Biology subjects

Wang, J.

Publications and source records attributed to Wang, J..

At least 505 records · Page 28Linked to original sources

bioRxiv2025

Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Background Muscle wasting, systemic inflammation, and functional decline are highly prevalent and detrimental in patients with advanced-stage non small cell lung cancer (NSCLC). Methods: In this cross sectional study, we investigated NSCLC associated muscle remodeling by analyzing skeletal muscle biopsies from patients with NSCLC (n = 18) and matched controls (n = 18) using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high resolution respirometry. Findings: NSCLC muscle was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix (ECM), together with remodeling of the inflammatory, immune, ECM and mitochondrial proteome. Additionally, mitochondrial respiratory capacity and morphology were altered in patients with NSCLC, which was associated with increased oxidative stress and dysregulated calcium handling. Concomitantly, we detected STAT3 activation and immune cell alterations, which may negatively impact skeletal muscle health in patients with NSCLC. Finally, we identified a shift in fibro-adipogenic progenitors (FAPs), favoring the CD90 subtype. Mechanistically, conditioned media from patient-derived FAPs reduced myotube width in vitro, uncovering a novel mechanism by which altered paracrine signaling from the muscle resident stromal compartment drives atrophy in cancer cachexia. Interpretation: These findings provide human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape accompany muscle wasting in NSCLC, which may inform therapeutic strategies to preserve skeletal muscle health in patients with cancer.

molecular biology↗

bioRxiv2025

Immune-Derived THBS1-CD47 Axis Induces Cellular Senescence and Suppresses Osteogenesis in Diabetic Periosteum

Type 2 diabetes mellitus (T2DM) weakens bone repair and increases fracture risk, but how the periosteal environment contributes to this problem is not fully understood. We found that diabetic mice showed thinning of the periosteum, reduced bone mass, and poor function of bone-forming cells. Using single-cell RNA sequencing, we discovered that immune cells and bone-lineage cells interact more strongly in diabetes through the THBS1-CD47 pathway. THBS1 was mainly produced by macrophages, while its receptor CD47 was abundant in osteogenic cells. Laboratory experiments showed that THBS1 blocked bone gene activity, increased inflammation and cell death, and damaged mitochondria, leading to higher oxidative stress. Knocking down CD47 reversed these effects, restoring bone cell activity and energy balance. In diabetic fracture models, blocking THBS1 improved callus formation and bone healing. These findings identify THBS1-CD47 as a key driver of periosteal dysfunction in T2DM and highlight it as a potential target to improve skeletal repair in diabetic patients.

cell biology↗

bioRxiv2025

Epithelial FOXP3 Drives Pancreatic Fibrosis through O-glycosylated IL-6

BACKGROUND & AIMSThe transcription factor FOXP3, known for specifying regulatory T cell fate, is unexpectedly expressed in the epithelium of precancerous pancreatic lesions. Here we investigate its non-immune role in initiating pancreatic fibrosis, a process driving therapeutic resistance and organ failure in pancreatic ductal adenocarcinoma (PDAC) with unknown origins in early neoplasia. METHODSUsing human tissues and genetically engineered mouse models, we analysed FOXP3 expression in premalignant lesions. We employed epithelial-specific FOXP3 knockout and knock-in strategies to determine its functional impact on fibrogenesis and neoplasia progression. Mechanistic studies included chromatin immunoprecipitation, glycomic analyses, and signalling assays. RESULTSFOXP3 was consistently expressed in the epithelial compartment of human and murine precancerous pancreas. Epithelial-specific deletion of FOXP3 attenuated pancreatic fibrosis and delayed neoplasia, whereas its knock-in induced spontaneous stromal activation and accelerated PanIN progression. Mechanistically, epithelial FOXP3 directly transactivated the glycosyltransferase GALNT1. GALNT1, in turn, mediated O-glycosylation of interleukin (IL)-6, which was essential for its rapid secretion. CONCLUSIONSOur study establishes epithelial-derived FOXP3 as a master regulator of early pancreatic fibrocarcinogenesis. It drives a glycosylation-dependent amplification loop for IL-6 signalling, orchestrating sustained stromal activation. This pathway represents a promising target for intercepting pancreatic fibrosis and carcinogenesis at its origin.

cancer biology↗

bioRxiv2025

MAAD: Multidimensional Antiviral Antibody Database

Antibodies have emerged as central components of therapeutic strategies against viral infectious diseases, functioning as key effectors in both prevention and treatment. While traditional antibody discovery has relied heavily on high-throughput screening, the field is now shifting toward rational antibody design, which requires integrative insights into sequence-structure-function relationships. However, the absence of a standardized and well-annotated antibody database integrating these multidimensional features hampers systematic exploration, cross-pathogen comparison, and rational antibody design. Here, we introduce a "Multidimensional Antiviral Antibody Database" (MAAD; http://www.xxx), a curated platform dedicated to antibody nanobody and single-chain variable fragment targeting three high-impact RNA virus families, Coronaviridae (SARS-CoV-1, SARS-CoV-2, MERS-CoV), Orthomyxoviridae (influenza virus), and Pneumoviridae (respiratory syncytial virus, human metapneumovirus), due to the large, high-quality datasets accumulated in recent years. MAAD further incorporates a suite of interactive analysis modules, including CDR annotation, similarity-based CDR3 sequence analysis, V/J gene usage profiling, sequence-based clustering and structure-based antigen-antibody interfaces residues with per-site entropy and mutation rate profiling. These features enable in-depth exploration of antibody sequence characteristics, thereby facilitating functional and structural insights for rational antibody design. Together, by bridging antibody sequence, structure and function, MAAD offers an open and standardized platform that advances comparative antiviral research and supports therapeutic antibody discovery.

bioinformatics↗

bioRxiv2025

N6-Methyladenosine Safeguards Mouse and Human Germline Competence

N6-Methyladenosine (m6A) regulation of germline entry in post-implantation-like-pluripotent states remains poorly defined. We characterized m6A depletion by Mettl3 or Mettl14 knock-down or METTL3 inhibition in in vitro models enabling primordial germ-cell-like-cell and somatic differentiation. Upon m6A depletion, mouse epiblast-like cells upregulated embryonic Ras (Eras) and PI3K-pAKT, facilitating EZH2 repression and depletion of H3K27me3. Consequently, enhancer activation promoted global gene deregulation and impaired germline entry. In mouse formative stem cells, ERAS-PI3K-pAKT upregulation resulted in unscheduled Blimp1 and Otx2 co-expression, germline entry deficiency and enhanced mesodermal differentiation. Conversely, upon m6A depletion, germline competent human pluripotent stem cells upregulated OTX2 through FGF-pERK activation, resulting in germline entry deficiency and enhanced neuroectodermal differentiation. meRIP-seq revealed preferential m6A deposition on mouse mesodermal and human neuroectodermal transcripts, suggesting a basis for differentiation bias following m6A depletion. We illustrate how decreasing m6A abundances impact signaling, chromatin epigenetics and transcript stabilities, constituting a powerful cell intrinsic barrier for germline entry.

developmental biology↗

bioRxiv2025

Brain endothelial PRMT5-ANGPTL4 axis regulates cerebellar inhibitory synaptogenesis and motor coordination

Brain vasculature is essential for central nervous system function, but its specific roles in synaptic development and motor function regulation are poorly understood. In this study, we identify a cerebrovascular signaling axis wherein endothelial PRMT5 critically regulates inhibitory synaptogenesis and motor coordination. Cerebrovascular-specific deletion of Prmt5 gene leads to excessive inhibitory synaptic input onto Purkinje cells and progressive motor deficits in mice. Mechanistically, PRMT5 deficiency epigenetically upregulates the expression of the secreted factor ANGPTL4 through reduced symmetric dimethylation of H3R8 and H4R3, along with increased H3K9 acetylation at the Angptl4 promoter, thereby driving excessive inhibitory synaptogenesis onto Purkinje cells. Importantly, Angptl4 deletion in brain endothelium normalizes inhibitory synaptic input onto Purkinje cells and restores motor coordination in PRMT5-deficient mice. Together, these findings define the endothelial PRMT5-ANGPTL4 axis as a key regulator of cerebellar inhibitory circuitry and motor function, highlighting cerebrovascular mechanisms as potential therapeutic targets for motor coordination disorders. Teaser Cerebrovascular PRMT5 prevents excessive inhibitory synaptogenesis via epigenetic repression of Angptl4.

neuroscience↗

bioRxiv2025

Multimodal AI Decodes Extreme Environment Functional Dark Matter Beyond Homology

Functional annotation of proteins from extreme environments represents a major bottleneck for bioresource discovery, as a vast reservoir of functional dark matter defies existing homology-based methods. We demonstrate that environmental pressures impart conserved physicochemical energy signatures that co-determine protein function with sequence and structure. Here we developed ACCESS, a multimodal graph neural network employing hierarchical contrastive learning with a tailored label-sample co-embedding to fuse energy, sequence, and structural information and overcome homology scarcity. ACCESS surpasses state-of-the-art methods including BLASTp and CLEAN in annotating low-identity enzymes. Applied to extreme environmental metagenomics, we constructed a function map of extremophile enzymes to expand the biocatalyst library, pinpointed functionally critical residues to guide rational design, and enabled large-scale, function-based macro-evolutionary analyses. This paradigm transcends the limitations of homology, illuminating protein dark matter and accelerating the exploration of the biospheres functional diversity for applications in biotechnology and therapeutic development.

bioinformatics↗

bioRxiv2025

Integrated Bioinformatics analysis and Metabolomic Responses in finding novel therapeutic approach to treat viral myocarditis

BackgroundMyocarditis is one of the most common health problems in young people. Despite imaging techniques and endomyocardial biopsies advancing, there is still inadequate for myocarditis characterization. Some studies have shown that myocarditis is closely associated with mitochondrial dysfunction. Therefore, this study was aimed to identify mitochondrial-related biomarkers and gene regulatory networks in myocarditis and potential therapeutic targets. MethodsWe downloaded GSE95368 dataset from GEO to get myocarditis gene expression profiles, then used EdgeR and AI algorithm for bioinformatics analysis of DEGs functions. Established CVB3-induced mouse myocarditis model via intraperitoneal injection, and assessed energy metabolism differences using targeted metabolomics. CVB3 stimulus induced myocarditis in H9C2 cells. We assessed mitochondrial dysfunction (ATP, MMP) with commercial kits, MAPK8 release via ELISA, and MAPK8, p-PI3K, p-AKT levels by western blot. Furthermore, a total of 8 patients primarily diagnosed with myocarditis were enrolled, and levels of MAPK8 and CK in serum were detected. SP600125, an inhibitor of MAPK8, was administrated to CVB3-infected mice to study its potential protective effect in viral myocarditis. ResultsWe obtained 77 DEGs enriched in myocarditis. Analysis yielded 11 modules, MEpurple module genes linked to myocarditis progression were identified via WGCNA. MAPK8, NAMPT and ALB are associated with mitochondrial function. CVB3-infected mice showed cardiac inflammation and high MAPK8 expression in serum or heart tissues.The target metabolism results indicated altered central carbon metabolism distinguished CVB3 group from control, with higher D-Glucose-1-phosphate and D-Glucose-6-phosphate and lower L-Cystine, dCMP, IMP and Xylulose-5-phosphate levels. CVB3 treatment caused mitochondrial dysfunction in H9C2 cells (decreased ATP, MMP), and increased MAPK expression. Western blot showed MAPK8 consolidated the levels of p-PI3K and p-AKT. CK activity was notably higher in myocarditis patients than healthy individuals. MAPK8 levels in myocarditis patients serum also exceeded those in healthy individuals. Pearson analysis indicated that MAPK8 and CK may contribute to myocarditis progression via distinct mechanisms. In CVB3-infected mouse model with SP600125 treatment, cardiac inflammation and MAPK8, p-PI3k, p-AKT expression were reduced, confirming MAPK8s crucial role in viral myocarditis. ConclusionOur study identified MAPK8 as a key biomarker of myocarditis, and it may be a potential therapeutic target for myocarditis.

pathology↗

bioRxiv2025

Temporal cueing improves audition with no evidence for attentional tradeoffs

Temporal cues help us focus attention at just the right moment. Whereas visual temporal attention selectively boosts perception at attended times at a cost to other moments, it remains unclear whether auditory temporal attention operates under the same constraints. To address this question, we designed a two-target temporal cueing task where participants discriminated the frequency sweep direction of one of two successive auditory stimuli, separated by 250 ms, while temporal attention was directed to one or both time points. We found that temporal attention improved auditory discrimination only for the first time point and could then remain sustained across the interval, without evidence of attentional tradeoffs in perceptual discriminability across time. Further, manipulating auditory feature uncertainty changed overall performance but did not modulate the impact of temporal attention or yield tradeoffs. Finally, comparison to previous data from a closely matched visual task confirmed that while temporal attention enhanced perception in both vision and audition, only vision shows tradeoffs at this timescale. Altogether the results suggest that the temporal constraints on attention are modality-dependent.

neuroscience↗

bioRxiv2025

Phase Behavior of TDP-43 and hnRNP H1: From Soluble and Aggregated States to Liquid-Like Droplets

Cytotoxic inclusions of TAR DNA-binding protein 43 (TDP-43) have been identified in various neurodegenerative diseases. Mediated by its low-complexity C-terminal domain (CTD), TDP-43 can undergo liquid-liquid phase separation (LLPS) and form aggregates and fibrils. These phase transitions are associated with pathological TDP-43 mislocalization and cytoplasmic aggregation. What determines whether and when TDP-43 adopts a liquid droplet state or forms solid aggregates, transiently or irreversibly? A full understanding of the underlying biophysical mechanisms will help explain the cellular toxicity of aberrant forms of TDP-43 and similar proteins, such as some of the large family of RNA-binding proteins. In this study, we generated recombinant full-length TDP-43 and maintained soluble-protein working solutions without the need of a solubility tag. By focusing on conditions that tune the electrostatic characteristics, we induced phase transitions among states of soluble TDP-43, solid aggregates, and liquid droplet phases in an expedient and controlled manner. We also obtained soluble working solutions of TDP-CTD and another crucial splicing factor, hnRNPH1, and investigated their phase behaviors as individual proteins and their interactions between each other during phase transitions. Using this system, we discovered a previously unreported aggregate-to-droplet transition and found evidence that phase separation of low-complexity domain (LCD)-containing proteins likely involves domain matching when they coaggregate out of solution.

molecular biology↗

bioRxiv2025

USP-ddG: A Unified Structural Paradigm with Data Efficacy and Mixture-of-Experts for Predicting Mutational Effects on Protein-Protein Interactions

Accurately estimating changes in binding free energy ({Delta}{Delta}G) is essential for understanding protein-protein interactions (PPIs) and guiding rational protein design. Existing deep learning approaches benefit from pre-training on large structural datasets, but they often require heavy computation and overlook data efficacy. In addition, prior models typically assume fixed backbone structures and ignore conformational dynamics, limiting generalization. We present USP-ddG, a unified structural paradigm for{Delta}{Delta} G prediction. USP-ddG integrates a dual-channel architecture with three complementary components: (i) inverse folding-based log-odds ratio, (ii) empirical energy terms from FoldX, and (iii) a geometric encoder with Gaussian noise to capture relaxed conformations. To enhance representation power, we introduce a framework that integrates feed-forward network (FFN) and Mixture-of-Experts (MoE) to model domain-invariant and -specific features, respectively. We further propose CATH-guided Folding Ordering (CFO), a data efficacy strategy that organizes samples to mitigate catastrophic forgetting and data distribution bias. USP-ddG consistently outperforms existing state-of-the-art (SoTA) methods on the SKEMPI v2.0 benchmark, including the challenging hold-out CATH test set. It achieves superior accuracy on both single- and multi-point mutations and demonstrates strong performance in antibody affinity optimization against H1N1 and HER2, and in assessing SARS-CoV-2 variants to hACE2. Ablation studies confirm the benefit of each component. These results highlight USP-ddG as a robust and data-efficient framework for modeling mutational effects on PPIs. AvailabilityUSP-ddG is publicly available at https://github.com/ak422/USP-ddG.

molecular biology↗

bioRxiv2025

A BCG toxic effector induces mitochondrial DNA compaction to refrain protective immunity

Innate immune memory typically emphasizes nuclear chromatin remodeling that determines transcriptional memory in monocytes and macrophages. Here, we show that compaction of mitochondrial DNA (mtDNA), governed by mitochondrial transcription factor A (TFAM) abundance and mtATP-dependent remodeling, defines the transcriptional and functional state of trained macrophages. While typical pathogen-associated molecular pattern (PAMPs) triggered mtDNA accessibility, Bacillus Calmette-Guerin (BCG) effector PE18 directly interacted with and activated SLC25A5 to reduce mtATP levels, thereby inhibiting TFAM degradation by AFG3L2. Accumulated TFAM restricts mtDNA accessibility, suppressing the transcription of the mtNd1 and thereby reducing mtNd1-mediated mtROS production, which diminishes the trained capacity of macrophages against secondary infections. Notably, BCG{Delta}pe18 maintains macrophages cytokine transcriptional capacity independent of classical nuclear histone modifications. Moreover, BCG{Delta}pe18 provides robust and lifelong protective immunity against Mycobacterium tuberculosis (Mtb) infection. These findings reveal mitochondrial genome as a regulatory entity in trained immunity, and suggest a potential strategy for improving vaccine performance.

immunology↗

bioRxiv2025

Electrophysiological profiling of exocytosis during early-stage development of the zebrafish lateral line

Hair cells of the zebrafish lateral line have proven to be a good model for studying hair cell function in a system that is easily genetically manipulated, rapidly develops and is experimentally accessible. However, characterization of potential developmental changes, and possible differences along lateral line position are lacking. Here, we used in vivo patch clamp to investigate the electrophysiological and exocytic properties of neuromast hair cells over early development across body location. Long depolarizations led to steady increases in membrane capacitance, presumably due to exocytosis of vesicles localized to ribbon synapses. The magnitude and kinetics of capacitance changes did not vary significantly across the L1 to L6 position of neuromasts along lateral line, but the magnitudes were found to be significantly smaller in hair cells found in the tail region across all developmental time points. For each region, we found no significant changes in capacitance responses between 3 and 7 days after fertilization. Hair cell capacitance responses were greatly reduced in animals injected with CRISPR/Cas9 with gRNAs targeted to otoferlin b. These results confirm the essential role of otoferlin b in neuromast hair cell function, and they establish the fidelity of CRISPR/Cas9 to rapidly mediate genetic removal of critical genes to study their impact on synaptic release.

neuroscience↗

bioRxiv2025

HapBridge: A Methylation-Guided Approach for Correcting Switch Errors and Bridging Phased Blocks in Long-Read Phasing

Long-read sequencing has substantially advanced haplotype phasing yet continues to face challenges in low-heterozygosity regions and switch errors caused by read noise. DNA methylation exhibits haplotype-specific patterns, providing complementary linkage information, but existing phasing algorithms have not fully leveraged these signals owing to their variability. Here, we present Hap-Bridge, a methylation-guided phasing framework that enhances single-nucleotide variant (SNV)-based phasing by detecting and correcting switch errors and bridging adjacent phased blocks. Evaluations on Oxford Nanopore R9/R10 and PacBio HiFi datasets show that HapBridge reduces switch errors by 3.07-18.72% and improves N50 length by 5.84-68.61% compared with Meth-Phaser, achieving higher phasing accuracy and contiguity. These results demonstrate that integrating methylation with sequence variation can provide a robust and intrinsic linkage signal that effectively improves haplotype continuity in long-read sequencing. HapBridge is publicly available at GitHub https://github.com/Humonex/HapBridge.

bioinformatics↗

bioRxiv2025

PyrMol: A Knowledge-Structured Pyramid Graph Framework forGeneralizable Molecular Property Prediction

Expert pharmaceutical chemists interpret molecular structures through a sophisticated cognitive hierarchy, transitioning from local functional moieties to spatial pharmacophores and, ultimately, to macroscopic pharmacological and physicochemical profiles. However, conventional Graph Neural Networks frequently overlook this high-level chemical intuition by treating molecules as single-scale atomic topology. To bridge this gap between human expertise and computational inference, we propose PyrMol, a knowledge-structured pyramid representation learning framework. By constructing heterogeneous hierarchical graphs, PyrMol orchestrates information flow across atomic, subgraph, and molecular levels. Crucially, the subgraph level systematically integrates three complementary expert views comprising functional groups, pharmacophores, and retrosynthetic fragments. To harmonize these explicit domain priors with implicit computational semantics, we introduce an adaptive Multi-source Knowledge Enhancement and Fusion module that dynamically balances their complementarity and redundancy. A Hierarchical Contrastive Learning strategy further ensures cross-scale semantic consistency. Empirical evaluations across ten benchmark datasets demonstrate that PyrMol outperforms 11 state-of-the-art baselines. Furthermore, its "plug-and-play" versatility provides a framework-agnostic performance boost for existing GNN architectures. PyrMol thus establishes a principled data-knowledge dual-driven paradigm for AI-aided Drug Discovery, effectively leveraging domain knowledge to catalyze advances in molecular property prediction.

bioinformatics↗

bioRxiv2025

Host EV derived lipids promote malaria parasite development via mosquito fatty acid oxidation

Malaria parasites must transition between mammals and mosquitoes, but how they adapt to such distinct environments is unclear. We show that blood from infected mammals buffers this environmental shift by packaging parasite-induced signals into extracellular vesicles (EVs). EVs internalized by mosquito midgut increases expression of VLCAD and raises levels of a 22-carbon fatty acid, driving fatty acid breakdown and acetyl-CoA production. The parasite exploits this metabolic shift to synthesize its own lipids during oocyst growth. Stable isotope tracing confirmed that13C4-labelled behenic acid is degraded and incorporated into parasite fatty acids. Lipidomic profiling further revealed that ceramides enriched in the EVs are key mediators. These findings identify a mechanism by which host bood-derived EVs reprogram mosquito lipid metabolism to promote parasite transmission.

microbiology↗

bioRxiv2025

LRMD: Reference-Free Misassembly Detection Based on Multiple Features from Long-Read Alignments

Genome assembly serves as the cornerstone of genomics research, with the detection of misassembly playing a crucial role in downstream analyses. Reference-free methods for misassembly detection, leveraging read alignments, enable us to circumvent the need for high-quality reference genomes and broaden their applicability. However, existing methods struggle to effectively utilize alignment data, leading to a noticeable deficiency in sensitivity for detecting misassemblies. We introduce LRMD, a novel reference-free tool for misassembly detection. LRMD integrates depth, clipping, and read pileup information derived from long-read-to-assembly alignments to significantly enhance sensitivity in identifying misassemblies. Experimental evaluations on both simulated and real datasets demonstrate that LRMD consistently outperforms existing tools in terms of sensitivity and F1-score. Notably, its results are closest to the reference-based evaluation tool QUAST. As an evaluation tool, LRMD also outputs metrics such as base quality, assembly size, contig N50, and others. LRMD is public available at http://github.com/sxfss/LRMD.

genomics↗

bioRxiv2025

Derivation, Characterizations, and Applications of Rabbit Haploid Embryonic Stem Cells

Haploid embryonic stem cells (haESCs), which contain a single set of chromosomes, provide powerful systems for investigating gene function and creating gene-edited animal models. haESCs have been derived from several mammalian species including human, mouse and rats, yet not from rabbits. Here, we report the derivation of parthenogenetic haESCs of rabbit (rbPhESCs) using an optimized culture medium. These cells maintain a stable haploid karyotype during long-term culture and own pluripotency features comparable to diploid embryonic stem cells derived from rabbit fertilized embryos. By integrating gene trapping cassette into ROSA26 locus, rbPhESCs offer an ideal platform for high-throughput functional genomic screening, as shown in haESCs from other mammals. Consistent with their parthenogenetic origin, rbPhESCs durably preserve maternal-specific imprinting patterns even after extended culture in serum-containing conditions, providing a valuable platform for generating disease models deficient in maternally expressed imprinted genes. Therefore, our findings expand the repertoire of mammalian haESCs and establish rbPhESCs as a valuable platform for genetic studies and biotechnological applications in rabbits.

cell biology↗