Biology subjects

Peng, S.

Publications and source records attributed to Peng, S..

At least 19 recordsLinked to original sources

bioRxiv2026

DNA-binding specificity recognition from predicted homologous protein-DNA structures

Predicting protein DNA-binding specificity is essential for understanding gene regulation and disease mechanisms. Existing deep learning methods typically infer specificity from a single protein-DNA complex structure, which limits their ability to capture the diverse geometric patterns underlying protein-DNA recognition. Homologous protein-DNA interfaces provide complementary structural evidence and richer geometric features related to interatomic interactions. To address the limited diversity and coverage of experimentally determined complexes, we constructed a large-scale library of predicted homologous protein-DNA complex structures. Building on this resource, we propose HomoDSP, a template-retrieval-based framework for accurate DNA-binding specificity prediction. Benchmark evaluations and validation on newly released JASPAR 2026 samples indicate that HomoDSP outperforms existing methods in both accuracy and generalization, with particularly substantial gains on high-error samples. Moreover, this performance is largely retained when AlphaFold3-predicted complex structures are used as input. Template- and residue-level interpretability analyses suggest that HomoDSP improves prediction by focusing on DNA-affinity residues across multiple homologous templates. Finally, universal Protein Binding Microarrays evaluations on AI-designed DNA-binding proteins show that HomoDSP rescues a baseline failure mode in which the baseline method produces incorrect predictions because of training-set bias. Together, these results support the use of homologous template interfaces as informative structural priors for decoding protein DNA-binding specificity.

bioinformatics↗

bioRxiv2026

Instant Prior-Free Resolution Enhancement for Cross-Modality Microscopy

The resolving power of optical microscopy is fundamentally constrained by the diffraction of light, limiting our ability to visualize subcellular structures. Computational methods, particularly deconvolution, can restore blurred images but critically depend on an accurate point spread function (PSF), whose estimation is often impractical and error-prone, leading to artifacts. Here, we introduce Nonlinear Fourier Re-weighting (NFR), a rapid algorithm that operates without any prior knowledge of the imaging system, achieving deconvolution-like effects through a single logarithmic mapping of the images Fourier spectrum. This non-iterative process re-balances spatial frequency components to computationally reverse the effects of optical blurring. We demonstrate that NFR robustly enhances resolution beyond the Sparrow limit and recovers authentic structural details. NFR excels where traditional methods fail, remaining effective in the presence of severe optical aberrations and high noise. Furthermore, NFR synergistically improves the output of super-resolution modalities like structured illumination microscopy (SIM), and its near-instantaneous processing enables real-time enhancement of dynamic biological processes, such as in vivo multi-photon microscopic imaging deep within scattering tissue. By decoupling high-fidelity image restoration from system modeling, NFR offers a powerful, accessible, and universally applicable tool for improving image quality across diverse microscopic techniques, facilitating the analysis of large datasets and the discovery of previously obscured biological phenomena.

bioengineering↗

bioRxiv2026

Symmetric Self-play Online Preference Optimization for Protein Inverse Folding

Multi-objective reinforcement learning based on predicted structure feedback has been introduced into protein inverse folding. However, existing methods typically rely on a single model to optimize multiple structural objectives via a scalarized reward, which can bias the optimization toward dominant objectives and limit the exploration of diverse solutions. Here, we propose a online Symmetric Self-play Preference Optimization (SSP) framework that decouples the optimization of multiple structural objectives by training separate preference models with distinct reward signals, while enabling interaction through a shared sampling pool. This design allows the models to explore diverse optimization trajectories without enforcing a single dominant direction. Extensive experiments on both natural and de novo binder backbone inverse folding tasks demonstrate that SSP consistently improves sequence design self-consistency compared to single-model and existing baselines. Further analysis shows that different structural objectives are only partially aligned and induce distinct optimization directions, as evidenced by metric correlation and white-box analyses. This supports the effectiveness of decoupling objectives to enable higher design quality in protein design.

bioinformatics↗

bioRxiv2026

Herbarium specimens reliably track plant phenological responses to climate change in understudied montane biomes

Long-term field observations typically are the "gold-standard" for inferences of phenological sensitivities in montane systems but are spatially limited. Herbarium specimens provide broader spatial coverage, but their utility to accurately capture montane phenology remains poorly known. We compared flowering phenology of 45 species inferred from herbarium specimens with comparable data from nearly 50 years of direct observations at the Rocky Mountain Biological Laboratory. Estimates of flowering time and phenological sensitivity to snow density were consistent between herbarium specimens and observations, but observations revealed secondary flowering peaks. Herbarium specimens additionally yielded shallower estimates of phenological sensitivity to spring temperature than did field observations. Across co-occurring species, "early" flowering individuals inferred from herbarium specimens, rather than the mean response across all individuals, may better approximate community-level phenological responses to temperature changes. We conclude that herbarium specimens are reliable resources for closing gaps in understanding phenological variation along elevational gradients of montane systems.

ecology↗

bioRxiv2026

Digital Twin Brain simulation and manipulation of a functional brain network underlying mental illness

Linking synaptic-level perturbations to distributed brain-network dynamics remains a central challenge for understanding and treating mental illness. Although recent whole-brain models can reproduce individual brain activity patterns, they largely function as descriptive simulators rather than mechanistic, intervention-capable systems. Here we present an intervention-capable digital twin of the human brain, integrating individual neuroanatomy and task-evoked dynamics within a neuronal-scale framework. Individualised digital twin brains recapitulate a participant-specific compact cortico-subcortical network phenotype that captures transdiagnostic psychopathology across population and clinical cohorts. In silico modulation of excitatory and inhibitory synaptic conductance produces bidirectional, heterogeneous network responses across individuals. Population-scale simulations stratify individuals and predict longitudinal symptom trajectories from DTB-derived response profiles. Independent pharmacological functional MRI data further validate the predicted baseline-dependent network responses in vivo. Together, these findings establish digital brain models as experimental platforms for mechanistic perturbation, behavioural prediction and stratification, providing a foundation for precision neuroscience and psychiatry.

neuroscience↗

bioRxiv2026

Disrupted dynamics of brain structure function coupling link genetic risk of Alzheimer's Disease and aging to cognitive decline in 34,067 adults

AbstractUnderstanding how a stable structural connectome supports flexible cognition, especially in aging, is a fundamental question in neuroscience. While static structure-function coupling (SFC) is well-studied, the dynamic decoupling of functional activity from structural constraints--dynamic SFC (DSFC)--remains poorly understood. Leveraging MRI data from 34,067 UK Biobank participants (ages 45-82), we characterized the distinct roles of SFC and DSFC in aging, cognition, and health. We found that SFC and DSFC followed spatially divergent aging trajectories: SFC declined primarily in sensorimotor systems, whereas DSFC decreased most prominently in higher-order networks. Both SFC and DSFC in higher-order networks were positively correlated with cognitive performance (e.g., fluid intelligence). However, the associations with mental and physical health diverged between the two measures: reduced DSFC was predominantly linked to health burdens in high-order default/limbic networks, whereas weakened SFC was primarily associated with health burdens in low-order sensory-motor networks. Genetic analyses revealed that Alzheimers risk, specifically APOE {varepsilon}4 dosage, significantly reduced DSFC in higher-order cognitive networks and SFC in visual cortex. Mediation analyses further demonstrated that aging and APOE {varepsilon}4-linked cognitive decline were mediated via visual SFC and ventral attention DSFC. These findings position static and dynamic coupling as complementary mechanisms: static SFC preserves network robustness, while dynamic SFC enables transient reconfiguration for complex integration. Together, our results highlight these dual mechanisms as crucial for maintaining cognitive flexibility, providing potential biomarkers for age-related neurodegeneration.

neuroscience↗

bioRxiv2025

A multivariate pattern metric of individualized hemispheric functional asymmetry

Functional asymmetry is a fundamental feature of human brain organization, yet existing measures of functional connectivity asymmetry rely mainly on univariate indices that miss distributed pattern structure. We introduce the Pattern Dissimilarity of Hemispheric Functional Connectivity (PDHC), a multivariate metric that quantifies the pattern-level distance between each individuals left- and right-hemisphere connectivity architecture. In over one thousand adults, PDHC showed high test-retest reliability, cross-atlas robustness, and strong individual specificity. Network analyses indicated that hemispheric similarity is anchored in conserved sensorimotor and subcortical systems, whereas higher-order networks drive divergence. Developmental data from infancy through early adulthood revealed a characteristic trajectory: dissimilarity declines sharply early in life and increases modestly thereafter. Twin and Turner syndrome samples further demonstrated moderate heritability and sensitivity to X-chromosome dosage. PDHC thus provides a reliable and individualized metric of hemispheric functional architecture, offering a scalable tool for probing lateralization across development, genetics, cognition, and clinical conditions.

neuroscience↗

bioRxiv2025

TRPV4 Promotes Histamine Receptor Signaling in Lymphatic Endothelial Cells

BackgroundThe control of lymphatic permeability and flow is essential for homeostatic regulation of tissue fluid balance and immune responses. Histamine has been identified as an important signaling mediator involved in the regulation of lymphatic function. Histamine is released from activated perilymphatic mast cells and may also be produced by lymphatic endothelial cells (LECs) in response to flow-induced shear stress. The non-selective cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) is an important mediator of signaling by GPCRs, including histamine receptors. TRPV4 is activated in response to shear stress and is functionally expressed by LECs. We hypothesized that histamine receptors and TRPV4 interact in LECs, leading to activation of distinct downstream signaling pathways. This study examined the mechanistic link between TRPV4 activity and histaminergic signaling in LECs. Principle ResultsHistaminergic Ca2+ signaling was examined in primary human LECs. Responses to histamine were mainly driven by the H1R histamine receptor, with some contribution by the H4R subtype, as determined using selective antagonists. H4R signaling in response to 4-methylhistamine was effectively prevented by either removal of extracellular Ca2+ or block of TRPV4 activity, consistent with TRPV4-dependence. Conversely, activation of H4R resulted in marked sensitization of subsequent responses to the selective TRPV4 agonist GSK1016790A. This interaction was mediated through a PLA2-dependent mechanism. TRPV4 activity was required for histamine receptor-evoked translocation of the Ca2+-dependent transcription factor NFATc1 and for cytoskeletal remodeling. By contrast, the release of cytokines in response to activation of either histamine receptors or TRPV4 were largely independent processes. ConclusionsThis study identifies TRPV4 as an important mediator of histaminergic signaling in LECs. The findings provide further support for the involvement of TRPV4 in defining the nature and magnitude of endothelial signaling downstream of GPCRs. HighlightsO_LIHistamine receptors are functionally expressed by primary human LECs C_LIO_LITRPV4 is an important driver of H4R-evoked Ca2+ signaling in LECs C_LIO_LIHistamine receptor activation sensitizes TRPV4 signaling in LECs C_LIO_LITRPV4 promotes histamine-evoked NFATc1 translocation to the nucleus of LECs C_LIO_LIHistamine and TRPV4 evoked cytokine release from LECs involve distinct mechanisms C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/690563v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@409b49org.highwire.dtl.DTLVardef@192f58dorg.highwire.dtl.DTLVardef@136fdd0org.highwire.dtl.DTLVardef@15175c6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Histamine exerts its effects on lymphatic endothelial cells through interaction with the H1R and H4R receptor subtypes. H1R activation promotes Ca2+ release from intracellular stores. Activation of the H4R leads to elevated intracellular Ca2+ through crosstalk with the non-selective cation channel TRPV4. Interaction between H4R and TRPV4 is mediated through a PLA2-dependent mechanism. TRPV4 enhances histamine-evoked NFATc1 activation and translocation and cytoskeletal remodeling. In contrast, histamine receptor- and TRPV4-mediated cytokine release appear to involve mechanistically independent processes. C_FIG

pharmacology and toxicology↗

bioRxiv2025

Neuroanatomical signatures of depression and anxiety in at-risk adolescents: A symptom-oriented perspective

BackgroundMajor depressive disorder (MDD) and generalized anxiety disorder (GAD) often emerge in adolescence. Identifying their symptom structures and neural biomarkers in youth with elevated risk is critical for early detection and developing interventions. This study investigated the central symptoms of MDD and GAD and identified the key brain regions ("brain bridges") linking structural neuroanatomy to symptoms in at-risk adolescents. MethodsA total of 1,568 adolescents at high risk for MDD and 413 adolescents at high risk for GAD were identified from the Adolescent Brain Cognitive Development (ABCD) study. Participants completed MDD and GAD symptom assessments and underwent Magnetic Resonance Imaging scanning. We constructed 10 psychological network models incorporating symptoms and brain structural indices to identify central symptoms and brain bridges. ResultsConcentration difficulties emerged as the shared core symptom, while self-hatred and irritability were the unique central symptoms for MDD and GAD, respectively. Left- and right-pallidum volumes exhibited the highest bridge centrality for MDD symptoms, whereas left-nucleus accumbens volume showed the highest bridge centrality for GAD symptoms. ConclusionOur findings highlight the pallidum and nucleus accumbens as key brain regions linking structural anatomy to symptom networks in high-risk youth. These results provide novel insights into early neurobiological markers of MDD and GAD from a symptom-oriented perspective and may inform targeted interventions.

neuroscience↗

bioRxiv2025

Hepatocyte FGFR2 Mediates the Antifibrotic Effects of FGF10 in Advanced Liver Fibrosis.

Fibroblast growth factor 10 (FGF10) supports epithelial repair, but its role in liver fibrogenesis remains uncertain. Here we found that hepatic FGF10 and its receptor FGFR2 decline with progression to advanced fibrosis in patient biopsies and in carbon tetrachloride (CCl4)- and diet-induced mouse models. Restoring hepatic FGF10 with recombinant human FGF10 or adeno-associated virus mediated liver-targeted expression attenuated and partially reversed established advanced bridging fibrosis, reduced inflammation, and decreased hepatocyte apoptosis, and these benefits required hepatocyte FGFR2 because hepatocyte-specific Fgfr2 deletion abolished protection. In primary hepatocytes, FGF10 activated FGFR2-FRS2, increased inhibitory GSK3{beta}(Ser9) phosphorylation, and suppressed NF-{kappa}B activation, reducing TGF-{beta}1 and other cytokines and thereby limiting paracrine hepatic stellate cells activation. The molecular and histologic benefits extended to metabolically primed steatohepatitis, supporting translatability beyond toxicant injury. Mechanistic signaling readouts confirm FGFR2 engagement, while the main text centers on the hepatocyte FGF10-FGFR2 axis as an intrinsic brake on fibrogenesis. Together, these data identify a hepatocyte-centric FGF10-FGFR2 axis as a negative regulator and potential regressor of fibrogenesis, highlighting it as a tractable therapeutic target in advanced liver fibrosis.

pharmacology and toxicology↗

bioRxiv2025

Identifying the therapeutic potential of Niclosamide in overcoming IFN-gamma dependent cancer immune evasion in the Tumor Microenvironment

BackgroundTumor cells frequently develop immune resistance through interferon-{gamma} (IFN-{gamma})-induced PD-L1 expression, acquisition of cancer stem cell (CSC)-like features, and adaptation to hypoxia within the tumor microenvironment (TME). Although IFN-{gamma} activates both STAT1 and STAT3, how these pathways interact to regulate immune evasion under hypoxia remains unclear. MethodsUsing the MC38 murine colorectal cancer model and T cell-tumor spheroid co-culture assays, we examined how IFN-{gamma} signaling through STAT1 and STAT3 influences PD-L1 expression, CSC plasticity, and cytotoxic T cell function under normoxic and hypoxic conditions. Pharmacologic inhibitors and siRNA knockdown were used to dissect pathway function, and Niclosamide, an FDA-approved anthelmintic, was evaluated as a dual STAT1/STAT3 inhibitor. ResultsWe found that IFN-{gamma} primarily induced PD-L1 through STAT1 activation, while CSC plasticity was associated with STAT3 signaling. STAT1 and STAT3 displayed reciprocal regulation--blocking one enhanced activation of the other. Niclosamide effectively inhibited phosphorylation of both STAT1 and STAT3, which led to suppressed PD-L1 upregulation and reduced CSC enrichment. In addition, it also partially inhibited hypoxia-induced HIF-1 expression. In co-culture assays, Niclosamide improved T cell infiltration and reduced exhaustion under hypoxic conditions, resulting in improved T cell killing. ConclusionsOur findings identified Niclosamide as a potent dual STAT1/3 inhibitor capable of reversing IFN-{gamma} and hypoxia-driven immune evasion. Repurposing Niclosamide may represent a promising strategy to enhance the efficacy of immune checkpoint blockade in solid tumors. key messagesInterferon-{gamma} (IFN-{gamma}) enhances cytotoxic T cell function but also promotes tumor immune evasion by upregulating PD-L1 and inducing cancer stem cell- like properties. Our study identifies a reciprocal regulatory mechanism between STAT1 and STAT3 in IFN-{gamma}-treated tumor cells that shapes immune evasion outcomes. We demonstrate that Niclosamide, an FDA-approved anthelmintic, acts as a dual STAT1/STAT3 inhibitor, effectively suppressing PD-L1 induction, limiting cancer stemness, and reducing HIF-1 expression under hypoxia. Niclosamide also restores T cell infiltration and decreases exhaustion in a 3D tumor spheroid model. By repurposing Niclosamide, this work provides a feasible approach to enhance the efficacy of immune checkpoint blockade and guide future translational and clinical studies in immunotherapies against solid tumors.

immunology↗

bioRxiv2025

Improved multimodal protein language model-driven universal biomolecules-binding protein design with EiRA

The interactions between proteins and biomolecules form a complex system that supports life activities. Designing proteins capable of targeted biomolecular binding is therefore critical for protein engineering and gene therapy. Here, we propose a new generative model, EiRA, specifically designed for universal biomolecular-binding protein design, which undergoes two-stage post-training, i.e., domain-adaptive masking training and binding site-informed preference optimization, based on a general multimodal protein language model. A systemic evaluation reveals the SOTA performance of EiRA, including structural confidence, diversity, novelty, and designability on 8 test sets across 6 biomolecule types. Meanwhile, EiRA provides a better characterization for biomolecular-binding proteins than generic model, thereby improving the predictive performance of various downstream tasks. We also mitigate severe repetition generation in the original language model by optimizing training strategies and loss. Additionally, we introduced DNA information into EiRA to support DNA-conditioned binder design, further expanding the boundaries of the design paradigm. Purification experiments and molecular dynamics simulations verified the manufacturability and DNA-binding ability of the designed highly differentiated protein. Remarkably, EiRA achieved the "one-shot" design of a Glucagon peptide binder with SPR-confirmed micromolar affinity.

bioinformatics↗

bioRxiv2025

O-GlcNAcylation-Ubiquitin Crosstalk of METTL1 Drives m7G Epitranscriptomic Collapse and Lipid Metabolic Reprogramming in Diabetic Cardiomyopathy

BackgroundMetabolic remodelling and memory in cardiomyocytes is a pivotal mechanism underlying cardiomyopathy pathogenesis. Clinical observations demonstrate persistent progression of hyperglycaemia-induced multiorgan damage following blood glucose stabilization, which is predominantly mediated through epigenetic regulation. While prior studies have identified epigenetic contributions to hyperglycaemic myocardial injury, the involvement of RNA methylation-particularly N7-methylguanosine (m7G) modification-in this regulatory network remains undefined. MethodsClinical specimens were collected from diabetic patients, and cardiomyocyte-specific METTL1 and ob/ob knockout murine models were established in parallel. Multiomic profiling (proteomics, glycoproteomics, ubiquitinomics, m7G-MeRIP sequencing, and metabolomics) was systematically conducted. The molecular mechanisms governing METTL1 regulation via O-GlcNAcylation and ubiquitination were elucidated through integrated in vitro and in vivo assays. A DUB siRNA library and computational strategies combining molecular docking with molecular dynamics simulations were employed for screening drugs targeting METTL1 O-GlcNAcylation, followed by in vivo therapeutic validation. ResultsComparative analysis of diabetic murine and human samples revealed strong METTL1 downregulation in cardiomyopathy contexts. Tamoxifen-inducible METTL1 knockout mice presented exacerbated diabetic cardiomyopathy phenotypes, confirming its cardioprotective function. Multiomic integration demonstrated that METTL1-mediated m7G modification critically regulates cardiomyocyte fatty acid metabolism. Mechanistically, hyperglycaemia was found to induce O-GlcNAcylation at the METTL1-T268 residue, suppressing m7G methyltransferase activity by 38% (p < 0.01). Subsequent investigations revealed that USP5 deubiquitinase activity is impaired under hyperglycaemic conditions, leading to accelerated METTL1 degradation. Notably, administration of the first-in-class small drug HIT106265621 significantly attenuated cardiomyopathy-associated pathological alterations in ob/ob mice in vivo. ConclusionHyperglycaemia promotes METTL1 O-GlcNAcylation, which impedes USP5-mediated deubiquitination, consequently reducing cardiomyocyte METTL1 protein levels and m7G modification. METTL1 deficiency drives diabetic cardiomyopathy progression through fatty acid metabolic dysregulation, inflammatory activation, and myocardial hypertrophy. Pharmacological inhibition of the OGT-METTL1 interaction using HIT106265621 has therapeutic potential for metabolic cardiomyopathy intervention.

pathology↗

bioRxiv2025

Global Protein-Ligand Binding Affinity Profiling via Photocatalytic Labeling

Protein-ligand binding, selectivity, and affinity dictate the effects of drugs and endogenous molecules in cells. Currently, potential protein-ligand interactions are identified by qualitative interpretation of proteomic, transcriptomic, or genomic data, then binding affinities of hits are measured using purified proteins or engineered reporter systems to validate and quantify the strength of individual interactions. Few methods enable simultaneous target identification and biophysical affinity measurement, and these either apply to specific enzyme classes or proteins with ligand-dependent shifts in stability. Here we describe a general platform, termed Affinity Map, which leverages competitive binding analysis, high fidelity photocatalytic labeling, and high throughput proteomics for global quantitative binding affinity profiling. We show that this method is applicable to major classes of ligands, including small molecules, linear peptides, cyclic peptides, and proteins, and can measure affinities between unmodified ligands and proteins in cell lysates, organ extracts, and live cell surfaces.

biochemistry↗

bioRxiv2025

Phase separation of Polycomb-like (PCL) proteins drive PRC2 complex condensates to regulate gene expression

Polycomb group (PcG) proteins function as two major multicomponent protein complexes: Polycomb repressive complex 1 (PRC1) and 2 (PRC2) to repress key developmental genes and maintain epigenetic memory of cell identity during development. Phase-separation has long been implicated in PRC1 mediated gene silencing, but it is still unclear whether PRC2 also utilize a similar mechanism to regulate gene expression. Here we report that Polycomb-like (PCL) proteins, PRC2 accessory factors, can phase-separate in vitro and generate dynamic puncta in vivo. Biochemical and cellular analyses reveal that PCL proteins (hereafter referred to as PCLs) have intramolecular interaction between N- and C-terminal domains, which make PCLs into more compact conformations. The intramolecular interaction not only controls the size of the PCLs phase separation droplets, but also affects the chromatin association of PRC2. Finally, we show that CpG islands, key DNA regulatory elements in mammalian promoters, disrupt the N-C intramolecular interaction of PCLs to expose their middle intrinsically disordered regions (IDRs), which in turn trigger PCLs driven PRC2 condensates formation. Together, this study provides a new perspective on the regulation of PRC2 by PCLs, implicating PCLs read CpG islands to fine-tune their oligomerization to overcome the threshold for PRC2 recruitment to corresponding genomic loci via multivalent interaction with CpG islands chromatin.

biochemistry↗

bioRxiv2025

The G-protein coupled receptor OXER1 is a tissue redox sensor essential for intestinal epithelial barrier integrity.

Generation of reactive oxygen species is an important part of the innate immune response. Generating microbicidal levels of reactive oxygen species (ROS) requires adaptation of mucosal barriers. High tolerance of ROS provides improved innate immune defenses against pathogens, whereas low tolerance renders host cells prone to chronic toxicity and mutagenesis, which can promote inflammation (e.g., in asthma and Crohns disease) and cancerogenesis. The mechanisms that sense and mediate host tolerance to ROS are little understood. In this study, we discover an unexpected role for the redox-sensitive, chemokine-like lipid 5-oxo-eicosatetraenoic acid (5-KETE) in redox adaptation. 5-KETE is known to attract leukocytes to damaged/infected mucosal barriers by signaling through its receptor, OXER1. Suggestive of a distinct non-immune function, we here report that the loss of the OXER1 ortholog Hcar1-4 causes barrier defects and baseline inflammation in the intestine of live zebrafish larvae. In zebrafish and cultured human cells, OXER1 signaling protects against oxidative nucleotide lesions by inducing DNA-protective Nudix hydrolases. Our data reveal the oxoeicosanoid pathway as a conserved ROS resilience mechanism that fortifies pathogen-exposed mucosal linings against increased oxidative stress in vivo.

immunology↗

bioRxiv2025

The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus to spatiotemporally regulate glycogenesis and myogenic differentiation

Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54nrb and undergoes liquid-liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.

cell biology↗

bioRxiv2024

Accurate nucleic acid-binding residue identification based on domain-adaptive protein language model and explainable geometric deep learning

Protein-nucleic acid interactions play a fundamental and critical role in a wide range of life activities. Accurate identification of nucleic acid-binding residues helps to understand the intrinsic mechanisms of the interactions. However, the accuracy and interpretability of existing computational methods for recognizing nucleic acid-binding residues need to be further improved. Here, we propose a novel method called GeSite based the domain adaptive protein language model and explainable E(3)-equivariant graph convolution neural network. Prediction results across multiple benchmark test sets demonstrate that GeSite is superior or comparable to state-of-the-art prediction methods. The performance comparison on low structure similarity and newly released test proteins demonstrates the robustness and generalization of the method. Detailed experimental results suggest that the advanced performance of GeSite lies in the well-designed nucleic acid-binding protein adaptive language model. Meanwhile, interpretability analysis exposes the perception of the prediction model on various remote and close functional domains, which is the source of its discernment. The data and source code of GeSite are freely accessible at https://github.com/pengsl-lab/GeSite.

bioinformatics↗