Biology subjects

Wang, L.

Publications and source records attributed to Wang, L..

At least 235 records · Page 13Linked to original sources

bioRxiv2026

Kindlin-2-Moesin interaction orchestrates sprouting angiogenesis via modulating endothelial membrane mechanics and VEGF signaling

Membrane mechanics play a crucial role in cellular signaling and fate determination, yet their impact on angiogenesis remains poorly understood. Here, we identify Kindlin-2 as a key regulator of sprouting angiogenesis via regulating endothelial membrane tension through its interaction with Moesin, a crucial linker protein between the cell membrane and the actin cortex. Mechanistically, Kindlin-2 binds to the N62 residue of Moesin, limiting its overactivation and maintaining proper membrane tension to facilitate VEGFR2 endocytosis and downstream signaling. Using both developmental and pathological models, we demonstrate that the interaction of Kindlin-2 and Moesin is enhanced in high angiogenic conditions, and endothelial Kindlin-2 deletion reduces angiogenesis. Furthermore, mutation of Moesin at N62 phenocopies the effects of Kindlin-2 loss. Together, these findings uncover a previously unrecognized mechanism linking membrane tension regulation to angiogenesis and provide new insights into targeting the Kindlin-2-Moesin axis for therapeutic intervention in neovascular diseases.

developmental biology↗

bioRxiv2026

CellSwarm: LLM-Driven Cell Agents Recapitulate Tumor Microenvironment Dynamics and Sense Indirect Genetic Perturbations

Agent-based models of the tumor microenvironment (TME) traditionally rely on hand-coded rules that cannot generalize beyond their programmed logic. Here we present CELLSWARM, a framework that replaces rule-based cell decision-making with large language model (LLM)-driven autonomous agents. Each simulated cell maintains persistent state, 14 signal pathways, and a memory stream, with an LLM serving as its cognitive core. Using structured knowledge bases for cancer-specific context, CELLSWARM recapitulates TNBC microenvironment composition with fidelity comparable to hand-coded rules (Jensen-Shannon divergence 0.144 vs. 0.146; P=0.012 vs. random, Mann-Whitney U test). Beyond matching rule-based performance, LLM-driven agents demonstrate three capabilities absent from rule-based models: cross-cancer generalization by swapping knowledge base entries, treatment response prediction concordant with clinical data (anti-PD-1: 17.6% simulated vs. 21% clinical), and sensing of indirect genetic perturbations that propagate through intermediate signaling cascades (IFN-{gamma} KO: Agent +15.7% vs. Rules +0.3%; P=0.005). CELLSWARM demonstrates that LLM-driven cell agents can recapitulate and extend TME simulation beyond the reach of hand-coded rules.

systems biology↗

bioRxiv2026

Heterozygote Advantage of a Single-Copy SNAP18 Truncation Allele Enables Dominant SCN Resistance and Yield Preservation in Soybean

Soybean cyst nematode (SCN, Heterodera glycines) is the most devastating pathogen threatening global soybean production. The long-term over-reliance on rhg1-a/b resistance has led to the rapid emergence of virulent SCN populations, creating an urgent demand for novel genetic resources to safeguard soybean yield. Here, we identified a rare gain-of-function allele, SNAP18lmm3, via map-based cloning of the lesion-mimic mutant (lmm3) in the SCN-susceptible Williams 82 (rhg1-c) background. This allele encodes a 24-amino-acid C-terminal truncation of SNAP18 and exhibits an unusual mixed dominance genetic profile: the autoimmune-related leaf lesion phenotype is recessive, whereas SCN resistance is dominant. Homozygous lmm3 plants suffer significant yield losses due to spontaneous cell death, but heterozygous (LMM3+/-) plants maintain normal growth, agronomic performance, and seed yield comparable to wild-type Williams 82 in SCN-free field environments. Critically, under artificial SCN inoculation in both field trials and controlled environments, LMM3+/- heterozygotes confer robust resistance, achieving a [~]4-fold yield advantage over SCN-infested Williams 82 and a [~]44% reduction in cyst formation relative to Williams 82. This resistance profile aligns with the broad-spectrum activity of the lmm3 homozygous mutant, supported by the conserved resistance mechanism of SNAP18lmm3. Transgenic expression of SNAP18lmm3 driven by the nematode-responsive HIP promoter (HIPpro) potently arrested nematode development at the J2 stage in transgenic hairy roots, as evidenced by the drastically reduced proportion of advanced-stage nematodes. Our findings establish SNAP18lmm3 as a potent, "plug-and-play" genetic resource that circumvents the limitations of traditional dosage-dependent resistance loci. This allele enables the development of high-yielding, SCN-resistant soybean cultivars through marker-assisted selection for the heterozygous state or precision genome editing, providing a practical solution for sustainable SCN management.

plant biology↗

bioRxiv2026

SNAP18 Truncation Triggers a Competitive Binding Switch Between NSF and ATG8f, Balancing Vesicular Trafficking and Autophagy for SCN Resistance in Soybean

Soybean cyst nematode (SCN, Heterodera glycines) poses the most devastating biotic threat to global soybean production. Traditional SCN resistance mediated by the Rhg1 locus predominantly relies on gene copy number expansion and elevated -SNAP protein dosage. Here, we report a novel resistance mechanism in a single-copy rhg1-c background, wherein a C-terminal 24-amino-acid truncation of SNAP18 (designated SNAP18lmm3) triggers a functional switch from vesicular trafficking to autophagic degradation. Biochemical assays and structural modeling demonstrate that this truncation severely impairs the canonical interaction between SNAP18 and N-ethylmaleimide-sensitive factor (NSF), disrupting SNARE complex recycling and inducing localized cytotoxicity. Concomitantly, the truncated SNAP18lmm3 exposes a binding interface for the autophagy-related protein ATG8f, routing the aberrant protein for selective autophagic clearance. This constitutively activated autophagic flux acts as a systemic detoxification system, preventing widespread cell death and ensuring normal plant growth under non-stressed conditions. Upon SCN infection, SNAP18lmm3 specifically hyper-accumulates within nematode-induced syncytia. This accumulation reaches levels fourfold higher than in adjacent cells, which overwhelms the local autophagic capacity and triggering targeted cell death that arrests nematode development. By elucidating this competitive molecular switch between NSF and ATG8f binding, our study establishes a "self-degrading toxin" model that resolves the inherent trade-off between plant growth and immunity. This work provides a new theoretical framework for engineering cellular homeostasis to enhance durable crop resistance against parasitic nematodes.

plant biology↗

bioRxiv2026

A human gut-BBB-brain microphysiological model for studying neurodegenerative diseases

The gut-brain axis has emerged as a crucial factor in neurodegeneration, with growing evidence linking gut dysbiosis and metabolic dysfunction to Alzheimers disease (AD) progression. Unfortunately, the lack of human-relevant in vitro models limits our ability to effectively explore the mechanism of this axis. To address this gap, we have developed a human induced pluripotent stem cell (iPSC)-derived gut-blood-brain barrier (BBB)-brain microphysiological system that enables systematic investigation of gut-brain interaction in the context of AD under controlled conditions. Our findings reveal that the interaction between gut and brain organoids can promote the maturation of brain organoids, making them more similar to their physiological characteristics in vivo. Additionally, co-culture gut and brain organoids better recapitulates the pathological features of AD. We also discovered that gut organoids of AD can trigger neurodegenerative disease manifestations in healthy brain organoids. In summary, our microphysiological system provides a novel and versatile in vitro platform for studying the interaction between the gut and brain in neurodegenerative diseases.

neuroscience↗

bioRxiv2026

Reconstructing multi-scale tissue spatial architecture from single-cell RNA-seq with REMAP

Understanding spatial organization of cells is critical for deciphering tissue function and disease. Single-cell RNA-sequencing (scRNA-seq) profiles transcriptomes at scale but loses spatial context, while spatial transcriptomics (ST) preserves spatial information but is constrained by cost and gene coverage. Here, we present REMAP, a deep learning framework that integrates gene expression with neighborhood-level gene-gene covariance to reconstruct multi-scale spatial organization of scRNA-seq data using one or multiple ST references. Across 2D and 3D mouse brain, human fetal cortex, and seven human cancer types, REMAP consistently outperformed existing approaches. Applied to a human multiple sclerosis atlas, REMAP resolved microglial neighborhood heterogeneity, and identified a rare pro-inflammatory microglia-astrocyte subpopulation. Across diverse cancers, REMAP recovered conserved spatially-defined cancer-associated fibroblast subtypes with known prognostic significance. By transforming cost-efficient single-cell datasets into spatially interpretable tissue maps, REMAP enables spatial hypothesis generation, microenvironment discovery, and population-scale inference of conserved and perturbed architectural principles in human disease.

genomics↗

bioRxiv2026

Sex-specific electrophysiology and cholinergic responses underlie differential mechanisms of arrhythmia vulnerability in rabbit atria

BackgroundSex differences in the epidemiology of atrial fibrillation are well-documented; however, the underlying mechanisms remain poorly understood. This gap in knowledge is compounded by limited data on sex-specific atrial electrophysiology in the absence of disease. ObjectivesThe aim of this study was to investigate sex differences in atrial electrophysiology and arrhythmia susceptibility in a translationally-relevant rabbit model. MethodsDual optical mapping of transmembrane voltage and Ca2+ was performed on intact atria of young (3.5-5 months) male and female rabbit hearts. Baseline atrial electrophysiology and arrhythmia susceptibility were investigated using rapid pacing and premature stimulation and further tested with the parasympathomimetic carbachol. Sex and regional differences in gene expression were assessed using qPCR. ResultsFemales exhibited similar action potential duration (APD), but greater APD heterogeneity across the atria at slower rates, along with longer Ca2+ transient durations compared to males. Greater APD heterogeneity in females was rate-dependent and comparable to males at faster pacing frequencies; however, it was associated with greater susceptibility to transient reentrant arrhythmias with premature stimuli. After carbachol application, males had heightened vulnerability to arrhythmia. This was associated with cholinergic-mediated APD shortening in both atria in males, but only in the right atrium in females. Sex differences in carbachol responses were linked to variations in muscarinic receptor and acetylcholine-activated potassium channel gene expression. ConclusionsThese findings demonstrate sex and regional differences in atrial electrophysiology at baseline and in response to cholinergic stimulation in the healthy heart that may contribute to sex-specific mechanisms of arrhythmia.

physiology↗

bioRxiv2026

ProteinConformers: large-scale and energetically profiled descriptions of protein conformational landscapes

Modeling protein conformational landscapes is essential for understanding dynamics, allostery, and drug discovery, yet existing resources lack diverse conformational coverage, energetic annotations, or benchmarking standards. ProteinConformers (https://zhanggroup.org/ProteinConformers) provides 2.7 million geometry-optimized conformations generated with a multi-seed molecular dynamics strategy, paired with 13.7 million energy evaluations and 5.5 million similarity annotations. It delivers continuous landscapes from non-native to near-native states, benchmarking framework for multi-conformation generators, and an interactive analysis platform.

bioinformatics↗

bioRxiv2026

A dimer peptide ligand of vascular endothelial growth factor slows the progression of human gastric tumors in mouse xenografts

Gastric cancer is among the most common cancers and represents a major public health problem worldwide. New therapeutic strategies and drugs are needed. Anti-angiogenic agents targeting the Vascular Endothelial Growth Factor (VEGF) are used in combination therapy in the clinic, although their efficacy remains modest. We believe that these large anti-VEGF antibodies could be advantageously replaced by smaller peptides with better tissue penetration. In this study, we evaluate the efficacy of a previously described dimer peptide ligand of VEGF, D6, in inhibiting the proliferation of gastric cancer cells and the growth of the corresponding murine xenograft. The activity of the D6 peptide in these assays was comparable to that of bevacizumab, the positive control antibody, although the peptide required repeated injections at higher molar concentrations. These promising results justify the continued optimization of the peptide dimer, currently under investigation in our laboratory.

pharmacology and toxicology↗

bioRxiv2026

Vitamin D deficiency alters prostate epithelial differentiation and increases prostate cancer aggressiveness in ex vivo and in vivo models

Here, we examined the consequences of biologically relevant vitamin D deficiency, a known risk factor for aggressive prostate cancer, using ex vivo and in vivo models. Phenotypic and single-cell RNA sequencing of mouse prostate organoids showed that vitamin D deficiency stunted luminal cell differentiation more than androgen deficiency, which is a known driver of prostate development. Mice fed a vitamin D-deficient diet showed significantly altered expression of androgen-responsive genes in their prostate luminal cells, as determined by single-cell RNA sequencing. MDA-PCa-2b human prostate cancer cells, when maintained for 6 months in 1,25-dihydroxyvitamin D, lost the ability to form xenografts, despite normal proliferation in vitro. RNA sequencing showed that these cells also had disruptions in androgen signaling and multiple cancer-related pathways. This study offers new insights and validation of vitamin Ds role in both benign and malignant prostate biology, underscoring its essential hormonal functions and supporting strategies for vitamin D supplementation to reduce prostate cancer risk in vulnerable populations. STATEMENT OF SIGNIFICANCEVitamin D is an essential hormone, however, the non-calcemic consequences of vitamin D deficiency remain poorly defined, despite its high prevalence in the population. This study demonstrates significant biological consequences of vitamin D deficiency on prostate cells at biologically relevant levels in multiple systems.

cancer biology↗

bioRxiv2026

An ancient monoaminergic signaling system coordinates contractility in a nerveless sponge

Chemical neurotransmission was a key animal innovation, enabling multicellular coordination of physiology and locomotion. Sponges are early-diverging animals that lack neurons and muscles, yet still coordinate contraction and relaxation of their filter-feeding water canals. Here, we show that Spongilla lacustris synthesizes the monoamines tryptamine, phenethylamine, and tyramine to elicit distinct canal behaviors. We identify previously uncharacterized decarboxylases and vesicular transporters coexpressed in secretory neuroid and metabolic cells. Using phosphoproteomics and label-free 3D imaging, we show that tryptamine activates GPCR signaling and Rho GTPases, remodeling adhesion and actomyosin networks in contractile canal epithelia to drive localized constrictions and whole-body deflations. Together, these findings define an ancestral monoaminergic system linking secretory and contractile cell types that predate neurons and was later elaborated for neuromodulation of synaptic transmission.

evolutionary biology↗

bioRxiv2026

Recruitment of SERK co-receptors determines signaling specificity within the systemin peptide family

The phytocytokine systemin (SYS1) regulates defense responses of tomato plants against herbivores and necrotrophic pathogens. For more than three decades, systemin signaling was thought to rely solely on SYS1, although the tomato genome encodes the precursors of at least three additional systemin-like peptides (SYS2, SYS3 and SYS4). We show that these recently discovered peptides are processed in a wound-inducible manner and act as genuine wound signals that activate early defense signaling via the receptor SYR1. Although all systemins depend on SYR1 for perception, the new peptides elicit downstream responses distinct from those triggered by SYS1, including sustained ethylene production and extensive transcriptional reprogramming. Signaling specificity is governed by a single C-terminal residue that determines the ability of SYS peptides to recruit SERK co-receptors into the receptor complex. The resulting increase in complex stability underlies the amplified and prolonged signaling responses observed for the new SYS peptides compared to SYS1. Our findings reveal how subtle sequence changes within the systemin peptide family can remodel receptor-co-receptor interactions to generate ligand-specific signaling outputs. This mechanism allows a single receptor to decode related ligands into distinct physiological responses and may represent a broader principle allowing for the diversification of peptide-mediated signaling in plants.

plant biology↗

bioRxiv2026

The genome of an aneuploid cultivar facilitates elucidating the genetic bases of trait polymorphisms in Phalaenopsis orchids

As an important ornamental crop, Phalaenopsis orchids exhibit extraordinary trait diversity with unclear genetic bases. Here, we present a haplotype-resolved, chromosome-level genome for an aneuploid cultivar Santiago. We reveal pervasive variation in the number and sequence among homoeologous genes. When serving as a reference, this genome facilitates the genetic understanding of trait variation in a hybrid population that is highly representative in trait polymorphisms. Specifically, nucleotide polymorphisms in a potential long-distance enhancer and the consequential expression variation of PsAGL6-2, presence/absence of PsMYB12 and b-type homoeologous gene of PsMYB2 determine lip morphology variation, presence/absence of venation-associated stripes and background pink color, respectively. Diverse functions of PsMYBx1 in repressing anthocyanin accumulation across different cultivars further enhances the color patterning diversity in Phalaenopsis. Our study provides a practical framework for using a highly heterogeneous, haplotype-resolved genome to decode phenotypic diversity and has the potential to promote marker-assisted breeding in Phalaenopsis.

genomics↗

bioRxiv2026

PlantMDCS: A code-free, modular toolkit for rapid deployment of plant multi-omics databases

With the rapid accumulation of diverse omics datasets, achieving efficient management and integrative analysis of plant multi-omics data remains a major challenge. Conventional solutions rely on constructing web-based databases, which often demand substantial programming expertise and long-term financial support. To address these limitations, we developed the Plant Multi-omics Database Construction System (PlantMDCS)-a locally deployable, user-friendly, and collaborative platform that unifies database construction and downstream multi-omics analysis within a graphical environment. PlantMDCS adopts a decoupled front-end/back-end architecture. The back end serves as the core engine for data management and computation, and is responsible for the storage, preprocessing, integration, and hierarchical association of multi-omics data. Once initialized, the front end supports the complete research workflow, including data import, querying, integrative analysis and visualization. All operations can be performed without programming, while local resource usage is dominated by disk storage required for user-provided datasets rather than sustained computational overhead. Benchmarking across plant species ranging from Arabidopsis to hexaploid wheat demonstrated that database construction can be completed within minutes, independent of genome size or data complexity. PlantMDCS is designed for local deployment to ensure data security, while allowing multi-user collaboration within local networks and supporting controlled remote access for teams distributed across different regions. Overall, PlantMDCS offers a secure and sustainable framework that integrates data management and analysis within a unified system. This design shifts multi-omics research away from fragmented file-based processing toward persistent, database-driven exploration, thereby enhancing analytical efficiency and reproducibility.

bioinformatics↗

bioRxiv2026

Plant-specific and conserved mechanisms of the polymerase-associated factor 1 complex in replication stress responses

DNA replication stress threatens genome stability in eukaryotes. The evolutionarily conserved kinase WEE1 is essential for the activation of the replication stress response. Although the polymerase-associated factor 1 complex (PAF1C) is highly conserved in eukaryotes, its role in the DNA replication stress response remains unclear. Here, we show that Arabidopsis PAF1C is essential for replication stress response. PAF1C-deficient mutants exhibit hypersensitivity to hydroxyurea (HU)-induced replication stress. Mechanistically, we uncover a plant-specific regulatory pathway in which WEE1 interacts with and phosphorylates the PAF1 subunit within its unique N-terminal domain, thereby preventing PAF1 polyubiquitination and subsequent proteasomal degradation to ensure PAF1 accumulation under stress. Genetically, overexpression of a phospho-mimetic PAF1 variant suppresses the HU hypersensitivity of wee1, revealing that PAF1 acts downstream of WEE1. However, the WEE1-PAF1 regulatory axis is absent in yeast, indicating its lineage-specific innovation. Further studies reveal that the replication factor C (RFC) complex interacts with and recruits PAF1 to the stalled replication forks. PAF1 then sequentially recruits the E2 ubiquitin-conjugating enzymes UBC1/2 and the E3 ubiquitin ligases HUB1/2 to promote histone H2B monoubiquitination (H2Bub), thereby facilitating replication fork stability. This RFC-dependent recruitment mechanism is conserved in yeast. Collectively, this study suggests that PAF1 regulates replication stress responses by integrating a plant-specific protein stability control mechanism (WEE1-PAF1) with a conserved recruitment mechanism (RFC-PAF1-UBC1/2-HUB1/2), uncovering a novel function of PAF1C and revealing new mechanisms of WEE1 and the RFC complex.

plant biology↗

bioRxiv2026

Spatial immune hubs defined by conserved activated dendritic cells are remodeled by immunotherapy

Dendritic cells (DCs) orchestrate anti-tumor immune responses, yet the full extent of their phenotypic diversity, and spatial dynamics within the tumor microenvironment (TME) remains incompletely understood. Here, we constructed an integrated atlas of tumor-infiltrating DCs by harmonizing single-cell transcriptomic data from 12 murine tumor studies and 28 published human cancer datasets, together with newly generated single-cell-resolved multiplexed tissue imaging across immunotherapy conditions in a murine model. We noted conserved transcriptional states across species, including canonical conventional type 1 DCs (cDC1s), diverse type 2 DC (cDC2) subpopulations, and two activation states characterized by CCR7 expression (CCR7+ DCs) or interferon-stimulated gene expression (ISG DCs). Spatial transcriptomics analyses from human TMEs revealed that CCR7+ DCs and ISG DCs reside in distinct T cell-enriched regions that are embedded within distinct signaling environments. High-dimensional multiplexed proteomic imaging demonstrated that these DC-T cell niches undergo divergent remodeling across multiple immunotherapy conditions. Notably, this spatial reorganization occurred despite minimal detectable changes in DC transcriptional states. This study delineates conserved DC activation states and their spatial organization within tumors and captures the therapy-dependent remodeling, providing a framework for studying therapy-associated remodeling of DC immune programs in cancer.

immunology↗

bioRxiv2026

Chlamydial Histones Control Developmental Fitness in the Next Infection Cycle

The unique chlamydial developmental cycle comprises three stages: primary differentiation of infectious elementary bodies (EBs) into reticulate bodies (RBs), RB replication, and secondary differentiation into progeny EBs. Extensive chromosome remodeling during RB-to-EB differentiation is thought to be mediated by the histones HctA and HctB. Here, we used an inducible CRISPR interference system to repress hctA, hctB, or both genes during development in Chlamydia trachomatis. Surprisingly, repression of either histone gene alone or in combination caused only modest reductions in EB yield and did not prevent nucleoid condensation during the parental developmental cycle. In contrast, when progeny EBs generated under histone-repressing conditions were used to initiate secondary infections in the absence of inducer, histone deficiency during EB maturation profoundly impaired fitness in the next infection cycle. Secondary cultures initiated with HctA-deficient EBs exhibited a delayed onset of genome replication, consistent with inefficient primary EB-to-RB differentiation, whereas combined repression of hctA and hctB caused both delayed genome replication and persistently reduced genome accumulation, indicative of defects in RB formation and subsequent growth. Repression of hctB alone did not measurably affect genome replication in secondary cultures. Together, these findings reveal a transgenerational role for chlamydial histones and establish chromosome organization during EB maturation as a key determinant of developmental fitness across infection cycles. IMPORTANCEChlamydial histones HctA and HctB are unusual among bacterial chromatin-binding proteins in that they share sequence homology with mammalian histones and are developmentally regulated during the formation of infectious particles. Here, we show that reduced expression of HctA and HctB has only modest effects on genome condensation and EB production, consistent with partial functional redundancy between the two histones and suggesting that additional chromatin factors contribute to EB chromosome compaction. In contrast, deficiency of HctA and HctB during EB maturation has profound consequences in the next infection cycle, impairing primary EB-to-RB differentiation and subsequent RB growth. These findings reveal a previously unrecognized transgenerational role for chlamydial histones and establish chromosome organization during EB maturation as a key determinant of developmental fitness across infection cycles.

microbiology↗

bioRxiv2026

Protenix-v1: Toward High-Accuracy Open-Source Biomolecular Structure Prediction

We introduce Protenix-v1 (PX-v1), the first fully open-source structure prediction model to attain superior performance to AlphaFold3 while strictly adhering to the same training data cutoff, model size, and inference budget. Beyond standard evaluations, we highlight the effectiveness of inference-time scaling behavior of Protenix-v1, demonstrating that increasing the sampling budget yields consistent improvements in prediction quality--a behavior previously observed in AlphaFold3 and largely absent from prior open-source models. In addition to improved accuracy, Protenix-v1 incorporates key capabilities including protein template integration and RNA MSA support. Furthermore, to better support real-world applications such as drug discovery, we additionally release Protenix-v1-20250630, a variant trained on a larger dataset (cutoff: June 30, 2025), delivering further improved prediction accuracy. Finally, we identify limitations in existing benchmarking practices and provide updated evaluation tools and year-stratified benchmarks to support more reliable and transparent assessment. Collectively, these contributions provide a robust foundation for the Protenix series and the broader field.

bioinformatics↗