably slower than for the 267 nm pump. The results underscore the importance of considering optical-laser wavelength and intensity in the dissociation dynamics of this prototypical chiral molecule that is a promising candidate for future studies of its asymmetric nature.
AbstractThe current study investigates the development and characterization of sustainable activated carbons (ACs) via chemo-thermal activation from the hull and core of sugarcane bagasse as a viable and renewable substitute for commercial ACs. Characterize ACs using XRD, FTIR, SEM, etc. The sorption kinetics of methylene blue (MB) onto AC(H) were well described by a pseudo-second-order model. Also, the controlling step in the MB sorption process was related to several intervening diffusion sorts, including intra-particle ones. The MB equilibrium data were also analyzed using linear and non-linear forms of Langmuir, Freundlich, and Temkin isotherms, revealing a better fit of Langmuir, with R2values > 0.97 in both modes. With adsorption capacities (qmax= 357.14 and 389.4 mg/g) in linear and non-linear modes, orderly. The activation energy (EDR) of 550.8 and 2500 J/mol in non-linear and linear further supports the dominance of chemisorption, implying the formation of chemical bonds between the MB and the functional groups present in the sorbent material. The spontaneous and exothermic nature of the MB sorption process at 291–323 K was confirmed by the thermodynamic parameters ΔH°, ΔS°, and ΔG°. The design expert program suggested 17 numerical possibilities for the maximum dye removal at the 99% desirability level using ANOVA within the experimental parameter range. The total cost of producing 1.0 g of AC(H) is estimated at 0.041 USD. These findings underscore the potential of AC(H) as a highly efficient adsorbent for MB removal, positioning it as a strong candidate for wastewater treatment applications.
AbstractShunt faults may cause significant fluctuations in the electrical output of the Synchronous Generators (SGs), leading to a loss of synchronization with the remaining power network. Electrical power analysis and the Durbin Watson (DW) statistic can be manipulated to diagnose the instability of the power quality parameters, and to discern between synchronous and asynchronous running of the generator. In this research, the computational techniques serve as a proper foundation of intelligent relay to anticipate and detect the generator Out-of-Step (OOS) situation following the fault presence. The protection strategy can identify sudden variations in several electrical waves in the OOS conditions, such as phase voltage, current, active power, reactive power, and power angle. To verify the performance of the method, a power model with real parameter data of its components is built using the software package of the Alternative Transient Program (ATP). The advanced algorithm is carried out and analyzed using the MATLAB application. Simulation results and analysis show that the protection plan has the ability to recognize the OOS events upon which the protective relay emits a tripping signal to both the annunciation panel and the generator circuit breakers. Whereas, it remains idle under acceptable synchronization conditions. As a consequence, the OOS is rapidly announced before the second pole-slipping occurrence. Furthermore, the algorithm is robust during the stable power swings, and the property of the protection redundancy is provided in this strategy. Additionally, it has the capability of estimating both the instability time and the frequency rate of the unstable power swings.
AbstractPhotoinduced intramolecular electron transfer (ET) is essential for understanding charge transport in biological and synthetic systems. This study examines ET in peptide His-Glu-Tyr-Gly (1) and the conjugate His-Gln(BP)-Tyr-Gly (2) with benzophenone (BP) as a photoactive electron acceptor and His or Tyr as donors. Time-resolved and field-dependent chemically induced dynamic nuclear polarization (CIDNP) techniques were employed to investigate ET mechanisms and kinetics. Peptide 1 with 3,3’,4,4’-tetracarboxy benzophenone as a photosensitizer initially forms two types of radical with radical center at either His or Tyr residue, the consequent intra- and intermolecular ET electron transfer from Tyr residue to the His radical takes place with rate constants ke(intra)=(1.5±0.5)×105s− 1and ke(inter)=(1.3±0.4)×107M− 1s− 1at pH 8.8. Conjugate 2 forms two types of biradicals under irradiation: with radical centers at Tyr and BP across the entire pH range, and with radical centers at His and BP at slightly basic pH. Field-dependent CIDNP revealed nonzero electronic exchange interaction (2Jex= − 8.78 mT) at acidic pH, indicating proximity between BP and Tyr radicals. Low-field CIDNP spectra showed strong emissive polarization patterns, with pH-dependent exchange interaction and biradical geometry. Notably, no electron transfer from tyrosine to histidine radicals was observed in the conjugate 2, distinguishing its behavior from peptide 1.
AbstractThe worldwide prevalence of type 2 diabetes mellitus (T2DM) is increasing swiftly.Cymbopogon proximus(C. proximus) is a wild herbaceous plant utilized as a potent remedy in Egyptian folk medicine, sometimes referred to as “Halfabar.” This study examined the hypoglycemic, hypolipidemic, and antioxidant properties of the methanolic extract from the aerial parts ofC. proximus, as well as its impact on pancreatic tumour necrosis factor-α (TNF-α) and Glucose Transporter-4 (GLUT4) in skeletal muscles within an experimental model of insulin resistance. Additionally, bioactive metabolites in the extract were analyzed via liquid chromatography-mass spectrometry (LC/MS) technology. Insulin resistance was induced by administering 1 mg/kg of dexamethasone to rats over a period of 14 days. The rats received two doses of the extract: a low dose of 100 mg/kg body weight and a high dose of 200 mg/kg body weight, along with the reference drug; Metformin (M) at a dose of 40 mg/kg body weight, supplied once daily by gastric tube for 14 days. The treatment of dexamethasone led to a significant (P< 0.05) elevation in serum fasting glucose, fasting insulin, HOMA-IR, and pancreatic TNF-α, along with a significant (P< 0.05) reduction in GLUT4 expression in skeletal muscles. Both extract and reference treatments significantly (P< 0.05) mitigated these abnormalities. The highest dose of the extract exhibited a significantly (P< 0.05) greater antioxidant impact, a more pronounced reduction in insulin levels and HOMA-IR, as well as an enhanced rise in GLUT4 expression and insulin sensitivity index compared to the lowest dose and the M. Histopathological and immunohistochemical analyses corroborate the biochemical results. The LC–ESI–MS/MS profiling resulted in the characterization and tentative identification of 95 metabolites’ structures. Identified substances purported to possess anti-diabetic effect include apigenin, luteolin, tricin flavone glycosides, cyanidin, malvidin anthocyanin glycosides, and caffeic acid. These findings suggest thatC. proximuscan mitigate insulin resistance. Additional clinical trials are necessary to validate these findings and assess the extract’s effectiveness in human insulin resistance.
AbstractThis study investigates the electronic properties of a proposed composite structure consisting of SiO2, Pb3O4, Bi2O3, and graphene oxide (GO) for glutamic acid (Glu) biosensing applications in aqueous media. Using Density Functional Theory (DFT) at B3LYP functional and SDD basis set, we examine the reactivity and electronic properties of the combination of these structures under weak and complex interaction scenarios with Glu. The study focuses on studying total dipole moments (TDM), HOMO/LUMO bandgaps, molecular electrostatic potential (MEP) maps, reactivity descriptors, and the density of states (DOS) for the proposed model molecules. The calculated TDMs and HOMO/LUMO bandgap energies highlight the highly reactive nature of the 3SiO2/GO/Pb3O4/Bi2O3“complex” structure toward the surrounding species. This is because it has the highest TDM (up to 35.1 Debye) and the lowest bandgap energy (decline significantly to 0.158 eV). The MEP maps for the interaction between 3SiO2/GO/Pb3O4/Bi2O3and Glu under the two proposed scenarios display markedly different MEP profiles, underscoring the substantial impact of the interaction type. Additionally, the interaction between 3SiO2/GO/Pb3O4/Bi2O3“complex” structure and Glu exhibits the highest ionization potential, electron affinity, and electronegativity. The plotted DOS curves of the interaction between the proposed composite structure (both weak and complex forms) and the target analyte reveal that the unoccupied states begin to emerge slightly below − 4.0 eV and − 5.0 eV, then extend towards 0.0 eV, indicating potential excitation energies for electrons. These findings boost the potential of the proposed 3SiO2/GO/Pb3O4/Bi2O3structure as a promising candidate for tailoring novel electrode materials for Glu biosensing applications, thereby advancing the development of effective biosensors.
AbstractMonosodium glutamate (MSG)-induced excitotoxicity is a major factor contributing to cognitive decline and neurodegeneration. Given the well-established roles of vitamin D (Vit D) and omega-3 polyunsaturated fatty acids (N-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in neuroprotection, the present study aimed at analyzing their possible neuroprotective efficacy against MSG-induced neurotoxicity in rats, concerning the behavioral performance, hippocampal histological integrity, and pathological protein accumulation, along with determination of the inflammatory marker levels and mRNA expression of vitamin D receptors (VDR) and other neurodegeneration-related genes. Fifty male Sprague Dawley rats were randomly allocated to a control, an MSG, and three treatment groups that received MSG and either Vit D or N-3 PUFA supplements in combinations or alone for 4 weeks. At the end of the study, five behavioral tests were conducted to assess cognitive functions, motor activity, and anxiety-related behaviors, and hippocampal tissues were analyzed for tau pathology, neuroinflammation, expression of VDR, and neurodegeneration-related markers. The results demonstrated that supplementation with Vit D (1 mcg/kg) and N-3 PUFAs (300 mg/kg EPA + DHA) profoundly attenuated MSG-induced neurodegeneration. The combined therapy decreased neuronal damage caused by MSG by 87% and tau pathology by 83%. The combined treatment further suppressed pro-inflammatory cytokines (TNF-α: 52%; IL-6: 65%) and elevated anti-inflammatory IL-10 by 2.8-fold, demonstrating a dual anti-inflammatory action. A major upregulation of hippocampal VDR by 4.6-fold was noted, with stabilization of calcium homeostasis and normalization of caspase-3 and α-synuclein expression. Our findings confirm that Vit D and N-3 PUFAs exhibit substantial synergistic neuroprotective abilities that might be mediated through synergistic VDR upregulation, providing a promising dietary intervention against MSG-induced excitotoxicity and highlighting their broader implications for supporting cognitive health and mitigating the adverse effects of other neurotoxins.
AbstractIndividuals with chronic low back pain (cLBP) may self-report about impairment of their back shape and function. As classical clinical diagnostic modalities seem to provide limited information on the pathogenesis of cLBP, interest has shifted to a more comprehensive approach of diagnosing cLBP. Self-reported outcome measurements in the form of either questionnaires or as part of clinical interview have gained interest. In theory, these self-reported assessments on one’s LBP provide the clinician with substantial information regarding the dominance of specific factors in a rather complex bio-psycho-social interplay of factors leading to cLBP. In order to analyze how well self-reported impairment (SRI) corresponds with objective measures, we evaluated the association between SRI and objectively measured back shape and function. In a cross-sectional study, we included 914 participants (207 asymptomatic, 480 non-chronic LBP (ncLBP), 227 cLBP). Participants were categorized into three groups: asymptomatic participants did not report back pain. Participants with back pain lasting for 12 weeks or more were categorized as cLBP patients, while participants with back pain for less than 12 weeks were classified as non-chronic LBP patients (ncLBP). Back function was quantified using finger-to-floor distance (FFD), Ott and Schober test, and 30 s sit-to-stand test (STS). Back shape and function were measured in standing position using a computer-assisted medical device. SRI was quantified during a clinical interview using a numerical 10–score-scale (1: unrestricted, 10: severely restricted). Higher SRI was associated with worse performance in every clinical test. Effect estimates ranged from small (Ott test: β = −0.05, CI −0.09–0.00, η2= 0.01; p = 0.05; Schober test: β = 0.08, CI −0.13 −0.04, η2= 0.01, p < 0.01) to moderate (FFD: β = 1.66, CI 1.27–2.19, η2= 0.05, p = 0.05; STS: β = −0.08, CI −0.82, CI −1.06–−0.59, η2= p < 0.01) in participants with ncLBP and cLBP. Higher SRI was associated with pathological back shape (hyperkyphosis, β = −0.03, CI = −0.29–0.51, η2= 0.01; p = 0.58 and hyperlordosis, β = 0.35, CI 0.04–0.65, η2= 0.02, p = 0.03) as well as attenuation of range of motion in the frontal and sagittal planes in every direction except for the thoracic range of extension. Effect sizes were small (η2= 0.01–0.04). This study demonstrated an association of SRI with objective back shape and function. Participants with ncLBP seem to have the highest correspondence between objective evaluation and SRI of back shape an function. In the future, these associations can be used to further personalize both diagnostic and therapeutic modalities for individuals suffering from LBP rather than generalizing treatment options.
AbstractTraditional restorative materials often fail to integrate seamlessly with natural tooth structures due to differences in chemical composition, leading to microleakage and related clinical problems. This study aims to create a material entirely composed of calcium phosphates, the main component of dental enamel, to repair minor enamel cavities. Inspired by the biomineralization process and employing the inorganic ionic polymerization strategy, a cohesive calcium phosphate mass was developed to repair minor enamel cavities. Calcium phosphate ionic clusters (CPICs) and three types of calcium phosphate powder were utilized; (bone-derived and synthetic hydroxyapatite; (BHA and SHA), and dried CPICs. Two different techniques, namely layer by layer (LbL) and premixing (PM), were employed to mix CPICs with one type of calcium phosphate powder to form a cohesive mass. Different analysis techniques were used including FTIR, XRD, SEM and TEM. Among the tested approaches, the mass formed by mixing BHA with CPICs using the PM technique demonstrated superior integration with enamel walls and infiltration of calcium phosphate particles into enamel. To the best of our knowledge, repairing cavitated enamel defects using a bioinspired approach with a material composed entirely of calcium phosphate has not yet been achieved.
AbstractThe negative impact of alcohol consumption on cancer development and progression is well-established in oncologic research, yet it receives surprisingly little attention from patients with cancer, the public, and even oncology professionals. A cancer diagnosis can lead to significant psychological distress, including high levels of depression and anxiety. For patients with cancer experiencing high levels of psychological burden, psycho-oncological care is available to help manage these symptoms and the overall impact of their condition. Alcohol consumption can serve as a coping mechanism for psychological stress. However, there is limited knowledge about the alcohol consumption patterns among this particularly vulnerable group of patients with cancer, as well as the patient- and disease-related factors associated with drinking. Patients with cancer are particularly susceptible to the harmful effects of alcohol. The aim of this study is to investigate the prevalence of potentially risky alcohol consumption among patients with cancer receiving psycho-oncological care over a six-month period and to identify sociodemographic, health-related, and psychosocial factors that may predict alcohol consumption after a cancer diagnosis. We conducted a secondary analysis using data from 300 patients with cancer (72 % female, mean age 52.74 years) treated at the outpatient clinic of the University Medical Center Hamburg-Eppendorf in Germany. Between 2013 and 2021 demographic, medical, and psychosocial information was collected using self-report questionnaires. A generalized longitudinal linear mixed model was used to determine the prevalence of risky and potentially harmful drinking behavior (AUDIT-C ≥ 2 for women and ≥ 3 for men) among patients with cancer as well as to identify patient characteristics associated with alcohol consumption. The results show that approximately 70% of the patients continued drinking after their cancer diagnosis, despite the known detrimental effects of alcohol on prognosis. At both time points, around 40 to 50% of female and male patients reported potentially harmful drinking behaviors (T0 (beginning of psychosocial treatment): 49.1% of female, 38.1% of male patients; T1 (6 months later): 41.2% of female and 42.9% of male patients). A higher number of comorbidities (OR = 0.707; 95% CI: 0.567–0.883), older age (OR = 0.983, 95% CI: 0.967–0.999, and higher levels of depressive symptoms (OR = 0.952, 95% CI: 0.907–0.998) were significantly associated with lower odds of risky alcohol consumption over the six-month period. In contrast, higher anxiety levels (OR = 1.075, 95% CI: 1.021–1.132) were associated with an increased likelihood of risky drinking. The significant proportion of patients with cancer consuming alcohol at levels that may worsen their cancer prognosis highlights the need for improved patient education and guidelines. The results can help identify high-risk patients who require close monitoring of their drinking behaviors during their survival period, and inform the implementation of better alcohol control measures in cancer care. By understanding alcohol consumption patterns and associated factors, we aim to promote healthier behaviors and improve treatment outcomes for patients with cancer in psycho-oncological care.
AbstractDue to the rise in power consumption in recent years, the rated capacity of the power system has increased, resulting in an increase in the presence of Distributed Generators (DGs) in electrical networks. As a result, short-circuit currents surge when shunt faults occur. Fault Current Limiters (FCLs) are an effective way to suppress fault currents in the power systems. On the other hand, FCLs have an impact on the response speed of the protective devices, such as over-current relays (OCRs), which increase the relay operating time, raising the electrical and mechanical stresses on the system equipment. This paper presents an adaptive OCR algorithm considering the FCLs effect without any delay time. The proposed algorithm includes two modules: (1) a Z-score algorithm based on both the mean and the standard deviation values of the input current data, which is used to detect fault conditions, and (2) tripping characteristic curves based on the current Mean Ratio, which are applied to estimate the appropriate operating time of the adaptive OCR. To verify the method performance, a power system with real parameters is simulated on the Alternative Transient Program platform, and the algorithm procedure is implemented in the MATLAB program. Extensive simulation studies of load changes and various fault types are conducted, encompassing a wide range of fault initiation angles, fault resistances, and fault zones. The quantitative findings of these studies are analyzed in the presence and absence of FCLs/DGs. The simulation results indicate that the proposed algorithm can operate online and adjust its operating time settings automatically. As a consequence, it is able to detect fault instances upon which the relay sends a tripping flag, yet remains inactive under normal operating conditions. The algorithm speed and sensitivity are controllable using a moving data window size. Moreover, it is characterized by being easy to use, reliable, and accurate. Furthermore, the Z-score of the phase current can be used to identify the faulty phase and classify the fault type. In addition, the algorithm can be integrated with other digital protection and automation systems to be applied in conventional and smart grids.
AbstractThe demand for gluten-free products for people suffering from a gluten allergy is increasing. Therefore, the aim of this study was to produce high-quality gluten-free pasta from brown rice flour (BRF), quinoa flour (QF) and chickpea flour (CPF), semolina flour (S) was used as control sample. The chemical composition of the raw materials showed the higher protein, carbohydrate and fat content of CPF, S and QF, respectively. In addition, the content of Ca, K, and Fe was higher in CPF. The total concentration of essential amino acids in CPF, BRF and QF was between 38.9 and 34.04%. Pasta was prepared with different levels of CPF, BRF, and QF. The quality of the pasta was evaluated chemically and physically. The chemical analysis showed that the formula (BRQ5) had the highest protein, fat, ash and fiber content. The color analysis showed that the darkness of the pasta increased with increasing QF. The overall acceptability of the different pasta showed that the control (S) had the highest acceptability, followed by BR and BRQ1. The analysis of the texture profile showed that the hardness of the uncooked control pasta was the highest. In summary, it can be recommended to produce gluten-free pasta with the BRQ1 formula.
AbstractThis study aimed to analyze the antibiotic resistance patterns and virulence profiles ofKlebsiella pneumoniae, a prevalent gram-negative pathogen linked to CLABSI patients globally. Of a total of 185 microbial isolates, 51 (27.5%) wereK.pneumoniaeisolates. The results of antimicrobial susceptibility testing using the disk diffusion method were compared to those of the VITEK-2. Phenotypic analysis revealed that 88.3% were biofilm producers and 50.9% were extended-spectrum beta-lactamase (ESBL) producers. Enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) revealed a discriminatory power of 0.7111 between ten selected isolates. The PCR detection of the virulence genes, includingFimH,rmpA,iutA, andfyuA, revealed that the ten selected isolates harbored all these genes, except one without thefyuAgene. The presence of thermpAand theiutAgenes confirmed them as hypervirulent (hv)K.pneumoniae. The genes (EAST-1,CNF-1) were present in 20% and 60% of the isolates, respectively. All isolates had theblaTEMandblaSHVresistance genes, while 50% had theblaNDMcarbapenemase resistance gene. In conclusion, all selectedK.pneumoniaeisolates were proven to be ESBL producers and carbapenem-resistant, highlighting significant multidrug resistance. We found a strong correlation between biofilm formation and multidrug resistance, as well as between phenotypic and genotypic detection of various virulence factors. Infections from hyKp strains represent a growing public threat. Our findings aim to enhance therapeutic options for patients and help reduce complications and mortality.
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ABSTRACTThere is increasing evidence that white matter fibres play an important role in tinnitus. A directed bilateral Mendelian randomization (MR) analysis based on genome‐wide association studies (GWAS) has been implemented to explore the impact of idiopathic tinnitus on the brain white matter (WM) integrity of different severity and stages at a causal level. The tinnitus‐related GWAS is derived from the research of 117,882 European participants, which contains accounts of tinnitus at different severities and stages. WM diffusion indices, which come from GWAS of 3144 brain imaging phenotypes from the UK Biobank, based on tract‐based spatial statistics and neurite orientation dispersion and density imaging, represent its integrity in this study. The primary estimate was inverse‐variance weighted, with heterogeneity and pleiotropy detected using MR Pleiotropy Residual Sum and Outlier and MR‐Egger. This study revealed a significant causal relationship between tinnitus and brain WM microstructural alterations, including changes primarily within the thalamic and acoustic radiation, limbic‐related fibre bundles, as well as fibres along the transmission pathways of auditory information from peripheral to central. Interestingly, we found that individuals exhibiting WM changes in the internal capsule, corticospinal tract and tapetum might have previously experienced tinnitus. Furthermore, moderate tinnitus patients exhibit the most pronounced WM integrity changes. This study substantiates that tinnitus can instigate substantial WM microstructural alterations mainly within the auditory‐thalamic‐limbic system and the auditory information transmission pathway from peripheral to central, while the reciprocal causality is not supported. Moreover, the data underscores that WM integrity changes vary depending on the severity and stages, and moderate tinnitus precipitates the most significant. Alterations in several specific WM fibre bundles indicate a history of tinnitus.
ABSTRACTExternalizing behaviors are particularly pronounced in the context of psychopathy. Recent neurobiological models suggest that psychopathy may be associated with abnormalities in brain network connectivity, which could contribute to its development and its links to externalizing behaviors. However, the specific structural networks contributing to psychopathy and its relation to externalizing behaviors remain poorly understood. In this study, we investigated the structural connectivity associated with psychopathy and its relation to externalizing behaviors in 82 young adults from the MPI Leipzig Mind‐Brain–Body dataset. A structural connectome–based prediction model with leave‐one‐out cross‐validation identified both positive and negative networks associated with psychopathy. Specifically, the positive network involved regions related to social‐affective processing, language, and reward systems, while the negative network was associated with regions involved in attention modulation. Furthermore, mediation analyses revealed two potential neural pathways from psychopathic traits to externalizing behaviors via emotional processing and attention modulation networks. These findings suggest that alterations in structural connectivity play a significant role in psychopathy and may underlie the externalizing behaviors observed in individuals with the disorder.
ABSTRACTLow‐frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) was shown to impair short‐term consolidation of a balance task, emphasizing the importance of M1 in balance skill consolidation. However, the disruptive mechanisms of rTMS on neural consolidation processes and their persistence across multiple balance acquisition sessions remain unclear. GABAergic processes are crucial for motor consolidation and, at the same time, are up‐regulated when learning balance skills. Therefore, this study investigated the impact of rTMS on GABA‐mediated short‐interval intracortical inhibition (SICI) and consolidation of balance performance. Participants (n= 31) underwent six balance acquisition sessions on a rocker board, each followed by rTMS (n= 15) or sham‐rTMS (n= 16). In the PRE‐measurement, SICI was assessed at baseline and after balance acquisition with subsequent rTMS/sham‐rTMS. In the POST‐measurement, this procedure was repeated to assess the influence of motor memory reactivation on SICI. In addition, SICI‐PRE and SICI‐POST were compared to assess longer‐term processes. Both groups achieved similar improvements within the balance acquisition sessions. However, they did not consolidate equally well, indicated by significant declines in performance for the rTMS group (p= 0.003) in the subsequent sessions. Adaptations in SICI were affected by rTMS (p= 0.024): while the sham‐rTMS group up‐regulated SICI, rTMS led to reductions in inhibition. The interfering effect of rTMS on both balance consolidation and up‐regulation of SICI suggests that increased intracortical inhibition is an important factor to protect and consolidate the newly acquired motor memory.
ABSTRACTEnsuring equitable access to research funding is crucial for fostering diversity, innovation and excellence in science. Despite progress, significant disparities remain, with underrepresented researchers—including women, racial and ethnic minorities, LGBTQIA+ individuals and those with disabilities—continuing to receive disproportionately less funding. These disparities not only hinder individual careers but also limit the breadth of perspectives that drive scientific discovery. Through discussions with major funding agencies, including the Dana Foundation, European Research Council (ERC) and ERA‐NET NEURON, we examine how equity, diversity and inclusion (EDI) are integrated into research funding allocation. We focus on three key areas: (1) How EDI is defined and prioritised (2) metrics for assessing and tracking progress and (3) strategies for mitigating bias in selection procedures. While agencies have implemented initiatives such as demographic data transparency, targeted funding mechanisms and bias‐awareness training, systemic challenges remain. Variability in data collection practices, barriers in peer review processes and limitations of interventions like double‐blind reviews highlight the need for ongoing reform. As EDI policies face growing political scrutiny and active efforts to dismantle existing frameworks, reinforcing and expanding strategies to ensure equitable funding distribution has never been more critical. The scientific community must continue advocating for evidence‐based approaches that improve transparency, accountability and fairness in research funding. Without sustained commitment, the progress made over the past decades is at risk of being reversed, undermining the diversity of thought and innovation essential to scientific advancement.
ABSTRACTRat whiskers comprise an “active sensing” system involving two functional subdivisions: long whiskers for object localization and short whiskers for object recognition. To explore their respective roles in orientation, rats were trained in a reaching–grasping task. Specifically, four consecutive salient frames were identified in control rats: (i) whisker touch (Wt), the long whiskers came into contact with the front wall; (ii) first nose touch (Fnt), the rat brought the nose into contact with the wall; (iii) poke (Pk), the rat inserted its nose through the slot and placed short whiskers on the shelf, exploring it until the pellet was detected; and (iv) nose elevation (Nel), the rat raised its nose until reach start. These frames were used to subdivide orientation behavior into three specific phases: Wt–Fnt, Fnt–Pk, and Pk–Nel. To determine their respective roles in orientation, the rats performed the task after either long whiskers trimming or short whiskers shaving. Data evidenced a temporary loss of orientation followed by a recovery specific to each experimental group. Trimmed rats presented incomplete trials with loss of invariance, longer Fnt–Pk duration, and an increased number of nose touches. Shaved rats displayed longer trial duration and longer Pk–Nel interval. This duality is explainable by a consecutive use of the two kinds of whiskers and confirms their different roles in the multisensory integration necessary for each orientation phase. The data suggest that the long whiskers can be viewed as a spatial orientation system acting as a precision mechanism guiding head position in the context of coherent behavior.
ABSTRACTLinguistic, motor, cognitive, and social‐behavioral functions are fundamental facets of a child's neurodevelopment and are influenced by both genetic factors and environmental factors, such as the home environment, including the parents' mental health. However, the nature of these influences remains largely unknown. Using a genotyped cohort of 391 7‐year‐old children with comprehensive phenotype data on linguistic, motor, cognitive, and social‐behavioral performance as well as data on parental mental health and the home environment, we performed regression analyses for the individual neurodevelopmental domains and principal components (PCs) capturing the variance across all domains simultaneously, where these outcomes were regressed on a polygenic score for educational attainment (PGS for EA) as a proxy for genetic factors and the Home Observation for Measurement of the Environment (HOME) as a proxy for environmental factors. HOME was significantly associated with all domains; the PGS for EA was nominally significantly associated (p≤ 0.05) with cognitive function only. In the principal component analysis, PC1 and PC2 captured 52.57% and 20.73% of the variance in our phenotypic data, respectively. HOME was significantly associated only with PC1, while the PGS for EA was significantly associated only with PC2. Significant differences between familial risk groups were observed for PC1. Our results suggest an important role for potentially modifiable environmental factors on child neurodevelopment across multiple domains. We identified two orthogonal dimensions capturing parts of phenotypic variance that were associated with either environmental or genetic factors, but not both, providing insight into the interplay between genes and the environment in neurodevelopment.
ABSTRACTThe structural model predicts the laminar patterns and strength of corticocortical connections. Here, we addressed whether the structural model extends to connections between the thalamus and prefrontal cortices, which are connected with the mediodorsal (MD) nucleus and with other thalamic nuclei. The prefrontal cortex is composed of a series of areas ranging from caudal orbital and medial limbic areas that have the simplest trilaminar architecture through successive areas that show increasing elaboration into six delineated layers. Here, we compiled detailed, quantitative tract‐tracing data from connectivity studies of the thalamus and cortex in macaques, which revealed that the structural model extends to thalamocortical connections. The phylogenetically ancient limbic areas were more diffusely connected with thalamic nuclei, projected to the thalamus from canonical Layer VI, and also substantially from Layer V, and were innervated more broadly by thalamic pathways that terminated in the middle and other layers. The pattern of thalamocortical connections became increasingly sharper for prefrontal areas with progressive laminar differentiation, with decreasing contribution of thalamic nuclei besides MD, sharpening of thalamic terminations to the middle cortical layers, gradual decreasing contribution by Layer V, and increased projection from canonical Layer VI to the thalamus. These findings support the hypothesis that the structural model can be extended to the broad thalamic connections and laminar‐specific interactions with the thalamus, tested in a series of prefrontal cortices with a gradual increase in laminar complexity.
ABSTRACTMounting evidence suggests that individuals with chronic low back pain exhibit changes in brain activity. However, changes in brain activity during the performance of salient motor tasks have not been fully described. Therefore, the purpose of this study was to investigate the differences in cortical activation and functional connectivity between individuals with and without chronic low back pain while performing condition‐specific motor tasks. Twenty‐three individuals with chronic low back pain and 19 asymptomatic individuals participated in this study. Whole brain activity and functional connectivity were measured, whereas participants performed three lumbopelvic motor tasks: modified bilateral bridge, left unilateral bridge, and right unilateral bridge. Whole‐brain analysis revealed no significant differences in brain activation between the groups when performing lumbopelvic motor tasks. An exploratory region of interest analysis demonstrated that individuals with chronic low back pain had significantly higher activation in the left insular‐opercular cortex, left midcingulate gyrus, right insular‐opercular cortex, right midcingulate gyrus, and right putamen. Functional connectivity analysis revealed significantly higher connectivity between the midcingulate gyrus, putamen, and insular‐opercular cortex in those with chronic low back pain compared to asymptomatic participants. Taken together, this study helps build on the existing literature by providing unique insights into the changes that occur during the performance of salient motor tasks in individuals with chronic low back pain.
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ABSTRACTSeemingly simple actions, like reaching for and lifting an object, involve the coordination of distinct neural pathways within the dorsal and ventral streams. These components can be differentially affected by repetition‐induced anterograde interference, where extensive practice on one task impairs performance on subsequent tasks. Repetition leads to rigid movement patterns, making it harder to adapt flexibly to new situations, especially in tasks with sensory uncertainty that require the brain to rely more on past experiences (i.e., sensorimotor memories). To explore this, we tested whether object‐use tasks, which depend on the ventral stream, are more affected by this interference than a simpler reach‐to‐button task with helpful visual cues. Participants completed two tasks: a reach‐to‐button task involving pressing buttons on either side of a symmetrical object and an object‐use task where the same object had a hidden, asymmetric center of mass (CoM). To measure interference, we manipulated how many times participants lifted the object with the weight on one side before switching it to the other side. Our results showed that interference was strongest in the object‐use task, where uncertain visual information forced participants to rely on sensorimotor memories. In contrast, the reach‐to‐button task, supported by helpful visual cues, showed no significant interference. This suggests that tasks relying on the ventral stream are more vulnerable to interference, particularly when sensory feedback is unclear. Our findings highlight how repetition affects different movement types and emphasize the need for a balance between repetition and flexibility in motor learning.
ABSTRACTNeurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid‐β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α‐synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood–brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.
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ABSTRACTAmong the various forms of exploration, rearing—where rodents stand on their hind legs—reflects the animal's processing of spatial information and response to environmental novelty. Here, we investigated the developmental trajectory of rearing in response to spatial novelty in a standard object–place recognition (OPR) task, with the OPR retrieval phase allowing for a direct comparison of measures of rearing, object exploration, and locomotion as indicators of spatial novelty and memory. Groups of male rats were tested on postnatal day (PD) 25, PD31, PD38, PD48, and at adulthood (PD84). The OPR task comprised a 5‐min encoding phase with the rat exposed to an arena with two identical objects and, 3 h later, a 5‐min retrieval phase in the same arena with one object being displaced to another arena zone. Rearing increased in response to spatial novelty (i.e., the displaced object) at retrieval relative to encoding, with this increase occurring first on PD31, and thus later than preferential object exploration‐based responses emerging already on PD25. Importantly, zone‐specific analyses during retrieval revealed an increase in rearing events in the (now empty) zone where the displaced object is used to be at encoding. This increase was only observed in adult rats (PD84) and likely indicates the presence of specific object–place associations in memory. These findings evidence rearing as behavior covering aspects of spatial novelty complementary to those of object exploration, thereby enabling a more comprehensive characterization of the emergence of spatial episodic memory during early life.
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ABSTRACTThe paraventricular nucleus of the thalamus (PVT) is a central node in brain networks controlling motivated behaviors. It processes inputs from cerebral cortex, brainstem, and hypothalamus and has efferents that project to a wide range of structures, including the nucleus accumbens (nAcc). It is known that PVT neurons projecting to the nAcc show c‐Fos activation in response to reward‐related cues, in well‐trained animals. We previously found that c‐Fos expression is also increased early in the conditioning process, during the first session of learning a new cue‐reward association in rats, but neurons with projections to nAcc were not identified in that study. Here, we tested the hypothesis that nAcc‐projecting PVT neurons would show this enhanced c‐Fos expression following first exposure to the association of a visual cue with a subsequent food reward. Male rats were stereotaxically injected in the nAcc with a retrogradely transported adeno‐associated virus construct leading to green fluorescent protein (GFP) expression in cell bodies of afferents from PVT. Following a single session of cue‐reward training, processing of the brains with dual immunohistochemistry for c‐Fos and GFP showed significantly higher density of double labelled neurons in the conditioned group, compared to controls in which the same number of cues and rewards were delivered at random intervals with respect to each other. Such activation of immediate early gene expression in PVT to nAcc projecting neurons very early in paired associative reward learning may have a role in modulating plasticity in the nAcc.
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ABSTRACTWhen encountering a potential threat, humans and animals engage in different strategic behaviours, such as orienting and defence, depending on the perceived threat imminence. Orienting has been associated with attentional immobility and heightened ‘stimulus intake’, while defence is linked to action preparation and ‘sensory rejection’. First, we replicated previous findings showing that humans exhibit either heart rate (HR) acceleration or deceleration in response to the same threat‐related picture content. Second, we provide direct evidence that orienting, as indexed by increased HR deceleration, leads to enhanced visuocortical processing of threat‐related images, as measured by steady‐state visual evoked potentials (ssVEPs). Excitation of motor‐relevant cortical circuits, assessed by beta‐band desynchronization, was reduced in relation to HR deceleration. Conversely, HR acceleration was associated with a reversed pattern: reduced visual processing and increased excitation of cortical motor circuits, as reflected in ssVEP and beta‐band modulations. While self‐reported measures of state and trait anxiety, along with valence, arousal and dominance ratings, did not account for variations in HR response patterns, shorter self‐paced viewing time of looming threat pictures was linked to defensive HR changes, whereas orienting‐like HR responses were associated with longer avoidance latencies.
ABSTRACTEstrogen deficiency after menopause contributes to various neurological disorders, including stress, anxiety, depression, and memory impairment. Hormone replacement therapy (HRT) is commonly used to mitigate menopausal symptoms, but its use is associated with significant adverse effects. As a result, phytoestrogens, plant‐derived estrogens structurally similar to HRTs, are preferred alternatives due to their lack of side effects associated with synthetic HRTs. Among these phytoestrogens, red clover (RC) has emerged as a potent medicinal herb used for the treatment of menopausal symptoms. Thus, the aim of the current study was to evaluate the effects of RC on neurological disorders in estrogen‐deficient rats subjected to chronic unpredictable mild stress (CUMS). Ovariectomy (OVX) was performed to induce estrogen deficiency, a condition that closely mimics menopause in females. CUMS, a model of chronic stress, was employed to mimic the stress and anxiety that commonly accompany menopause. Significant changes in physiological, neurobehavioral, biochemical, molecular, and histopathological alterations in the brain hippocampal region were observed in OVX, CUMS, and OVX + CUMS group rats, indicating enhanced neuronal deficits compared with control group rats. Treatment with RC supplementation, 17‐β estradiol (E2), and fluoxetine (Flx) significantly restored the pathological alterations caused by both CUMS and estrogen deficiency toward normal. E2 and Flx were included in the study to serve as established treatments for postmenopausal symptoms and stress‐related disorders, providing a basis for comparison with RC. In conclusion, our study demonstrated the immense potential of RC in alleviating neurological disorders associated with estrogen deficiency and chronic stress.
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ABSTRACTMotor imagery (MI) engages higher cognitive functions such as memory, attention, and the transformation of sensory information in various ways, depending on the current goal. MI can be used to reproduce in the mind a possibly exact copy of an earlier motor experience (isomorphic motor imagery [IMI]) or to transform earlier experiences into new mental representations (transmorphic motor imagery [TMI]). Our study aimed to identify electroencephalographic (EEG) patterns of brain oscillations that can distinguish these two types of MI focused on differences in the frontal midline theta (FMΘ), central parietal beta (CPβ), and sensorimotor rhythms (SMR). Twenty subjects (14F; 18–25 years) participated in the study. Experimental stimuli were generated using a haptic interface to stimulate force feedback during hand clamping. The subjects had to squeeze the interface handle, memorizing the sensations associated with this movement. Then, they mentally reproduced the action they had just performed (IMI) or imagined stronger/weaker sensations (TMI). The study findings demonstrate significant differences in FMΘ and CPβ oscillation activity when comparing IMI and TMI. The IMI condition exhibits similar brain rhythm activity to working memory, probably due to its function of reproducing a previous motor experience. In contrast, oscillation patterns during TMI resemble introspective activity typical of multimodal sensory transformations. Additionally, we observed differences in the parietal delta and theta, in line with prior research on actual movement. Results may suggest that controlling movement kinematic parameters is critical when MI replicates sensory experiences, whereas creating new representations from experiences may require less stringent control.
ABSTRACTUnderstanding the neural correlates of short‐term memory is crucial, particularly in the context of aging. In this electroencephalography (EEG) study, we investigated the impact of aging on the brain activity underlying short‐term memory and perception of dissimilarity of auditory sequences. Fifty‐four participants were divided into two groups: (i) 29 young adults (20–30 years old) and (ii) 25 older adults (60–80 years old). We used a variation of the same/different task employing pairs of tone sequences and asking participants to rate the degree of dissimilarity of the second sequence in comparison to the first one. Sequences could be either identical (same), totally different, or with transposed tones. Behavioral results showed a lower level of perceived dissimilarity in different sequences in older compared to young adults. The memory task induced a fronto‐central negative slow wave (NSW) that was significantly higher in the 20–30 group for all three conditions. NSW was higher in the same than in the different and transposed conditions but only in young adults. In transposed sequences, NSW amplitude was modulated by the perception of dissimilarity. The P50 component to first sound of the second sequence was significantly higher in older adults. The N1 was more negative in the same than in the different and transposed conditions. The P2 was higher in the same than in the transposed condition.
ABSTRACTDysregulation of the mesolimbic reward circuitry is implicated in the pathophysiology of stress‐related illnesses such as depression and anxiety. These disorders are more frequently diagnosed in females, and sex differences in the response to stress are likely to be one factor that leads to enhanced vulnerability of females. In this study, we use subchronic variable stress (SCVS), a model in which male and female mice exhibit distinct behavioral, transcriptional, and immunological alterations, to investigate sexually divergent mechanisms of regulation of the ventral tegmental area by stress. Using slice electrophysiology, we find that female, but not male, mice have a reduction in the ex vivo firing rate of VTA dopaminergic neurons following SCVS. Surprisingly, both male and female animals show an increase in inhibitory tone onto VTA dopaminergic neurons and an increase in the firing rate of VTA GABAergic neurons. In males, however, this is accompanied by a robust increase in excitatory synaptic tone onto VTA dopamine neurons. This supports a model by which SCVS recruits VTA GABA neurons to inhibit dopaminergic neurons in both male and female mice, but males are protected from diminished functioning of the dopaminergic system by upregulation of excitatory synapses. Thus, SCVS leads to both shared and disparate changes in the organization of the VTA in males and females.
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ABSTRACTThe degree to which motor imagery engages the motor system or relies on perceptual/cognitive processes is a continuing debate. Here, we used the size weight illusion to create dissociation between perception and action to address the nature of motor imagery. Participants alternated lifting bricks of equal mass but where one brick was larger than the other, resulting in a perceptual illusion. Fifty‐seven participants were divided into three groups differing in the modality used for training (motor imagery, MI; and overt execution, OE) and exposure to the size weight illusion pretraining, one (MI‐2) and five (MI‐10 and OE) lifts of each brick. We hypothesized that the MI groups would use lifting dynamics post‐training consistent with the illusion, whereas the OE group would maintain accurate lifting forces. Contrary to our hypothesis, the OE and MI‐10 groups maintained the effect of the illusion post‐training. In the MI‐2 group, perception of the bricks' weight changed to reflect the participant's belief that large objects are heavy, and they correspondingly adjusted their lifting force post‐training. These results demonstrate that perceptual and motor processes are engaged during motor imagery and that the simulation of the motor component of the movement during motor imagery guides the performed action.
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