Biology subjects

Zheng, Y.

Publications and source records attributed to Zheng, Y..

At least 163 records · Page 9Linked to original sources

bioRxiv2025

A Comprehensive Reference Catalog of Human Skin DNA Virome Reveals Novel Viral Diversity and Microenvironmental Influences

IntroductionHuman skin serves as a dynamic habitat for a diverse microbiome, including a complex array of viruses whose diversity and roles are not fully understood. ObjectivesThis study aims to enhance our understanding of this skin viral diversity through the construction of a detailed, non-redundant DNA viral reference catalog. MethodsA total of 2,760 skin metagenomes from six published skin studies were collected. A skin virome catalog was constructed using methods independent of reference databases. Viral characteristics were identified through cross-cohort meta-analysis and used to characterize viral features across different skin environments. ResultsWe identified 20,927 viral sequences, which clustered into 2,873 viral operational taxonomic units (vOTUs). Among these, 2,610 represent previously unrecorded viral sequences, uncovering a substantial breadth of viral diversity on human skin. The results also highlight significant differences in viral communities that are associated with varying skin microenvironments. The oily skin is enriched in Papillomaviridae; the dry skin area is enriched in Autographiviridae, Inoviridae and Mitoviridae; and the moist skin is enriched in Herelleviridae, indicating the adaptive nature of viruses. We also investigated the relationship between bacteriophages and bacteria on the skin surface. We found that skin bacteria such as Pseudomonas, Klebsiella, and Staphylococcus are infected by phages from the class Caudoviricetes. ConclusionThis comprehensive skin DNA viral catalog significantly advances our understanding of the viromes role within the skin ecosystem. The findings highlight the adaptive nature of viruses to different skin microenvironments and their interactions with resident bacteria. This catalog serves as a valuable resource for further epidemiological and therapeutic research, potentially leading to better management and treatment of skin conditions influenced by the skins virome.

microbiology↗

bioRxiv2025

Response to anti-angiogenic therapy is affected by AIMP protein family activity in glioblastoma and lower-grade gliomas

BackgroundGlioblastoma (GBM) is a highly vascularized, heterogeneous tumor, yet anti-angiogenic therapies have yielded limited survival benefits. The lack of validated predictive biomarkers for treatment response stratification remains a major challenge. Aminoacyl tRNA synthetase complex-interacting multicomplex proteins (AIMPs) 1/2/3 have been implicated in CNS diseases, but their roles in gliomas remain unexplored. We investigated their association with angiogenesis and their significance as predictive biomarkers for anti-angiogenic treatment response. MethodsIn this multi-cohort retrospective study we analyzed glioma samples from TCGA, CGGA, Rembrandt, Gravendeel, BELOB and REGOMA trials, and four single-cell transcriptomic datasets. Multi-omic analyses incorporated transcriptomic, epigenetic, and proteomic data. Kaplan-Meier and Cox proportional hazards models were used to assess the prognostic value of AIMPs in heterogeneous and homogeneous treatment-groups. Using single-cell transcriptomics, we explored spatial and cell-type-specific AIMP2 expression in GBM. ResultsAIMP1/2/3 expressions correlated significantly with angiogenesis across TCGA cancers. In gliomas, AIMPs were upregulated in tumor vs. normal tissues, higher- vs. lower-grade gliomas, and recurrent vs. primary tumors (p<0.05). Upon retrospective analysis of two clinical trials assessing different anti-angiogenic drugs, we found that high-AIMP2 subgroups had improved response to therapies in GBM (REGOMA: HR 4.75 [1.96-11.5], p<0.001; BELOB: HR 2.3 [1.17-4.49], p=0.015). AIMP2-cg04317940 methylation emerged as a clinically applicable stratification marker. Single-cell analysis revealed homogeneous AIMP2 expression in tumor tissues, particularly in AC-like cells, suggesting a mechanistic link to tumor angiogenesis. ConclusionsThese findings provide novel insights into the role of AIMPs in angiogenesis, offering improved patient stratification and therapeutic outcomes in recurrent GBM.

bioinformatics↗

bioRxiv2025

Nucleosome Engagement Regulates RORγt Structure and Dynamics

ROR{gamma}t is a key transcriptional regulator that supports protective pathogen clearance but also drives autoimmune disorders. Genetic studies have identified ROR{gamma}t mutations that selectively protect from autoimmunity without compromising host defense. Herein, we describe the molecular principles governing how ROR{gamma}t selectively drives these context-dependent gene programs. Structural studies revealed the selectivity-determining mutations lie in an -helix, the C-terminal extension (CTE), which nucleates when ROR{gamma}t engages partially occluded DNA response elements at nucleosome entry/exit sites. In ex vivo Th17 cells, the CTE is required for full genomic occupancy and expression of inflammatory effector genes, while residual DNA binding supports partial occupancy that, alongside context-dependent transcription factors, induces lineage-stabilizing gene expression. These findings support a model where ROR{gamma}t uses distinct chromatin binding modes to engage an expansive chromatin landscape to activate target gene programs, explaining the complex phenotypes of CTE mutant mice.

biophysics↗

bioRxiv2025

Total whole-arm chromosome losses predict malignancy in human cancer

Aneuploidy is observed as gains or losses of whole chromosomes or chromosome arms and is a common hallmark of cancer. Whereas models for the generation of aneuploidy in cancer invoke mitotic chromosome segregation errors, whole-arm losses might occur simply as a result of centromere breakage. We recently showed that elevated RNA Polymerase II (RNAPII) level over S-phase-dependent histone genes predicts rapid recurrence of human meningioma and is correlated with total whole-arm losses relative to gains. To explain this imbalance in arm losses over gains, we have proposed that histone overexpression at S-phase competes with the histone H3 variant CENP-A, resulting in centromere breaks and whole-arm losses. To test whether centromere breaks alone can drive aneuploidy, we ask whether total whole-arm aneuploids can predict outcome across different cancer types in large RNA and whole-genome sequencing databanks. We find that total whole-arm losses generally predict outcome, suggesting that centromere breakage is a major initiating factor leading to aneuploidy and the resulting changes in the selective landscape that drive most cancers. We also present evidence that centromere breakage alone is sufficient to account for whole-arm losses and gains, contrary to mitotic spindle error models for generation of aneuploidy. Our results suggest that therapeutic intervention targeting histone overexpression has the potential of reducing aneuploidy and slowing cancer progression. Significance StatementGain or loss of whole chromosome arms following centromere breaks is frequent in cancer, but whether or not there is a common initiating event is unknown. Here we show that the total number of whole-arm losses predicts patient outcomes across cancer types, suggesting a causal relationship. This general excess of losses over gains is not predicted by mitotic error models of aneuploidy but rather suggests that centromere breaks themselves initiate whole-arm aneuploidies. Insofar as aneuploidy reshapes the selective landscapes that drive most cancers, our results have potential clinical implications.

cancer biology↗

bioRxiv2025

High-throughput 3D super-resolution imaging in deep tissue

Fluorescence images obtained with optical microscopes intrinsically suffer from blur and noise, which can be partially reversed by the deconvolution process. However, the deconvolution process is ill-conditioned, leading to a trade-off between detail preservation and noise suppression. Here, we develop 3D-FUDIP to fully decouple the deconvolution process into two parts: deblurring and denoising, achieving an 8-fold improvement in spatial resolution. By adopting the Poisson model, which obeys the quantum nature of photons, our 3D-FUDIP can be successfully applied to various noise conditions, especially low-light conditions where the photon number is generally extremely small. The results show that our 3D-FUDIP improves the SNR by up to 6-fold with only a one-fifth photon budget. Besides, 3D-FUDIP boosts the spatial bandwidth product (SBP) by one order of magnitude, allowing more spine details to be resolved within a larger imaging volume. By synergizing deep learning with these advances, we propose 3D-FUDIPn to further improve the imaging resolution. We demonstrate 3D-FUDIPs performance in various imaging systems, including confocal, two-photon, and light-sheet microscopes, showing compatibility and potential applications in biological science.

neuroscience↗

bioRxiv2025

DeepSeMS: a large language model reveals hidden biosynthetic potential of the global ocean microbiome

Microbial biosynthetic diversity holds immense potential for discovering natural products with therapeutic applications, yet a substantial quantity of natural products derived from uncultivated microorganisms remains uncharacterized. The intricate nature of biosynthetic enzymes poses a major challenge in accurately predicting the chemical structures of secondary metabolites solely based on genome sequences using current rule-based methods. Here, we present DeepSeMS, a large language model designed to predict the chemical structures of secondary metabolites from various microbial biosynthetic gene clusters. Built on the Transformer architecture, DeepSeMS innovatively identifies sequence features using functional domains of biosynthetic enzymes, and incorporates feature-aligned chemical structure enumeration for training data augmentation. External evaluation results show that DeepSeMS predicts more accurate chemical structures of secondary metabolites with a Tanimoto coefficient up to 0.6 compared with the ground truth, significantly outperforming antiSMASH and PRISM with coefficients of only 0.14 and 0.45 respectively. Moreover, DeepSeMS successfully predicted secondary metabolites for 96.60% of cryptic biosynthetic gene clusters, surpassing existing methods with success rates less than 50%. Leveraging DeepSeMS, we characterized over 65,000 novel secondary metabolites from the global ocean microbiome with previously undocumented structural types, ecological distribution, and biomedical applications especially antibiotics. A login-free and user-friendly web server for DeepSeMS (https://biochemai.cstspace.cn/deepsems/) has been launched, featuring an integrated global ocean microbial secondary metabolites repository to expedite the discovery of novel natural products. Collectively, this study underscores the great capacity of a large language model-driven method in revealing hidden biosynthetic potential of the global ocean microbiome.

synthetic biology↗

bioRxiv2025

Generalization but not strengthening of negative memories drives the development of depression-like behaviors

Individuals with depression exhibit intensified and generalized negative memories. However, how prior memories actually influence onset and/or progression of depression, particularly whether the strengthening or the generalization of prior memories play a key role, is poorly understood. Here, we introduced behavioral paradigms to differentiate between memory strengthening and generalization, and found that negative experiences that produced memory overgeneralization, but not strengthening, induced depression-like behaviors. Furthermore, we identified that the medial prefrontal cortex (mPFC) to the bed nucleus of the stria terminals (BNST) projection functionally linked memory generalization to depression, together with single-cell calcium imaging which revealed a significant overlap in the mPFCBNST neuronal ensemble encoding depression-like behaviors with that encoding generalized memory, but not memory strength. Circuit-based transcriptomic analysis and chromophore-assisted light inactivation demonstrated that triggering actin remodeling in the mPFCBNST neurons, a memory consolidation mechanism enhanced generalization while reducing memory strength, also induced depression-like behaviors. Collectively, these findings suggest generalization of negative memories as a primary factor that drives depression-like behaviors, highlighting the importance of early identification of individuals at risk for depression who exhibit overgeneralized negative memories, and targeting overgeneralized negative memories in the treatment of depression.

animal behavior and cognition↗

bioRxiv2025

SPTnet: a deep learning framework for end-to-end single-particle tracking and motion dynamics analysis

Single-particle tracking (SPT) provides high-resolution spatial-temporal information on biomolecule dynamics. However, localization inaccuracies, limited track lengths, heterogeneous fluorescence backgrounds, and potential molecular motion blur pose significant challenges that hinder the accurate extraction of movement trajectories and their underlying motion behavior. The conventional SPT pipeline struggles to comprehensively address detection, localization, linkage, and motion parameter inference simultaneously, resulting in information loss during sequential processing. To overcome these challenges, we propose SPTnet, an end-to-end deep learning framework that leverages a Transformer-based architecture to optimize trajectory and motion parameter estimations in parallel through a global loss. SPTnet bypasses traditional SPT processes, directly inferring molecular trajectories and motion parameters from fluorescence microscopy videos with a precision approaching the statistical information limit. Our results demonstrate that SPTnet outperforms conventional methods under commonly encountered but challenging conditions such as short trajectories, low signal-to-noise ratio (SNR), heterogeneous backgrounds, motion blur, and especially when molecules exhibit non-Brownian behaviors.

biophysics↗

bioRxiv2025

The Proteomics Landscape of Pattern Triggered Immunity in the Arabidopsis Leaf Apoplast

The apoplast is a critical interface in plant-pathogen interactions particularly in the context of pattern-triggered immunity (PTI), which is initiated by recognition of microbe-associated molecular patterns (PAMPs). Our study characterizes the proteomic profile of the Arabidopsis apoplast during PTI induced by flg22, a 22 amino acid bacterial flagellin epitope, to elucidate the output of PTI. Apoplastic washing fluid (AWF) was extracted with minimal cytoplasmic contamination for LC-MS/MS analysis. We observed consistent identification of PTI enriched and depleted peptides across replicates with limited correlation between total protein abundance and transcript abundance. We observed topological bias in peptide recovery of receptor-like kinases with peptides predominantly recovered from their ectodomains. Notably, tetraspanin 8, an exosome marker, was enriched in PTI samples. We additionally confirmed increased concentrations of exosomes during PTI. This study enhances our understanding of the proteomic changes in the apoplast during plant immune responses and lays the groundwork for future investigations into the molecular mechanisms of plant defense under recognition of pathogen molecular patterns.

plant biology↗

bioRxiv2025

Interferometric Ultra-High Resolution 3D Imaging through Brain Sections

Single-molecule super-resolution microscopy allows pin-pointing individual molecular positions in cells with nanometer precision. However, achieving molecular resolution through tissues is often difficult because of optical scattering and aberrations. We introduced 4Pi single-molecule nanoscopy for brain with in-situ point spread function retrieval through opaque tissue (4Pi-BRAINSPOT), integrating 4Pi single-molecule switching nanoscopy with dynamic in-situ coherent PSF modeling, single-molecule compatible tissue clearing, light-sheet illumination, and a novel quantitative analysis pipeline utilizing the highly accurate 3D molecular coordinates. This approach enables the quantification of protein distribution with sub-15-nm resolution in all three dimensions in complex tissue specimens. We demonstrated 4Pi-BRAINSPOTs capacities in revealing the molecular arrangements in various sub-cellular organelles and resolved the membrane morphology of individual dendritic spines through 50-{micro}m transgenic mouse brain slices. This ultra-high-resolution approach allows us to decipher nanoscale organelle architecture and molecular distribution in both isolated cells and native tissue environments with precision down to a few nanometers.

neuroscience↗

bioRxiv2025

Information Shielding Through Neural Deactivation: A Fundamental Mechanism of Human Information Processing

Information processing is a core issue in cognitive neuroscience. The brain can either accept or shield information. However, information shielding has traditionally been regarded as a byproduct of other cognitive processes that prepare brain areas for activation, with the accompanying brain deactivation seen as merely supportive. Here, we offer an alternative perspective, demonstrating that people can directly perform information shielding without engaging other cognitive processes. Using information shielding as a novel investigative lens, we provide direct evidence that deactivation serves as a primary mechanism in its own right. We found that information shielding was characterized by a deactivation-dominant neural dynamic, with initial executive control region activation giving way to increased sensory region deactivation, especially after a 3-second boundary. Neural decoding results further confirmed this deactivation trend. This deactivation pattern was consistent across both auditory and visual modalities. Furthermore, non-invasive brain stimulation demonstrated a causal relationship between the deactivation pattern and information shielding, and we found that this deactivation mechanism extended to general unnecessary information processing, regardless of whether the necessity was determined objectively or subjectively. This challenges the conventional emphasis on activation as the primary mode of information processing and opens new fundamental avenues for understanding inhibitory cognitive processes.

neuroscience↗

bioRxiv2025

Aberrant Modular Dynamics of Functional Networks in Schizophrenia and Their Relationship with Neurotransmitter and Gene Expression Profiles

IntroductionNumerous studies have emphasized the time-varying modular architecture of functional brain networks and its relevance to cognitive functions in healthy participants. However, how brain modular dynamics change in schizophrenia and how these alterations relate to neurotransmitter and transcriptomic signatures have not been well elucidated. MethodsWe harmonized resting-state fMRI data from a multi-site sample including 223 patients and 279 healthy controls and applied the multilayer network method to estimate the regional module switching rate (flexibility) of functional brain connectomes. We examined aberrant flexibility in patients relative to controls and explored its relations to neurotransmitter systems and postmortem gene expression. ResultsCompared with controls, patients with schizophrenia had significantly higher flexibility in the somatomotor and right visual regions, and lower flexibility in the left parahippocampal gyrus, right supramarginal gyrus, right frontal-operculum-insula, bilateral precuneus posterior cingulate cortex, and bilateral inferior parietal gyrus. These alterations were associated with multiple neurotransmitter systems and weighted gene transcriptomic profiles. The most relevant genes were preferentially enriched for biological processes of transmembrane transport and brain development, specific cell types, and previously identified schizophrenia-related genes. ConclusionsThis study reveals aberrant modular dynamics in schizophrenia and its relations to neurotransmitter systems and schizophrenia-related transcriptomic profiles, providing insights into the understanding of the pathophysiology underlying schizophrenia.

neuroscience↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2025

Genetically Defined Organoid Models Reveal Mechanisms Driving Squamous Cell Neoplastic Evolution and Identify Potential Therapeutic Vulnerabilities

Upper aerodigestive squamous cell carcinoma (UASCC) is an aggressive and lethal neoplasm, with its early neoplastic transformation mechanisms remaining poorly understood. Here, we characterize over 25 genetically-defined organoid models derived from murine and human oral/esophageal tissues harboring key driver mutations. Double knockout of TP53 and CDKN2A induced morphological dysplasia, hyperproliferation, loss of squamous differentiation, and tumorigenicity, which were further exacerbated by additional driver mutations (e.g., PIK3CA, NOTCH1, KMT2C). Single-cell analysis revealed an expansion of quiescent basal cells and proliferative squamous cells, alongside a loss of differentiated squamous cells during malignant transformation. A distinct senescence program, regulated by ANXA1, was markedly diminished during early neoplastic evolution. Mechanistically, the ANXA1-SMAD3-p27KIP1 pathway was identified as a critical regulator of this senescence program, acting to suppress neoplastic features in organoid models. Lastly, our high-throughput, single-organoid-resolution drug screens unexpectedly revealed PIK3CA-driven organoids exhibited sensitivity to Mitomycin C and Onalespib. This study provides novel mechanistic insights into early neoplastic evolution and underscores the value of genetically-defined organoid models for investigating cancer biology and identifying targeted therapies.

cancer biology↗

bioRxiv2025

1,3- and 1,4-linked Polysaccharides Uptake in Intestinal Cells Relies on Clathrin/Dynamin 1/Rab5-dependent Endocytosis

Natural polysaccharides are considered to be a promising feedstock for manufacturing sustainable materials. However, polysaccharides are believed by most biologists that they could not be absorbed by intestinal mucosa to enter circulation system owing to their high hydrophilicity and large molecule size. Herein, {beta}-1,3-linked glucan (GFPBW1) and -1,4-linked glucan (WGE) is used as the model polysaccharide and the transport experiments show that different linked and charged polysaccharides can permeate Caco-2 cell monolayers. The in vivo experiments demonstrate that GFPBW1 and WGE are detectable in rodent plasma and liver after oral administration the isotope (99mTc, 3H) and fluorescein labeled polysaccharides. Further study show that polysaccharide uptake requires clathrin heavy chain (CLTC) and its associated factors Rab5 and dynamin1 in intestinal cells using gene-knockdown strategies and inhibitors. Strikingly, polysaccharide absorption is attenuated in both CLTC intestine deficient mice and Rab5, dynamin1 conventional-knockout mice. Importantly, membrane receptors bone morphogenetic protein receptor type IA (BMPRIA), Dectin-1 and epidermal growth factor receptor (EGFR) are also critical for specific structural polysaccharide internalization. These findings provide novel insight to understand polysaccharide absorption mechanism and lay foundation for oral polysaccharide- based new drugs development.

pharmacology and toxicology↗

bioRxiv2024

Muller's Ratchet and Gene Duplication

Copy number of genes in gene families can be highly variable among individuals and may continue to change across generations. Here, we study a model of duplication-selection interaction, which is related to Haighs mutation-selection model of Mullers ratchet. New gene copies are generated by duplication but fitness of individuals decreases as copy number increases. Our model comes in two flavours: duplicates are copied either from a single template or from any existing copy. A duplication-selection equilibrium exists in both cases for infinite size populations and is given by a shifted Poisson or a negative binomial distribution. Unless counteracted by synergistic epistasis, finite populations suffer from loss of low copy-number haplotypes by drift, forcing them into a regime called run-away evolution in which new copies accumulate without bound nor equilibrium. We discuss a few empirical examples and interpret them in the light of our models. Generally, large gene families appear too over-dispersed to fit the single template model suggesting a dynamic, and potentially accelerating, duplication process.

evolutionary biology↗

bioRxiv2024

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Red-shifted GRAB acetylcholine sensors for multiplex imaging in vivo

The neurotransmitter acetylcholine (ACh) is essential in both the central and peripheral nervous systems. Recent studies highlight the significance of interactions between ACh and various neuromodulators in regulating complex behaviors. The ability to simultaneously image ACh and other neuromodulators can provide valuable information regarding the mechanisms underlying these behaviors. Here, we developed a series of red fluorescent G protein-coupled receptor activation-based (GRAB) ACh sensors, with a wide detection range and expanded spectral profile. The high-affinity sensor, rACh1h, reliably detects ACh release in various brain regions, including the nucleus accumbens, amygdala, hippocampus, and cortex. Moreover, rACh1h can be co-expressed with green fluorescent sensors in order to record ACh release together with other neurochemicals in various behavioral contexts using fiber photometry and two-photon imaging, with high spatiotemporal resolution. These new ACh sensors can therefore provide valuable new insights regarding the functional role of the cholinergic system under both physiological and pathological conditions.

neuroscience↗