bluuebunny/crossref_metadata_2025_split huggingface dataset:
A method for identifying spatially divergent selection in structured populations
Authors: do O Isabela , Gaggiotti Oscar , de Villemereuil Pierre , Goudet Jerome 
Published: February 2025

AbstractSpecies occupy diverse, heterogeneous environments, which expose populations to spatially varied selective pressures. Populations in different environments can diverge due to local adaptation. However, neutral evolution can also drive population divergence. Thus, testing for local adaptation requires a neutral baseline for population differentiation. The classicalQST-FSTcomparison was developed for this purpose. Yet,QST-FSTfrequently fails to account for the complexities of population structure because the theory underlying this comparison assumes that all subpopulations are equally related, resulting in inflated false positive rates in metapopulations that deviate from the island model. To address this limitation we use estimates of between- and within-population relatedness to model population structure. Using those relatedness matrices, we infer the between- and within-population ancestral additive genetic variances under a mixed-effects model. Under neutrality, these inferred variances are expected to be equal. We propose here a test to detect selection based on the comparison of these two estimates of the ancestral variance and we compare its performance with earlier solutions. We find our method is well calibrated across various population structures and has high power to detect adaptive divergence.Author summaryPopulations of the same species often face different environmental pressures, driving them to adapt locally. However, even in the absence of adaptation, subpopulations can diverge due to random genetic drift and limited migration. Distinguishing between adaptive evolution and random divergence is a central challenge in evolutionary biology. Traditional methods, such asQST–FSTcomparison, assume equal relatedness among subpopulations—a simplification that rarely holds in complex real-world scenarios, leading to flawed conclusions. To overcome this limitation, we developed a novel method that incorporates genetic relatedness among subpopulations, leveraging quantitative genetic theory to estimate ancestral additive genetic variances. Our approach provides a powerful tool for testing local adaptation, reliably distinguishing adaptive divergence from drift across a variety of population structures.
A randomised clinical trial of STAtin therapy for Reducing Events in the Elderly (STAREE): Statistical analysis plan
Authors: Wolfe Rory , Heritier Stephane , Zomer Ella , Chatterton Mary Lou , Curtis Andrea , Spark Simone , Flanagan Zachary , Chong Trever T-J , Cloud Geoffrey C , Nelson Mark R , Nicholls Stephen J , Moran Chris , Reid Christopher M , Zoungas Sophia 
Published: February 2025

ABSTRACTThe STAREE randomised controlled trial of 9971 community-dwelling older adults without cardiovascular disease, diabetes or dementia is designed to compare daily 40mg atorvastatin to placebo. We present a statistical analysis plan to pre-specify the analytical approaches that will be taken when reporting the main findings from the trial. The plan describes the analysis approach for the co-primary endpoints: (a) death, dementia, and persistent physical disability; (b) major cardiovascular events; and all secondary endpoints. A pre-specified economic evaluation is also included as part of this plan.
APOEandTREM2variants differentially influence glial fibrillary acidic protein and neurofilament light in plasma of UK Biobank participants
Authors: Freudenberg-Hua Yun , Giliberto Luca , D’Abramo Cristina , Li Wentian , Ma Yilong , Goate Alison , Koppel Jeremy 
Published: February 2025

AbstractPlasma levels of protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers, but it is unclear how risk genes for Alzheimer’s disease (AD) influence levels of these biomarkers. We investigated the association of the established high-effect variants for AD inAPOEandTREM2with these biomarkers, using data from over 50,000 participants from the UK Biobank (UKB). The results show thatAPOE4is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. TheAPOE4effect on GFAP increases with age and the number ofAPOE4alleles. The risk variants R47H and R62H inTREM2are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. Higher levels of both GFAP and NEFL in midlife are significantly associated with greater risk for incident dementia. In contrast, the protectiveAPOE2allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for AD differentially affect dementia protein biomarkers across age, indicating gene specific pathways with potential therapeutic implications.
Alternative splicing broadens antiviral diversity at the humanOAS2locus
Authors: Davies Emma L. , Sowar Hanna , Balci Arda , Moorhouse Elliot , Wickenhagen Arthur , Turnbull Matthew L. , Palmarini Massimo , Wilson Sam J. , Fletcher Adam J. 
Published: February 2025

AbstractInterferons (IFN) are cytokines that regulate the expression of hundreds of genes during viral infections to generate a broadly antiviral environment in the stimulated cell. Antiviral breadth is provided by the concurrent expression of many individual IFN-stimulated genes (ISG), each encoding a protein with often exquisite antiviral specificity. Here, we show that mechanistic plasticity at a single genetic locus is a novel mechanism to diversify the antiviral profile of human cells. Through alternative splicing, theOAS2gene encodes two antiviral molecules with distinct target specificities. The shorter OAS2 p69 isoform blocks the replication of seasonal human coronavirus OC43 (HCoV-OC43), while the longer p71 isoform restricts the replication of picornavirus Cardiovirus A (EMCV). The restriction profile is determined by the variable length OAS2 C-terminal tail. Remarkably, the antiviral mechanisms underlying these distinct antiviral profiles are either RNase L dependent or independent, suggesting that splicing divides ‘classic restriction’ versus ‘virus sensing’ systems across two distinct OAS2 polypeptides. Together, our data reveal that the humanOAS2locus uses alternative splicing and mechanistic plasticity to diversify antiviral profiles.
Myelin transcription factors 1 and 3 have overlapping but distinct roles in insulin secretion and survival of human β cells
Authors: Hu Ruiying , Yagan Mahircan , Wang Yu , Tong Xin , Doss Teri D. , Liu Jinhua , Xu Yanwen , Simmons Alan J. , Lau Ken S. , Stein Roland , Liu Qi , Gu Guoqiang 
Published: February 2025

AbstractIslet β-cell dysfunction, loss of identity, and death, together known as β-cell failure, lead to reduced inulin output and Type 2 diabetes (T2D). Understanding how β-cells avoid this failure holds the key to preventing or delaying the development of this disease. Here, we examine the roles of two members of the Myelin transcription factor family (including MYT1, 2, and 3) in human β-cells. We have reported that these factors together prevent β-cell failure by repressing the overactivation of stress response genes in mice and human β-cell lines. Single-nucleotide polymorphisms in MYT2 and MYT3 are associated with human T2D. These findings led us to examine the roles of these factors individually in primary human β-cells. By knocking downMYT1orMYT3separately in primary human donor islets, we show here that these TFs have distinct functions. Under normal physiological conditions, highMYT1expression is required for β-cell survival, while highMYT3expression is needed for glucose-stimulated insulin secretion. Under obesity-induced metabolic stress, MYT3 is also necessary for β-cell survival. Accordingly, these TFs regulate different genes, with MYT1-KD de-regulating several in protein translation and Ca2+binding, while MYT3-KD de-regulating genes involved in mitochondria, ER, etc. These findings highlight not only the family member-specific functions of each TF but also the multilayered protective function of these factors in human β-cell survival under different levels of metabolic stress.HighlightsMYT1-KD compromises human β-cell survival but not insulin secretionMYT3-KD compromises human β-cell insulin secretion but not survivalMYT3-KD compromises human β-cell viability in obesityMYT1 and MYT3 regulate overlapping but distinct sets of genes
An Experimental and Multiphysics Simulations Study ofClostridium carboxidivoranssp. 624 for Acid and Alcohol Production in CO2/H2
Authors: Tiong Yong Wei , Yong Ashriel , Nalaparaju Anjaiah , Nguyen Hoang-Huy , Koh Li Quan , Wong Roong Jien , Yee Lim Ron Tau , Ow Dave Siak-Wei , Zhang Jia , Nguyen Van Bo , Wong Fong Tian , Lim Yee Hwee 
Published: February 2025

AbstractBiotechnological advancements in carbon utilization, particularly CO2gas fermentation, present a sustainable alternative to energy-intensive chemical catalysis.Clostridium carboxidivoranssp. 624, a clostridial acetogen, employs the Wood-Ljungdahl pathway to fix CO2, producing valuable acids and alcohols. In this study, we systematically investigate the metabolic dynamics of CO2/H2fermentation, focusing on optimizing temperature and media conditions to enhance yield. Notably, batch fermentation at 25°C achieved the highest reported acetate concentration of 4.38 g/L, with butyrate and hexanoate detected at lower yields. To further optimize fermentation performance, we examined the impact of the liquid-to-gas volume ratio (VL/VG) on product distribution. Acetate remained dominant, while VL/VG= 4 enhanced longer-chain acid production, due to improved gas solubility and substrate bioavailability. The enriched liquid phase at VL/VG= 4 also drove higher total acid (5.341 g/L) and alcohol (0.411 g/L) production. Moreover, the acid-to- alcohol ratio was 13 for VL/VG= 4, promoting alcohol conversion, while a higher ratio of 18 for VL/VG= 1 maintained an acetogenic profile. To complement the experimental insights, a kinetic model coupled with 3D computational fluid dynamics simulations was developed to elucidate spatial inhomogeneity and its impact on reaction kinetics. This comparative analysis identified key optimized parameters, including maximum reaction rates, half-saturation concentrations, and inhibition rates, which serve as critical guidelines for enhancing fermentation performance. By leveraging real-time computational modelling to refine bioreactor design, this approach facilitates the transition toward scalable CO2bioprocessing. These findings advance of sustainable chemical manufacturing, reinforcing CO2bioconversion as a strategy for carbon-negative biotechnology.
Convergence of efficient and predictive coding in multimodal sensory processing
Authors: Tavoni Gaia 
Published: February 2025

AbstractThe existence of pathways connecting different sensory modalities in the brain challenges the traditional view of sensory systems as operating independently. However, the reasons and mechanisms underlying these interactions remain largely unknown, and no computational framework currently addresses these questions. We propose a theory of sensory processing in canonical circuits – networks of excitatory and inhibitory neurons ubiquitously found in the brain. Our theory incorporates cross-modal feedback and demonstrates that these networks can orchestrate precise mathematical computations through distinct circuit components. These computations generate neural codes that are simultaneously efficient and predictive, unifying two classical coding schemes. Our framework treats unimodal processing as a special case and accounts for olfactory-visual and auditory-somatosensory interactions observed in experiments, while offering new predictions about the role of neural feedback in optimizing multimodal codes. By bridging normative theories of sensory coding, this study provides insights into the principles governing interactions between the senses.
Predicting input signals of transcription factors inEscherichia colithrough metabolomics and transcriptomics
Authors: Trouillon Julian , Huber Alexandra E. , Trabesinger Yannik , Sauer Uwe 
Published: February 2025

AbstractThe activity of bacterial transcription factors (TFs) is typically modulated through direct interactions with small molecules. However, these input signals remain unknown for most TFs, even in well-studied model bacteria. Identifying these signals typically requires tedious experiments for each TF. Here, we develop a systematic workflow for the identification of TF input signals in bacteria based on metabolomics and transcriptomics data. We inferred the activity of 173 TFs from published transcriptomics data and determined the abundance of 279 metabolites across 40 matched experimental conditions inEscherichia coli. By correlating TF activities with metabolites abundances, we successfully identified previously known TF-metabolite interactions and predicted novel TF effector metabolites for 41 TFs. To validate our predictions, we conductedin vitroassays and confirmed a predicted effector metabolite for LeuO. As a result, we established a network of 80 regulatory interactions between 71 metabolites and 41E. coliTFs. This network includes 76 novel interactions that encompass a diverse range of chemical classes and regulatory patterns, bringing us closer to a comprehensive TF regulatory network inE. coli.
Lamin B loss in nuclear blebs is rupture dependent while increased DNA damage is rupture independent
Authors: Chu Catherine G. , Lang Nick , Walsh Erin , Zheng Mindy D. , Manning Gianna , Shalin Kiruba , Cunha Lyssa M. , Faucon Kate E. , Kam Nicholas , Folan Sara N. , Desai Arav P. , Naughton Emily , Abreu Jaylynn , Carson Alexis M. , Wald Zachary L , Khvorova-Wolfson Dasha , Phan Leena , Lee Hannah , Pho Mai , Prince Kelsey , Dorfman Katherine , Bahiru Michael Seifu , Stephens Andrew D. 
Published: February 2025

AbstractThe nucleus houses genetic information and functions separate from the rest of the cell. Loss of nuclear shape results in nuclear ruptures. Nuclear blebs are deformations identified by decreased DNA density, while lamin B levels vary drastically. To determine if decreased lamin B levels are due to nuclear rupture, we used immunofluorescence to measure levels of lamin B and emerin, a nuclear envelope protein that enriches to sites of nuclear rupture. We observed that cell types that exhibit decreased levels of lamin B also show an enrichment of emerin in nuclear blebs. Oppositely, in other cell types, nuclear blebs display maintained levels of lamin B1 and showed no emerin enrichment. To determine how nuclear rupture affects DNA damage, we time lapse imaged nuclear rupture dynamics then fixed the same cells to conduct immunofluorescence of γH2AX and emerin. We find that DNA damage levels are higher in blebbed nuclei independent of nuclear rupture. Thus, we confirm that lamin B1 loss in nuclear blebs is due to nuclear rupture and blebbed nuclei have increased DNA damage that is independent of rupture.Summary statement (180-200 characters):We measured lamin B and DNA damage in blebbed nuclei to determine the effect of nuclear rupture. We find that nuclear rupture causes loss of lamin B in nuclear blebs but that increased DNA damage in blebbed nuclei is independent of rupture.
A computational architecture incorporating shallow brain networks: integrating parallel cortical and subcortical processing
Authors: Lee Kwangjun , Baracco Lorenzo , Pennartz Cyriel M. A. , Suzuki Mototaka , Mejias Jorge F. 
Published: February 2025

AbstractArtificial neural networks commonly have deep hierarchical structures that were originally inspired by the neuroanatomical evidence of cortico-cortical connectivity pattern found in the mammalian brain. Largely neglected in those models are non-hierarchical aspects of brain architecture, namely the subcortical pathways and the interactions between cortical and subcortical areas regardless of their hierarchical locations. Inspired by this principle, we present a computational model combining cortical hierarchical processing with subcortical pathways based on neuroanatomical evidence. We show the versatility of our model by implementing the cortical hierarchy in two alternative ways—a convolutional feedforward network and a predictive coding network. Both model variants can replicate behavioral observations in humans and monkeys on a perceptual context-dependent decision-making task. The model also reveals that subcortical structures lead decisions for easy trials while the more complex hierarchical network is necessary for the harder trials. Our results suggest that the parallel cortico-subcortical processing explored in the model represents a fundamental property that cannot be neglected in understanding the computational principles used by the brain.SignificanceArtificial intelligence and computational neuroscience models, particularly deep learning and predictive coding architectures, have been traditionally dominated by cortico-centric hierarchical frameworks. However, extensive neurobiological evidence suggests that cortical areas, regardless of their hierarchical classification, are deeply interconnected with subcortical structures in real brains. We propose here a computational framework demonstrating that parallel cortical-subcortical architectures can yield complex and more flexible computational capabilities, aligning with the observed behavior in the mammalian brain. Our model addresses key limitations in existing deep learning and predictive coding networks, offering a more biologically plausible and functionally advantageous alternative.
Enteric neural crest development inAstyanax mexicanussurface fish and cavefish
Authors: Perera Pavani Ponnimbaduge , Webster Kaitlyn , Riddle Misty R 
Published: February 2025

AbstractThe enteric nervous system (ENS) regulates gastrointestinal (GI) functions such as secretion, blood flow, and motility, yet how its structure and function evolve with dietary adaptations remains unclear.Astyanax mexicanus, a teleost fish with surface and cave morphotypes, offers a model to explore these changes; cavefish exhibit altered GI motility and transit that may help them adapt to their unique diet. We compared early ENS development in surface fish and cavefish, tracking enteric neural crest cell (ENCC) migration and differentiation usingphox2bband HuC/D markers. We found that ENCCs reach the gut by 36 hours post-fertilization (hpf) in both morphotypes but migrate and differentiate more rapidly along the gut tube in cavefish. To explore the genetic basis of this difference, we used available genomic datasets to compare the predicted peptide sequences of genes important for ENS development in other species and identified mutations that could impact protein function, for example in the endothelin signaling genes important for ENCC migration and differentiation. We specifically examined the expression ofendothelin-3 (edn3)andendothelin receptor-b (ednrb)during ENCC migration and found that the localization ofedn3, but notednrb, is consistent with a role in ENS development. Overall, our findings positionA. mexicanusas a model for studying evolution of ENS development.
Activity Protects Spinal Premotor Interneurons from Microglial Phagocytosis and Transneuronal Degeneration After Corticospinal Injury
Authors: Pathan Jasmine , Amer Alzahraa , Yoshida Yutaka , Martin John H. 
Published: February 2025

AbstractSpinal premotor circuits play a fundamental role in motor control. The corticospinal tract (CST) provides control signals to premotor circuits in the spinal cord, guiding voluntary skilled movements. Unilateral selective lesion of the CST in the medullary pyramidal tract (PTX) produces transneuronal degeneration, whereby Choline Acetyltransferase-positive (ChAT) premotor interneurons contralesionally undergo non-apoptotic degeneration by microglial phagocytosis. Evidence shows that transneuronal degeneration has an activity dependence: MCX inactivation produces transneuronal degeneration and spinal DC neuromodulation after PTX ameliorates it. This study expands our understanding of transneuronal degeneration mechanisms by examining the activity-dependence of degeneration vulnerability and the implications for motor recovery in a mouse model of a complete CST lesion model (bilateral PTX). We address four key unanswered questions: Are Chx10 (VGlut2) interneurons, the largest spinal interneuron class to receive direct synaptic connections from the CST vulnerable to transneuronal degeneration after CST loss; using DREADD neuromodulation, what are effective sources of presynaptic activation for protecting spinal premotor interneurons after CST loss; how are ameliorating transneuronal interneuron degeneration and reducing microglial activation associated; and does effective rescue of interneuron degeneration rescue grip strength after injury? Transneuronal degeneration is a pervasive pathophysiological change injury; CST lesion produces significant Chx10 interneuron loss. Multiple sources of neuronal DREADD activation—motor cortex, reticular formation, and spinal interneurons—are effective in ameliorating transneuronal degeneration. Interneuron rescue is strongly associated with ameliorating inflammation, showing potential causality between interneuron degeneration and inflammation after CST lesion. Finally, rescuing spinal interneurons was associated with restoring function. Our findings demonstrate the interplay between neuronal activity, microglia actions mediating transneuronal degeneration, and motor recovery following CNS injury.
A piece of evidence for pathogenesis of cerebral small vessel disease caused by blood-brain barrier dysfunction —— Based on the STRIVE-2 imaging features
Authors: Yang Yi , Ma Huide , Liu Bowei , Wu Rong , Sun Sujuan , Li Xia , He Yu , Wang Shumin 
Published: February 2025

AbstractBackgroundBlood-brain barrier (BBB) dysfunction caused by endothelial cell injury is one of the widely accepted pathogenesis of small cerebral vessel disease (CSVD). However, the early microcirculation studies were notably deficient in providing compelling imaging evidence, which has hampered a comprehensive understanding of the pathophysiological processes underlying BBB dysfunction in CSVD. The onset of CSVD is insidious and the clinical manifestations are diverse, diagnosis of CSVD relies primarily on neuroimaging information currently. These MRI imaging features mainly represent the end-stage brain parenchyma injury, rather than the vascular lesion itself. Therefore, clarifying the pathophysiological processes related to cerebral microcirculation in CSVD is of great significance for early treatment intervention of CSVD.MethodsTwenty rats were used to prepare CSVD animal model by ultrasound combined with ultrasonic microbubble contrast agent. MRI, functional ultrasound (fUS) imaging and ultrasound localization microscopy (ULM) were used to evaluate microcirculation changes in acute and chronic models.ResultsCurrently, our research has successfully validated that the imaging characteristics of this model align with the four established criteria outlined in the STRIVE-2 classification. FUS shows increased microflow velocity in the molding area, which can be used for initial evaluation of CSVD models in the acute phase. ULM has revealed a progressive reduction in the density of both the short cortical arteries and the long medullary arteries, along with their respective branches, over time. Concurrently, there has been a noted deviation in blood flow velocity.ConclusionThis model offers compelling evidence at the microvascular level, suggesting that blood-brain barrier (BBB) dysfunction is a central pathophysiological mechanism in the etiology of CSVD. Then it provides a straightforward, efficient, and widely applicable tool and continuous monitoring method for the further investigation of CSVD from the macroscopic to the microscopic circulation level, with significant long-term implications for CSVD diagnosis and treatment.