Biology subjects

Zheng, W.

Publications and source records attributed to Zheng, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Long-read RNA-seq resolves isoform-level and context-specific regulatory architecture of complex traits in cattle

Traditional short-read RNA-seq lacks the resolution to fully capture full-length isoforms and complex alternative splicing, leaving a "missing regulation" gap in existing molecular atlases. Here, we present a population-scale, multi-omics dissection of bovine complex traits using matched deep whole-genome sequencing (30x), long-read (ONT) and short-read RNA-seq, as well as metabolome data from 432 dairy cows across four distinct lactation stages. We expanded the bovine transcript atlas with 13,177 novel isoforms and fine-mapped 1,088,900 regulatory effects across 11 diverse molecular phenotypes. Notably, long-read mapping uncovered 606 genes with isoform expression quantitative trait loci (12.8%, eQTL) and 1,116 genes with detailed splicing QTL (sQTL) (31.8%) that were missed by conventional short-read mapping. We further showed that lactation-specific regulation was profoundly mediated by the metabolic microenvironment (46.8%) and cellular composition (4.3%). Across genome-wide associations (GWAS) of 90 bovine complex traits, isoform-level and context-specific regulatory effects captured GWAS loci missed by short-read eQTL and sQTL analyses, increasing colocalized loci from 35.2% to 60.3%. These regulatory variants also exhibited evolutionary constraints with human immune and metabolic loci. Our study establishes an invaluable resource (https://cattleblr.farmgtex.org) demonstrating that long-read transcriptomics is essential for resolving the complexity of regulatory mechanisms underlying mammalian physiology.

genetics↗

bioRxiv2026

Integrating Histology with Spatial Molecular Programs Using a Multimodal Foundation Model

Histopathological assessment remains central to cancer diagnosis and stratification, yet its mechanistic interpretation remains limited without molecular context. To address this, we developed SQUALL, a multimodal foundation model integrating histology with spatial molecular programs. For pretraining, we assembled histMol, a large-scale corpus of 1.76 billion paired histology-spatial transcriptomics spots/bins across 33 tissues and 12 platforms from 3,446 tissue sections. Following pretraining, SQUALL enables transcriptome-wide virtual biomarker profiling, prognostically relevant spatial niches discovery, and integrative disease progression modeling. Leveraging its multimodal embeddings, SQUALL identifies niches associated with tertiary lymphoid structure (TLS) maturation and ovarian cancer relapse, reconstructs molecular trajectories of breast cancer invasion across 325,112 spots, and uncovers underlying transcriptional programs. Applied to whole-slide images from 898 patients, SQUALL outperforms existing pathology foundation models in outcome prediction while enabling interpretable risk stratification. Together, these results establish spatially aligned multimodal pretraining as a new paradigm for extending molecular insights into pathology images.

bioinformatics↗

bioRxiv2026

Beyond Phase Estimation: A Multidimensional Gating Framework for Robust Real-Time Closed-Loop Neural Stimulation

Neural oscillatory phase is widely used as a control variable in real-time closed-loop stimulation, yet its validity under strict causal constraints and noisy conditions has rarely been systematically examined. We introduce a Multidimensional Gating Framework (MGF), a plug-in and estimator-agnostic module that determines whether phase information should be admitted into control by evaluating instantaneous amplitude, narrowband signal-to-noise ratio (SNR), and spectral peak ratio (PR) within a strictly causal window. Using causal streaming replay on a public resting-state EEG dataset, we benchmarked Hilbert based phase estimation and endpoint-corrected Hilbert estimation with and without MGF. Among feasible subjects, MGF significantly reduced phase dispersion for both estimators, while robustly suppressing catastrophic phase errors. In contrast, ungated approaches exhibited systematic failures under the same conditions.

neuroscience↗

bioRxiv2026

G4 Eurasian avian-like H1N1 swine influenza viruses exhibit enhanced pathogenicity potential in mice and pigs

Currently circulating swine influenza viruses (SIVs) mainly include H1N1, H1N2, and H3N2 subtypes. In this study, two G4 genotype Eurasian avian-like (EA) H1N1 SIVs were isolated from 556 samples collected between 2023 and 2026. A systematic analysis was conducted on the two EA H1N1 isolates (FYD30 and YZF69) to assess their pandemic potential. The hemagglutinin (HA) proteins of both H1N1 viruses possessed residues 225E and 228S, indicating enhanced affinity for human-like -2,6-linked sialic acid receptors, which was confirmed by receptor-binding assays. Polymerase activity tests demonstrated that the two SIVs exhibited significantly higher activity in mammalian cells, relative to avian cells, which is consistent with the efficient replication in mammalian cells. Challenge experiments revealed that both H1N1 caused significant pathogenicity in mice and pigs, with YZF69 exhibited higher virulence than FYD30. The higher virulence of YZF69 may be attributed to its molecular features, including the NP Q357K mutation, and an additional glycosylation site in HA. In conclusion, currently circulating EA H1N1 SIVs have acquired key molecular signatures of mammalian adaptation, exhibit enhanced virulence in mammals, and continue to undergo extensive reassortment driven by international swine trade. These findings highlight the potential pandemic risk of SIVs and underscore the urgent need for strengthened surveillance.

microbiology↗

bioRxiv2026

Origin and evolution of grapevine genomes

Grapevines (Vitis) belonging to grape family (Vitaceae) are symbolic fruit crops pivotal to human civilization. The evolutionary history of grapevines divergent from other Vitaceae plants remains mysterious, requiring a family-wide whole-genome phylogenomic analysis. Here, we conduct chromosome-level phylogenomics to investigate the origin and evolution of grapevines using 29 genome assemblies of five genera Vitis, Parthenocissus, Ampelopsis, Tetrastigma, and Cissus, 27 of which are newly released in this study. Phylogenomic and macrosynteny analysis unanimously support Ampelopsis as a sister lineage to Parthenocissus, placing both closer to Vitis, with introgression and incomplete lineage sorting contributing to these relationships. Ancestral genome reconstruction delineates the major chromosome rearrangement events in Vitaceae karyotype evolution, highlighting the conserved karyotype in Vitis and the extensive karyotypic reorganization in Tetrastigma and Cissus. Pan-3D genome analysis highlights the contributions of structural variants (SVs) to the variation of A/B compartments and topologically associated domains (TADs), revealing a strong purifying selection of SVs at TAD boundaries. We further demonstrate that Helitron transposons drive the expansion and expression regulation of NLR immune-receptor genes in Vitis. Importantly, we discovered an NLR gene VbRpv35 from wild grapevine V. bellula resistant to downy mildew (DM), whose heterologous expression in V. vinifera confers enhanced DM resistance. Taken together, we provide phylogenomic insight into the origin and evolution of grapevines and valuable resources for grapevine improvement and understanding angiosperm evolution.

genomics↗

bioRxiv2026

EA-PheWAS: Integrating Phenotype Embeddings with PheWAS for Enhanced Gene-Phenotype Discovery

Phenome-wide association studies (PheWAS) enable systematic exploration of relationships between genetic variants and clinical phenotypes derived from electronic health records (EHRs). Conventional regression-based PheWAS treats phenotypes separately and relies on binary phenotype representations, which limits statistical power for rare variants and rare phenotypes and reduces the ability to detect associations with phenotypes that are distributed across clinical codes. To address this limitation, we first developed EmbedPheScan, a phenotype embedding-based prioritization framework that summarizes the phenotypic profiles of rare loss-of-function variant carriers in a continuous embedding space. We then proposed EA-PheWAS by combining these embedding-derived signals with conventional regression-based PheWAS results using the aggregated Cauchy association test. Using the UK Biobank whole-exome sequencing and EHR data, we show that the proposed methods maintain appropriate false-positive control. We then performed genome-wide phenome scans across all genes and across biologically defined gene classes to evaluate EA-PheWAS relative to conventional PheWAS and EmbedPheScan, consistently finding that EA-PheWAS outperformed the other two methods. We illustrate the utility of EA-PheWAS focusing on four genes representing distinct scenarios, including strong-effect disease genes (PKD1, PKD2), genes with large numbers of rare LoF carriers (NF1), and genes with extremely sparse carrier counts (FBN1).

genetics↗

bioRxiv2026

The cytoplasmic lattice in mammalian eggs sequesters ubiquitination machinery and tubulin in reserve

The cytoplasmic lattice (CPL) in mammalian eggs is essential for early embryonic development, but its molecular components, structural organization, and functional capacity have remained elusive. Here, using cryo-electron microscopy, we show that the CPL filament in mouse eggs contains repeating units with a periodicity of [~]37 nm, and determine its high-resolution, native structure and complete subunit composition. The CPL architecture organizes maternal-effect proteins, ubiquitination machinery, and tubulin into a highly structured reservoir. Maternal-effect proteins form the scaffold of the CPL to sequester a UBE2D-UHRF1 E2-E3 ubiquitination module and three distinct FBXW E3 ubiquitin ligases, notably all in activity-excluded states. The CPL further contains an {beta}-tubulin heterodimer in a GTP-bound state with a calcium ion coordinated to -tubulin, suggesting microtubule assembly-competent tubulin held in reserve. The CPL structure is capped at each end by a terminal unit that lacks a PADI6 dimer, a scaffold component, thereby preventing further oligomerization. Interactions between maternal-effect proteins in adjacent CPL units promote the assembly of a three-dimensional lattice in the egg cytoplasm. Taken together, our work defines how CPL assembly and architecture prime mammalian eggs for ubiquitin-mediated protein degradation and cytoskeletal remodeling during the egg-to-embryo transition.

biophysics↗

bioRxiv2026

Integrated single-cell and bulk transcriptomic analysis leverages liver metastasis-related genes to develop a prognostic model for colorectal cancer patients

PurposeDifferentially expressed genes (DEGs) between colorectal cancer liver metastasis (CRLM) epithelium and primary colorectal cancer (CRC) epithelium (LMR DEGs) identified based on single-cell RNA sequencing (scRNA-seq) data may become new biomarkers for CRC prognosis. MethodsAn scRNA-seq dataset was used to describe the cellular landscape of primary CRC and CRLM and identify LMR DEGs. Prognostic LMR DEGs were identified in the bulk RNA-seq dataset. Based on the prognostic LMR DEGs, multiple machine learning algorithm combinations were compared in terms of their C-index, and the best model was selected for the construction of the LMR score. ResultsAmong the 2070 LMR DEGs, 426 prognostic LMR DEGs were ultimately obtained. The combination of the randomized survival forest (RSF) model and ridge regression had the highest C-index and was therefore used to construct a 15-gene scoring system (LMR score). In the external validation set, the 1- and 5-year AUCs of the LMR score were greater than those of the AJCC stage and other scoring systems constructed with a similar dataset. In addition, the LMR score was closely associated with factors that influence CRC outcomes, such as immune infiltration. ConclusionThe LMR score may be a reliable new biomarker for predicting the prognosis of patients with CRC.

cancer biology↗

bioRxiv2026

ASFV early protein p30 suppresses antiviral type I IFN induction by targeting TRIM21 and RIG-I like receptor signaling adaptor MAVS

African swine fever (ASF) is a highly pathogenic disease caused by the African swine fever virus (ASFV) infection, which can affect pigs of all ages and breeds, posing significant threat to the global pig farming industry. The ASFV p30 protein is an early-expressed viral structural protein; however, its function is not fully understood. In this study, the interaction of viral p30 with host TRIM21 was identified. The ectopic TRIM21 inhibited ASFV replication, while knockdown or knockout of TRIM21 promoted ASFV replication. Further, p30 was found to interact with RIG-I-like receptor (RLR) signaling adaptor MAVS, and during ASFV infection, p30-TRIM21-MAVS interacted with each other. Mechanistically, TRIM21 activated the K27 polyubiquitination of MAVS to induce IRF3 mediated type I interferon (IFN) production, whereas p30 counteracted TRIM21 activated MAVS K27 polyubiquitination to evade RLR signaling mediated antiviral IFN induction. In summary, our study revealed a novel function of ASFV p30, and provided new insights into the immune evasion of ASFV.

immunology↗

bioRxiv2026

Species-specific regulation of porcine STING stability and antiviral signaling via its K61 mediated K48 ubiquitination and proteasome degradation

The cGAS-STING pathway has been widely recognized as a critical DNA-sensing pathway that plays a broad-spectrum antiviral role. Livestock, especially pigs, represents one of the most important meat sources. In this study, we identified a key lysine 61 (K61) of porcine STING (pSTING) that plays an essential role in its degradation and antiviral signaling in a species-specific manner, with K61 as the major lysine of pSTING for K48-linked ubiquitination. After virus infection, pSTING recruits the E3 ligase, RNF5, which specifically assembles a K48-linked ubiquitin chain at K61, thereby mediating pSTING proteasomal degradation and reducing its antiviral activity. Meanwhile, the deubiquitylation of K61 is mediated mainly by deubiquitinase USP20, which enhances the stability and antiviral activity of pSTING. Together, given the relatively few lysine numbers in livestock STINGs and species-specific K61 regulation of pSTING stability and antiviral function, the K61 and its specific regulatory enzymes of pSTING could serve as potential targets for breeding of antiviral pigs and design of antiviral drugs, respectively.

immunology↗

bioRxiv2026

Topological Entanglement in Intrinsically Disordered Proteins: Sequence, Structural, and Functional Determinants

Intrinsically disordered proteins (IDPs) populate heterogeneous conformational ensembles that are difficult to characterize using conventional structural descriptors. As a result, it remains unclear which ensemble features meaningfully connect sequence composition to biological function. Here, we employ entanglement-based measures derived from knot theory to provide complementary insight into IDP organization. Using the human IDRome database, we analyze two continuous entanglement descriptors, the writhe and the second Vassiliev invariant (V2), across more than 28,000 simulated disordered sequences. We show that these entanglement measures exhibit structured, low-dimensional variation across the database and display distinct relationships with sequence composition and ensemble geometry. Writhe primarily reflects compaction-dependent coiling tendencies that are largely recoverable from coarse sequence and structural features, whereas V2 captures higher-order topological organization that is less predictable from simple metrics. Embedding the resulting distribution features reveals functionally enriched regions of entanglement space, and ortholog simulations demonstrate that these signatures are evolutionarily conserved. Together, these results establish entanglement as a biologically relevant dimension of IDP organization and provide a rigorous, complementary framework for linking its sequence, ensemble structure, and molecular function.

biophysics↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

A Multi-Dataset Transcriptomic Analysis Unravels Core Mechanisms Involving Vitamin D Metabolism and Inflammatory Pathways for Frailty Diagnosis.

Frailty is a prevalent geriatric syndrome, and the shortage of objective biomarkers restricts its early diagnosis and intervention. This study aimed to identify robust molecular signatures and diagnostic markers for frailty using bioinformatics analyses of multiple independent datasets. Two transcriptome datasets (GSE144304, n=80; GSE287726, n=70) were obtained from the GEO database. We performed differential gene expression analysis, GO, KEGG and GSEA enrichment, and machine learning (70% training / 30% validation) to screen and validate core biomarkers. Numerous shared differentially expressed genes were identified. Vitamin D metabolism, ABC transporter, and inflammatory/immune pathways were consistently enriched and confirmed by GSEA. Machine learning models based on these signatures showed favorable diagnostic performance. Our study demonstrates that vitamin D metabolic disorders and chronic inflammation are core molecular features of frailty. The identified biomarkers provide new strategies for basic research, early clinical diagnosis, and therapeutic target development for frailty.

bioinformatics↗

bioRxiv2026

High-Fidelity Long-term Whole-embryo Lineage and Fate Reconstruction by Iterative Tracking with Error Correction

Reconstructing the complete cell lineages and fate maps of a living embryo has remained a central challenge in developmental biology. Here we introduce ITEC (Iterative Tracking with Error Correction), a fully unsupervised method that automatically reconstructs the lineage of every cell in the embryo with high fidelity. ITEC was validated with manually annotated lineages on four cross-species datasets including zebrafish, mouse, and Drosophila. We reconstructed the developmental lineages of a zebrafish embryo from terabyte-scale data of total 18.5 million cells with an estimated accuracy of over 99.7%. With ITEC, we revealed spatiotemporal dynamics of key morphogenetic processes such as somite boundary formation, demonstrated the various patterns of spatial sorting among adjacent organs or anatomical regions, and identified associations between cellular movement and spatial transcriptomics. ITEC provides a powerful platform for retrospective fate mapping and systematic exploration of developmental dynamics at the cellular scale and single-embryo level.

bioinformatics↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

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

Mutant FGFR3 restricts bone yet expands cortex via ERK-mediated self-repression

FGFR3 gain-of-function mutations cause achondroplasia 1,2, the most common form of dwarfism, yet trigger paradoxical cerebral overgrowth and skeletal stunting 3-9. Here, we demonstrate that Fgfr3-K644E mutant drives enhanced ERK activation, which then represses Fgfr3 expression and downregulates ERK signaling. In the developing cortex, this mechanism transiently expands cortical stem cells by activating ERK, then shifts signaling to downregulate Fgfr3/ERK/PKA and enhance YAP/TAZ, promoting cerebral overgrowth and premature ependymal maturation. In growing bones, Fgfr3-K644E mutant first elevates ERK to inhibit chondrocyte pre-hypertrophy, then downregulates Fgfr3/ERK/PKA and upregulates YAP/TAZ to accelerate premature hypertrophy and ossification. Our findings establish that FGFR3 mutations limit bone yet expand cortical size via an ERK negative feedback loop, revealing a unified disease mechanism and novel therapeutic targets.

developmental biology↗

bioRxiv2026

Astrocyte-induced internal state transitions reshape brainwide sensory, integrative, and motor computations

Animals rapidly adapt to changing circumstances by shifting how they perceive, integrate, and act. Such flexibility is often attributed to transitions between internal states that exert widespread influence across the brain. Yet the mechanisms that drive state transitions and how they reconfigure brainwide computation remain unclear. Larval zebrafish, when actions are rendered futile by decoupling visual flow feedback from swimming in virtual reality, enter a temporary passive, energy-preserving state. In this state, astrocyte calcium levels are elevated, and swim reinitiation requires greater accumulated visual motion. Using whole-brain, cellular-resolution activity imaging, we observed widespread circuit alterations underlying this disengaged state: neuronal visual responses weakened, visual motion integration over time became dramatically leakier, motor inhibition increased, and motor preparation slowed, together suppressing conversion of sensory evidence into action. Astrocyte calcium rose during futile swimming, tracked the emergence and resolution of these brainwide changes, and was both necessary and sufficient to drive them. Thus, astrocytes orchestrate internal states that profoundly reshape neural computations, most powerfully at intermediate integrative processing stages, to meet changing demands. HighlightsO_LIInternal state change alters brainwide neuronal processing at every stage of the sensorimotor transformation C_LIO_LIEffects are most powerful at integrative stages through stimulus memory collapse C_LIO_LIAs state resolves, amplification of sensory representations synergizes with reduced motor inhibition for action reinitiation C_LIO_LIAstrocyte activity drives these brainwide adaptive shifts in neuronal dynamics C_LI

neuroscience↗