Biology subjects

Wang, J.

Publications and source records attributed to Wang, J..

At least 631 records · Page 35Linked to original sources

bioRxiv2025

Quantifying spatiotemporal decoupling of GDGT-temperature relationships in a deep alpine lake

Glycerol dialkyl glycerol tetraethers (GDGTs), membrane lipids produced by archaea and some bacteria, are widely used in paleoclimate reconstructions due to their empirical relationship with temperature. However, their application in lakes is complicated by uncertainties in source attribution and environmental controls on their distribution. To address these constraints, we analyzed both branched and isoprenoid GDGTs (brGDGTs and isoGDGTs) in settling particles collected over 19 months using sediment traps at four depths (10, 15, 25 and 35 m) in Lake Lugu, a deep, stratified alpine lake in southwestern China. GDGT fluxes showed synchronous spatiotemporal variations across depths, with higher values during winter mixing than summer stratification, suggesting in situ production enhanced by nutrient upwelling during lake overturn. Correlations between GDGT distributions and high-resolution water temperature profiles revealed strong temperature sensitivity in isoGDGTs, particularly the Ring Index (RI), with peak correlations linked to mean temperatures [~]20 days prior to trap recovery, indicating a clear temporal lag in GDGT-temperature relationship. Moreover, stronger correlations with temperatures at overlying depths, implying vertical transport of isoGDGTs and a dominant autochthonous origin from the upper water column. In contrast, brGDGTs displayed weak or non-significant temperature dependence, likely reflecting distinct microbial sources or other controlling factors. These findings underscore the utility of isoGDGT-based proxies, particularly RI, while highlighting the importance of accounting for spatiotemporal offsets in GDGTs production when reconstructing paleotemperatures in deep, stratified lakes.

ecology↗

bioRxiv2025

Structure-Guided Design of a Bioactive Covalent Small Molecule Targeting a Riboswitch

Small molecule ligands targeting structured RNA elements hold promise for modulating RNA function, serving as chemical probes and potential therapeutics. In this study, the characterization of phenylglyoxal-based covalent probe designed to target unpaired guanine residues in structured RNAs is reported. A structure-guided design strategy was employed to modify covalently unpaired guanines critical for flavin mononucleotide (FMN) binding to the FMN riboswitch. Covalent modification occurs at the designed site and modulates riboswitch function in a cellular reporter system, highlighting the potential of covalent mechanisms of action for bioactive RNA ligands.

biochemistry↗

bioRxiv2025

AAV6-HCN4t-mediated biological pacing as a potential life-saving therapy for congenital complete heart block

Congenital complete heart block (CCHB) is a life-threatening condition in fetuses due to severe bradycardia. Maternal administration of {beta}-adrenergic agonists is used to increase fetal heart rates, but its effectiveness is limited and lost over time most likely due to insufficient expression of HCN channels in some individuals. We report the development of an injectable gene therapy that produces reliable cardiac pacemaker function in the presence of {beta}-adrenergic stimulation. Intramyocardial injection of adeno-associated viral serotype 6 vectors expressing HCN4t (AAV6-HCN4t) into the left ventricular apex significantly increased ectopic pacing frequency and heart rate in response to isoproterenol in rats with complete heart block, and this effect remained stable throughout the 4 weeks of follow-up. Injection of AAV6-HCN4t showed similar reliable biological pacing in complete heart block pigs. These results suggest that AAV6-HCN4t generates robust biological pacing in the presence of isoproterenol, providing the foundation for a potentially life-saving therapy for in utero CCHB.

physiology↗

bioRxiv2025

Approaching an Error-Free Diploid Human Genome

Complete human genomes now resolve regions long inaccessible to genetic analysis, yet repetitive and structurally complex sequences remain prone to assembly errors because of limitations in current assembly algorithms. We introduce a support-based framework founded on the principle that each sequencing read provides independent evidence for the underlying genome sequence. Implemented through Sufficient Alignment Support (SAS), the framework identifies regions lacking concordant read support, localizes residual errors, and guides correction. Applying SAS to T2T-YAO, a haplotype-resolved Han Chinese genome, produced a support-validated assembly in which nearly all sequences outside unresolved rDNA arrays and long homopolymer tracts are supported by independent sequencing evidence. This work establishes a scalable framework for genome validation and provides a support-validated East Asian diploid reference for investigating human genomic diversity.

genomics↗

bioRxiv2025

Retinal pigment epithelium-derived PD-L1 reprograms microglial cells and protects against retinal degeneration in mouse models of experimental AMD and genetic retinitis pigmentosa

Retinal degeneration is a leading cause of blindness and a significant health burden during aging worldwide. Because of its complex pathogenic mechanisms, however, effective interventions applicable to multiple retinal degenerations remain limited. Excessive microglia-mediated inflammation is a common pathological feature of different retinal degenerative diseases, and inhibiting these overactive inflammatory responses by reprogramming microglia may provide a therapeutic strategy with broad-spectrum potential. Here, we uncover a novel retinal pigment epithelium (RPE) homeostatic signal, PD-L1, that drives the reprogramming of activated microglial toward a retinal-protective phenotype. Using multiple analyses, including gene expression profiling bioinformatics, adeno-associated virus-mediated RPE-specific gene overexpression, pharmacological, and genetic manipulations, we show that RPE cells upregulate the expression of PD-L1 to modulate microglia for protection against retinal degeneration in an experimental dry AMD mouse model. Bioinformatics enrichment analysis of the high-expression gene signatures of subretinal microglia in AMD patients, combined with pharmacological blocking of NF-{kappa}B activity or using Nlrp3 knockout mice, show that PD-L1/PD-1 signaling suppresses NF-{kappa}B activation in microglia, thereby inhibiting NLRP3 inflammasome priming and attenuating microglia-mediated excessive inflammation. Furthermore, the overexpression of PD-L1 by the AAV8 virus exerts similar microglial reprogramming and retinal protective effects to alleviate retinal degeneration in a preclinical model of retinitis pigmentosa. These findings reveal that RPE-derived PD-L1 suppresses inflammatory reprogramming of subretinal microglia and mitigates retinal degeneration, highlighting a promising proof of concept for PD-L1 as a potential therapeutic target for the broad treatment of retinal degenerative diseases.

genetics↗

bioRxiv2025

Exploring polycyclic scaffolds as adamantane replacements in M2 channel inhibitors of Influenza A virus

The increasing resistance of influenza A viruses to adamantane-based antivirals underscores the need for new inhibitors targeting both wild-type (WT) and mutant M2 ion channels. Here, we report the synthesis and biological evaluation of polycyclic cage amines designed to replace the adamantane scaffold as M2 inhibitors. These include ring-contracted and ring-expanded analogues, evaluated both as primary amines and as aryl-/heteroaryl-substituted derivatives. Most of the polycyclic amines inhibited the WT M2 channel as demonstrated by electrophysiological assays. Among them, compound 10, a 3,4,8,9-tetramethyltetracyclo[4.4.0.03..0.]decan-1-amine, emerged as a triple blocker active against M2 WT, M2 L27F, and M2 V27A channels. In contrast, compound 6c, a noradamantane-isoxazole derivative, showed selective inhibition of the S31N mutant. Although no antiviral activity was observed against influenza A virus in infected cell assays, both compounds 6c and 10 displayed significant antiviral activity against human coronavirus 229E. Furthermore, compound 10 demonstrated favourable pharmacokinetic properties. MD simulations show that noradamantane 6c binds inside the M2 S31N pore, with its ammonium forming H-bonds to Asn31 and the isoxazole positioned near Val27, restricting water entry. In contrast, larger polycyclic amines likely cannot access the pore due to steric hindrance.

pharmacology and toxicology↗

bioRxiv2025

Intracellular auto-circularizing RNA using human tRNA splicing elements

Circular RNAs (circRNAs), a type of covalently closed RNA, have emerged as crucial regulatory factors in gene expression and development across various organisms. Understanding their formation and functional mechanisms holds potential for therapeutic applications, including novel RNA vaccines against diseases such as COVID-19. However, practical challenges still exist in the preparation of circRNAs. In this study, we explored the influence of human tRNA splicing elements on circRNAs formation and identified effective sequences for intracellular auto-circularization. We developed a generic auto-circularizing RNA (acRNA) framework template, optimized various key components of circRNAs formation, and proposed a more efficient and precise intracellular auto-circularization method. This study provides novel insights into the production mechanism of circRNA and establishes a simple and effective method for intracellular auto-circularization.

cell biology↗

bioRxiv2025

MSF-CPMP: A Novel Multi-Source Feature Fusion Model for Prediction of Cyclic Peptide Membrane Permeability

Cyclic peptides are becoming attractive molecules for drug discovery because of their properties with inherent stability and structural diversity. However, the high potential of cyclic peptide drugs is challenged by the limited membrane permeability cross cell membrane. To predict cyclic peptide membrane permeability (CPMP), an increased number of computational models or tools are designed and used. But these existing algorithms or models do not appropriately capture feature diversity of cyclic peptides. In this study, we introduce a novel multi-source feature fusion model called MSF-CPMP, which aims to increase the accuracy of predicted CPMP. The MSF-CPMP model incorporates three features extracted from SMILES sequences, graph-based molecular structures, and physicochemical properties of cyclic peptides. By benchmarking with other machine learning and deep learning-based methods, MSF-CPMP achieved the highest levels of the evaluation metrics such as accuracy of 0.9062 and AUROC of 0.9546, and further validated MSF-CPMP robustness in learning capabilities and efficacy of its multi-source fusion. Our result demonstrates that MSF-CPMP outperforms other methods in predicting CPMP, that provides also exemplifies the power of advanced deep learning methods in tackling complex biological challenges, offering contributions to computational biology and clinical treatment. Code is available at https://github.com/wanglabhku/MSF-CPMP Author summaryWe have recognized that cyclic peptides are one type of main macro-molecular drugs useful for treatment of human diseases. However, the structural diversity of cyclic peptides results in limited permeability across cell membranes which is challenging drug research or industrial development. Previously some computational models or tools including machine learning or deep learning ones tried to solve this problem, but they still are not efficient. There are urgent requirement for more effective methodologies. Thus, we introduce a novel multi-source feature fusion model called MSF-CPMP. Our aim is to enhance accuracy and efficiency of predicted CPMP. We carried out evaluation of performance metrics by comparative analysis between MSF-CPMP and other machine learning or deep learning methods. Our result demonstrates that MSF-CPMP outperforms other models in predicting CPMP. We further validated MSF-CPMP robustness in learning capabilities and efficacy of its multi-source feature fusion. In the future we would further improve our methods that can integrate broader biomedicine and biomedical information and provide guide for drug diversity in clinically treating complex human diseases.

bioinformatics↗

bioRxiv2025

TopoLa: A Universal Framework to Enhance Cell Representations for Single-cell and Spatial Omics through Topology-encoded Latent Hyperbolic Geometry

Recent advances in cellular research demonstrate that scRNA-seq characterizes cellular heterogeneity, while spatial transcriptomics reveals the spatial distribution of gene expression. Cell representation is the fundamental issue in the two fields. Here, we propose Topology-encoded Latent Hyperbolic Geometry (TopoLa), a computational framework enhancing cell representations by capturing fine-grained intercellular topological relationships. The framework introduces a new metric, TopoLa distance (TLd), which quantifies the geometric distance between cells within latent hyperbolic space, capturing the networks topological structure more effectively. With this framework, the cell representation can be enhanced considerably by performing convolution on its neighboring cells. Performance evaluation across seven biological tasks, including scRNA-seq data clustering and spatial transcriptomics domain identification, shows that TopoLa significantly improves the performance of several state-of-the-art models. These results underscore the generalizability and robustness of TopoLa, establishing it as a valuable tool for advancing both biological discovery and computational methodologies.

bioinformatics↗

bioRxiv2025

Population-level super-pangenome reveals genome evolution and empowers precision breeding in watermelon

Pangenomes are increasingly critical for harnessing crop genetic diversity, yet their resolution and utility are often limited by insufficient sampling of high-quality genome assemblies. Here, we report a population-level watermelon super-pangenome constructed from 138 reference-grade assemblies, including 135 newly generated near-gapless genomes representing all seven watermelon species. The super-pangenome captures approximately one million structural variants (SVs), enabling accurate variant genotyping across ~900 watermelon accessions and substantially expanding variant discovery both across and within species. Broader sampling within the pangenome provides insights into genome evolution among watermelon species and sheds light on the origin of cultivated watermelon. SV-inclusive genome-wide association studies enhance trait mapping resolution and identify a copy number variation upstream of ClFCI1 that regulates flesh color intensity in a dosage-dependent manner. Leveraging this comprehensive variation map, we developed high-accuracy genomic prediction models for 18 agronomic traits. Together, our findings and genomic resources establish a foundational framework for dissecting complex traits and accelerating precision breeding in watermelon, while offering a valuable model for SV-resolved pangenomics in crop species.

plant biology↗

bioRxiv2025

A high-quality bread wheat genome unravels adaptive evolution of wheat end-use quality

Understanding the genetics of superior dough performance is essential for improving wheat end-use quality. Here, we presented a de novo assembly of the genome of JM44, a Chinese wheat cultivar known for its exceptional end-use quality. The JM44 genome achieved reference-level quality (QV = 66.74), depicting a complete picture of complex regions containing gluten genes. Our microsynteny analysis across the Triticum-Aegilops complex showed that high-molecular-weight glutenin subunits (HMW-GSs) loci are highly conserved, while low-molecular-weight glutenin subunits (LMW-GSs) and -/{beta}-gliadins exhibited greater structural variation. These variable loci appear to have been preferentially selected by humans and contributed substantially to the evolution of wheat quality traits. Moreover, we observed that epistatic interactions between gluten genes are strong in modern cultivars, but markedly weaker in landraces, indicating the importance of epistatic selection during modern breeding. Our findings shed light on the genomics and evolution of wheat quality traits, providing valuable guidance for future breeding efforts.

genomics↗

bioRxiv2025

Loss of vitamin C biosynthesis protects from a parasitic infection

The ability to synthesize essential molecules is sometimes lost in evolution. A classic example is ascorbate (Vitamin C), which is synthesized in most animals by L-Gulonolactone Oxidase (GULO), an enzyme lost multiple independent times in animal evolution. This event is thought to be evolutionarily neutral, however, GULO-deficient animals including humans need to obtain ascorbate from their diet and are susceptible to ascorbate deficiency and scurvy. We therefore hypothesized that this disadvantage of GULO loss is offset by physiological benefits. Here we show that ascorbate deficiency protects mice from schistosomiasis, a debilitating parasitic disease which afflicts 250 million people. Schistosoma mansoni worms required host ascorbate to produce eggs in vivo. Consequently, ascorbate-deficient mice were protected from schistosomiasis pathologies and transmission. Intermittent ascorbate deficiency protected Gulo-deficient mice from both scurvy and schistosomiasis mortality. The effects of ascorbate on schistosome reproduction were mediated by ascorbate-dependent histone demethylation which promoted vitellocyte development in female schistosomes. We propose that vitamin deficiencies are not always detrimental but can protect animals from pathogens which need to obtain vitamins from their host.

biochemistry↗

bioRxiv2025

Functional screening of TCR-like antibodies for targeted cancer immunotherapy

Although hybridomas and display technologies have long been used in antibody discovery, identifying TCR-like antibodies that recognize major histocompatibility (MHC)-presented neoantigens remains an inefficient process. Here, we present a functional screening approach for antibody discovery based on T cell-specific functionality. By constructing Synthetic T cell receptor and Antigen Receptor (STAR)-T cells expressing antibody libraries and co-culturing them with target cells, we observed distinct antigen-specific STAR endocytosis and T cell activation. These two indicators are combined into an E-A functional index, which we demonstrate as an effective screening strategy for identifying antibodies with strict antigen sensitivity and specificity. Using this E-A functional screening method, we successfully discovered antibodies or nanobodies targeting cell-surface tumor antigens and neoantigens presented by human leukocyte antigen (HLA). These antibodies exhibited potent anti-tumor efficacy both in vitro and in vivo. Moreover, converting these antibodies into chimeric antigen receptors (CARs) and bispecific antibodies also induced T cell activation and tumor killing. In summary, our study establishes a robust functional screening strategy for identifying antibodies or TCR-like nanobodies targeting tumor-specific neoantigens, offering significant potential for advancing targeted cancer therapies.

immunology↗

bioRxiv2025

Remodeling of the immune-metabolic landscape triggered by long-term high-altitude exposure

Growing evidence indicates that immunological and metabolic outcomes are key mediators of long-term high-altitude exposure (LTHAE) adaption, but the underlying mechanisms remain poorly understood. This study employs plasma metabolomics and peripheral blood single-cell transcriptomic sequencing to analyze the metabolic and immune dynamic regulation in 46 young male lowlanders following a 90-day adaptation period at high altitude. Single-cell analysis shows a pattern of "innate immune activation and adaptive immune suppression" under LTHAE, characterized by facilitated maturation of neutrophils, enhanced cytotoxicity of CD56dim NK cells, and increased immune responsiveness of cDC2 and pDC, while inhibited maturation of plasmablasts and suppressed immune responsiveness of CD8{square}TEM and CD4+ T cells. Plasma metabolic analysis reveals significant alterations, involving enhanced steroid hormone synthesis, unsaturated fatty acid and amino acid metabolism under LTHAE, which in turn are associated with immune remodeling. Moreover, transcriptomic-metabolic integration analysis indicates the molecular mechanisms of enhanced aerobic oxidation efficiency under LTHAE. Collectively, these findings provide integrated insights into immune-metabolic landscape remodeling and suggest potential mutual regulatory relationship between immune and metabolic state following LTHAE, offering a molecular foundation for high-altitude adaptation research.

genomics↗

bioRxiv2025

Actin-modulated nuclear shape controls adaptive reprogramming in cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) exhibit striking plasticity, enabling them to adapt to external cues such as therapeutic and mechanical stress in the tumor microenvironment (TME). Here, we uncover a shared mechanotransduction pathway through which both BRAF inhibition and matrix stiffness converge in nuclear remodeling to drive CAF activation. Mechanistically, BRAF inhibitors (BRAFis) accelerate RAS-dependent RAF homo and heterodimerization and ERK signaling, leading to GSK-3{beta} inactivation and Rho kinase (ROCK) activation. In parallel, stiff substrates engage integrin receptors to directly activate ROCK signaling. Activation of ROCK induces actin stress fiber assembly, generating mechanical forces that deform the nucleus. In both contexts, nuclear reshaping promotes {beta}-catenin translocation and actin polymerization through a feedback loop that continuously enforces CAF activation and promotes melanoma progression. Notably, pharmacological inhibition of ROCK activity blocks both BRAFi- and stiffness-induced nuclear remodeling and {beta}-catenin accumulation, identifying the ROCK-cytoskeleton-nucleus axis as a critical regulator of CAF adaptation and functionality. Collectively, these findings reveal a mechanically tuned nuclear signaling hub that integrates chemical and physical cues to promote stromal adaptation and suggest ROCK inhibition as a strategy to counteract therapy-induced fibroblast reprogramming and improve therapy response.

cancer biology↗

bioRxiv2025

Putative long-range mossy fiber sprouting and regional hypermetabolic capacity in the hippocampus of patients with mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) is pathologically characterized by neuronal loss in the dentate hilus, CA3 and CA1 regions, and mossy fiber (MF) sprouting into the inner molecular layer (iML). The latter forms aberrant excitatory circuities that are considered to facilitate recurrent seizures, with the subiculum also being related to epileptogenic activation. We recently identified a distinct expression of -smooth muscle actin (SMA) at the MF terminals in human hippocampus. This prompted us to explore MF sprouting in resected hippocampi (n=20) from patients with MTLE relative to postmortem control (n=20) using SMA along with reference markers for pathological cross-validation. Compared to control, neuronal loss assessed with neuron-specific nuclear antigen and sortilin immunolabeling reached CA1 in all resected hippocampi. SMA, zinc transporter 3 and {beta}-secretase 1 immunolabeling in the iML tended to be increased. The MF-related markers also revealed a preserved fibrous band extending across CA1 to subiculum. Cytochrome c oxidase immunolabeling also increased in iML and subiculum in the MTLE group. Taking together, the current findings point to the existence of long-range MF sprouting and a regional hypermetabolic compacity in the hippocampal formation of patients with drug resistant MTLE.

neuroscience↗

bioRxiv2025

Structural insights into Measles virus RNA synthesis: C protein-mediated regulation of replication-transcription switch and allosteric inhibition by ERDRP-0519

Nonsegmented negative-sense RNA viruses (nsNSVs) rely on a multifunctional RNA-dependent RNA polymerase (RdRP) complex for transcription and replication. In measles virus (MeV), the nonstructural protein C has long been implicated in regulating RNA synthesis, yet its precise role remains unclear. Here, we show that the MeV C protein directly associates with the RdRP complex. Using cryo-electron microscopy, we determined atomic-resolution structures of the MeV polymerase with and without C, revealing that C binding stabilizes the accessory domains of L and locks the complex into a replication-competent elongation state. Biochemical data further show that C promotes N protein recruitment, enhancing polymerase processivity through facilitating encapsidation during replication. Additionally, we also resolved high-resolution structures of MeV and Nipah virus (NiV) polymerases bound to ERDRP-0519, an orally available morbillivirus inhibitor. Unexpectedly, the compound occupies a previously unrecognized allosteric pocket within the RdRp domain, rather than the predicted PRNTase domain, overlapping conserved resistance sites. This binding induces conformational changes in palm subdomain, blocking RNA template and nucleotide engagement, thereby halting RNA synthesis. These findings uncover distinct regulatory and inhibitory mechanisms in paramyxovirus polymerases and provide a structural framework for the rational design of broad-spectrum antivirals targeting MeV, NiV, and potentially other clinically relevant nsNSVs.

microbiology↗

bioRxiv2025

NTM-DB: A Comprehensive Non-Tuberculosis Mycobacteria Genomic Database

Non-tuberculous mycobacteria (NTM) are a major group of environmental bacteria, with approximately one-third of them causing serious human infections, particularly respiratory diseases. The global rise in the prevalence and severity of NTM infections has posed a major public health challenge. While high-throughput sequencing has generated vast genomic data on NTM, there remains a lack of comprehensive resources for cross-species genomic analysis. To address these limitations, we have developed a specialized database called NTM-DB (https://ngdc.cncb.ac.cn/ntmdb) tailored for NTM researchers and clinicians. NTM-DB offers the most comprehensive collection of NTM genomic and bioinformatic resources, including 16,469 genome assemblies (13,134 newly assembled genomes), 189 type/standard strain genomes representing 177 species and 12 subspecies, 705 MLST types, 33,240 resistance genes, and 74,315 virulence genes. A user-friendly interactive website has been constructed to enable efficient browsing, MLST profiling, searching, online analysis, and downloading of the aforementioned data. Notably, with online analysis tools, users can perform customized genotyping, cross-species phylogeny, pan-genome, and virulence and drug resistance gene annotation analyses using our data and/or their uploaded data. Overall, with its comprehensive data, intuitive interface, and powerful analysis tools, NTM-DB serves as an important resource and reference for NTM researchers and clinicians, improving diagnosis and treatment for various NTM-related diseases, and supporting both scientific discovery and clinical practice.

microbiology↗