Biology subjects

Xu, Y.

Publications and source records attributed to Xu, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2026

Learning the All-Atom Equilibrium Distribution of Biomolecular Interactions at Scale

Biomolecular functions are governed by dynamic conformational ensembles rather than static structures. While models like AlphaFold have revolutionized static structure prediction, accurately capturing the equilibrium distribution of all-atom biomolecular interactions remains a significant challenge due to the high computational cost of molecular dynamics (MD). We present AnewSampling, a transferable generative foundation framework designed for the high-fidelity sampling of all-atom equilibrium distributions, which is the first model to faithfully reproduce MD at the all-atom level. It uses a quotient-space generative framework to ensure mathematical consistency and leverages the largest self-curated database of protein-ligand trajectories to date, with over 15 million conformations. Statistically, AnewSampling consistently outperforms all prior generative methods on the ATLAS monomer benchmark, and the all-atom capabilities of AnewSampling enable close statistical alignment with ground-truth MD for evaluating atomic biomolecular interactions in protein-ligand dynamics. Furthermore, AnewSampling successfully recovers coupled ligand and side-chain motions in CDK2 systems, overcoming a major sampling hurdle inherent to conventional MD. AnewSampling enables rapid exploration of conformational landscapes prior to intensive simulations, elucidating fundamental biophysical mechanisms and accelerating the broader design of functional biomolecules.

bioinformatics↗

bioRxiv2026

CEACAM5/6+ Tumor Cells and IL-1β+ Macrophages Drive Resistance to Chemo-immunotherapy in Gastric Cancer

Chemo-immunotherapy is a first-line treatment for advanced gastric cancer, yet response rates remain limited and resistance mechanisms are poorly defined. Here we generate a single-cell atlas of 542,121 cells from 35 patients treated with anti-PD-1 plus chemotherapy, profiling pre- and post-treatment tumors linked to clinical response. Integrating spatial transcriptomics, immunohistochemistry, and bulk RNA sequencing, we identify two temporally distinct resistance programs. Intrinsic resistance in pre-treatment non-responders is marked by enrichment of CEACAM5/6 tumor cells that form immune-excluded spatial niches characterized by macrophage recruitment and CD8 T-cell exhaustion. Acquired resistance in post-treatment non-responders is driven by expansion of IL-1{beta} macrophages, which induces coordinated NF-{kappa}B activation across tumor and stromal compartments, promoting PD-L1 upregulation, epithelial-mesenchymal transition, and chronic inflammation. These findings delineate an evolutionary trajectory of resistance and nominate CEACAM5/6 and IL-1{beta} as predictive biomarkers and therapeutic targets to improve anti-PD-1-based combination strategies.

cancer biology↗

bioRxiv2026

PROTOTYPE-BASED CONTINUAL LEARNING FOR SINGLE-CELL ANNOTATION

Large-scale single-cell atlases provide an increasingly comprehensive view of cellular diversity, but their continued expansion across studies poses a fundamental challenge: preserving consistent cell identities while capturing biological variation in cellular states. Most existing annotation frameworks are built around static references, making it difficult to incorporate newly generated datasets into established cellular representations without retraining on historical data. When updated sequentially, these methods are further constrained by catastrophic forgetting and batch-specific biases, limiting scalability and the continuity of knowledge integration. Here we introduce scEvolver, a continual learning framework for single-cell annotation that incrementally accumulates knowledge through memory-guided refinement of cell-type prototypes without revisiting historical data. Across sequencing platforms, tissue contexts and molecular modalities, scEvolver supports robust annotation and external query mapping with substantially fewer labelled reference cells. By preserving consistent cell-type semantics across datasets while capturing biologically meaningful within-class heterogeneity, scEvolver enables the identification of epithelial cell-state transitions in inflammatory gut disease. External mapping to the healthy Human Lung Cell Atlas further reveals shared cell-state deviations across multiple diseases, including an FCGR3A+ inflammatory monocyte programme in sarcoidosis, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, highlighting scEvolvers potential to characterize context-specific cellular dynamics in complex disease settings.

bioinformatics↗

bioRxiv2026

Developmental Elimination of Electrical Synapses by UNC-51/UNC-76-Mediated Vesicular Transport

Neural circuit maturation requires precise elimination of transient synaptic connections, but how electrical synapses are eliminated remains unknown. Using C. elegans PLM mechanosensory neurons, we found that gap junctions form transiently during early development and are subsequently eliminated as the circuit matures. These transient electrical synapses drive high-frequency calcium oscillations, and optogenetic ablation of early gap junctions abolishes calcium dynamics and disrupts chemical synapse formation, demonstrating their critical developmental function. Through forward genetic screening, we identified the conserved kinase UNC-51/ULK as essential for elimination. UNC-51 phosphorylates the kinesin adaptor UNC-76/FEZ to initiate RAB-10-dependent retrograde trafficking, progressively depleting innexin proteins from the synaptic site. Disrupting this pathway prevents elimination, causing persistent electrical synapses and neuronal hyperactivity. These findings establish a conserved framework for developmental elimination of functionally essential transient electrical connectivity.

cell biology↗

bioRxiv2026

Mitochondria Organize Gap Junctions to Enable Neural Circuit Scaling

Neural circuits must maintain function during dramatic growth-driven expansion. While chemical synapses can be independently reorganized in pre- and postsynaptic neurons, gap junctions physically couple partner cells, requiring coordinated spatial redistribution--a process whose mechanisms remain unknown. Using the C. elegans mechanosensory circuit, we show that gap junctions undergo stereotyped developmental reorganization, transitioning from clustered to dispersed configurations as partner neurites elongate. Forward genetic screening identified RIC-7, a mitochondrial adaptor protein, as essential for this redistribution. Loss of RIC-7 prevents gap junction dispersal, trapping partner neurites at clustered sites and severely impairing electrical transmission. Mechanistically, RIC-7 directs mitochondrial positioning to gap junctions, where mitochondria recruit the microtubule-organizing component PTRN-1 to locally enhance microtubule dynamics. Disrupting mitochondrial transport (miro-1;mtx-2 mutants) or PTRN-1 function phenocopies ric-7 defects, while metabolic dysfunction does not, establishing a non-metabolic role for mitochondria in organizing synaptic architecture. Remarkably, RIC-7 expression in one neuron alone suffices to restore gap junction and partner neurite distribution across both coupled cells. Structural modeling suggests mechanical adhesion between docked hemichannels enables this coordinated reorganization. These findings establish mitochondria as mobile organizers of synaptic spatial architecture, demonstrate that proper junction distribution is essential for electrical transmission efficacy, and reveal how cell-autonomous mechanisms can achieve bilateral structural coordination during circuit growth.

neuroscience↗

bioRxiv2026

Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13

Intestinal intraepithelial lymphocytes (IEL), including conventional CD8{beta} T resident memory (Trm) cells and unconventional CD8 T cells, promote tissue integrity. Here, we studied the G-protein coupled receptor signals regulating IEL positioning, homeostasis, and function. Deficiency in heterotrimeric G-protein subunit G13 or its effector Arhgef1 caused an intestine-specific loss of all types of CD8+ TCR{beta} and TCR{gamma}{delta} IEL. G13-deficient IEL exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8{beta}+ Trm upon infection was intact in the absence of G13-signaling, but the cells had poor access to the villous niche and defective survival that could be rescued by increasing TGF{beta}+ or interleukin (IL)15. In vivo CRISPR/Cas9 screening identified GPR132 as a G13-coupled receptor that regulates CD8{beta}+ IEL homeostasis and migration to lysophosphatidylcholine. Mice bearing G13-deficient T cells suffered more severe colitis and increased colorectal tumor growth. The selective requirement for G13-signaling for IEL positioning and survival in the villous niche has implications for therapeutic intervention.

immunology↗

bioRxiv2026

ALKBH5 Promotes Hepatic Gluconeogenesis via m6A-mediated Stabilization of Ogt mRNA

Excessive hepatic glucose production is a hallmark of fasting hyperglycemia in type 2 diabetes mellitus, yet the epitranscriptomic mechanisms that sustain this dysregulation remain incompletely understood. Here, we show that dexamethasone/forskolin-induced gluconeogenic activation triggers widespread remodeling of RNA m6A methylation in mouse primary hepatocytes. Among the m6A regulators examined, the demethylase ALKBH5 is robustly induced both in vitro and in fasted livers. This induction is mediated by the glucocorticoid receptor, which binds to the Alkbh5 promoter and activates its transcription. Functionally, ALKBH5 overexpression enhances gluconeogenic gene expression and glucose production, whereas both global and hepatocyte-specific Alkbh5 knockout mice exhibit suppressed hepatic gluconeogenesis. Mechanistically, we identify Ogt as a primary downstream target, defining an ALKBH5-OGT epitranscriptomic axis in hepatocytes. ALKBH5 demethylates and stabilizes Ogt mRNA, thereby elevating OGT expression and promoting gluconeogenic gene expression. Consistently, the pro-gluconeogenic effects of ALKBH5 are largely abrogated by OGT knockdown. Finally, pharmacological inhibition of ALKBH5 with 18l effectively improves glucose tolerance and suppresses hepatic gluconeogenesis in both wild-type and db/db mice. Together, these findings reveal a glucocorticoid-responsive epitranscriptomic mechanism whereby ALKBH5 stabilizes Ogt mRNA to drive gluconeogenesis and highlight ALKBH5 as a promising therapeutic target for type 2 diabetes mellitus.

molecular biology↗

bioRxiv2026

Spinal cord regeneration deploys adult molecular programs that do not recapitulate embryonic development

Adult zebrafish reverse paralysis after spinal cord injury. Their regenerative capacity is stem cell-dependent and often attributed to potent progenitors that retain embryonic radial glial features and reenact developmental programs after injury. To explore the extents to which regeneration recapitulates development, we integrated single-cell RNA-sequencing datasets spanning development, adult homeostasis and adult regeneration. We found immune cell maturation and neuronal differentiation extend into the juvenile stages, while only 25% of injury-responsive adult progenitors recapitulate larval progenitor identities. By annotating larval progenitors based on their dorso-ventral identities and chronological age, we inferred the spatio-temporal features of adult sox2+ progenitors. This analysis showed the dorso-ventral progenitor identities that guide spinal cord development are not faithfully maintained in homeostatic or regenerating adults. This study reports a genome-wide, single-cell examination of similarities and differences between development and regeneration and indicates adult tissue regeneration repurposes developmental pathways into newly acquired regenerative functions rather than recapitulating development.

developmental biology↗

bioRxiv2026

A cryo-EM processing pipeline for microtubules using CryoSPARC

Microtubules are cytoskeletal filaments typically characterized by a discontinuous helical lattice of /{beta}-tubulin heterodimers. Microtubules can also adopt variable lattice architectures both in vitro and in cellular contexts. Pseudo-helical averaging processing strategies have been developed to generate cryo-EM reconstructions of microtubules with and without decorating protein-binding partners, but these pipelines can be difficult to implement for the average user, especially for undecorated filaments. Here, we describe MiCSPARC, a cryo-EM processing pipeline developed around CryoSPARC (Punjani et al., 2017), which leverages automated particle picking and fast 3D refinement times in CryoSPARC to determine structures of both decorated and undecorated microtubules. We generated reconstructions of undecorated GDP microtubules, as well as kinesin-1 motor domain-decorated GMPCPP filaments at resolutions of up to 2.8 [A], demonstrating the robustness of the pipeline. Based on its convenient implementation and ability to routinely generate high-resolution, seam-corrected microtubule reconstructions, MiCSPARC should provide a valuable tool for understanding microtubule dynamics, microtubule-associated proteins, and microtubule-targeting agents.

biophysics↗

bioRxiv2026

Vagus Nerve Stimulation Ameliorates Epilepsy via a Gut Microbiota-Butyrate-Vagus Nerve-Brain Axis

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical-translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve-dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid-producing bacteria, including Akkermansia muciniphila, Prevotella, Alistipes, and Odoribacter. Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota-butyrate-vagal pathway essential for the therapeutic effects of VNS, highlighting the gut-brain axis as a target for epilepsy treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/707138v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@8243e6org.highwire.dtl.DTLVardef@37f0e6org.highwire.dtl.DTLVardef@a8b321org.highwire.dtl.DTLVardef@1887342_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIVagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. C_LIO_LIVNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila, in both humans and mice. C_LIO_LITransplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. C_LIO_LIAkkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway. C_LI

neuroscience↗

bioRxiv2026

ProtFlow: Flow Matching-based Protein Sequence Design with Comprehensive Protein Semantic Distribution Learning and High-quality Generation

Designing protein sequences with desired properties is a fundamental task in protein engineering. Recent advances in deep generative models have greatly accelerated this design process. However, most existing models face the issue of distribution centralization and focus on local compositional statistics of natural sequences instead of the global semantic organization of protein space, which confines their generation to specific regions of the distribution. These problems are amplified for functional proteins, whose sequence patterns strongly correlate with semantic representations and exhibit a long-tailed functional distribution, causing existing models to miss semantic regions associated with rare but essential functions. Here, we propose ProtFlow, a generative model designed for comprehensive semantic distribution learning of protein sequences, enabling high-quality sequence generation. ProtFlow employs a rectified flow matching algorithm to efficiently capture the underlying semantic distribution of the protein design manifold, and introduces a reflow technique enabling one-step sequence generation. We construct a semantic integration network to reorganize the representation space of large protein language models, facilitating stable and compact incorporation of global protein semantics. We pretrain ProtFlow on 2.6M peptide sequences and fine-tune it on antimicrobial peptides (AMPs), a representative class of therapeutic proteins exhibiting unevenly distributed activities across pathogen targets. Experiments show that ProtFlow outperforms state-of-the-art methods in generating high-quality peptides, and AMPs with desirable activity profiles across a range of pathogens, particularly against underrepresented bacterial species. These results demonstrate ProtFlows effectiveness in capturing the full training distribution and its potential as a general framework for computational protein design.

bioinformatics↗

bioRxiv2026

Multi-agent reasoning enables predictive design of living materials

Artificial intelligence is increasingly used to accelerate scientific discovery, but most successful frameworks operate within well-defined molecular, protein or materials spaces. Living materials present a more formidable computational problem because functions emerge from context dependent coupling among cells, matrices, fabrication processes and evaluation conditions. Here we introduce LiveMat, a multi-agent reasoning framework that transforms unstructured literature into a computable design space for living materials. LiveMat standardizes 34,215 living material records, integrating 16,769 microorganism and 17,446 polymer entries into a knowledge graph linking living components, abiotic matrices, functional outputs, evaluation contexts and performance metrics. Benchmarking across five large language models shows that living material reasoning is limited mainly by cross-domain feature integration rather than coarse classification. LiveMat overcomes this limitation through constraint decomposition, provenance-aware extraction, consistency checking and expert-anchored ranking. In a prospective wound-healing task, it prioritizes a four-component design with state-of-the-art in vivo performance, establishing a scalable infrastructure for interpretable, evidence-grounded living material discovery.

biochemistry↗

bioRxiv2026

Identification of a neural basis for anorexia nervosa

Anorexia nervosa (AN) is a severe, often fatal, psychiatric disorder characterized by self-imposed food restriction, hyperactivity, and profound affective disturbances. Despite its high morbidity and mortality, the neural mechanisms underlying AN remain poorly defined, largely because no animal model has fully recapitulated its core behavioral manifestations. Here, we demonstrate that aberrant activation of glutamatergic neurons in the mediobasal hypothalamus (MBH) is sufficient to induce AN-like phenotypes in mice, including self-starvation leading to death, hyperactivity, anhedonia, social avoidance, and heightened anxiety, which were reproduced by targeted activation of MBH neurons expressing steroidogenic factor 1 (SF1)/ estrogen receptor (ER). Mechanistically, the AN-like phenotypes were rescued by ablating release of glutamate or brain-derived neurotrophic factor (BDNF). Conversely, BDNF overexpression in SF1/ER neurons was sufficient to promote AN-like behaviors through increasing glutamate release. Thus, BDNF-dependent enhancement of glutamatergic signaling from SF1/ER neurons drives AN-associated phenotypes, providing a potential target for therapeutic intervention.

neuroscience↗

bioRxiv2026

Zwitterionic polymer coating enabled chronic dopamine sensing and electrophysiology recording in free-moving mice

The brains complex network relies on both electrical and chemical signaling to support its physiological and cognitive functions. To fully understand neural circuit dynamics and their dysfunctions, it is crucial to simultaneously detect neurotransmitters and modulators alongside electrophysiological signals. The striatal dopamine circuits are integral to neurological processes such as movement, reward, learning, and circadian rhythm regulation, making it highly desirable to monitor both neural activity and dopamine (DA) levels in freely behaving animals. One promising approach involves the implantation of multimodal microelectrode arrays (MEAs). However, chronic electrochemical sensing of DA in freely moving animals faces significant challenges, including biofouling of sensing electrodes and the instability of Ag/AgCl reference electrodes. In this study, we developed two complementary strategies--surface grafting and photo crosslinking--to coat the MEA and implanted Ag/AgCl reference electrodes, respectively, with zwitterionic poly(sulfobetaine methacrylate) (PSB). The surface-grafted thin PSB coating effectively inhibits protein fouling and inflammatory responses to the MEA, while the PSB hydrogel protects the Ag/AgCl electrodes from delamination in vivo, ensuring a stable reference potential. By coating both the Ag/AgCl reference electrodes and flexible polyimide MEAs with PSB and PEDOT/CNT, we achieved stable DA detection and electrophysiological recordings in freely moving mice over a four-week period. Weekly electrochemical impedance spectroscopy confirmed the long-term stability of the implanted electrodes. Our method enables multidimensional analysis of behavioral patterns, electrophysiological activity, and DA dynamics, providing a comprehensive approach for neuroscience research. This work advances neurochemical and electrophysiological methodologies by offering reliable tools for longitudinal investigations of brain function in freely behaving animals.

bioengineering↗

bioRxiv2026

Characterization of the Gut Microbiota and Serum Metabolomics in Patients with Type 2 Diabetes Mellitus and Newly Diagnosed Acute Coronary Syndrome

Biomarkers for the early identification of acute coronary syndrome (ACS) risk remain inadequately investigated, particularly in patients with type 2 diabetes mellitus (T2DM), for whom timely clinical intervention may substantially enhance prognostic outcomes. The gut microbiota and serum metabolites may serve as pivotal mediators in the occurrence and progression of ACS among patients with T2DM, and whether these factors can be used for the precise discrimination of patients with T2DM complicated by ACS remains to be explored. Overall, 76 participants were enrolled (38 patients diagnosed with T2DM complicated by ACS and another 38 with T2DM without ACS). 16S rRNA sequencing combined with untargeted LC-MS metabolomics revealed a dysregulated gut-serum axis in patients with T2DM complicated by ACS: enrichment of proinflammatory microorganisms (Enterococcus spp.), reduction of butyrate producers (Butyricimonas spp.) and concomitant dysregulation of circulating lipid metabolites-upregulation of PC(16:0/9:0 (CHO)) and arachidonic acid alongside downregulation of cholesterol sulfate. By integrating multiomics data and applying various feature selection methods, we subsequently identified six key biomarkers. The final constructed combined model robustly distinguished patients with T2DM complicated by ACS from those with T2DM alone (AUC = 0.983), outperforming the other single omics models. Our study revealed that the gut microbiota and related serum metabolites serve as key mediators in the onset and progression of ACS among patients with T2DM, and demonstrated their potential value as noninvasive biomarkers for the early diagnosis of T2DM complicated by ACS. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSWe combined 16S rRNA sequencing with untargeted LC-MS metabolomics to dissect the gut-serum axis in patients with T2DM complicated by newly diagnosed ACS. We identified distinct gut microbial and serum metabolic signatures that distinguish ACS progression within the T2DM population. A multiomics classifier integrating clinical, microbial, and metabolic variables achieved robust diagnostic performance (AUC = 0.983) and outperformed single omics models. What Are the Clinical Implications?Integrated multiomics biomarkers facilitate the early identification of ACS progression in patients with T2DM, offering novel avenues for precision prevention, dynamic clinical surveillance, and individualized therapeutic strategies. Dysregulations of the gut microbiota and serum metabolome may play an important role in the development and progression of ACS in patients with T2DM.

microbiology↗

bioRxiv2026

Individual Brain Structure Deviations and its Gene Expression Signatures in Early-Onset Schizophrenia

BackgroundSchizophrenia is a highly heritable mental disorder associated with widespread anatomical alterations during neurodevelopment. Converging evidence suggests transcriptomic architecture underlying brain abnormalities in schizophrenia, while how individualized brain morphological deviations relate to gene expression levels remains unclear. MethodsTo investigate individual-level brain deviations and its transcriptomic signatures in schizophrenia, this study collected T1-weighted MRI data from 95 early-onset schizophrenia (EOS) patients and 99 typically developing (TD) controls. Normative modeling was used to measure individual deviations in cortical thickness and subcortical volume. Partial least squares regression was calculated to capture covarying patterns between structural deviations and whole-brain gene expression levels. Clustering analysis was performed on latent brain-gene covarying components, and the results were further functionally decoded through gene enrichment analyses. ResultsGroup-level comparisons suggested patients with EOS showed consistently decreased z-scores of cortical thickness in the frontal and temporal lobe regions, while increased inter-individual variability in the lingual gyrus. Clustering analysis of z-scores with transcriptomic signatures identified two distinct brain-gene covarying subtypes. Subtype 1 showed thickening cingulate gyrus, thinning occipital pole, and atrophic subcortical nuclei. Subtype 2 exhibited widespread cortical thinning across the frontal, parietal, temporal, and limbic regions, but enlarged subcortical nuclei. Genes underlying two subtypes were both enriched for neurodevelopmental diseases. However, subtype 1 was associated with synaptic transmission, and subtype 2 was related to cytoskeletal and neuronal connectivity. ConclusionThis study reveals individual-level anatomical deviations and transcriptomic heterogeneity in early-onset schizophrenia. The findings provide an individualized brain-gene coupling framework for understanding pathophysiology of schizophrenia during brain development.

molecular biology↗

bioRxiv2026

Transient activation of potent progenitor cells is required for spinal cord regeneration

Adult zebrafish exhibit full recovery following spinal cord injury. Transient expansion of stem cell-like progenitors is thought to underlie their regenerative capacity. Yet, our understanding of the identities and contributions of the crucial stem cell populations that direct spontaneous neural repair remains limited. Moreover, while most neural regeneration research is centered on promoting proliferative repair, the regulatory mechanisms that reinstate quiescence post-repair are unknown. Here, we determined the molecular identities and cellular contributions of sox2+ progenitors during spinal cord repair. Genetic lineage tracing shows zebrafish spinal progenitors, while quiescent in uninjured tissues, self-renew and differentiate into neurons and glia after injury. By single-cell sequencing, sox2+ cells are heterogeneous and biased towards neuronal or glial fates in both homeostatic and regenerating tissues. By screening for transcription factors that are differentially expressed in acute versus chronic spinal cord injury, we find the Bach1 transcription factors control transient progenitor cell activation by acting as dual activators and repressors of sox2 expression. This study elucidates the molecular diversity and contributions of sox2 expressing cells during spinal cord repair and identifies a transcriptional regulatory switch by which progenitor cells expand after injury and restore quiescence after regeneration is completed.

neuroscience↗

bioRxiv2026

The orientation of cholesterol's hydroxyl group affects its membrane dynamics and intracellular transport

The brain, though less than 10% of body mass, contains about 25% of total cholesterol (CHL), emphasizing CHLs key role in neuronal function. Many CHL actions are stereospecific, as shown by differences from its 3-hydroxy epimer, epicholesterol (epiCHL). How this minor structural change alters membrane properties and sterol transport remains unclear. Here, we compare fluorescent analogs of CHL (cholestatrienol, CTL) and epiCHL (epicholestatrienol, epiCTL), which closely mimic their natural counterparts. Biophysical membrane properties, such as flip-flop, acyl-chain ordering, and interbilayer transfer, depend on the orientation of the 3-hydroxy group. Similarly, transport by sterol transport proteins (STPs) and intracellular trafficking of the sterols in human astrocytes are stereospecific. Treatment with 25-hydroxycholesterol increases uptake of both epimers, but only CTL shows enhanced esterification and lipid droplet storage. These findings demonstrate that subtle cholesterol structural changes affect cellular homeostasis and establish epiCTL as a useful probe of sterol stereospecificity and trafficking.

biophysics↗