Biology subjects

Zuo, W.

Publications and source records attributed to Zuo, W..

At least 19 recordsLinked to original sources

bioRxiv2026

Extinction in Random Environments

An important currency for individuals is their lifetime reproductive success (LRS), which is random simply due to demographic stochasticity. That randomness determines extinction probability. However, the distribution of LRS is also significantly affected by environmental variation. Previously we have shown (for a random environment that follows a Markov chain) how LRS is affected by an individual's birth environment. But our previous analysis severs the temporal linkage between a parent's birth environment and the environments into which its offspring are born. Here, we show how to compute the exact joint probability distribution of LRS for lineages spanning multiple environmental states (assuming a Markovian environment). From this joint distribution, we derive exact lineage extinction probabilities that fully incorporate demographic stochasticity, environmental frequency, and temporal autocorrelation. Applying our framework to Pacific Chinook salmon (semelparous with extreme early mortality) and European roe deer (iteroparous with delayed maturity), we demonstrate that initial birth states shape lineage fate. For salmon, the initial environment permanently separates trajectories; a poor birth state leads to near-certain extinction regardless of subsequent environmental shifts. For roe deer, we discover a counterintuitive dynamic where highly persistent poor conditions can rescue highly vulnerable individuals by expanding the right tail of reproduction. Furthermore, our exact calculations reveal that aggregated one-dimensional LRS distributions homogenize the reproductive landscape, overestimating extinction risks for lineages originating in poor environments and underestimating them for those in good environments. Accurately predicting evolutionary viability and the establishment of advantageous mutations requires preserving the environmental covariance. As global climate change amplifies environmental volatility, utilizing exact joint demographic models is critical for assessing true extinction risks.

evolutionary biology↗

bioRxiv2026

Aging-associated regulatory B-like cells establish a lung-selective immunosuppressive niche to promote pulmonary metastasis

While aging is the primary risk factor for cancer development and a critical driver of metastasis, yet how aging selectively remodels specific distant organs to favor tumor colonization remains unclear. Here, we demonstrate that host aging selectively enhances susceptibility to lung metastasis in an inflammation-dependent manner, without uniformly affecting other organs. Single-cell RNA sequencing reveals that the aged lung accumulates PD-L1CTLA-4IgMIgD- regulatory B (Breg)-like cells, representing the immune population most amplified by the cooperative effects of aging and tumor burden. Trajectory analysis delineates their differentiation from naive B cells, driven by Il10, Ctla4, Cd274, and Egr1 upregulation. This program is evolutionarily conserved, increasing progressively with human chronological lung age. Mechanistically, aged CD140a adventitial fibroblasts drive CXCL13-dependent B-cell reprogramming into a senescent state. These Breg-like cells directly impair natural killer cell cytotoxicity and CD4 T-cell responses, accelerating pulmonary colonization. Our findings reveal a targetable, lung-specific age-associated stromal-immune axis driving metastatic organotropism.

immunology↗

bioRxiv2026

LUstiGE, Light responsive Ustilago maydis Gene Expression: Optogenetic control of morphogenesis and pathogenesis in the corn fungal pathogen Ustilago maydis

The basidiomycete Ustilago maydis is a well-characterized model organism for studying pathogen-host interactions and of great interest for a broad spectrum of biotechnological applications. We set here to develop light inducible molecular tools to enable dynamic studies on signaling networks and fungi-host communication, and for metabolic engineering approaches. In particular, light-controlled, optogenetic switches provide quantitative, spatio-temporal control capabilities, are minimal invasive and reversible. We engineered two blue light-inducible LOV-domain-based gene expression switches, to up- (Blue-ON) and down-regulate (Blue-OFF) gene expression, and performed a functional characterization in sporidia and hyphae of U. maydis. Profiting from the dynamic control ranges and rapid kinetics, we implemented the optoswitches to control cell morphology by initiating the transition from a haploid sporidial cellular morphotype to filaments upon regulation of the levels of the polarity factor Rac1 and its constitutive active mutant Q61L. In addition to showing how expression level of effectors can be precisely regulated as an approach to understand fungi-plants interaction, we show in two proof-of-principle applications targeted control over U. maydis filamentous fungal invasion of plant tissue and the mechanisms of tumor formation. For this we placed under Blue-ON and Blue-OFF control two U. maydis effectors, See1 (Seedling efficient effector 1) and TIN2 (Tumor inducing 2), and tumor formation was assayed on maize leaves. Taken together, this study established blue-light switches as effective tools to control morphogenesis and pathogenesis in U. maydis.

synthetic biology↗

bioRxiv2026

lncRNA-ISM1 Promotes Hepatocellular Carcinoma Progression through RBM10-Mediated Alternative Splicing of ISM1 and Akt-S6-Dependent Glucose Metabolic Reprogramming

A low-glucose microenvironment can induce metabolic abnormalities in tumour cells, including hepatocellular carcinoma (HCC) cells, and enhance cancer cell stemness. Isthmin-1 (ISM1) is a recently identified adipokine that promotes glucose uptake and enhances cellular metabolism. While the activity of the ISM1 protein is regulated by glycosylases, its transcriptional and posttranscriptional regulation remain poorly understood. A novel alternatively spliced variant of ISM1 (ISM1-AS) was recently identified. Unlike canonical ISM1, ISM1-AS lacks an AMOP domain, a key structural element required for ISM1 function, suggesting the loss of its metabolic regulatory activity. In this study, we found that ISM1 expression was significantly reduced in HCC tissues and correlated with poor prognosis. Functional assays revealed that ISM1 overexpression markedly suppressed HCC cell proliferation and invasion, whereas ISM1-AS overexpression had the opposite effect. Importantly, ISM1 co-overexpression attenuated the oncogenic effects of ISM1-AS. Knockdown of the antisense transcript lncRNA-ISM1 reduced ISM1-AS expression while increasing ISM1 expression, thereby suppressing HCC proliferation and migration. Mechanistically, lncRNA-ISM1 regulated ISM1 alternative splicing by interacting with RBM10, thereby altering the balance between ISM1-AS and ISM1. This shift activated the Akt-S6 signalling pathway, promoting glycolysis and HCC progression. In vivo experiments further confirmed that the lncRNA-ISM1/ISM1-AS/ISM1 axis drives tumour growth via Akt-S6 activation. Our findings demonstrate that lncRNA-ISM1 promotes HCC progression through the RBM10-mediated alternative splicing of ISM1 and activation of the Akt-S6 signalling pathway, highlighting its potential as a therapeutic target for HCC.

molecular biology↗

bioRxiv2026

Oxytocin Modulation of Spinal Circuits Drives Therapeutic Benefits of Massage

Across social species, social touch enhances well-being and reduces pain -- two seemingly distinct benefits that enhance survival. Yet where and how the nervous system integrates these functions, and whether a single mechanism could serve both, remains unknown. Here we show that massage triggers oxytocin release, which shapes both pain and touch reward at the earliest stage of central processing -- the spinal cord -- through a single, state-dependent circuit mechanism. We report that in humans, massage enhances well-being, effects that correlate with endogenous oxytocin release. In mice, gentle touch activates hypothalamic oxytocin neurons that project directly to the spinal dorsal horn. Genetic manipulation of spinal oxytocin circuits alters behavioral responses to both gentle touch and noxious stimuli. Spinal calcium imaging and slice electrophysiology reveal that oxytocin acts on both excitatory and inhibitory spinal neurons to sculpt the relative activity of spinal ascending systems that convey both social touch and pain to the brain. Extending these findings to humans, we show that oxytocin receptors are also expressed on spinal excitatory and inhibitory neurons, and that endogenous oxytocin during massage correlates with altered spinal touch processing. Thus, spinal oxytocin signaling provides an evolutionarily conserved mechanism for the therapeutic benefits of massage.

neuroscience↗

bioRxiv2025

CAD-C: An engineered nuclease enables repair-free in situ proximity ligation and nucleosome-resolution chromosome walks in human cells

Chromosome conformation capture (3C)-derived methods have become an indispensable tool in the study of gene regulation. The three-dimensional contacts probed by 3C methods depend strongly on the properties of the enzyme used to fragment chromatin prior to proximity-driven ligation. Micrococcal nuclease (MNase), used in Micro-C, increases resolution at the expense of low ligation efficiency and the need for extensive enzyme titration. To overcome these limitations, we engineered a TEV protease-activatable caspase-activated DNase (CAD) to enable an efficient, low-sequence-bias, and high-resolution proximity ligation assay we call CAD-C. CAD-C was successful on the first attempt for each human cell line tested and the resulting datasets capture loops, TADs, compartments, and stripes similarly to Micro-C. However, compared to Micro-C and Hi-C, CAD-C shows enhanced sensitivity for promoter-enhancer loops. Leveraging the ligation-competent DNA ends produced by CAD cleavage, we show that CAD-C is compatible with a highly streamlined, repair-free protocol and produces multi-step CADwalks, consecutive ligations between nucleosomal or sub-nucleosomal fragments. With these walks, we probe local chromatin fiber folding contacts, nucleosomal and sub-nucleosomal footprints, and long-range nuclear organization regimes in human cell lines. CAD-C is an efficient, robust chromatin structure assay that can span sub-nucleosomal to chromosomal length scales in a single experiment.

genomics↗

bioRxiv2025

Benchmarking Alignment Strategies for Hi-C Reads in Metagenomic Hi-C Data

BackgroundMetagenomics combined with High-throughput Chromosome Conformation Capture (Hi-C) offers a powerful approach to study microbial communities by linking genomic content with spatial interactions. Hi-C enhances shotgun sequencing by revealing taxonomic composition, functional interactions, and genomic organization from a single sample. However, aligning Hi-C reads to metagenomic contigs presents challenges, including the varying insert size of Hi-C paired-end reads, multi-species complexity, and gaps in assemblies. Although many benchmark studies have evaluated general alignment tools and Hi-C data alignment, none have specifically addressed metagenomics Hi-C data. ResultsHere, we selected seven alignment strategies that have been used in Hi-C analyses: BWA MEM -5SP, BWA MEM default, BWA aln default, Bowtie2 default, Bowtie2 -very-sensitive-local, Minimap2 default, and Chromap Hi-C default. We benchmarked them on one synthetic and seven real-world environments, and evaluated these tools based on the number of inter-contig Hi-C read pairs and their influence on downstream tasks, such as binning quality. ConclusionOur findings show that BWA MEM -5SP consistently outperforms other tools across all environments in terms of inter-contig read pairs and binning quality, followed by BWA MEM default. Chromap and Minimap2, while less effective in these metrics, demonstrate the highest computational efficiency.

bioinformatics↗

bioRxiv2025

scWGBS-GPT: A Foundation Model for Capturing Long-Range CpG Dependencies in Single-Cell Whole-Genome Bisulfite Sequencing to Enhance Epigenetic Analysis

Single-cell DNA methylomes are challenging to interpret because of sparse CpG coverage and the complexity of genome-wide sequences. We present scDNAm-GPT, a universal foundation model that uses context-aware CpG tokenization, a Mamba backbone, and cross-attention to capture both local and global DNA methylation patterns. Trained on over one million single cells from 35 human and mouse tissues, scDNAm-GPT enables accurate cell clustering, zero-shot prediction of CpG effects on gene expression, improved trajectory inference, and reference-free deconvolution of cell types from cell-free DNA. The model hierarchically learns regulatory features, and its attention maps highlight functionally relevant regions, demonstrating high biological interpretability. These results establish scDNAm-GPT as a scalable and generalizable framework for single-cell epigenomic analysis, offering new opportunities to dissect epigenetic regulation in health and disease. Code is available at GitHub (https://github.com/ChaoqiLiang/scDNAm-GPT).

bioinformatics↗

bioRxiv2025

A recombinant hybrid provides insights into gene regulation, pathogenesis and tumorigenesis of phytopathogenic smut fungi

The maize smut fungi Ustilago maydis and Sporisorium reilianum are closely related and have similar genomes in terms of size and synteny. While U. maydis induces tumors locally at sites of infection, S. reilianum systemically colonizes the host and causes symptoms in the inflorescences. To investigate the genetic basis of these differences, an interspecific recombinant hybrid (rUSH) with the mating type system of S. reilianum was generated. rUSH exhibited extensive in-planta proliferation, showing a S. reilianum-like phenotype at all developmental stages except teliospore formation. Transcriptome profiling revealed that expression of pathogenicity-related effector gene orthologs was induced in rUSH, but not in a wild-type hybrid control. Multiple transcriptome comparisons identified 253 differentially expressed one-to-one effector orthologs with distinct regulatory patterns, including cis-, trans-, and rUSH-specific regulation. Functional analysis via CRISPR/Cas9 mutagenesis uncovered three novel virulence factors among the rUSH-specific regulated effectors. Ultimately, rUSH facilitated to identify the transcription factor UmHdp2 as key regulator of U. maydis-induced tumorigenesis. Together, these findings highlight the utility of a recombinant, interspecific hybrid in unraveling the molecular mechanisms underlying pathogenic differences in closely related fungal pathogens.

microbiology↗

bioRxiv2024

Autophosphorylation of the oncogenic protein TEL-ABL confers resistance to the allosteric ABL inhibitor asciminib

Chromosomal translocations that fuse the ABL1 gene to BCR and TEL cause human leukemias. Oligomerization and the loss of an inhibitory myristoylation modification lead to unregulated kinase activity of the BCR-ABL and TEL-ABL fusion proteins. ATP-competitive ABL inhibitors, such as imatinib and ponatinib, are effective against both fusion proteins. We discovered that asciminib, an allosteric inhibitor of BCR-ABL that binds to the myristoyl binding site in the ABL kinase domain, is >2000-fold less potent against TEL-ABL than BCR-ABL in cell-growth assays. This is surprising because the ABL components of the two fusion proteins, including the asciminib binding sites, have identical sequence. We deleted a short helical segment in the ABL kinase domain that closes over asciminib when it is bound. This deletion results in asciminib resistance in BCR-ABL, but has no effect on TEL-ABL, suggesting that the native autoinhibitory mechanism that asciminib engages in BCR-ABL is disrupted in TEL-ABL. We show, using mammalian cell expression and single-molecule microscopy, that BCR-ABL is mainly dimeric while TEL-ABL forms higher-order oligomers. Oligomerization can promote trans-autophosphorylation of ABL, and we find that a regulatory phosphorylation site in the SH3 domain of ABL (Tyr 89) is highly phosphorylated in TEL-ABL. This phosphorylation is expected to disassemble the autoinhibited conformation of ABL, thereby preventing asciminib binding. We show that TEL-ABL is intrinsically susceptible to inhibition by asciminib, but that increased phosphorylation results in resistance. Our results demonstrate that different ABL fusion proteins can have dramatically different responses to allosteric inhibitors due to differential phosphorylation. One Sentence SummaryWhen TEL-ABL is phosphorylated, it is insensitive to asciminib. However, when TEL-ABL is dephosphorylated by a phosphatase, asciminib sensitivity is restored.

biochemistry↗

bioRxiv2024

Degradation of indole-3-acetic acid by plant-associated microbes

Plant-associated microbiota affect pant growth and development by regulating plant hormones homeostasis. Indole-3-acetic acid (IAA), a well-known plant hormone, can be produced by various plant-associated bacteria. However, the prevalence of microbes with the capacity to degrade IAA in the rhizosphere has not been systematically studied. In this study, we analyzed the IAA degradation capabilities of bacterial isolates from the roots of Arabidopsis and rice. Using genomics analysis and in vitro assays, we found that 21 out of 189 taxonomically diverse bacterial isolates possess the ability to degrade IAA. Through comparative genomics and transcriptomic assays, we identified iac-like or iad-like operon in the genomes of these IAA degraders. Additionally, the regulator of the operon was found to be highly conserved among these strains through protein structure similarity analysis. Some of the IAA degraders could utilize IAA as their sole carbon and energy source. In planta, most of the IAA degrading strains mitigated Arabidopsis seedling root growth inhibition (RGI) triggered by exogenous IAA. Importantly, we observed increased colonization preference of IAA degraders from soil to root according to the frequency of the biomarker genes in metagenome-assembled genomes (MAGs) collected from different habitats, suggesting that there is a close association between IAA degraders and IAA-producers. In summary, our findings further the understanding of the functional diversity and roles of plant-associated microbes.

microbiology↗

bioRxiv2023

From disturbances to nonlinear fitness and back.

Disturbances can occur as short-lived pulses (e.g., storms) or sustained presses (e.g., chronic drought). Much work in ecology has developed methods to help predict how natural populations respond to disturbances, but analyses of pulse and press disturbances has been largely disconnected. We present a unified matrix framework that links presses and pulses within the same analytical approach, showing how transient nonlinearities and demography shape fitness. We find that transient responses to pulse disturbances accumulate to determine the long-term response to press disturbances. For structured-population models, this cumulative change is given by a new Transient Response Matrix (TRM). Strikingly, the TRM also yields the second derivatives of population growth rate with respect to matrix elements. Thus, there is an intimate but unexpected relationship between nonlinear selection pressures on demographic rates, and the transient dynamics of populations. This relationship yields a strong correlation between TRM and generation time across 439 unique plant and animal species (2690 population models). We also show that the TRM is directly related to Cohens cumulative distance measure for populations converging to stability. Our framework provides ecologists with a general tool to predict population responses to diverse environmental changes.

ecology↗

bioRxiv2023

CRISPR/Cas9 ribonucleoprotein-mediated mutagenesis in Sporisorium reilianum

Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9) has become the state of art for mutagenesis in filamentous fungi. Here, we describe a RNP-mediated CRISPR/Cas9 for mutagenesis in Sporisorium reilianum. The efficiency of the method was tested in vitro with a cleavage assay as well as in vivo with a GFP-expressing S. reilianum strain. We applied this method to generate frameshift-, knock-in- and knock-out mutants in S. reilianum without a resistance marker by using an auto-replicating plasmid for selection. The RNP-mediated CRISPR/Cas9 increased the mutagenesis efficiency and firstly enables a marker-free genome editing in S. reilianum.

genetics↗

bioRxiv2023

Genetically-encoded probes to determine nonspecific hydrophobic and electrostatic binding in cells

Proteins interact nonspecifically with other components in the crowded cell through associative interactions. This environmental stickiness alters for example folding stability, protein diffusion, and aggregation propensity. However, the magnitude and variation in nonspecific electrostatic and hydrophobic binding energies in the cell are unclear. Here, we develop genetically-encoded fluorescence excitation ratiometric probes to determine nonspecific binding interactions. We determine hydrophobic and electrostatic interactions by systematically varying a sensing peptide on the probe. The sensors are verified in vitro and tested in HEK293T, where the nonspecific binding is highest for highly cationic and hydrophobic domains. Perturbing the cell by energy depletion increases the dependence of binding strength on peptide electrostatics, showing that the cellular conditions tune the nonspecific interaction architecture in cells. The sensors will allow estimation of nonspecific interactions and how these interactions may change in response to stresses.

biophysics↗

bioRxiv2023

Enhlink infers distal and context-specific enhancer-promoter linkages

Enhancers play a crucial role in regulating gene expression and their functional status can be queried with cell type precision using using single-cell (sc)ATAC-seq. To facilitate analysis of such data, we developed Enhlink, a novel computational approach that leverages single -cell signals to infer linkages between regulatory DNA sequences, such as enhancers and promoters. Enhlink uses an ensemble strategy that integrates cell-level technical covariates to control for batch effects and biological covariates to infer robust condition-specific links and their associated p-values. It can integrate simultaneous gene expression and chromatin accessibility measurements of individual cells profiled by multi-omic experiments for increased specificity. We evaluated Enhlink using simulated and real scATAC-seq data, including those paired with physical enhancer-promoter links enumerated by promoter capture Hi-C and with multi-omic scATAC-/RNA-seq data we generated from the mouse striatum. These examples demonstrated that our method outperforms popular alternative strategies. In conjunction with eQTL analysis, Enhlink revealed a putative super-enhancer regulating key cell type-specific markers of striatal neurons. Taken together, our analyses demonstrate that Enhlink is accurate, powerful, and provides features that can lead to novel biological insights.

bioinformatics↗

bioRxiv2023

Data-driven prediction of colonization outcomes for complex microbial communities

Complex microbial interactions can lead to different colonization outcomes of exogenous species, be they pathogenic or beneficial in nature. Predicting the colonization of exogenous species in complex communities remains a fundamental challenge in microbial ecology, mainly due to our limited knowledge of the diverse physical, biochemical, and ecological processes governing microbial dynamics. Here, we proposed a data-driven approach independent of any dynamics model to predict colonization outcomes of exogenous species from the baseline compositions of microbial communities. We systematically validated this approach using synthetic data, finding that machine learning models (including Random Forest and neural ODE) can predict not only the binary colonization outcome but also the post-invasion steady-state abundance of the invading species. Then we conducted colonization experiments for two commensal gut bacteria species Enterococcus faecium and Akkermansia muciniphila in hundreds of human stool-derived in vitro microbial communities, confirming that the data-driven approach can successfully predict the colonization outcomes. Furthermore, we found that while most resident species were predicted to have a weak negative impact on the colonization of exogenous species, strongly interacting species could significantly alter the colonization outcomes, e.g., the presence of Enterococcus faecalis inhibits the invasion of E. faecium. The presented results suggest that the data-driven approach is a powerful tool to inform the ecology and management of complex microbial communities.

ecology↗

bioRxiv2023

SpatialCTD: a large-scale TME spatial transcriptomic dataset to evaluate cell type deconvolution for immuno-oncology

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular resolution. The task of cell type deconvolution has been introduced to disentangle discrete cell types from such multi-cellular spots. However, existing datasets for cell type deconvolution are limited in scale, predominantly encompassing data on mice, and are not designed for human immuno-oncology. In order to overcome these limitations and promote comprehensive investigation of cell type deconvolution for human immuno-oncology, we introduce a large-scale spatial transcriptomic dataset named SO_SCPLOWPATIALC_SCPLOWCTD, encompassing 1.8 million cells from the human tumor microenvironment across the lung, kidney, and liver. Distinct from existing approaches that primarily depend on single-cell RNA sequencing data as a reference without incorporating spatial information, we introduce Graph Neural Network-based method (i.e., GNNDO_SCPLOWECONVOLVERC_SCPLOW) that effectively utilize the spatial information from reference samples, and extensive experiments show that GNNDO_SCPLOWECONVOLVERC_SCPLOW often outperforms existing state-of-the-art methods by a substantial margin, without requiring single-cell RNA-seq data. To enable comprehensive evaluations on spatial transcriptomics data from flexible protocols, we provide an online tool capable of converting spatial transcriptomic data from other platforms (e.g., 10x Visium, MERFISH and sci-Space) into pseudo spots, featuring adjustable spot size. The SO_SCPLOWPATIALC_SCPLOWCTD dataset and GNNDO_SCPLOWECONVOLVERC_SCPLOW implementation are available at https://github.com/OmicsML/SpatialCTD, and the online converter tool can be accessed at https://omicsml.github.io/SpatialCTD/.

bioinformatics↗

bioRxiv2023

A transcriptional activator effector of Ustilago maydis regulates hyperplasia in maize during pathogen-induced tumor formation

Ustilago maydis causes common smut in maize, which is characterized by tumor formation in aerial parts of the host. Tumors result from the de novo cell division of highly developed bundle sheath and subsequent cell enlargement. However, the molecular mechanisms underlying tumorigenesis are still largely unknown. Here, we characterize the U. maydis effector Sts2 (Small tumor on seedlings 2), which promotes the division of hyperplasia tumor cells. Upon infection, Sts2 is translocated into the maize cell nucleus, where it acts as a transcriptional activator, and the transactivation activity is crucial for its virulence function. Sts2 interacts with ZmNECAP1, a yet undescribed plant transcriptional activator, and it activates the expression of several leaf developmental regulators to potentiate tumor formation. Contrary, fusion of a suppressive SRDX-motif to Sts2 causes dominant negative inhibition of tumor formation, underpinning the central role of Sts2 for tumorigenesis. Our results not only disclose the virulence mechanism of a tumorigenic effector, but also reveal the essential role of leaf developmental regulators in pathogen-induced tumor formation.

plant biology↗