Biology subjects

Zheng, X.

Publications and source records attributed to Zheng, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Dynamic dorsal body morphology encodes engineering design principles of fish propulsion and hydrodynamics

Understanding how biological shape and movement interact with surrounding fluids represents a fundamental challenge at the intersection of biology, physics, and engineering. Fish locomotion exemplifies this challenge: body morphology and swimming kinematics together determine the hydrodynamic forces and flow structures that enable efficient propulsion and maneuverability. Whereas biologists have long sought to connect morphological variation to swimming performance, traditional morphometric approaches provide limited insight into the fluid mechanical consequences of shape differences. Similarly, although computational fluid dynamics can reveal detailed flow physics, simulating hydrodynamics across diverse and dynamic morphologies remains prohibitively expensive for systematic investigation. To bridge this gap, we introduce a data-driven framework that connects fish body shape dynamics to hydro-dynamic performance through compact morphospace parameterization and reduced-order modeling. Using CFD simulations of 15 fish species from the Digital Life Project database (www.digitallife3d.org/3d-model), we generate hydrodynamic datasets capturing the shape-flow relationship. Principal Component Analysis (PCA) extracts four dominant shape parameters from dorsal body profiles, which are then integrated into an Inverse-Design with Dynamic Mode Decomposition (ID-DMD) framework to model the resulting fluid dynamics. The resulting modal analysis suggests that locomotion strategies emerge from specific shape-flow interactions. We further demonstrate the frameworks utility through single- and multi-objective shape optimization, showing how it enables efficient exploration of the morphology-hydrodynamics relationship. This approach offers a novel analysis and design tool for understanding how biological form and motion interact with fluid mechanics, with applications ranging from bio-inspired vehicle development to evolutionary biomechanics.

biophysics↗

bioRxiv2026

Functional Landscape of Motifs within the Sarbecovirus Spike Cytoplasmic Tail

Sarbecoviruses exhibit extensive diversity in host range and zoonotic potential. Although the ectodomain of the viral spike protein has been well characterized, the functional landscape of the cytoplasmic tail (CT) remains poorly defined. To address this gap, we systematically generated CT truncation variants of representative spike proteins from all major ACE2-utilizing clades to define the roles of conserved host factor-interacting motifs associated with COPI, COPII, FERM, and SNX27. Using vesicular stomatitis virus (VSV)- and lentivirus-based pseudotyping systems, we evaluated viral entry in cells expressing varying levels of ACE2 and TMPRSS2. Our results demonstrate that CT-associated motifs differentially regulate viral infectivity. Specifically, truncation of the COPI- or SNX27-binding motifs markedly reduces entry efficiency, whereas disruption of the COPII-binding motif produces the opposite outcome. By contrast, removal of the FERM-binding motif consistently enhances infectivity across lineages. Mechanistically, truncation of this motif increases spike expression, cell surface localization, incorporation into virions, and particle stability. Importantly, despite these pronounced effects on viral infectivity, deletion of the FERM-binding motif does not affect antigenicity, receptor dependence, or sensitivity to protease inhibitors, as demonstrated by neutralization and inhibition assays. In addition, this approach substantially increases spike protein density on virus-like particles (VLPs). Collectively, by extending the analysis beyond SARS-CoV-1 and SARS-CoV-2, our study reveals a generalizable mechanism in which cytoskeletal anchoring mediated by the FERM-binding motif acts as a limiting determinant of viral assembly. These findings provide a practical framework for optimizing pseudovirus platforms and guiding vaccine development against emerging viral threats.

microbiology↗

bioRxiv2026

Lamins and lineage-relevant transcription factors coordinate gene expression in lineage development

HighlightsO_LILamin-A and lamin-B1 are essential for midgestational embryogenesis. C_LIO_LILamin-A/B1 are required for proper yolk sac endoderm (YSE) gene regulation. C_LIO_LILamin-A/B1 maintain LADs organization and chromatin interactions in YSE. C_LIO_LILamin-A/B1 and YSE transcription factors support proper YSE gene expression. C_LI Lamins are intermediate filament proteins functioning as ubiquitous structural components of the nuclear lamina that interact with and organize the Lamina-Associated chromatin Domains (LADs). LADs remodel during development and lamins maintain LADs and gene expression profile specific to a given cell type. How ubiquitous lamins achieve cell-type-specific functions during development remains unknown. We show lamin-A and -B1 are required for mouse midgestational embryogenesis and maintain LADs, 3D chromatin interactions, and gene expression in the yolk sac endoderm (YSE). Both lamin-regulated genes and remodeled LADs in YSE cells contain binding motifs of YSE-relevant transcription factors. By analyzing changes in chromatin interactions upon lamin-A and -B1 knockout, we reveal that chromatin neighborhoods maintained by these lamins can influence gene expression orchestrated by YSE-relevant transcription factors. Our findings explain how the ubiquitously expressed lamins can collaborate with lineage-relevant transcription factors to maintain LADs and gene expression programs in specific cell types.

developmental biology↗

bioRxiv2026

Rapid phylogenomic analysis for viral surveillance and metagenomic profiling with Omni2Tree

Phylogenomic surveillance is limited not by sequencing throughput, but by the difficulty of converting heterogeneous raw data into reliable evolutionary inference, particularly for low-titer and contaminated viral field samples. Here we present Omni2Tree, an assembly-free framework that reconstructs viral phylogenies directly from raw sequencing reads and generates easily shareable interactive reports and genome-wide entropy profiles to identify diversification. In H5N1 benchmark analyses, Omni2Tree maintained accurate placement and topological stability even under low coverage, unlike assembly or reference based methods. Omni2Tree generated an annotated phylogeny for 64-sample H5N1 field surveillance dataset from the eastern USA in under 3 hours. Omni2Tree recovered known phylogenetic structure and key variability insights across 1,328 hepatitis C virus and 707 human cytomegalovirus datasets, and resolved co-infecting respiratory viruses in clinical metagenomic samples. By enabling direct analysis from raw reads, Omni2Tree supports faster, more portable, and more decentralized phylogenomic surveillance across outbreak, clinical, and resource-limited settings.

bioinformatics↗

bioRxiv2026

A telomere-to-telomere (T2T) pig genome assembly reveals Y chromosome diversity and structural variations of Wuzhishan pigs

BackgroudWuzhishan (WZS) pigs are native to Hainan Province of China, and serve as both important agricultural resources and biomedical models. Although the published WZS pig genome (T2T-pig1.0) even achieving telomere-to telomere (T2T) completeness, substantial genetic diversity still exists within the same pig breed, another WZS pig genome named WZS-T2T was assembled in this study. ResultsMultiple sequencing data were used to assemble genome, and finally yielded a [~]2.68 Gb telomere-to-telomere genome, with N50 length [~]142.87 Mb, and annotated protein coding genes of 23,100. Compared to T2T-pig1.0, QV and BUSCO value was higher, and the Y chromosome (ChrY) length was longer in WZS-T2T than that of T2T-pig1.0. ChrY of two WZS pigs shared 11 genes, including sex differentiation-related genes of SHOX, PRKX, and DDX3X, and SRY; however, energy metabolism gene SLC25A4 and the macrophage-related receptor gene CSF2RA of ChrY were specific to WZS-T2T. An inversion SV on chromosome 10 with length [~]33.86 Mb was identified between two WZS pigs, and three proofs were proposed for proving the accuracy sequence orientation of WZS-T2T.The genetic diversity was consistent with LD decay speed in population different analysis. WZS pigs exhibited higher genetic diversity than other four pig populations (Tunchang pigs, Yuxi black pigs, Large White pig, and Duroc pigs) examined in this study, and presented slower LD decay compared to other four breeds. ConclusionsTherefore, WZS-T2T provided a higher-quality assembly, and potential advantages of both agricultural production and biomedical targets for WZS pigs.

genomics↗

bioRxiv2026

The ABI5-WRKY45-LSU1 axis confers tolerance of Arabidopsis thaliana to cadmium

Abscisic acid (ABA) is involved in Cd tolerance in Arabidopsis, but the underlying mechanisms are unclear. In this study, we revealed that the ABI5-WRKY45-LSU1 axis confers the tolerance of Arabidopsis to Cd stress. Under Cd stress, the biosynthesis of ABA is increased, and the expression of transcription factor ABI5 is upregulated. Accordingly, the abi5-8 mutants show increased Cd sensitivity. ABI5 directly binds the ABRE element in the WRKY45 promoter to activate its transcription. Overexpression of WRKY45 rescues the Cd-hypersensitive phenotype of the abi5-8 mutant, placing WRKY45 downstream of ABI5. Transcriptome analyses identified LSU1 as a potential WRKY45 target. qRT-PCR, DUAL-LUC and EMSA experiments verified that WRKY45 binds the W-box cis-element in the LSU1 promoter to activate its expression. Overexpression of LSU1 enhances Cd tolerance by promoting the biosynthesis of non-protein thiols (NPT), glutathione (GSH), and phytochelatins (PC). Moreover, overexpression of LSU1 suppresses Cd sensitivity in the wrky45 mutant, confirming LSU1 acts downstream of WRKY45. On the other hand, we found that ATP sulfurylase 1 (APS1) interacts with LSU1 based in vitro and in vivo evidences. LSU1 stabilizes APS1, slows its degradation, and enhances APS1 activity, thus leading to increased NPT, GSH, and PC accumulation and improved Cd detoxification. Notably, overexpressing LSU1 did not rescue the Cd sensitivity of the aps1-1 mutant, indicating that LSU1 acts upstream of and depends on APS1. In short, we demonstrated a novel ABI5-WRKY45-LSU1 axis that regulates Cd tolerance through sulfur assimilation and phytochelatin synthesis. HighlightsO_LICadmium stress triggers ABA biosynthesis and ABI5 expression; ABI5 directly binds to ABRE motifs in the WRKY45 promoter and activates its transcription. C_LIO_LIWRKY45 transcriptionally activates LSU1, and LSU1 interacts with APS1 to stabilize it and elevate ATP sulfurylase activity, acting in an APS1-dependent manner. C_LIO_LIThe ABI5-WRKY45-LSU1 module enhances Arabidopsis Cd tolerance by boosting sulfur assimilation and GSH/PC-mediated Cd detoxification, rather than reducing Cd uptake. C_LI

molecular biology↗

bioRxiv2026

Decoding Single-Cell Omics of Perturbation Responses Using DeSCOPE

Deciphering cellular responses to genetic perturbations is fundamental to modeling gene regulatory networks and understanding mechanisms that change cellular phenotypes. However, current computational approaches often fail to outperform simple baseline models, highlighting a critical bottleneck in their generalizability and robustness. Here, we present DeSCOPE, a lightweight conditional variational autoencoder framework for predicting genetic perturbation responses spanning transcriptomic, epigenomic, and broader multi-modal landscapes. We systematically benchmarked DeSCOPE across diverse datasets under two challenging out-of-distribution settings: unseen genes and unseen cell types. DeSCOPE uniquely surpasses simple baselines in the unseen gene scenario, and achieves substantially improved performance for unseen cell types while requiring fine-tuning with far fewer perturbed genes. Finally, DeSCOPE demonstrates superior performance in predicting combinatorial multi-gene perturbations. Overall, DeSCOPE serves as a versatile multi-modal virtual cell model that can effectively guide the design of therapeutic targets that change cellular phenotypes. DeSCOPE is available at https://github.com/wanglabtongji/DeSCOPE.

bioinformatics↗

bioRxiv2026

Density-dependent facilitation of livestock by small mammal ecosystem engineers

Small mammals and large herbivores have co-evolved in grasslands for millions of years, yet how they interplay remains unclear. Although large herbivores can significantly affect the smaller ones, the reversal effect is largely unknown. On the Qinghai-Tibetan Plateau, plateau pikas (Ochotona curzoniae) are often considered pests that compete with livestock at high densities. Using field experiments, we show that the presence of pikas facilitates weight gains of yaks (Bos grunniens) by improving vegetation composition at a moderate density level. Compared to the pika-present treatment, pika removal dramatically increased cover of the poisonous Stellera forbs by two-fold, reducing the abundance and protein content of palatable grasses and sedges, yak foraging efficiency, and yak weight gain by up to 42%. Notably, we found a humped relationship between yak weight gains and pika burrow densities in the pika-present plots; the facilitative effect of pikas on yaks was highest at about 200 burrows/ha, but shifted to a competitive effect at pika densities exceeding 400 burrows/ha. These results provide the first empirical evidence that maintaining a moderate density of small mammalian herbivores can benefit growth performance of livestock by improving vegetation composition. Our study highlights the significance of moderate populations of ecosystem-engineering small mammals in sustaining pastoral productivity in rangelands.

ecology↗

bioRxiv2026

Concordant transcriptional and morphological remodeling revealed by in vivo Perturb-CLEAR

The principle that form follows function has long guided thinking in biology and architecture alike. In the nervous system, however, form does more than reflect function: neuronal morphology actively constrains input patterns, synaptic integration, and circuit wiring. During postnatal neurodevelopment, dendritic architectures are assembled and remodeled through genetically encoded programs and activities, transforming molecular programs into circuit architecture. However, dendritic morphogenesis has been difficult to quantify at scale while systematically testing how genetic variants, including neurodevelopmental disorder (NDD) risk genes, alter these structures in vivo. We developed Perturb-CLEAR, which integrates pooled CRISPR screening and whole-mount imaging to quantify brain-wide cytoarchitecture, and paired it with Perturb-seq to link structural phenotypes to transcriptomic changes. Applying Perturb-CLEAR to the developing mouse cortex revealed morphogenesis trajectories accompanied by transcriptomic dynamics. Moreover, systematic perturbation of NDD risk genes uncovered gene-specific multimodal phenotypes. Adnp perturbation remodels basal dendrites in L4/5 IT (intratelencephalic) neurons but not other dendritic compartments or cell types, alongside consistent transcriptional shifts. Combined morphology and transcriptome analyses link NDD risk genes to concordant multimodal cellular phenotypes in the developing brain, highlighting diverse paths of perturbation effect propagation across modalities.

neuroscience↗

bioRxiv2026

Population-scale interpretation of RNA isoform diversity enabled by Isopedia

Alternative splicing generates extensive transcriptomic complexity, yet "novelty" is often inflated because of incomplete reference annotations, with 20-70% of transcripts in RNA-Seq studies labeled as novel. Isopedia provides an expandable data structure for reference-agnostic isoform annotation, which we demonstrate here through a population-scale catalog of 1,007 long-read datasets spanning 37 diverse biological contexts. By transitioning from reference-dependent to evidence-weighted annotation, Isopedia provides the frequency-based context necessary to distinguish stochastic noise from biologically active isoforms. In HG002 benchmarks, Isopedia reduced apparent isoform novelty by up to 26-fold, achieving a >95% annotation rate even for low-abundance isoforms typically missed by standard catalogs. The framework further supports systematic exploration of challenging loci such as pseudogenes and gene fusions. Isopedia transforms isoform discovery into a systematic interpretation of the human transcriptome, providing a critical foundation for clinical and functional RNA research. Isopedia is open source and freely available: https://github.com/zhengxinchang/isopedia.

bioinformatics↗

bioRxiv2026

MRN-ATM Pathway Activation in CD4 T-Cell Senescence during Chronic Hepatitis B Virus Infection

T-cell senescence is a hallmark of immune dysfunction in persistent viral infections, characterized by DNA damage accumulation and telomere erosion. However, the mechanisms driving CD4 T-cell senescence in the context of chronic hepatitis B virus (HBV) infection remain poorly defined. In this study, we demonstrated that people with chronic HBV infection exhibited CD4 T-cell senescence, marked by elevated KLRG1, along with increased DNA damage and telomere shortening, compared to HS. Notably, activation of the MRN-ATM (MRE11/RAD50/NBS1-Ataxia Telangiectasia Mutated Protein) pathway was prominent in CD4 T cells from HBV patients. Importantly, suppression of MRN attenuated ATM phosphorylation and its downstream signaling molecules, and inhibition of ATM reduced the production of proinflammatory cytokines in CD4 T cells derived from both HBV patients and HS. These results suggest that in chronic HBV infection, the virus induced CD4 T-cell senescence, telomere erosion, and DNA damage, while concurrent activation of the MRN-ATM pathway may serve as a compensatory mechanism to preserve CD4 T-cell function. Elucidating this relationship between T-cell senescence and DNA damage repair helps to understanding the mechanisms underlying HBV persistence and providing potential therapeutic targets against chronic HBV infection.

immunology↗

bioRxiv2026

Genome-scale functional mapping of the mammalian whole brain with in vivo Perturb-seq

Functional genomics studies have provided critical insights into cell type-specific gene regulatory programs, but to date most have been conducted in wild-type tissues or cell cultures. Here, we present a gene expression functional atlas across the mouse brain. We use an enhanced in vivo Perturb-seq platform to analyze transcriptome-wide responses to loss of 1,947 disease-associated genes, profiling over 7.7 million cells spanning major brain regions and neuronal populations. We find striking cell-type-specific essentiality and transcriptional programs and show that closely related disease genes such as two NMDA receptor subunits can drive opposing transcriptional programs. Together, this work reveals insights into the genetics and mechanisms of neurodevelopmental, psychiatric, and neurodegenerative diseases in vivo, paving the way for the design of future genetic medicine.

genomics↗

bioRxiv2026

In vivo multiomic Perturb-seq with enhanced nuclear gRNA capture

In vivo CRISPR screening with joint transcriptomic and chromatin readouts has been limited by inefficient recovery of gRNAs from nuclei. Here, we developed in vivo multiomic Perturb-seq, an effective platform combining nuclear transcript anchoring with gRNA-specific capture and amplification to enable high-fidelity, high-recovery gRNA assignment and scalable perturbation-resolved single-nucleus multiomics. Applying this platform to interrogate neurodevelopmental disorder risk genes in the developing cortex reveals cell-type-specific transcriptomic and epigenomic perturbation phenotypes.

genomics↗

bioRxiv2026

STING agonist-mediated endothelial cell activation drives NK cells and neutrophils-dependent pulmonary inflammation

Stimulator of interferon genes (STING) agonists and derivative molecules have been extensively developed for tumor immunotherapy. However, systemic exposure toxicity risks have constrained clinical trial progression and even threatened patient lives. Currently, systematic toxicity assessments for STING agonists remain lacking, with the mode of action for major organ injury yet to be elucidated. Here, we focused on STING agonist-induced lung injury, revealing that systemic administration of STING agonists caused pulmonary hemorrhage, inflammatory alterations, and respiratory dysfunction. Through single-cell RNA sequencing and immune deletion studies, we found that lung endothelial cells could be stimulated by STING agonists and then secreted chemokines and IL-15 to recruit and activate NK cells. NK cells could induce endothelial cell apoptosis via IFN-{gamma}. Tbx21+ NK subpopulations, which activated by endothelial cells, could produce chemokines to recruit neutrophils. Neutrophils secreted IL-1{beta} through positive feedback pathways and form neutrophil extracellular traps during lung injury. This study elucidates the critical role of the endothelial cell-NK cell-neutrophil axis in mediating STING agonist-associated pneumonia, offering insights for developing intervention strategies for STING agonist toxicity.

pharmacology and toxicology↗

bioRxiv2026

Atypical cortical encoding of the low-frequency temporal dynamics of natural speech identifies children with Developmental Language Disorder

Developmental Language Disorder (DLD) is a neurodevelopmental condition that causes significant difficulties in understanding and using spoken language. Here we use electroencephalography (EEG) recorded during natural speech listening with 9-year-old children to identify dynamic neural processing patterns that characterize children with DLD compared to typically-developing age-matched controls. We applied Principal Components Analysis (PCA) to identify spatial ensembles of channels that represented distinct (uncorrelated) sources of cortical activity, and explored phase-amplitude coupling (PAC) between delta (0.5-4 Hz), theta (4-8 Hz) and low-gamma (25-40 Hz) oscillations. We then isolated EEG common spatial patterns (CSP) that identified children with DLD. The PAC analyses identified the delta band as a key source of group differences, and only delta-low gamma PAC differed significantly between participant groups. The CSP analyses also identified the delta band as a key mechanistic source of group differences. The findings are suggestive of distinct atypical low-frequency neural dynamics during speech encoding for children with DLD, which could be targeted by novel interventions.

neuroscience↗

bioRxiv2026

Achieving spatial multi-omics integration from unaligned serial sections with DIME

Learning integrated representations from spatial multi-omics data is a fundamental challenge, particularly in the context of "diagonal integration", where data are collected from serial tissue sections across distinct omics modalities. Existing methods typically rely on the assumption of feature intersection to construct a common metric space, a prerequisite that is absent in this setting. To address this, we propose the Diagonal Integration Model for Spatial Multi-omics Embedding (DIME), a novel deep learning framework that couples a graph contrastive learning objective with cross-modal correspondence. This global correspondence is established by a hybrid alignment strategy: it first anchors high-confidence regions using Coherent Point Drift with Linear Assignment, and then extends matching to the entire tissue manifold via an Optimal Transport formulation encoding relative geodesic distances. Designed to balance inter-modal guidance with intra-modal structure preservation, DIME enables robust fusion and denoising. Experiments on simulated and real human tissue datasets demonstrate DIMEs superior robustness and versatility, where its learned representations achieve outstanding clustering accuracy and unlock the identification of biologically meaningful spatial domains. The code is available at: https://github.com/Spyyyyyyy/DIME

bioinformatics↗

bioRxiv2026

Transplanting ANXA1- CD8+ Naive T cells Delay Aging Through Senolysis

Immunosenescence is a hallmark of aging, yet strategies using defined immune subsets to counteract it are largely unexplored. We performed paired scRNA/TCR-seq on CD45 cells from human bone marrow (15 donors, 3-91 years). T cells were the most altered lineage, with CD8 naive T cell contraction and functional impairment. We identified an expanding ANXA1 CD8 naive subset with senescence signatures and impaired function. ANXA1-deficient CD8 T cells exhibited increased resting stemness and enhanced activation/cytotoxicity upon stimulation. ANXA1- cells showed senolytic activity in vitro and reduced senescence burden in vivo. Monthly transfer of syngeneic ANXA1- CD8 naive T cells into aged mice extended median lifespan by >30 weeks, improving cardiac function, bone density, motor coordination, and marrow immune microenvironment. Our study identifies ANXA1 as critical in CD8 naive T cell aging and establishes ANXA1- cell transfer as a strategy to counter immunosenescence and promote healthy aging.

immunology↗

bioRxiv2026

Rapid and Quantitative Phage Susceptibility Test by Ramanome

Antimicrobial resistance poses an escalating global threat, renewing interest in bacteriophage therapy as a precision alternative to antibiotics. However, clinical translation remains hindered by the lack of rapid and quantitative phage susceptibility testing (PST) platforms capable of evaluating host range, infection potency, and effective multiplicity of infection (MOI). Here we present RPST, a ramanome-based phenotypic platform that captures infection-induced remodeling of bacterial macromolecular composition to unify these diagnostic requirements within a single workflow. RPST integrates four Raman biomarkers into a Composite Infection Index (CII), enabling rapid and lysis-independent discrimination between susceptible and resistant bacterial populations within [~]1 hour, with 96.0% categorical concordance (24/25) to plaque assays. As a continuous population-level metric, CII quantifies the proportion of infected cells, allowing quantitative ranking of phage potency against shared hosts. By resolving CII trajectories across the MOI and time, RPST further determines the minimal effective MOI, which is the lowest phage-to-bacterium ratio sustaining self-propagating infection, thereby defining the lower boundary for therapeutic feasibility. Together, these capabilities transform PST from static compatibility assays into a dynamic and quantitative framework that bridges in vitro infectivity assessment and infection dynamics relevant to phage therapy. Impact StatementBased on the rapid emergence of antimicrobial resistance, this study introduces RPST, a novel ramanome-based phage susceptibility testing platform. RPST detects phage-induced biochemical remodeling in bacteria within [~]1 hour, achieving 96.0% concordance with gold-standard plaque assays. By integrating four Raman biomarkers into a Composite Infection Index, it not only distinguishes susceptible from resistant strains but also quantifies phage potency and determines the minimal effective multiplicity of infection required for self-sustaining infection. This transformative approach moves beyond binary diagnostics to offer a dynamic, quantitative framework for precision phage therapy, significantly accelerating therapeutic decision-making and enhancing our ability to combat resistant infections.

microbiology↗