Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Blood-brain barrier-traversing multivalent TGFβ trap for anti-cancer immunomodulation of gliomas

Clinical studies have revealed that glioblastoma (GBM) is refractory to immunotherapy, such as immune checkpoint inhibitors (ICIs), due to the immunosuppressive tumor microenvironment (TME) primarily intensified by intratumoral upregulation of transforming growth factor-{beta} (TGF{beta}). Primary GBM tumor bulks are surgically removed in clinic, but invasive tumor cells infiltrated into surrounding normal brain tissue cannot be eradicated by systemic therapy due to the integral blood-brain barrier (BBB), leading to near-inevitable tumor recurrence. To address these translational challenges, we have engineered a TGF{beta}-inhibiting protein nanocage comprising human heavy-chain ferritin protein and TGF{beta} receptor II ectodomain that enables BBB penetration and multivalent TGF{beta} entrapment, respectively. We demonstrate that the nanocage platform, denoted T{beta}R2-HFt, following systemic administration, traverses the BBB, and extensively modulates immunosuppressive TME, both stromal and immune components, thereby potentiating the therapeutic efficacy of a clinically used ICI in multiple mouse glioma models. Notably, a majority of the glioma-bearing animals that received surgical tumor resection, followed by treatment with T{beta}R2-HFt and the ICI, survived the tumor and resisted tumor rechallenge, providing a potential means to control GBM in a durable manner.

bioengineering↗

bioRxiv2026

The mammalian-adaptive PB2-E627K substitution preserves viral fitness of clade 2.3.4.4b H5N1 HPAIV in birds.

Since emerging in 2020, clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) has disseminated globally, causing substantial infection and mortality in wild birds and poultry. Additionally, numerous spill-over events into mammals have occurred, including mass mortalities and sporadic human infections. Such events can drive the acquisition of mammalian-adaptive mutations, which further increase the risk to humans; the most well characterised mutation is the glutamate to lysine change at amino acid position 627 in the polymerase basic 2 protein (PB2-627K). Across avian influenza viruses, PB2-627K enhances polymerase activity and replication in mammalian cells, increasing zoonotic and pandemic potential. However, bioinformatic analyses indicate that PB2-627K remains rare among clade 2.3.4.4b H5N1 viruses circulating in avian populations. Here, we investigated the impact of PB2-627K on viral fitness in avian hosts to assess the potential for mammalian-adapted viruses to re-establish in birds, mimicking infection of avian species following scavenging on mammalian species where PB2-627K has already emerged. Using a representative H5N1 virus (European genotype AB), PB2-627K increased polymerase activity and replication in human cells without compromising replication in avian cells. A mammalian-derived PB2-627K H5N1 isolate from a fox exhibited comparable replication kinetics and transmission efficiency in chickens and ducks to a closely related PB2-627E virus. Notably, PB2-627K remained genetically stable at consensus level following infection and transmission in both avian hosts. These findings demonstrate that mammalian-adaptive mutations acquired during spill-over can be maintained in avian populations, potentially elevating zoonotic risk and underscoring the importance of surveillance for such mutations in birds.

microbiology↗

bioRxiv2026

trFlow: ultrafast all-atom protein conformational ensemble generation via conditional flow matching

Generating diverse, all-atom protein conformations remains challenging, especially for recovering alternative functional states and modeling conformational ensembles. We present trFlow, an ultrafast approach for generating all-atom conformations using geometry-guided flow matching. trFlow leverages three core innovations: (1) a hybrid single- and multi-step sampling scheme that balances accuracy and speed; (2) a decoupled representation-generation architecture that maximizes computational efficiency; and (3) fine-tuning on NMR ensembles to better capture conformational heterogeneity. Extensive benchmarking across dual-conformation proteins, NMR ensembles, and a CASP16 dynamic target shows that trFlow outperforms competing methods in recovering challenging states and reproducing experimental heterogeneity, while being an order of magnitude faster than existing all-atom approaches. These results establish trFlow as a practical and scalable framework for large-scale generation of all-atom conformational ensembles.

bioinformatics↗

bioRxiv2026

Low-Density Lipoprotein Cholesterol and Cerebral Pericyte Dysfunction in Acute Ischemic Stroke: Clinical and Experimental Evidence

Background: Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cerebrovascular disease, but its effects on the cerebral microcirculation are poorly defined. We investigated whether LDL-C is associated with pericyte dysfunction in acute ischemic stroke (AIS) and explored underlying mechanisms. Methods: Serum soluble platelet-derived growth factor receptor-{beta} (sPDGFR{beta}) was measured in two independent AIS cohorts (n=97 and n=86). Cerebral pericyte transcriptional responses to LDL-C were analyzed by single-cell RNA sequencing in Apoe-knockout mice fed control or high-fat diet (n=4 [male/female: 2/2]/group), and cultured human brain pericytes were exposed to purified human LDL cholesterol with or without N-acetyl-L-cysteine. Results: Higher serum sPDGFR{beta} was associated with greater neurological deficit and circulating neurofilament light chain. LDL-C positively correlated with sPDGFR{beta} in both clinical cohorts. High-fat diet induced coordinated suppression of type-I interferon pathways, and a positive shift in reactive oxygen species-related transcriptional programs in mouse pericytes; exploratory sex-by-diet analyses suggested larger transcriptional responses in females. In cultured human pericytes, LDL-C induced oxidative-stress, lipid-handling, and ferroptosis-associated transcriptional programs while suppressing type-I interferon signaling. Cross-species enrichment analysis showed that LDL-C-induced and -repressed signatures in cultured pericytes aligned with the sex-by-diet interaction in Apoe-knockout mice. LDL-C also reduced cell-surface PDGFR{beta} and increased sPDGFR{beta} release in cultured pericytes, which were significantly attenuated by N-acetyl-L-cysteine, whereas LDH activity increased numerically but not significantly. Conclusions: Clinical and experimental findings support an LDL-pericyte axis linking atherogenic lipid stress to cerebral microvascular dysfunction, with possible sex-dependent modulation of oxidative stress and type-I interferon signaling as potential mechanisms.

neuroscience↗

bioRxiv2026

Molecular signatures of genetically defined jugular nociceptors and their responses to allergic airway inflammation

Abstract Rationale: Vagal sensory neurons are molecularly and functionally diverse, and they play critical roles in visceral sensation and homeostasis. The vagal system is anatomically divided into jugular and nodose ganglia, which exhibit distinct peripheral innervation patterns and physiological functions. Although recent transcriptomic studies have characterized nodose neuronal subtypes in detail, the molecular profiles of jugular sensory neurons remain poorly defined. Objectives: To define the molecular profiles of genetically identified jugular sensory neurons and determine the transcriptional responses of jugular and nodose airway afferents to allergic airway inflammation. Methods: We performed deep transcriptomic profiling of two genetically defined jugular nociceptor populations, MrgprC11 and MrgprD neurons, and compared them with airway-innervating P2ry1 nodose neurons and Phox2b nodose neurons. We further examined transcriptional changes of MrgprC11 and P2ry1 neurons following OVA-induced allergic airway inflammation. Measurements and Main Results: Transcriptomic analyses revealed distinct molecular signatures of jugular nociceptive neurons and identified subtype-specific genes across diverse functional categories. Following OVA challenge, MrgprC11 and P2ry1 neurons exhibited strikingly divergent transcriptional responses. More than 400 genes that were differentially expressed in both neuronal populations were regulated in opposite directions. GO enrichment analysis suggested that MrgprC11 jugular neurons adopted a metabolically restrained state with reduced translation and bioenergetic activities, whereas P2ry1 nodose neurons exhibited metabolically active state with enhanced translation and bioenergetic activities. Conclusions: These findings provide new insight into vagal sensory neuron diversity and reveal distinct transcriptional adaptations of jugular and nodose airway afferents during allergic inflammation.

neuroscience↗

bioRxiv2026

Identification of Mitochondrial-Lipid Metabolism-Related Diagnostic Targets in Osteoarthritis: Integrative Multi-omics Data and Experimental Validation

Objective: Osteoarthritis (OA) is a degenerative joint disease associated with metabolic dysregulation. This study aims to identify mitochondrial-lipid metabolism-related hub genes and explore their mechanisms in OA. Methods: Training (GSE55235) and validation (GSE55457 and GSE82107) cohorts were retrieved from the Gene Expression Omnibus (GEO) database. Candidate genes were derived by overlapping differentially expressed genes, mitochondrial-lipid metabolism-related genes, and weighted gene co-expression network analysis module genes. Machine learning algorithms were applied to screen hub genes. The diagnostic performance, functional pathways, immune infiltration, regulatory networks, drug interactions, and molecular docking of the hub genes were systematically evaluated. An interleukin-1{beta}-stimulated chondrocyte OA model was assayed for cell viability, interleukin-6 (IL-6), apoptosis, and hub-gene expression via Cell Counting Kit-8, enzyme-linked immunosorbent assay, flow cytometry, and reverse transcription-polymerase chain reaction. Results: Twenty-five candidate genes were screened, from which six hub genes (alpha-methylacyl-CoA racemase [AMACR], uncoupling protein 2 [UCP2], acyl-CoA thioesterase 7 [ACOT7], aldehyde dehydrogenase 3 family member A2 [ALDH3A2], armadillo repeat containing X-linked 2 [ARMCX2], and monoamine oxidase A [MAOA]) were further identified. The six hub genes exhibited robust diagnostic ability in the training cohort, correlated with immune-cell infiltration, and participated in lipid-metabolism pathways. In the OA model, chondrocyte viability was reduced, while IL-6 levels and apoptosis rate were elevated; five hub genes were markedly upregulated, whereas MAOA was significantly downregulated. Conclusion: Mitochondrial-lipid metabolism-related hub genes may serve as potential diagnostic biomarkers for OA, providing new insights into OA pathogenesis and potential therapeutic targets.

cell biology↗

bioRxiv2026

Multi-Modal Kinome Profiling Discovers Mesenchymal-Like Polarity Networks that Underly Directed Hepatocellular Carcinoma Cell Migration

Metastasis and associated therapy resistance remain the principal drivers of cancer related death, and there is a pressing need for a deeper mechanistic understanding and anti-metastatic therapies. For patients that suffer from hepatocellular carcinomas (HCCs), which are the most common primary liver cancers, frequent systemic metastasis results in bleak 5-year survival prognoses of only 4%. To metastasize, carcinoma cells must acquire an invasive phenotype, which typically requires switching from an epithelial-like apical-basal polarity to the front-rear polarity of mesenchymal-like cells. Signaling cues that originate in the tumor microenvironment can activate cellular morphogenic programs that drive polarity switching, like the epithelial-mesenchymal transition (EMT). Protein kinases control most cell signaling pathways and are highly actionable drug targets; however, systematic studies determining the kinases that underly the epithelial-mesenchymal polarity switch (EMPS) are lacking. We developed an assay platform that integrates mass spectrometry (MS)-based kinome profiling, broadly capturing kinase network activity, with chemical genetic screening using selective kinase inhibitors and quantitative phase imaging (QPI), serving as the phenotypic readout. Applying this approach that we dubbed morphokin-MS, to epithelial-like HCC cell lines that we induced to undergo EMPS identified a conserved network of 12 kinases that contributed to HCC cell polarity switching and directed cell migration; MS-based kinome profiling of 17 HCC patient tumors showed that these kinase are frequently upregulated in human tumors. morphokin-MS also revealed that death-associated protein kinase 3 (DAPK3) is one of the principal drivers of the EMPS and directed HCC cell migration. Thus, our mechanistic studies revealed that DAPK3 forms a complex with DAPK1 and filamin-A inter-acting protein 1-like (FILIP1L), which act as scaffold proteins that recruit DAPK3 to the centrosome. Pharmaco-logical and genetic inhibition of the DAPK1-DAPK3-FILIP1L complex blocked centrosome repositioning and microtubule polarization toward the leading edge of mesenchymal-like HCC cells, directed cell migration, and invasion. Our morphokin-MS method and comprehensive kinome profiling data will serve as a valuable resource for the cancer research community; our discovery of an inducible mesenchymal-like DAPK1-DAPK3-FILIP1L polarity complex that controls centrosome positioning in motile HCC cells may lead to the development of novel therapeutics for combatting cancer metastasis.

cancer biology↗

bioRxiv2026

Latent generative search unlocks de novo design of untapped biomolecular interactions at scale

De novo protein design has advanced rapidly, yet designing binders to polar, solvent-exposed epitopes and small, flexible ligands remains challenging. Such hydrated surfaces and flexible molecules, including carbohydrates, provide few of the hydrophobic contacts favoured by current methods and have largely resisted de novo binders. To address this challenge, here we introduce latent generative search for binder design, a novel framework that uses reward-guided search at inference time to steer the Proteina-Complexa generative model. The model codesigns sequence and structure - generating them together in a continuous latent space - and thereby removes the inverse-folding step on which current methods rely. In a screen of more than one million designs by multiplexed phage display, latent generative search produced more validated binders than every other method tested, its codesigned sequences surpassing post hoc redesign. It delivered high-affinity binders across therapeutic receptors, a viral attachment protein and intracellular signalling targets. Our approach also accessed previously untapped biology, generating the first de novo proteins that bind a free carbohydrate, including one that discriminates between blood-group antigens - a polar, flexible target class beyond the reach of current design methods.

bioengineering↗

bioRxiv2026

Seasonal influenza vaccine strain selection by quantifying viral fitness

The long-standing challenge of seasonal influenza vaccines providing poor protection is attributed to the rapid and continuous evolution of the virus. In theory, the recommendation of vaccine strain is to predict the dominant strain with best fitness in the upcoming season. Here, we develop FutureFlu, a biologically-grounded framework that quantifies the fitness score of influenza variants in upcoming seasons, by integrating metrics on three levels: molecular genetic divergence, individual immune escape, and population-scale transmission dynamics. The fitness scores of influenza variants present strong positive correlation with their actual observed frequencies in the next seasons. Validation across 24 seasons of three influenza subtypes shows FutureFlu recommends antigenically matched vaccine strains more frequently than annual recommendations, particularly for challenging subtypes: 83.3% versus 45.8% seasons for A/H3N2, and 75.0% versus 33.3% seasons for B/Victoria. Furthermore, FutureFlu significantly outperforms the currently used methods in vaccine strain selection whether or not there is available antigenic data from hemagglutination inhibition (HI) assay, which provides a valuable supplement for WHO vaccine recommendation. To support global public health implementation, an open online platform (futureflu.com.cn) has been established to offer real-time viral fitness predictions and vaccine recommendations.

evolutionary biology↗

bioRxiv2026

Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer

Obesity has an adverse effect on survival of women with ovarian cancer (OC), supporting a link between obesity, metastatic progression, and therapeutic response, but comprehensive mechanistic insight is lacking. In pre-clinical models of diet-induced obesity and OC, mice fed a high fat diet (HFD) exhibit substantially increased tumor burden relative to low fat diet (LFD) mice and respond poorly to standard-of-care (SOC) chemotherapy. Both HFD murine tumors and tumors from women with BMI>30 show increased expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of lipogenesis and lipid transport. The objective of this study was to assess whether inhibition of SREBP1 processing could improve SOC chemotherapy response in obesity-associated OC. We evaluated the FDA-approved drug Nelfinavir (NFV), a pharmacologic inhibitor of site-2 protease that blocks SREBP1 processing, in combination with SOC (paclitaxel+carboplatin) chemotherapy in preclinical models of diet-induced obesity and OC. Our results demonstrate significantly improved therapeutic response, corresponding changes in intra-tumoral adipocytes, and reprogramming of the obesity-driven ascites immune microenvironment. These findings support a model in which NFV-mediated inhibition of SREBP1 processing disrupts obesity-associated metabolic pathways linked to immune suppression and therapeutic resistance, thereby enhancing response to SOC chemotherapy in obesity-associated OC. Collectively, these results highlight metabolic targeting as a strategy to improve therapeutic outcomes in obesity-associated ovarian cancer.

cancer biology↗

bioRxiv2026

Genetic regulation of circulating metabolome in cattle

The circulating metabolome is a vital intermediate layer linking genetics to complex phenotypes, yet existing genome-wide studies-even in humans-rarely capture dynamic physiological contexts or cellular regulatory mechanisms. Here, we present the Cattle Metabolome Atlas (https://cattlema.farmgtex.org/), a comprehensive resource of 3,436 plasma metabolites and 4,851 serum metabolites from 4,651 animals with matched sequence-level genotypes across highly dynamic parity and lactation stages. We mapped 728 plasma and 622 serum metabolite quantitative trait loci (mQTL), revealing widespread context-dependent regulatory architectures. Integrating these mQTL with the multi-tissue expression quantitative trait loci (eQTL) and single-cell atlas of 59 tissues demonstrates that 74-79% of mQTL colocalize with eQTL across 29 tissues, prioritizing the liver as the primary systemic hub and resolving metabolic programs at single-cell resolution. Furthermore, we charted 538 causal gene-tissue-metabolite-trait cascades across 11 complex traits in cattle. Finally, cross-species analyses demonstrate partial evolutionary conservation of genetic metabolism between cattle and humans, establishing this atlas as a powerful asset for cattle genetics and genomics, selective breeding, and comparative biology.

genetics↗

bioRxiv2026

OmniSyn unifies target-aware molecular generation and optimization within a synthesis-native LLM framework across the human proteome

Designing target-specific bioactive molecules with actionable synthesis routes for the human proteome holds enormous potential for expanding therapeutic discovery, but remains a challenge. Existing target-aware generative models often depend on protein structures and generate molecules before assessing synthetic feasibility. Here we present OmniSyn, a protein-sequence-conditioned Mixture-of-Experts (MoE) language model that couples a task-conditioned interaction module with a synthesis-action decoder to generate molecules with explicit synthesis traces, thereby unifying de novo ligand generation, synthesizability projection and hit-to-lead (H2L) optimization within synthesis-traceable chemical space. OmniSyn is pre-trained with self-distillation and post-trained with task-specific reinforcement learning (RL) to adapt expert routing and optimize molecular properties across design modes. On unseen protein targets from MolGenBench, a real-world drug-discovery benchmark, OmniSyn achieves state-of-the-art performance across de novo design and H2L optimization, including target-awareness and hit-rediscovery metrics, despite relying only on protein sequences rather than three-dimensional (3D) pocket structures. By embedding synthesis planning into the design process, OmniSyn shifts molecular generation from a generate-then-filter paradigm toward design-with-synthesis paradigm, transforming virtual predictions into experimentally actionable candidates. Independent AiZynthFinder evaluation yielded retrosynthetic success rates of 68.47% for de novo generation and 71.92% for H2L optimization, improving over the strongest baselines by 61.3% and 184.2%, respectively, and supporting the synthetic feasibility of OmniSyn-generated molecules. In synthesizability projection, OmniSyn further converts outputs from external generative models into close analogues with improved retrosynthetic feasibility while preserving molecular similarity. Having established strong benchmark performance and external retrosynthetic feasibility, we next applied OmniSyn at human-proteome scale, spanning more than 21,000 targets. Rapid sequence-conditioned sampling enabled the construction of, to our knowledge, the largest human-proteome-scale generative virtual library, comprising 2.7 billion target-specific molecules, each accompanied by model-derived synthesis traces and target-specific prioritization scores. By enabling scalable target-specific molecular design with synthesis-aware generation across the human proteome, OmniSyn opens new opportunities for exploring previously inaccessible therapeutic targets, including those lacking experimentally resolved structures.

bioinformatics↗

bioRxiv2026

Catalytic and inhibitory architecture of comammox ammonia monooxygenase

Complete ammonia oxidizers (comammox) are widespread nitrifiers that can dominate ammonia oxidation in diverse environments by efficiently converting ammonia to nitrate within a single cell, yet the molecular basis distinguishing their ammonia monooxygenase (AMO) from those of canonical bacterial AMO remains unresolved. Here we report cryo-electron microscopy (cryo-EM) structures of AMO from the comammox Nitrospira inopinata (NiAMO) in inhibitor-free and allylthiourea (ATU)-bound states at 2.47 and 2.68 angstrom, respectively. NiAMO displays distinctive auxiliary-subunit organization, copper-site configuration and hydrophobic-channel architecture. Integrative molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations support a methyl-plastoquinol (methyl-PQH2)-coupled, CuD-centric catalytic model, with CuC potentially facilitating quinone redox cycling. N. inopinata exhibited broad susceptibility to several known nitrification inhibitors, and ATU-bound NiAMO structure localized the inhibitor to the CuC-CuD region, accompanied by constriction of the hydrophobic channel, which is consistent with the competitive role of ATU demonstrated in recovery assays. Multi-omics analyses further revealed an energy-limited stress response to ATU, including induction of urea transport and utilization systems. Collectively, these findings define a methyl-PQ-linked catalytic and inhibitor-responsive architecture of comammox AMO and establish a mechanistic framework for lineage-aware management of nitrification in natural and engineered ecosystems.

biophysics↗

bioRxiv2026

Functional Ultrasound Characterization of Spatiotemporal Cerebral Hemodynamic Responses Evoked by Whisker Stimulation

Functional ultrasound imaging (fUS) measures task-associated changes in cerebral blood volume (CBV) with fine spatial sampling and rapid acquisition, supporting functional mapping and brain-signal decoding. As an indirect measure of neural activity, fUS-CBV signals are shaped by neurovascular coupling and vascular dynamics, which influence the spatial and temporal stimulus information available for decoding. Consequently, the functional distinctions accessible in fUS-CBV signals require characterization under controlled experimental conditions. Here, controlled whisker stimulation in awake, head-fixed mice was used to characterize these decoding-relevant response properties. Whisker identity and number, stimulation duration, and inter-stimulus interval were systematically varied. All-whisker stimulation produced contralaterally dominant responses in the primary somatosensory barrel field and ventral posteromedial thalamic nucleus. Different whisker inputs were associated with distinguishable cortical response distributions, while stimulation involving more whiskers produced broader representative activation patterns. Across durations of 0.5 s to10 s, brief stimulation generated measurable stimulus-associated signals, and response magnitude, persistence, and spatial distribution varied with stimulus duration. For paired 2-s stimuli, trial-level separability was already high at the shortest tested 1-s gap, corresponding to a 3-s onset-to-onset spacing, and reached 100% at gaps of 3 s or longer. Building on the experimentally characterized spatiotemporal response properties of fUS-CBV signals, a proof-of-concept modeling and decoding framework was developed, comprising cross-animal spatial prediction, classification of short versus long stimulation from S1BF {Delta}CBV time courses with known stimulus onset, and modeling of paired-event separability. Together, the results show that fUS-CBV signals retain structured spatial and temporal information about controlled sensory input after neurovascular transformation. These measured response properties characterize the spatiotemporal boundaries within which neural activity can be reliably distinguished using fUS-CBV signals, providing constraints for the development of fUS-based decoding models and the design of stimulation paradigms suitable for reliable fUS decoding.

neuroscience↗

bioRxiv2026

Natural Variation in Maize Shikimate Dehydrogenase Alters Enzyme Activity and Kernel Homoserine Accumulation.

Metabolic diversity in maize kernels determines nutritional quality and end-use value. Therefore, understanding its genetic basis is essential for crop improvement and elucidating plant metabolic regulation. Here, we integrated metabolite profiling with metabolite-based genome-wide association studies (mGWAS), structural modeling, enzyme kinetics, and genome-scale metabolic simulations to identify genetic determinants of kernel metabolite variation in 265 maize inbred lines. Profiling of 57 metabolites revealed inter-genotypic variation, with homoserine among the most variable metabolites. mGWAS identified 62 locus-trait associations implicating 788 candidate genes, including 154 encoding metabolic enzymes. A major association for homoserine mapped to the shikimate dehydrogenase gene Sad1 on chromosome 10. Four tightly linked coding-region SNPs, including three non-synonymous variants, defined two Sad1 haplotypes associated with differential homoserine accumulation, independent of gene expression variation. Structural analysis and recombinant enzyme assays showed that these substitutions occur within catalytic and cofactor-binding domains and alter catalytic efficiency. Genome-scale metabolic modeling indicated that variation in SAD1 activity influences plastidial oxaloacetate availability for aspartate and homoserine biosynthesis through redox-coupled flux via the malate-oxaloacetate shuttle. Together, our results indicate that Sad1 allelic variation alters enzyme function and amino acid accumulation, linking the shikimate pathway, redox metabolism, and amino acid biosynthesis in maize kernels.

plant biology↗

bioRxiv2026

A virus co-opts vector's m⁶A machinery for adaptive compensation

Insect vectors harbor diverse viruses that threaten human health and agricultural production, yet the genetic basis of mutualistic virus-vector interactions remain elusive. This underscores a long-standing paradox in pest management: viruses that cause destructive diseases also facilitate vector adaptation in ways that benefit both parties. Here we show that the globally devastating tomato yellow leaf curl virus (TYLCV) acts as a Cooperative Partner, co-opting its vector's m6A epitranscriptomic machinery to offset the reproductive fitness costs of neonicotinoid resistance in the whitefly. In resistant vectors, TYLCV infection alleviates reproductive deficits via the m6A-dependent pathway, where the methyltransferase METTL14 and demethylase ALKBH4 coordinately stabilize vitellogenin (Vg) transcripts to boost female fecundity. Mechanistically, the viral C2 and CP proteins directly interact with METTL14 and ALKBH4, respectively, remodeling their RNA binding affinity to facilitate mA modification on Vg. Disrupting either of these viral-vector protein interactions restores a reproductive cost phenotype in viruliferous resistant vectors, offering novel targets for sustainable pest control. Our findings uncover a fundamental role of epigenetic marks in adaptive trait, reshaping beneficial virus-vector relationships and providing new insights for innovative public health and crop protection strategies to address global challenges.

microbiology↗

bioRxiv2026

A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

Non-coding regulatory variation drives complex traits, domestication, and evolutionary adaptation, yet the sheep genome lacks high-resolution functional annotation. Here we present SheepEpimap, a multi-tissue regulatory atlas harmonizing 516 CUT&Tag histone modifications, ATAC-seq, and RNA-seq datasets across 43 adult tissues in sheep. We annotated 2.93 million cis-regulatory elements, yielding 557,441 enhancer-gene pairs and 145,407 variants with allele-specific effects. By training a sequence-to-function deep-learning model, we decoded the base-pair syntax of chromatin accessibility, annotated transcription factor motif instances genome-wide, and constructed 12,210 tissue-specific gene regulatory networks (GRNs). Integrating this resource with multi-tissue expression quantitative trait loci, selection sweeps, and genome-wide association studies prioritized non-coding variants driving domestication and complex traits. Finally, cross-species analysis revealed that sequence-conserved, tissue-matched enhancers were significantly enriched in the heritability of complex traits and diseases in humans. In summary, SheepEpimap (https://genome.ucsc.edu/s/mengzhu/SheepEpimap) provides an open-access foundational ecosystem for sheep functional genomics, precision breeding, and comparative biology.

genetics↗

bioRxiv2026

Membrane-gated SNARE zippering focuses energy for fusion

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) drive stagewise membrane fusion by zippering into membrane-bridging four-helix bundles. Yet the conformations underlying successive fusion stages and the coupling of folding energy to bilayer remodeling remain unclear. Using optical tweezers, we measured the intermediates, energetics, kinetics, and force dependence of individual synaptic SNARE complexes assembled in cis on single membranes and in trans between apposed membranes. Membrane-anchored cis-SNAREs assembled through N-terminal and cooperative C-terminal/linker-domain transitions, whereas their transmembrane domains showed little intrinsic dimerization. Syntaxin retained membrane-dependent helical continuity through its linker domain before zippering was complete. PIP2 strengthened but slowed late zippering. In trans, membrane repulsion arrested single trans-SNARE complexes in a half-zippered state. G{beta}{gamma} further clamped this intermediate and inhibited late zippering; G-GDP, but not G-GTP{gamma}S, relieved the clamp, revealing a nucleotide-dependent mechanism for GPCR-mediated inhibition of neurotransmitter release. Modeling suggests that cooperative late zippering, syntaxin linker helicity, and concerted action of multiple SNAREs focus folding energy released over a long distance onto short-range membrane apposition. Thus, mechanically gated SNARE zippering is regulated by membrane forces, lipids, and regulatory proteins.

cell biology↗