Biology subjects

Ye, J.

Publications and source records attributed to Ye, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure

Mitochondrial cristae disintegration is a hallmark of heart failure, yet how oxidative phosphorylation (OXPHOS) dysfunction triggers this structural collapse remains unclear. Here we identify acetylation of the complex I subunit NDUFA13 at lysine 7 (K7) as a metabolic sensor coupling OXPHOS dysfunction to cristae remodelling. OXPHOS inhibition drove NDUFA13-K7 hyperacetylation, inducing conformational compaction and translocation to the intermembrane space. Acetylated NDUFA13 competitively engaged PHB2 through its coiled-coil domain, displacing PHB1 and disassembling prohibitin scaffolds. The acetylation-mimetic NDUFA13-K7Q induced cristae fragmentation in vitro, and cardiomyocyte-specific K7Q knock-in mice showed accelerated mortality and cristae loss under pressure overload, accompanied by impaired TCA cycle flux, defective fatty acid oxidation and selective depletion of polyunsaturated cardiolipins. These findings establish NDUFA13-K7 acetylation as a reversible switch converting bioenergetic failure into pathological cristae remodelling and metabolic reprogramming, highlighting therapeutic potential for targeted deacetylation.

cell biology↗

bioRxiv2026

Pan-cancer nucleosome landscapes reveal tumor heterogeneity and inform cell-free DNA-based detection

Background: Nucleosome positioning and occupancy are fundamental features of chromatin organization, yet their variation across human cancers and potential utility for noninvasive cancer detection remain poorly characterized. Methods: We systematically characterized nucleosome organization across 410 primary tumors spanning 23 cancer types using ATAC-seq, establishing a high-confidence pan-cancer nucleosome atlas validated by independent MNase-seq data. We characterized shared and cancer-type-enriched nucleosome patterns, investigated their associations with tumor heterogeneity and regulatory alterations, and evaluated tissue-derived nucleosome signatures for cancer classification and detection using circulating cell-free DNA (cfDNA). Results: The atlas identified shared and cancer-type-enriched nucleosomes associated with distinct regulatory programs. Notably, nucleosome occupancy provided information complementary to chromatin accessibility for tumor stratification and revealed molecular heterogeneity within individual cancers, including subgroups associated with Basal-like breast cancer. In hepatocellular carcinoma, differential nucleosome analysis revealed cancer-associated chromatin remodeling involving regulatory pathways, transcription factor motifs, and candidate genes. Importantly, tissue-derived nucleosome signatures were detectable in cfDNA, enabling classification among three cancer types (AUROC = 0.877) and colorectal cancer detection (AUROC = 0.930), with an AUROC of 0.773 in an independent validation cohort. We also developed OncoNucAtlas, a publicly accessible database facilitating exploration of these nucleosome landscapes. Conclusions: Our study cancer-associated nucleosome organization as a complementary source of epigenomic information and demonstrates the potential of tissue-derived nucleosome signatures for cfDNA-based cancer detection. The pan-cancer atlas provides a resource for investigating tumor heterogeneity and developing noninvasive cancer detection approaches.

bioinformatics↗

bioRxiv2026

ASTRA enables zero-shot super-resolution of spatial transcriptomics across capture geometries

Spatial transcriptomic super-resolution recovers tissue organization obscured by coarse sampling, but fitting a model to each section greatly increases computational cost and reduces practicality. We introduce ASTRA, a cross-platform pretrained model that reconstructs expression from histology and measured RNA by zero-shot inference. Training with arbitrarily shaped count-bearing regions, termed parents, enables one frozen model to accommodate dense bins and separated spots. Across six held-out Visium HD sections, ASTRA achieved higher correlations under dense-bin and pseudo-Visium sampling, lower dense-bin errors and substantially shorter processing times than existing methods. It improved colorectal tissue segmentation and tumor-boundary recovery. In real colorectal Visium, reconstruction spatially resolved a stromal transcriptional state supported by measured RNA. The same checkpoint supported regional and nucleus-associated analyses across 43 invasive lobular carcinoma sections and within-spot interpretation across 92 triple-negative breast cancer sections. ASTRA establishes a reusable framework for practical, cohort-scale spatial transcriptomic super-resolution across platforms.

bioinformatics↗

bioRxiv2026

Loss of DNA Demethylase Enhances Arsenic Resistance Via Reducing of PIN2 Antisense Long Noncoding RNA

DNA methylation dynamics regulate diverse plant stress responses, but the mechanisms governing arsenic (As) tolerance through epigenetic pathways remain largely unknown. Here we report that Arabidopsis mutants lacking the DNA demethylase, REPRESSOR OF SILENCING (ROS1), show substantially enhanced As resistance. Integrating transcriptome and methylome data, we found that PIN-FORMED 2 (PIN2), encoding an auxin efflux carrier that also transports As out of cells, represents a key ROS1 target. In ros1, we observed increased methylation in the last exon of PIN2, a region functioning as the promoter for an antisense long non-coding RNA (lncRNA). Hypermethylation of the promoter suppresses the antisense lncRNA, which follows reduction of sense PIN2 transcription. As a result, PIN2 expression increases in ros1 mutants during As exposure, enhancing As tolerance. Analysis of ros1 pin2 double mutants confirmed that PIN2 acts downstream of ROS1 in As tolerance. Our study demonstrates an epigenetic pathway in which ROS1 regulates As tolerance by controlling PIN2 expression through antisense lncRNA-mediated transcriptional interference, offering new epigenetic strategies using plants in heavy metal contaminated environments.

plant biology↗

bioRxiv2026

π-MNovo improves de novo peptide sequencing through microbial-domain adaptation and evidence-guided candidate selection

The high taxonomic and strain-level diversity of microbial communities makes it difficult for reference databases to fully represent the protein sequences present in metaproteomic samples, limiting database-dependent peptide identification. De novo peptide sequencing can recover peptide sequences directly from tandem mass spectra without relying on reference databases, providing complementary peptide evidence for metaproteomics. However, most existing de novo sequencing models were developed largely from non-microbial proteomic data and lack specific adaptation to microbial spectra. Here, we established a dedicated microbial spectral resource comprising more than 10 million annotated high-quality tandem mass spectra from 72 cultured microbial isolates, with peptide digests from each isolate separated into five high-pH reversed-phase fractions to increase the opportunity for deeper and more diverse peptide sampling. Using this resource, we developed {pi}-MNovo, which combines adaptation to microbial spectra with evidence-guided candidate selection to improve full-length peptide sequencing precision. On a seven-species external benchmark, {pi}-MNovo achieved 66.30% complete-peptide recall under the same residue-mass-based complete-peptide matching criterion applied to all models, exceeding four published models by 6.9-21.7% in relative recall, with consistent gains across species and peptide-length groups. In two independent metaproteomic datasets, {pi}-MNovo increased reference-supported taxonomic coverage, while synthetic-community analysis recapitulated the designed abundance ranking. From pFind-unidentified spectra, {pi}-MNovo recovered 1,587 pFind-unreported, reference-matched peptides that passed spectrum-evidence filtering. These results show that {pi}-MNovo expands recoverable peptide evidence and enhances the utility of de novo sequencing for metaproteomic analysis.

bioinformatics↗

bioRxiv2026

Single-cell immune repertoire atlas maps coordinated circulating adaptive immune states in inflammatory bowel disease

Single-cell studies have defined immune states in inflammatory bowel disease (IBD), but how adaptive receptor histories organize circulating immunity remains unclear. We generated a single-cell transcriptomic atlas of peripheral blood from 249 participants with Crohn's disease, ulcerative colitis, or non-IBD control status, including 182 with productive TCR and BCR recovery. Expanded TCR clonotypes marked inflammatory-memory and cytotoxic states, while distinct but similar paired TCRs shared inflammatory programs across participants. BCR lineage maturation linked IgA-associated mucosal and plasma B cell programs to somatic mutation and class switching, distinguishing maturation-associated biology from clonal expansion. Helper, regulatory, and cytotoxic T-cell programs covaried with B-cell states, and inferred interactions nominated reciprocal antigen-presentation and helper pathways. Repertoire-based machine learning distinguished diagnosis, inflammation, and contemporaneous six-month treatment-response status. Together, this atlas connects receptor architecture to coordinated systemic immune remodeling, establishes a foundation for repertoire-informed patient stratification, and prioritizes candidate mechanisms of IBD pathogenesis.

immunology↗

bioRxiv2026

Single-cell profiling reveals stromal niche and α5β1 regulation of neutrophil phenotypes in ulcerative colitis

Background and Aims: Fibroblast-neutrophil interactions are implicated in ulcerative colitis (UC) treatment resistance, but whether fibroblasts modify neutrophil inflammatory activity remains unclear. We investigated responses to fibroblast exposure, stromal depletion, and 5{beta}1-directed treatment. Methods: We integrated human and mouse colonic single-cell RNA sequencing (scRNA-seq), spatial protein profiling (CODEX), fibroblast-neutrophil coculture, and dextran sulfate sodium (DSS) mouse colitis with fibroblast activation protein (FAP) ablation or 5{beta}1-directed treatment. Readouts included cellular representation and protein fluorescence via flow cytometry, neutrophil extracellular trap (NET)-associated elastase activity, RNA programs and epithelial responses using scRNA-seq. Results: Inflamed UC tissue contained higher fractions of inflammatory fibroblasts and oncostatin M (OSM)- and CXCR4-associated neutrophils. Inflammatory fibroblasts had higher FAP-5{beta}1 module scores, and proximity to FAP-high fibroblasts was associated with higher neutrophil OSM and CXCR4 fluorescence. UC fibroblasts increased neutrophil OSM, CXCR4 and myeloperoxidase (MPO) fluorescence and NET-associated elastase activity relative to control fibroblasts, while 5{beta}1-directed treatment attenuated these responses. Both mouse FAP ablation and 5{beta}1 blockade in DSS colitis reduced histologic inflammation and overall neutrophil frequency. Ablation broadly reduced recovered neutrophil representation, whereas blockade increased OSM-positive and PADI4-positive percentages within neutrophils despite lower MPO fluorescence within these subsets. Both interventions were associated with lower epithelial chemokine scores but distinct absorptive and mucus/secretory responses. Conclusions: Fibroblast exposure modifies neutrophil inflammatory phenotype and effector-associated activity, identifying candidate therapeutic pathways in UC. Evaluating these responses alongside neutrophil representation and tissue inflammation could inform pharmacodynamic assessment of stromal-directed therapies.

immunology↗

bioRxiv2026

LucaCell: a sequence-centric foundation model for cross-species single-cell analysis

Single-cell foundation models have transformed transcriptomic analysis, yet most rely on fixed gene identifiers that limit transfer across species and data types. Here we present LucaCell, a sequence-centric foundation model that represents genes through pre-trained mRNA sequence embeddings rather than static gene annotations. Gene expression is discretized into bins and modeled with a Transformer encoder, enabling sequence-informed cell representation without a fixed gene-ID vocabulary. Pre-training on 85 million human and mouse single cells, LucaCell is evaluated on human, mouse and lemur gene expression profiles, human chromatin accessibility data, unaligned reads from more than 50 prokaryotic taxa, and five influenza A virus genomes. LucaCell enables manual-mapping-free cross-species cell type annotation and an alignment-free microbial embedding framework that simultaneously distinguishes bacterial species identity and intra-species physiological states. It also improves gene expression reconstruction by incorporating donor-specific exonic SNP information into mRNA sequence embeddings, and predicts cellular viral load across influenza A virus strains while highlighting infection-like transcriptional states in mock-infected cells. These results show that sequence-informed gene representation can improve the generalization of single-cell foundation models across species, data types, and predictive tasks.

bioinformatics↗

bioRxiv2026

Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome

Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism-related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1-/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1-/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment rescues did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS.

neuroscience↗

bioRxiv2026

Pto evolved from malectin-like RLKs phosphorylates AvrPtoB to promote Prf-mediated immunity in Solanum pimpinellifolium

Bacterial speck, caused by Pseudomonas syringae pv. tomato (Pst), is a devastating disease of tomato that severely limits global tomato productivity. Understanding the molecular mechanisms underlying Pst and tomato is essential for developing disease resistant varieties. Here, we demonstrate that Pto, the first disease-resistance gene conferring recognition of a specific pathogen, phosphorylates Pst type III effector AvrPtoB at serine 335 site. This post-translational modification triggers the dissociation of the Prf immune complex, enhancing immune signaling and reducing bacterial pathogenicity. Furthermore, evolutionary analyses indicate that Pto-associated proteins originated from malectin-like receptor kinases (MLRs) through loss of the extracellular domain. Crucially, we identified two key amino acid substitutions, Arg158 and Glu258 in Pto, which replace the ancestral lysine residues in MLRs (SpHREK1-1, SpHERK1-2 and SpHERK1-3). These substitutions stabilize Pto by preventing degradation mediated by AvrPtoB's E3 ubiquitin ligase activity. Our findings reveal a novel mechanism, by which Pto phosphorylates a bacterial effector to trigger enhanced immunity and elucidate the key evolutionary adaptations that have shaped Pto into a stable resistance protein.

plant biology↗

bioRxiv2026

A targeted bispecific TGFBR2 antagonist antibody demonstrates cell selectivity and enhanced potency on human fibroblasts

Beyond its critical roles in development and tissue homeostasis, TGF{beta} signaling promotes key aspects of cancer progression and is a primary driver of fibrosis. Although blocking TGF{beta} signaling has great therapeutic potential for cancer and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), preclinical and clinical studies revealed that non-specific alteration of the pathway can have severe adverse consequences; therefore, inhibiting TGF{beta} signaling in a cell-type specific manner may avoid systemic toxic effects while preserving potential therapeutic effects. The parasitic helminth Heligmosomoides polygyrus has evolved cell-type-targeted modulators of TGF{beta} signaling. With insights from the development of other targeted signaling modulators and using the worm proteins as a guide, we sought to develop a human-fibroblast-targeted TGFBR2 antagonist. Here, we report mechanistic insights into the targeted worm TGFBR2 antagonist TGM6 and fusion proteins containing the TGM6 targeting domains. We created a bispecific antibody TGFBR2 antagonist that binds PDGFRA as a targeting receptor and demonstrates cell selectivity and enhanced potency in fibroblasts. Our findings suggest a viable path for developing targeted TGF{beta} signaling antagonists as therapeutics for cancer and tissue fibrosis.

cell biology↗

bioRxiv2026

Bexobrutideg: A Selective, Catalytic Degrader of Bruton's Tyrosine Kinase Overcomes Inhibitor Resistance and Suppresses Autoantibody-Mediated Disease

Brutons tyrosine kinase (BTK) transduces B-cell receptor (BCR), Toll-like receptor (TLR), and Fc receptor (FcR) signaling, and overactivation of these pathways drives B-cell malignancies and antibody-mediated autoimmune disease. Small molecule inhibitors block the enzymatic functions of BTK, but this inhibition is undermined by resistance mutations, several of which abolish BTKs kinase activity yet promote oncogenic signaling through BTK scaffolding functions. We report the discovery and characterization of bexobrutideg (NX-5948), a heterobifunctional degrader that recruits cereblon (CRBN) to selectively degrade BTK while sparing molecular glue neosubstrates. We demonstrate that bexobrutideg acts catalytically, degrading thousands of copies of BTK per molecule per hour, and this event-driven pharmacology renders it resilient to mutations that confer resistance to both covalent- and noncovalent-inhibitors. Bexobrutideg is orally bioavailable, driving deep and durable BTK degradation across species. Bexobrutideg demonstrates strong efficacy in wild-type and ibrutinib-resistant lymphoma models and robustly suppresses pathway activation in models of autoimmune disease.

cancer biology↗

bioRxiv2026

DNA-Programmed Condensate-Membrane Wetting and Cellular Internalization

Deformable condensates offer dynamic interfaces for biomolecule delivery, yet membrane adhesion does not necessarily lead to cellular internalization. The physical transition that determines whether a membrane-bound soft material remains surface-anchored or proceeds through wetting towards productive uptake remains poorly understood, particularly at active living-cell membranes. Here, we engineer sequence-defined DNA condensates through liquid-liquid phase separation (LLPS) and program their interfacial behavior by tuning sticky-end valency and cholesterol organization. These molecular designs precisely regulate condensate fluidity, fusion dynamics and internal organization, generating distinct states of weak contact, persistent anchoring and rapid wetting. Increasing cholesterol-mediated affinity does not enhance uptake. Instead, productive internalization emerges from a balance between membrane adhesion and condensate fluidity and deformability. Native membrane composition further modulates condensate interfacial fate across mammalian cells and plant protoplasts. DNA condensates enrich and deliver CpG ODNs, mRNA ([~]2000 nt) and proteins, while cargo loading experiments reveal that preserving condensate architecture is essential for functional delivery. Our findings identify wetting competence as a design parameter for controlling soft material engagement and cellular entry.

biophysics↗

bioRxiv2026

Group size and activity influence shoal choice in Goldfish: Replication of zebrafish findings using a drift-diffusion model

Animals often rely on social information when making movement decisions. In zebrafish, classic work showed that shoal size and shoal activity both bias shoal choice. Here we extend these effects in Goldfish (Carassius auratus) and extend them with a drift-diffusion model (DDM) account of individual evidence accumulation under dynamic social cues. Using a three-chamber linear arena, we quantified a focal fishs position for 10 minutes while manipulating (i) numerical differences between flanking shoals and (ii) their activity (swimming speed) via temperature manipulation. ANOVA on time-proportion choices confirmed robust attraction to larger shoals; when shoal sizes were equal, the more active shoal was preferred. In combined manipulations, activity effects dominated at small numbers but saturated as group size increased, indicating a threshold-like integration where activity dominates at small shoal sizes (<3 fish) but saturates at larger sizes. We formalize these processes with a bounded DDM in which a sigmoidal stimulus function maps shoal size and average speed to momentary evidence, subject to random perturbations. The model reproduces the observed psychometric relations between relative numerosity, velocity differences, and choice. Our results (i) generalize zebrafish findings to a carp species with distinct ecology and physiology, and (ii) provide a compact mechanistic link between social cues and individual decision trajectories in dynamic social contexts.

animal behavior and cognition↗

bioRxiv2026

Plant growth forms shaping biodiversity patterns can guide conservation planning on the Qinghai-Tibet Plateau

Plant growth forms effectively reflect profound evolutionary adaptations that underpin ecosystem functioning; however, how their biogeographic disparities influence conservation prioritization remains poorly understood. We here integrate a comprehensive phylogeny with high-resolution distribution data for 14,468 vascular plant species across the Qinghai-Tibet Plateau, showing that growth-form identity decouples the spatial patterns of taxonomic and phylogenetic diversity, with distinct forms exhibiting marked differences in geographic range sizes and elevational optima (2,200-3,300 m). Although herbs dominate plant assemblages across spatial scales, their proportional abundance decreases along a northwest-to-southeast aridity gradient, yielding to structurally complex, non-herbaceous forms in humid, species-rich regions. Consequently, priority conservation areas derived for individual growth forms exhibit low spatial similarity. Despite this divergence, we identify trees and climbers as highly effective umbrella growth forms: prioritizing these functional groups captures [≥]75% of the multidimensional diversity of all other growth forms within a minimal spatial footprint. Our findings demonstrate that accounting for growth-form-based functional identity is essential for maximizing conservation efficacy, providing a scalable framework for biodiversity hotspots worldwide.

ecology↗

bioRxiv2026

The Hidden Landscape of Missed Effects in Human Functional Neuroimaging

Functional neuroimaging aims to uncover brain processes underlying behavior and disease, yet studies are often underpowered to detect these effects. How this literature has shaped our understanding of brain function remains unknown, and little guidance exists for planning better powered studies. An underappreciated barrier is that commonly reported effect sizes across the brain are inflated, biasing study planning. Here, we introduce a correction for this inflation bias and show how more accurate studies can be planned using corrected effect size benchmarks from a mega-analysis of 63 typical studies across seven large datasets (52,979 participants). We find that common methods of planning studies based on uncorrected effects lead to roughly half the expected detections at typical sample sizes, with limited spatial overlap with original findings. These missed effects collectively explain meaningful additional variance in the desired outcome. We show how to recover missed effects by planning not only for power but also for a target number of detections via corrected benchmarks, or by taking a whole-brain approach with multivariate effects that individual research groups can detect (n < 50 compared to n > 1,000 for a typical univariate effect). These findings lay the groundwork for more informed study planning and a richer understanding of the widespread nature of brain effects, with implications for shared challenges (and solutions) across biomedicine.

neuroscience↗

bioRxiv2026

Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance

Computational protein engineering provides a powerful approach to address longstanding clinical challenges. Severe insulin resistance syndromes caused by mutations in the insulin receptor (IR) are life-threatening disorders for which effective long-term therapies remain lacking. Here, we define the in vivo activity and therapeutic potential of RF-409, a de novo-designed IR agonist that activates the receptor through a mechanism distinct from insulin. RF-409 exhibits markedly prolonged circulation compared to insulin and produces sustained improvements in glucose homeostasis without detectable adverse effects on body composition or liver function. In a patient-derived IR D707A mouse model of severe insulin resistance, RF-409--but not insulin--activates the mutant receptor, restoring glucose regulation and ameliorating hyperglycemia, hyperinsulinemia, lipoatrophy, and pancreatic atrophy. Mechanistically, RF-409 engages the IR through a noncanonical binding geometry while stabilizing an active conformation resembling that induced by insulin. Phosphoproteomic profiling shows that RF-409 elicits broadly insulin-like signaling with distinct temporal features in receptor-proximal regulation. Together, these findings establish a framework for reactivating dysfunctional receptors and suggest broader applications beyond rare receptoropathies, including diabetes and liver disease.

pharmacology and toxicology↗

bioRxiv2026

Auxin promotes GPI-anchored protein-mediated trafficking of ABP1 to enable cell-surface auxin signaling

Rapid auxin responses are triggered by Auxin-Binding Protein 1 (ABP1) signaling; however, the coupling of hormone perception to signaling activation is unclear. ABP1, a cell surface auxin receptor, is localized to endoplasmic reticulum (ER), raising a fundamental question of where auxin is perceived and how signaling-competent receptors are mobilized to cell surface. Herein, we established a dark-induced auxin synthesis system in Arabidopsis hypocotyl; abp1 mutants showed pronounced elongation. Auxin dose-dependently stimulates LORELEI-like glycosyl-phosphatidylinositol-anchored protein 1 (GPI-AP, LLG1) interaction with ABP1, driving their outward trafficking from ER. However, this complex dissociated in acidic apoplast, facilitating H+-ATPase-mediated auxin signaling. Our findings reveal how intracellular auxin perception is converted into rapid cell-surface signaling, establishing a mechanistic framework for fast auxin responses and uncovering a GPI-AP-mediated trafficking mechanism for ER-retained receptors.

plant biology↗