Biology subjects

Bai, Y.

Publications and source records attributed to Bai, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Is Manganese the Root Cause of Human Mental Disorders?

Mental health disorders are increasing globally and emerging as a leading public health challenge. The etiology of mental disorders is traditionally attributed to a complex interplay of genetic predispositions and social behaviors. Here, we challenge this view and propose that environmental contamination -- specifically, exposure to manganese (Mn) -- is a critical, yet overlooked, driver for the occurrence of mental disorders. Mn is widely used in various aspects of our lives, such as Mn steel for urbanization, agricultural fertilizer, electronic vehicle batteries, and mobile phone. Through laboratory experiments, we demonstrated that Mn exposure slightly enhanced the bacterial stress sensitivity, evidenced by altered gene expression in two-component systems and their Mn(II) oxidation function. Therefore, we hypothesized that cosmopolitan environmental Mn could increase the stress sensitivity of urban airborne microbiomes. Through comparative analysis of downloaded airborne microbiome datasets from eight cities, we found that urbanization levels show a significant positive correlation with the stress sensitivity of airborne microbiomes. Given that airborne particles can enter the human body and potentially impact health, we hypothesized that increased stress sensitivity in airborne microbiomes may influence the human gut microbiome, thereby contributing to mental disorders. To test this, we analyzed two publicly available metagenomic datasets of human gut microbiomes from both mental disorder patients and healthy controls. However, limited differences in stress sensitivity were observed between the groups, partly due to the lack of RNA-seq data for more precise functional profiling. Based on these findings, we propose a pathway linking environmental Mn exposure to increased stress sensitivity in the airborne microbiome, potentially inducing mental disorders.

microbiology↗

bioRxiv2025

A Comprehensive Treatment-Induced Resistance Atlas of Glioblastoma Reveals a Fibrotic Niche Shielding the Tumor from Immunotherapy

Therapeutic resistance in IDH-wildtype glioblastoma (GBM) is driven by an intricate interplay between cellular plasticity and protective microenvironmental niches. By constructing the GRIT-Atlas--a massive transcriptomic compendium encompassing nearly one million high-quality single cells across 17 cohorts--and cross-analyzing it with 48 independent Visium spatial transcriptomics sections, we discover a recurrent "Spatial Resistance Triad" comprising mesenchymal-like (MES-like) malignant cells, myeloid-derived suppressor cells (MDSCs), and collagen-secreting cancer-associated fibroblasts (CAFs). This large-scale spatial integration reveals that the triad physically fortifies microvascular proliferation (MVP) and pseudopalisading necrosis (PAN) niches. To substantiate these findings at true single-cell resolution, we deploy high-plex spatial molecular imaging (CosMx SMI) to map over 400,000 single cells across a clinical validation cohort. This high-resolution architecture firmly validates the triads geography and, critically, provides structural gradient evidence unmasking a spatiotemporal continuum wherein PAN emerges as a direct functional consequence of MVP advancement and subsequent vascular collapse. Mechanistically, stromal CAF-derived COL6A1 engages CD44 receptors on MES-like cells to accelerate a potent neural stemness cascade within these protective domains. Utilizing a blood-brain barrier (BBB)-penetrant multi-library compound screen, we identify Lacidipine as a multi-modal stromal disruptor that successfully silences CAF activation and halts matrix secretion. Incorporating Lacidipine into the standard chemo-immunotherapy backbone (TMZ + anti-CSF1R) completely dismantles the protective desmoplastic matrix niche, forcing a profound collapse of intracranial tumor burden and dramatically extending overall survival in orthotopic models. Collectively, our study leverages unprecedented single-cell and spatial scale to provide a definitive blueprint of GBM therapeutic evasion, establishing matrix-targeted intervention as a mandatory prerequisite for successful glioblastoma eradication.

cancer biology↗

bioRxiv2025

Whole-Brain Convergence of Real-World Visual Expertise beyond Faces: Meta-Analytic Evidence for Core-Adaptive Neural Architecture

Visual expertise--the ability to discriminate highly similar exemplars quickly and accurately within a category--supports skilled performance across real-world domains and is supported by distributed neural systems. We focus on non-face expertise to test cross-domain convergence in acquired real-world visual skills, treating faces separately because socially embedded, sensitive-period-constrained processing could blur this inference. It remains unresolved whether non-face expertise across heterogeneous domains converges on a shared, domain-general whole-brain architecture, or instead recruits domain-contingent neural configurations that vary with task and stimulus demands. We conducted a coordinate-based meta-analysis of 22 task-fMRI studies spanning 11 real-world non-face expertise domains (579 participants, 210 peak-activation foci). Primary analysis revealed a robust, right-lateralized parieto-temporo-occipital circuit centered on the middle occipital gyrus, middle temporal gyrus, angular gyrus and adjoining inferior parietal lobule. We propose that this circuit constitutes a domain-general neural core that integrates fine-grained visual features with semantic associations while supporting attention-guided recognition of visually similar objects in expert performance. Subgroup and meta-regression analyses uncovered a complementary adaptive component, the engagement of which varied systematically with representational and contextual factors. Pictorial stimuli and expert-novice contrasts reliably strengthened recruitment of the right-hemisphere core, whereas symbolic stimuli engagement toward left temporal regions while selectively re-engaging right-core nodes. In addition, male-skewed samples showed attenuated left-hemisphere activation. Together, these findings delineate a stable right-hemisphere neural scaffold underlying non-face visual expertise, flexibly supplemented by left-hemisphere systems as a function of stimulus format, task demands, and demographic context, providing a whole-brain reference framework for future studies. HighlightsO_LIA coordinate-based meta-analysis integrates 22 whole-brain task-fMRI studies of real-world non-face visual expertise. C_LIO_LIResults delineate a core-adaptive architecture supporting non-face expertise across domains. C_LIO_LIA right-lateralized parieto-temporo-occipital core (AG, MOG, MTG, adjoining IPL) shows convergent recruitment across non-face domains. C_LIO_LIAdaptive left-hemisphere regions (MTG/STG/ITG/IFG; plus FG/IOG/insula) are flexibly engaged with task and stimulus demands. C_LIO_LIFindings refine neurocognitive accounts of perceptual expertise and provide a domain-spanning whole-brain reference framework for future studies. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/696823v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14119a6org.highwire.dtl.DTLVardef@fb04cforg.highwire.dtl.DTLVardef@1f8cd35org.highwire.dtl.DTLVardef@168798a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

MS4MS: LLMs-driven Multi-agent System for Small-molecule Identification via LC-MS/MS

Small molecule identification is central to research fields such as drug discovery, but in complex systems like Traditional Chinese Medicine (TCM), traditional mass spectrometry analysis methods remain constrained by bottlenecks including insufficient database coverage, fragmented analysis workflows, and poor result interpretability. To address these limitations, we developed MS4MS, a large language model-driven multi-agent system that enables an end-to-end automated pipeline from raw data to small molecule identification. Validation on a public benchmark demonstrates that MS4MS achieves state-of-the-art performance in molecular formula prediction. Furthermore, its innovative small molecule identification agent enables efficient and interpretable compound elucidation. Verification using herbal extracts indicates MS4MSs outstanding performance regarding analytical coverage and the discrimination of isomers. Consequently, MS4MS offers a novel, accurate, interpretable, and high-throughput end-to-end automated strategy for small molecule identification, overcoming the analytical bottlenecks of traditional mass spectrometry in natural products and complex TCM systems.

bioinformatics↗

bioRxiv2025

Physiological Significance of Bacterial Mn(II) Oxidation

Bacterial oxidation of Mn(II) to Mn(III/IV) oxides is widespread in nature and proceeds markedly faster than abiotic oxidation. However, the physiological role of this process remains unclear. Building on recent evidence that environmental stress determines bacterial Mn(II)-oxidation activity, we used Pseudomonas putida KT2440--a known Mn(II)-oxidizing bacterium--to investigate the potential drivers and benefits of this reaction. Using RNA-seq, we observed up-regulation of starvation-related two-component system genes during Mn(II) oxidation, supporting the idea that nutrient limitation acts as a trigger. This led us to hypothesize that introducing an external antagonistic stressor could further accelerate the onset and rate of Mn(II) oxidation. To test this, we established a synthetic microbial community in which KT2440 was confronted with Pseudomonas aeruginosa PAO1, which possesses both contact-dependent and diffusible antagonistic systems. Across multiple assays measuring oxidation initiation time, manganese oxide accumulation, and bacterial survival, the presence of PAO1 significantly accelerated Mn(II) oxidation by KT2440. More importantly, Mn(II) oxidation strongly enhanced KT2440 survival under antagonistic pressure. Correlation analysis indicated a positive relationship between survival rate and oxidation intensity. Fluorescence microscopy and agent-based modeling further confirmed that this protective effect is contact-dependent. By integrating these results with earlier findings, we propose that the physiological significance of bacterial Mn(II) oxidation lies in enhancing the survival fitness of the oxidizer under stressful conditions.

microbiology↗

bioRxiv2025

CellBin:a generalist framework to process spatial omics data to cell level

Spatial omics has rapidly expanded with increasingly diverse imaging modalities, molecular targets, and chip sizes. However, no general framework currently exists to construct cell level matrices that are robust across platforms and omics types. Here we present CellBin, a universal and scalable frame-work that unifies image stitching, cell segmentation, and spot-to-cell mapping for multiple spatial omics technologies. CellBin integrates a multi-field weighted stitching algorithm for large-area images, a family of U-Net-based models trained across diverse staining modalities, and an optimized computational architecture for high-throughput processing. Across five technological platforms and three omics data types, CellBin achieves robust segmentation and accurate single-cell matrix construction, consistently outperforming seven state-of-the-art methods in F1-score, cell size precision, and annotation accuracy. By providing a generalizable, cross-platform solution, CellBin bridges multiple spatial omics, enabling unified, high-resolution cell level analyses across technologies.

bioinformatics↗

bioRxiv2025

Adjacent Rare-Earth Separation via a Protein Atomic Ruler

The separation of rare-earth elements (REEs) poses a formidable challenge due to their nearly identical ionic radii and chemical properties. Here, we present a transformative strategy for REE separation using a multimetal ion-stacking metalloprotein framework (MIF) that functions as an atomic ruler, effectively amplifying subtle differences in REE ionic radii. This approach achieves exceptional selectivity, enabling the separation of all 13 adjacent REE pairs with ultrahigh purity (up to 99.999%). Remarkably, the MIF retains its lanthanide-binding capacity over 410 consecutive absorption-desorption cycles, demonstrating outstanding stability. Structural insights reveal that the MIFs densely packed REE coordination environment magnifies minute radius variations--a key mechanism underlying its unparalleled separation efficiency. Our MIF-based strategy offers a sustainable, scalable solution to rare-earth separation in industrial applications.

biophysics↗

bioRxiv2025

Cryo-EM structure of influenza polymerase bound to the cRNA promoter provides insights into the mechanism of virus replication

Influenza virus polymerase (FluPol) synthesizes the complementary RNA (cRNA) and the viral RNA (vRNA) using distinct de novo initiation strategies during genome replication, known as internal and terminal initiation, respectively. The de novo initiation mechanisms, especially the internal initiation process, which includes a template realignment process, is still not well understood. Here, we present a cryo-electron microscopy structure of H5N1 FluPol bound to the cRNA promoter. In combination with structural analyses and structure-guided mutagenesis studies, we identified several previously unreported structural features of FluPol essential for internal initiation. The B loop adopts an "open" conformation, allowing translocation of the 3' terminus of cRNA (3'-cRNA) template into the catalytic cavity. The dynamic of incoming 3'-cRNA template is limited by the priming and realignment loop (PR loop), which facilitates the cRNA template realignment process. An asparagine cluster above the catalytic cavity is required for polymerase activity. Our findings provide structural insights into the mechanism of replication internal initiation of FluPol.

microbiology↗

bioRxiv2025

Neuronal HDAC9: A key regulator of cognitive and synaptic aging, rescuing Alzheimer's disease-related phenotypes

Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimers disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces A{beta} deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.

neuroscience↗

bioRxiv2025

OmniPath: integrated knowledgebase for multi-omics analysis

Analysis and interpretation of omics data largely benefit from the use of prior knowledge. However, this knowledge is fragmented across resources and often is not directly accessible for analytical methods. We developed OmniPath (https://omnipathdb.org/), a database combining diverse molecular knowledge from 168 resources. It covers causal protein-protein, gene regulatory, miRNA, and enzyme-PTM (post-translational modification) interactions, cell-cell communication, protein complexes, and information about the function, localization, structure, and many other aspects of biomolecules. It prioritizes literature curated data, and complements it with predictions and large scale databases. To enable interactive browsing of this large corpus of knowledge, we developed OmniPath Explorer, which also includes a large language model (LLM) agent that has direct access to the database. Python and R/Bioconductor client packages and a Cytoscape plugin create easy access to customized prior knowledge for omics analysis environments, such as scverse. OmniPath can be broadly used for the analysis of bulk, single-cell and spatial multi-omics data, especially for mechanistic and causal modeling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/675512v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17c2b6borg.highwire.dtl.DTLVardef@1069835org.highwire.dtl.DTLVardef@1f2ce76org.highwire.dtl.DTLVardef@1d0b34f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Post-inhibitory rebound firing drives hypothalamic activation for male mating

Many behaviorally relevant limbic circuits are dominated by inhibitory connections, raising the question of how neuronal activation arises in such contexts. In male mating, both activation of mPOA and its inhibitory inputs are essential--a paradox previously ascribed to disinhibition. Here, we show that the mPOA largely lacks local inhibitory circuits, arguing against disinhibition. Instead, in vivo recordings reveal that mount-active mPOA neurons are suppressed prior to behavioral onset, and this inhibition negatively correlates with subsequent activation, consistent with post- inhibitory rebound firing (PIR). A biologically plausible conductance-based model demonstrates that synaptic inhibition interacts with T-type Ca{superscript 2} currents -- the ionic basis of PIR -- to promote mPOA neuron firing. Experimentally, bidirectional manipulations of mPOA T-type Ca{superscript 2} channels confirm this mechanism: knockdown reduces PIR and impairs male mating, while overexpression enhances mating. Together, these results identify PIR as a critical mechanism by which inhibition promotes activation in limbic circuits to drive male mating.

neuroscience↗

bioRxiv2025

Evolutionary innovation within conserved gene regulatory networks underlying biomineralized skeletons in Bilateria

Biomineralized skeletons have evolved convergently across animals, yet exhibit remarkable diversity in structure and development. However, the evolutionary origins of gene regulatory networks underlying biomineralized skeletons remains elusive. Here, we report comprehensive developmental profiling of transcriptomic and chromatin dynamics in a bivalve mollusc, Crassostrea nippona. We provide evidence for a biphasic regulatory program orchestrating larval and adult shell formation, involving the coordinated activity of ancient transcription factors and dynamic chromatin remodeling. Comparative analyses suggest a conserved developmental toolkit was co-opted for larval exoskeleton formation in the common lophotrochozoan ancestor. In contrast, limited regulatory conservation was observed between lophotrochozoans and echinoderms with regards to the formation of biomineralized skeletons, despite both relying on a heterochronic activation of ancestral regulators. Together, our findings support a hierarchical model where dynamic chromatin decouples rapidly evolving effectors from deeply conserved regulators, allowing modular innovations within conserved gene regulatory networks. This study highlights how epigenetic dynamics bridge evolutionary conservation and novelty, offering a framework for understanding the independent evolution of biomineralization across Bilateria through combinatorial regulatory evolution.

evolutionary biology↗

bioRxiv2025

Decoding cancer metabolism: A pan-cancer proteomics perspective

Metabolic reprogramming fuels cancer progression, but whether common metabolic patterns exist across tumor types remains elusive. To address this, we developed parseMetab, an R package that integrates large-scale proteomic, transcriptomic, and spatial transcriptomic datasets from 24 human cancers and 3,226 samples to map pan-cancer metabolic dysregulation. Strikingly, glycan biosynthesis pathways - especially those driving fucosylation and sialylation - were consistently upregulated, while early sugar nucleotide precursors were suppressed. Nucleotide metabolism was broadly enhanced, uncovering conserved metabolic programs that enable tumor growth, adaptation, and immune evasion. Our results highlight universal metabolic vulnerabilities that may be therapeutically exploited across diverse cancer contexts. Significance statementWhile metabolic reprogramming is a known hallmark of cancer, identifying universal patterns across diverse tumor types remains a major challenge. We developed parseMetab, a computational framework to integrate large-scale proteomic and transcriptomic data from over 3,200 samples across 24 human cancers. Our analysis reveals a striking, conserved "glyco-switch": tumors consistently prioritize the production of complex, immune-evading surface sugars (fucosylation and sialylation) while depleting their own internal sugar precursor pools. Furthermore, we demonstrate that nucleotide metabolism is broadly hyperactivated across nearly all studied malignancies. By defining these ubiquitous metabolic signatures, this study uncovers conserved vulnerabilities that transcend specific cancer types, providing a map for developing broad-spectrum metabolic therapies to combat tumor growth and immune evasion.

cancer biology↗

bioRxiv2025

Tumor-draining lymph node derived CD8⁺ T cells sustain durable systemic immunity after neoadjuvant IL-15 and PD-1 blockade.

The tumor-draining lymph node (tdLN) serves as a critical reservoir of tumor-reactive T cells, yet its contribution to preventing metastatic recurrence remains poorly understood. In this study, we investigate CD8 T cell clonal dynamics and memory responses induced by neoadjuvant anti-PD-1 therapy. We demonstrate that PD-1 blockade promotes the emergence of protective CD8 T cell memory, enriched with tumor-relevant clones that persist in the lymph nodes of long-term survivors. Furthermore, we show that combination of a neoadjuvant IL-15 superagonist with PD-1 blockade significantly increases clonal diversity, cytotoxicity, and clonal persistence in non-draining lymph nodes. These changes result in enhanced systemic antitumor immunity and durable memory that prevents tumor relapse. Our findings establish the tdLN as a critical immunologic hub that can be therapeutically targeted by IL-15 to augment PD-1 blockade efficacy and support a rationale for a phase II neoadjuvant combination immunotherapy trial in early-stage NSCLC. One sentence summaryNeoadjuvant IL-15 with PD-1 blockade expands lymph node clonal diversity and preserves stem-like CD8 T cell features, yielding superior antitumor efficacy, durable memory, and reduced metastatic recurrence.

immunology↗

bioRxiv2025

StCEL-based platform enables detection and sequencing of native sialoglycoRNA

Glycosylated RNAs (glycoRNAs) are an emerging class of biomolecules characterized by glycans attached to RNA molecules. Currently, glycoRNA detection remains largely confined to cellular models, substantially impeding its functional characterization and clinical translation. Here, we developed sialyltransferase-mediated chemical enzymatic labeling (StCEL), in which azido-modified sialic acid was transferred to the natural sialic acid on sialoglycoRNA, enabling the detection of native sialoglycoRNA across diverse biological samples with high specificity and sensitivity. Using StCEL, we found that sialoglycoRNA was significantly upregulated in multiple cancer types. StCEL combined with a microplate reader was applied to detect sialoglycoRNA in large-scale samples, revealing that elevated sialoglycoRNA levels correlate positively with tumor malignancy and poor patient prognosis. Furthermore, StCEL-based sialoglycoRNA enrichment and sequencing identified dysregulated sialoglycoRNAs in tumor tissues. Collectively, StCEL establishes a multifunctional platform that enables sensitive and specific detection of sialoglycoRNA, alongside sequencing analysis, demonstrating significant potential for clinical translation.

molecular biology↗

bioRxiv2025

Human ribosome interactions reframe neomycin toxicity

Aminoglycosides such as neomycin are clinically limited by toxicity, commonly attributed to the inhibition of mitoribosomes. Here, we re-evaluate this mechanism by integrating Cryo-EM and functional assays to assess neomycins binding potential in vitro with its cellular engagement and functional consequences. Cryo-EM revealed extensive multi-site binding of neomycin on both human mitochondrial and cytosolic ribosomes in vitro, including conserved regions of the decoding center. In contrast, ribosomes isolated from neomycin-treated cells show markedly remodeled occupancy patterns, with no detectable neomycin bound to the mitoribosomes and reduced occupancy at a subset of cytosolic ribosome sites. However, neomycin remained functionally active in cells, inducing widespread stop-codon readthrough while having minimal effects on global mitochondrial and cytosolic protein synthesis. These findings reveal a disconnect between structural binding potential and cellular target engagement and identify disruption of translational fidelity, rather than global translational inhibition, as a major cellular consequence of neomycin exposure.

biochemistry↗

bioRxiv2025

Metabolite Interactions Mediate Beneficial Alliances Between Bacillus and Trichoderma for Effective Fusarium Wilt Control

Bacteria-Fungi Interactions play a crucial role in soil nutrient cycling and plant disease suppression. Bacillus and Trichoderma exhibit antagonism when inoculated on laboratory media, global soil sample analysis reveals a positive correlation between these two genera in addition to enhanced plant-pathogen Fusarium oxysporum (FOC) suppression and plant growth promotion. Here, we depict a complexity of interactions in a cross-kingdom consortia of Bacillus velezensis and Trichoderma guizhouense. Transcriptomic profiling revealed that in the presence of fungi, the key stress sigma factor of B. velezensis activates expression of biosynthetic genes for antimicrobial secondary metabolite production. Among these, surfactin induces T22azaphilone production in T. guizhouense that hinders oxidative stress. Both surfactin and T22azaphilone contribute to Bacillus and Trichoderma maintenance in soil in the presence of FOC. Finally, FOC-secreted fusaric acid temporarily inhibits B. velezensis growth while it is efficiently degraded by T. guizhouense. These metabolite-mediated interactions reveal how competing soil microorganisms could form effective alliances that ultimately enhance plant protection against soil-borne pathogens.

microbiology↗

bioRxiv2025

Predicting the Evolutionary and Functional Landscapes of Viruses with a Unified Nucleotide-Protein Language Model: LucaVirus

Predicting viral evolution and function remains a central challenge in biology, hindered by high sequence divergence and limited knowledge compared to cellular organisms. Here, we introduce LucaVirus, a multi-modal foundation model for viruses, trained on 25.4 billion nucleotide and amino acid tokens covering nearly all known viruses. LucaVirus learns biologically meaningful representations capturing relationships between sequences, protein/gene homology, and evolutionary divergence. Using these embeddings, we developed downstream models that address key virology tasks: identifying hidden viruses in genomic "dark matter", annotating enzymatic activities of uncharacterized proteins, predicting viral evolvability, and identifying antibody candidates for emerging viruses. LucaVirus achieves state-of-the-art results in three tasks and matches leading models in the fourth with one-third the parameters. Together, these findings demonstrate the power of a unified foundation model to comprehensively decode the viral world and establish LucaVirus as an efficient and versatile platform for AI-driven virology, from virus discovery to functional and therapeutic predictions.

bioinformatics↗