Biology subjects

Qin, W.

Publications and source records attributed to Qin, W..

At least 19 recordsLinked to original sources

bioRxiv2026

Charting sex divergence in the human brain across the lifespan

Biological sex fundamentally shapes human brain organization, but sex-specific normative neuroanatomical trajectories across the lifespan remain largely uncharted. Here, we constructed independent, sex-specific lifespan brain charts using structural neuroimaging data from 59,915 healthy individuals (29,760 males and 30,155 females) ranging in age from 266 postconception days to 100 years. By examining 296 structural phenotypes across global, cortical, and subcortical measures, these models revealed widespread sex differences in maturational timing, with males reaching peak milestones later than females. These trajectories demonstrate that sex differences evolve dynamically, with phenotype-specific windows of emergence and maximal separation. Compared with conventional sex-pooled references, sex-specific models achieved superior predictive accuracy and reduced misestimation of individual deviations in healthy populations. Across five neuropsychiatric conditions, sex-specific models improved the detection of extreme deviations and revealed both shared and sex-dependent patterns of disorder-related neuroanatomical abnormalities. These sex-specific charts establish tailored normative references for assessing brain development, ageing, and disease.

neuroscience↗

bioRxiv2026

Computational design of a versatile, zero-radius proximity labeling enzyme

The ability to map protein interactomes and organelle proteomes is foundational for achieving a molecular understanding of living cells. Proximity labeling (PL) provides a powerful strategy for this, but existing enzymes and photocatalysts are limited by their spatial resolution, reliance on biotin, and/or in vivo compatibility. Here we report FlexID, an engineered promiscuous ligase that catalyzes the rapid attachment of diverse small-molecule probes to proximal endogenous proteins. Critically, FlexID operates through a zero-radius, direct-contact mechanism, offering superior spatial precision compared to existing PL tools. We engineered FlexID by combining the strengths of sequence- and structure-trained computational models to enhance its catalytic activity and structural stability. Biophysical analysis revealed that specific conformational changes in FlexID improve its ability to recognize diverse target proteins while simultaneously preventing the premature release of the reactive intermediate. We demonstrate FlexID's versatility through in vivo proximity labeling, comprehensive organelle proteome mapping, and a high-throughput, fluorescence-based screen for molecular glues. Our work shows that computational methods can be harnessed to create mechanistically distinct PL enzymes and establishes FlexID as a flexible, high-resolution tool for mapping protein interactions and proteomes in living cells.

bioengineering↗

bioRxiv2026

A novel AR molecular glue degrader via bivalent engagement of the N-terminal domain and RNF213-UBE2J2 complex

Targeted protein degradation enables the elimination of disease-relevant proteins through induced proximity between E3 ligases and substrates. Current androgen receptor (AR) therapies act via the ligand-binding domain (LBD) but fail against constitutively active LBD mutants or splice variants such as AR-V7. Here, we identify GZL626, a small-molecule degrader that induces proteasome-dependent degradation of both full-length AR and AR-V7. GZL626 suppresses AR transcriptional activity, inhibits proliferation of AR-positive prostate cancer cells, and blocks SARS-CoV-2 infection. Mechanistically, GZL626 binds the intrinsically disordered AR N-terminal domain (NTD) and promotes formation of a noncanonical RNF213-UBE2J2-AR ternary complex that drives AR ubiquitination and degradation. The AR DNA-binding domain (DBD) acts as a structural hub within this assembly. Distinct from PROTACs or classical molecular glues, GZL626 engages both AR and RNF213 bivalently, remodeling protein interactions to stabilize a functional E3-E2-substrate complex. These findings establish GZL626 as a first-in-class NTD degrader with potential to overcome resistance in advanced prostate cancer.

biophysics↗

bioRxiv2026

Multidimensional atlas of RNA-regulated proteins revealed by RNA-dependent thermal proteome profiling

RNA and proteins interact pervasively in cellular processes, yet the functional relevance of most RNA-binding proteins remains unknown. To address this, we developed RNA-dependent thermal proteome profiling (RTPP), a method that identifies RNA-regulated proteins (RRPs) by detecting changes in a proteins structural stability upon RNA binding, without requiring crosslinking or enrichment. Applying RTPP in HEK293T cells revealed 1,664 RRPs, including 257 previously undetected RNA-binding "orphans". One such orphan, SGK3, binds the lncRNA CASC15, facilitating its PtdIns(3)P binding, endosomal recruitment and kinase activity. We further generated a tissue-specific RRP atlas, identifying interactions unique to particular organs, including hippocampus-specific RRPs dysregulated in Alzheimers disease. Integrating RTPP with proximity labeling resolved RNA-binding heterogeneities across subcellular compartments. Live-cell RNase treatment also uncovered proteins associated with cell surface RNA, revealing that RO60 form nanoscale clusters with glycoRNA. RTPP provides a powerful approach to decipher functional RNA-protein interactions across multiple biological dimensions.

molecular biology↗

bioRxiv2026

Heterochromatin organization and liquid-liquid phase separation: it is not about if but about when

Heterochromatin is a membraneless compartment within the cell nucleus. In recent years, a controversy arose on whether heterochromatin organization is driven by liquid-liquid phase separation or not. While many heterochromatin proteins were shown to undergo liquid-liquid phase separation in vitro, other studies reported that this does not happen in cells. Here, we tested the ability of heterochromatin proteins to generate heterochromatin barrier compartments in cells. We found that, while several proteins (H1.0, H1.4, HP1alpha, HP1beta, Mbd1, Mbd2 and MeCP2) form barrier compartments in mouse and/or human cells this differs between cell types. In addition, not all compartments in the same cell form barriers. We established and experimentally validated a model that predicted the ability to form barrier compartments is dependent on the protein accumulation in heterochromatin followed by the competition between compartments for the nucleoplasm pool of the protein and resulted in larger size for the barrier compartments. These findings resolve the existing controversy and rationalize how in cells heterochromatin compartments form and compete to establish dynamic barriers to the entry and exit of its components. HighlightsHeterochromatin barrier formation differs between proteins, cell lines and heterochromatin compartments within the cell. Barrier formation depends on heterochromatin anchors, including ligands and other scaffolds. Barrier compartments are defined by their larger size and higher protein enrichment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/729812v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@a63021org.highwire.dtl.DTLVardef@a20362org.highwire.dtl.DTLVardef@8c2390org.highwire.dtl.DTLVardef@72dde3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

A Long-lived Avatar for Modeling Age-Related Vascular Disease

BackgroundCurrent microphysiological models do not support long-term investigations into the chronic effects of vascular risk factors and the development of vascular diseases. Prolonged culture frequently leads to cellular senescence and loss of functional integrity, resulting in variability and inconsistency in modeling chronic vascular responses. Here we aimed to develop and sustain a long-term multicellular human vascular avatar, addressing the critical need for long-term disease modeling and drug testing. MethodsTo identify the optimal media for longevity, cell identity and function were assessed by morphology, qPCR, beta-gal staining, ELISA, bulk RNA-seq and single cell RNA-seq analysis. After optimizing the culture media, iPSCs-derived ECs and VSMCs from unaffected and Hutchinson-Gilford Progeria Syndrome (HGPS) donors were grown in Gravitational Lumen Patterning (GLP) Vessel- Chips for 1-6 months to generate a long-lived vascular avatar for the study of vascular aging. ResultsGuided by quantitative morphological analyses and bulk RNAseq profiling, we generated a novel optimized culture media VSL (VEGF, SB431542 as a TGF-{beta} inhibitor, low fetal bovine serum) that enhances the long-term health of vascular endothelial cells (ECs). Furthermore, we modified the VSL formulation (mVSL) by modulating 8Br-cAMP, FGF, PDGF, and a cell viability enhancer HMH1015 levels to enhance EC-VSMC (vascular smooth muscle cell) crosstalk and support long-term cellular viability. Subsequently, we maintained and characterized a human vascular avatar with a three-dimensional extracellular matrix environment and 3D vascular architecture for over 180 days. Finally, we demonstrated that this long-lived human vascular avatar enabled modeling vascular aging using iPSC-derived vascular cells from patients with Hutchinson-Gilford Progeria Syndrome (HGPS). ConclusionsWe have successfully engineered and maintained a human vascular avatar for over 180 days. The vascular avatar provides a robust platform for modeling disease-associated vascular aging and for evaluating therapeutic strategies targeting chronic vascular disorders.

bioengineering↗

bioRxiv2026

Sex stratified analyses enable new genetic insights into brain imaging phenotypes

Sex differences are commonly observed in neuroimaging phenotypes and in the risk of brain diseases, yet the underlying genetic mechanisms remain poorly understood. We investigated sex differences in the genetic architecture of 805 neuroimaging phenotypes in 22,950 males and 22,950 females matched for sample size and covariates, and systematically compared sex-stratified with sex-combined genetic analyses. We found eight variant-trait associations with significant sex differences, 235 fine-mapped sex-dominant causal associations, 457 sex-dominant colocalizations with sex hormones, and 96 sex-dominant colocalizations with schizophrenia. Compared with sex-combined analysis, sex-stratified analysis identified 47 new genetic associations, 170 new fine-mapped causal associations, 1,019 new colocalizations with sex hormones, and 191 new colocalizations with schizophrenia. Additionally, sex-stratified analysis improved global heritability and genetic-correlation estimates and enhanced polygenic prediction for certain phenotypes. This work highlights the need to routinely perform sex-stratified genetic association analyses to elucidate sex-specific and sex-shared genetic control of neuroimaging phenotypes and related disorders.

genetics↗

bioRxiv2026

Whole-brain cellular-resolution functional network properties of seizure susceptibility

Despite its prevalence and clinical impacts, epilepsy remains incompletely understood in terms of the population dynamics that mediate seizure susceptibility, initiation, and propagation across brain-wide networks. In this study, we have performed calcium imaging in zebrafish, brain-wide and at cellular resolution, at baseline and as seizures are induced using the GABAA receptor antagonist pentylenetetrazol (PTZ). We have then modeled the network architecture in wild-type and scn1lab-/- larvae, which are seizure-prone and serve as a model for Dravet syndrome. scn1lab-/- larvae show increased pair-wise correlations between neurons when exposed to PTZ, and graph analyses of these correlations revealed genotype-specific network alterations during seizures, identifying regions and metrics linked to seizure onset. Using generative network modeling, we then explored the wiring rules that govern activity in these networks, identifying specific network properties linked to seizure susceptibility that were only detectable using large-scale, cellular-resolution data. Even at baseline in the absence of seizures, these rules differed by genotype in a way that enabled the identification of scn1lab-/- larvae and predicted individuals seizure risk independently of their observable phenotype. These findings uncover the cellular-resolution network properties of a zebrafish model of Dravet syndrome and establish a predictive framework for seizure susceptibility grounded in multi-scale functional connectivity.

neuroscience↗

bioRxiv2026

Gq-pathway activation in hippocampal CA1 astrocytes rescues ischemia-induced memory deficits and synaptic plasticity

More than 30% of stroke survivors develop post-stroke cognitive impairment (PSCI), for which current neuron-centric therapies not only lack cellular specificity but also carry risks of adverse effects such as epilepsy. Here, we explore the therapeutic potential of astrocytes by chemogenetically activating Gq signaling in hippocampal astrocytes, which rescues memory deficits and synaptic plasticity impairments in a mouse model of ischemic stroke. Gq activation restores dendritic complexity, spine density, and long-term potentiation in hippocampal CA1 neurons. Fiber photometry further reveals that astrocytic Ca{superscript 2} signals precede neuronal activity by 600 ms during novel environment exploration, indicating that astrocytes prime memory encoding. In contrast, Gi pathway activation induces pathological neuronal hyperactivity without cognitive improvement. These findings establish that astrocytes regulate post-stroke recovery through pathway-specific calcium signaling and uncover a previously unknown temporal hierarchy in astrocyte-neuron communication during memory processing, offering a new glia-targeted strategy to overcome the limitations of current neuromodulation approaches for PSCI.

neuroscience↗

bioRxiv2026

In vivo-compatible spatial multi-omics via hydrogen peroxide-independent APEX2 labeling

Proximity labeling (PL) technologies like APEX2 have transformed spatial multi-omics in live cells, but their long-standing dependence on hydrogen peroxide (H2O2) disrupts redox signaling and prevents use in live animals. Here we introduce H2O2-independent APEX2 (Hi-APEX), which uses a clickable tetrazine-phenol probe, requiring no enzyme engineering. We show that APEX2 directly catalyzes TP radical formation without H2O2 via a mechanism requiring the probes tetrazine group and a key histidine residue. We benchmarked Hi-APEX-based spatial multi-omics by mapping the mitochondrial matrix and dynamic secretomes. Hi-APEX significantly outperforms traditional APEX in capturing redox-sensitive processes such as stress response and ferroptosis, enabling discovering authentic stress granule components and protein interaction networks for mitochondria-localized GPx4. One mGPx4 interactor TRMT61B--known to regulate mitochondrial m{superscript 1}A modifications--promotes ferroptosis. Crucially, Hi-APEX achieves full in vivo compatibility, enabling direct PL in tumor xenografts and hippocampal neurons, thereby expanding PL-based spatial multi-omics from cellular systems to living organisms.

biochemistry↗

bioRxiv2026

Large-scale quantum computing framework enhances drug discovery in multiple stages

Coherent Ising machines (CIMs) excel at solving large-scale combinational optimization problems (COPs), but their insufficient long-term stability has hindered their applications in compute-intensive tasks like computer-aided drug discovery (CADD). By improving fiber vibration isolation and temperature control system, we have implemented a 2000-node CIM named QBoson-CPQC-3Gen achieving stable solutions over one hour on large-scale COPs. Graph-based encoding schemes were further introduced to realize a CIM-based CADD workflow including allosteric site detection, protein-peptide docking and intermolecular similarity calculation. CIM-based methods demonstrated superior speed and accuracy than heuristic algorithms. Especially, QBoson-CPQC-3Gen identified 2 novel druggable sites and bioactive compounds for 6 targets, which were further validated in vitro, in-cell and by crystal structures. Our contributions established a quantum-computing framework for multi-stage drug discovery, representing a significant advancement in both quantum computing applications and pharmaceutical research.

bioinformatics↗

bioRxiv2026

CLEAR-HPV: Interpretable Concept Discovery for HPV-Associated Morphology in Whole-Slide Histology

Human papillomavirus (HPV) status is a critical determinant of prognosis and treatment response in head and neck and cervical cancers. Although attention-based multiple instance learning (MIL) achieves strong slide-level prediction for HPV-related whole-slide histopathology, it provides limited morphologic interpretability. To address this limitation, we introduce Concept-Level Explainable Attention-guided Representation for HPV (CLEAR-HPV), a framework that restructures the MIL latent space using attention to enable concept discovery without requiring concept labels during training. Operating in an attention-weighted latent space, CLEAR-HPV automatically discovers keratinizing, basaloid, and stromal morphologic concepts, generates spatial concept maps, and represents each slide using a compact concept-fraction vector. CLEAR-HPVs concept-fraction vectors preserve the predictive information of the original MIL embeddings while reducing the high-dimensional feature space (e.g., 1536 dimensions) to only 10 interpretable concepts. CLEAR-HPV demonstrates consistent concept structure across TCGA-HNSCC, TCGA-CESC, and CPTAC-HNSCC, providing compact, concept-level interpretability through a general, backbone-agnostic framework for attention-based MIL models of whole-slide histopathology. All original code, preprocessing scripts, and trained model checkpoints are available on GitHub (https://github.com/Wang-ML-Lab/CLEAR-HPV))

bioinformatics↗

bioRxiv2025

MicroRNA-383-5p alleviates hemorrhagic transformation and improves outcomes after endovascular recanalization for acute ischemic stroke

BackgroundHemorrhage transformation (HT) after reperfusion therapy is linked with poor outcomes in acute ischemic stroke patients. This study aimed to determine the role of neuronal microRNA-383 in alleviating HT-associated injury using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation reoxygenation (OGD/R) models. MethodsIn neurons following OGD/R, the family of miR-383 and NADPH oxidase (NOX) expression was evaluated. After miR-383-5p intervention and small interfering RNA, reactive oxygen species (ROS) and neuronal injury were assessed. Two hundred and five hyperglycemic rats were used to establish the HT model induced by mechanical reperfusion after 5-hour MCAO, followed by 3 and 6 hours of reperfusion, and treated with intravenous administration of miR-383-5p agomir before reperfusion. Brain water content, hemorrhage severity, infarct volume, blood-brain barrier (BBB) disruption, neuronal apoptosis, ROS production, miR-383-5p and NOX4 expression, and BBB-associated proteins were assessed. ResultsMiR-383-5p expression significantly decreased in OGD/R-treated neurons, while miR-383-3p expression did not differ. Elevating miR-383-5p levels reduced neuronal injury, ROS overproduction, and NOX4 overexpression as a target of miR-383-5p, shown in OGD/R-treated neurons. In the MCAO model, increased miR-383-5p suppressed NOX4 upregulation, alleviated brain edema, infarct volume, and hemorrhage severity, reduced neuronal apoptosis and ROS overproduction, and preserved BBB integrity after mechanical reperfusion for ischemia, thereby improving short-term neurological outcomes. ConclusionsMiR-383-5p alleviates oxidative stress injury and neuronal apoptosis, and preserves BBB integrity by regulating NOX4. Neuronal miR-383-5p could become a potential target for intervention to decrease HT and ameliorate outcomes in endovascular reperfusion treatment for acute ischemic stroke.

neuroscience↗

bioRxiv2025

Sampling Function-Related Metastable States of Proteins With DASH

Rational discovery of function-specific protein modulators as well as activity-enhanced engineering proteins underscore the need to identify function-related metastable states (FMSs) of proteins. However, current experimental and computational methods struggle to generate these states directly from their native state (NS), likely because the NS [->] FMS transition is non-spontaneous. To address this challenge, we introduce Deep learning guided Adaptive sampling with seed Selection and Hopping (DASH), integrating both deep learning and physical functions to guide molecular dynamics (MD) simulation towards FMS. DASH successfully sampled NS [->] FMS transitions in 18 cases across two tasks: protein activation and cryptic allosteric site opening. DASH combined with secondary-structure collective variables is further able to sample folding of disordered regions. Compared to existing methods, DASH demonstrates superior performance while requiring comparable simulation time. Crucially, we applied DASH to sample new conformations of proteins, by which revealing new folding states, previously unknown allosteric sites, and potential activators. These predictions have been further verified in wet-lab experiments and crystal structures determinations. Collectively, our framework provides a robust strategy for function-specific pharmacy research and could accelerate future drug discovery efforts.

bioinformatics↗

bioRxiv2025

Mapping Core Components of Membrane-less Organelles in Living Cells by Phase-APEX2 Proximity Labeling

Membrane-less organelles (MLOs), formed via liquid-liquid phase separation, are crucial for organization of biomacromolecules and cellular processes, yet their dynamic nature challenges compositional analysis. Conventional proximity labeling methods lack the specificity to overcome high background and systematic biases inherent in studying these condensates. Here we introduce Phase-APEX2, a three-input AND-gate strategy that dramatically enhances labeling specificity. By integrating a split-APEX2 system with a light-controlled H2O2 generator, we developed Phase-APEX2 platforms for two application contexts: Phase-APEX2-MS for proteomics and Phase-APEX2-seq for genomics. Our analyses revealed not only the core interactomes of the nucleolus and stress granules with high accuracy but also uncovered distinct "molecular grammars" governing their assembly and a surprising link between nucleolar dynamics and the transcriptional regulation of mitosis-related genes. This highly specific and adaptable platform opens new avenues for exploring the composition and function of diverse biomolecular condensates.

cell biology↗

bioRxiv2025

Elevated Temperatures Representing Heatwave Conditions Shift Active Nitrifying Communities and Their Viruses in Tidal Flats and Agricultural Soils

Global heatwave intensification associated with climate change will impact the nitrogen cycle, yet its effect on specific nitrifier groups or their interactions with viruses remains unclear. Using 13CO2-DNA-based stable isotope probing (SIP) coupled with metagenomics, we show that elevated temperatures associated with heatwave conditions restructure active nitrifying communities and their viruses in Yangtze River estuary tidal flats and adjacent agricultural soils. In tidal flats, high temperatures shifted active ammonia-oxidizing archaea and bacteria (AOA and AOB), and nitrite-oxidizing bacteria (NOB) from marine to terrestrial ecotypes. In contrast, heatwave conditions stimulated terrestrial ecotypes of AOA but suppressed AOB in agricultural soils. 13C-labeled nitrifier-infecting viruses also showed temperature-driven shifts in activity, lifestyle, and auxiliary metabolic genes in concert with hosts. Notably, AOA viruses carried the plastocyanin gene, potentially augmenting host metabolism. These findings demonstrate heatwaves drive complex shifts in nitrifier communities and their interactions with viruses, impacting global nutrient cycling under climate extremes.

microbiology↗

bioRxiv2025

Endocytome profiling uncovers cell-surface protein dynamics underlying neuronal connectivity

Endocytosis actively remodels the neuronal surface proteome to drive diverse cellular processes, yet its global extent and circuit-level consequences have defied comprehensive interrogation. Here, we introduce endocytome profiling: a systematic, cell-type-specific approach for mapping cell-surface protein (CSP) dynamics in situ. Quantitative proteomic analysis of developing olfactory receptor neuron (ORN) axons generated an endocytic atlas comprising over 1,100 proteins and revealed the extent to which the surface proteome is remodeled to meet distinct developmental demands. Targeted interrogation of a junctional CSP showed that its endosome-to-surface ratio is precisely balanced to enable developmental axon pruning while preserving mature axon integrity. Multi-omic integration uncovered wide-spread transcellular signaling and identified a growth factor secreted by neighboring neurons to direct ORN axon targeting via endocytic regulation of its receptor. Endocytome profiling thus provides unprecedented access to cell-surface proteome dynamics and offers a powerful platform for dissecting proteome remodeling across diverse cell types and contexts.

neuroscience↗

bioRxiv2025

Hugin-AstA circuitry is a novel central energy sensor that directly regulates sweet sensation in Drosophila and mouse

Taste sensation plays a crucial role in shaping feeding behavior and is intricately influenced by internal states like hunger or satiety. Despite the identification of numerous neural substrates regulating feeding behavior, the central neural substrate that linked energy-sensing and taste sensation remained elusive. Here, we identified a novel neural circuitry that could directly sense internal energy state and modulate sweet sensation in the Drosophila brain. Specifically, a subset of neuropeptidergic neurons expressing hugin directly detected elevated levels of circulating glucose via glucose transporter Glut1 and ATP-sensitive potassium channel. Upon activation, these neurons released hugin peptide and activated downstream Allatostatin A (AstA)+ neurons via its cognate receptor PK2-R1. Subsequently, the activation of AstA+ neurons then directly inhibited sweet sensation via AstA peptide and its cognate receptor AstA-R1 expressed in sweet-sensing Gr5a+ neurons. We also showed that neuromedin U (NMU), the mammalian homolog of fly hugin, served as an energy sensor to suppress sweet sensation. Therefore, these data identify hugin+ neuron as a glucose-responsive central energy-sensing module that modulates sweet sensation across species.

neuroscience↗