Biology subjects

Zheng, Y.

Publications and source records attributed to Zheng, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Microbial Invasion and Immunosuppression Drives Adenoma Progression in Early Colorectal Cancer Development

Several inherited predispositions to colorectal cancer exist, most notably familial adenomatous polyposis (FAP), which typically involves a germline loss-of-function mutation in one APC allele. A second hit in APC or related loci leads to aberrant Wnt signalling, triggering adenoma formation with near-complete penetrance. Yet, substantial variability in disease onset and severity, even among siblings with identical APC germline mutations, implicates environmental modifiers. Emerging evidence points to the gut microbiome as a critical regulator of adenoma initiation and progression, particularly in early-onset CRC. Here, we show that bacterial invasion is associated with neutrophil immunosuppression, T-cell exclusion and adenoma progression in a porcine model of FAP. Longitudinal mapping of progressing and regressing polyps using single-cell RNA sequencing, spatial transcriptomics and integrated microbiome profiling resolved the cellular and microbial architecture underlying these divergent lesion states. Single-cell RNA-seq identified 35 cell subpopulations and showed that regressing polyps are enriched for central-memory CD4+ T cells, cytotoxic CD8+ T cells and inflammatory neutrophils, whereas progressing polyps contain immunosuppressive/PD-L1-associated neutrophils, regulatory and dysfunctional T cells. Spatial transcriptomics with a custom host panel and targeted bacterial probes linked bacterial-high adenomatous regions to immunosuppressive neutrophil niches and T cell exclusion, while regressing lesions showed predominantly lumen-adjacent bacterial localization and spatially organized immune surveillance. These results provide a spatially resolved map of cellular and microbial organisation in early colorectal polyp progression and regression and reveal a microbiome-driven, neutrophil-mediated mechanism of early tumour progression with implications for CRC interception. Grant support: This study was funded by the German Research Foundation (DFG) through SFB1371 "Microbiome signature" (Project no. 395357507; TF, DS, FE, DH) and by the German Ministry for Research and Education (BMBF) through Mi-EOCRC consortium project (Project no. 01KD2102D; KF and DH).

cancer biology↗

bioRxiv2026

A vascular chip for disease-relevant flow shear stress topology

Vascular chips have advanced endothelial mechanobiology by enabling controlled responses to hemodynamic cues, yet disease-relevant wall shear stress (WSS) modeling remains limited. Simplified one-dimensional flow shear systems, designed mainly for physiological mechanobiology, miss the topological organization of pathological flow, whereas patient-specific vascular models capture complex hemodynamics but sacrifice generality and imaging compatibility. Here we develop a programmable vascular chip that converts disease-associated WSS topology into a physiologically parameterized experimental input. The device reconstructs a representative pathological shear-topology field on endothelial layer, supports stationary and physiologically paced oscillatory flow modes, and integrates matched unidirectional-shear references within the same chip. Using this system, we show that oscillatory WSS topology destabilizes endothelial monolayers, drives asymmetric collective emergent behaviors, impairs actin-nuclear mechanotransduction, accompanied by nuclear softening and enhanced perinuclear nanoparticle uptake. Integrated live-cell imaging, fluorescence analysis, Brillouin microscopy, and transport assays enable multimodal phenotyping across collective, subcellular mechanical and functional scales. By making disease-relevant WSS topology experimentally controllable, this vascular-chip framework bridges computational hemodynamics and experimental mechanomedicine, supporting standardized vascular disease modeling and functional screening.

bioengineering↗

bioRxiv2026

A microbial metabolite reduces alcohol-induced inflammation via dual modulation of NF-κB and Interferon pathway

Background and aimsAlcohol-associated hepatitis (AH) is characterized by excessive inflammation and blunted antiviral interferon (IFN) responses. We hypothesized that specific gut microbiome-derived metabolites could selectively enhance interferon signaling while limiting NF-{kappa}B mediated inflammation, thereby restoring immune balance in AH. Our goal is to identify microbiome-derived metabolites that differentially regulate the NF-{kappa}B and IFN signaling pathways. Methods and resultsWe used human monocytic THP1-Dual cells, which secrete reporters for NF-{kappa}B and IFN signaling, to model innate immune responses and screened a library of 152 gut microbiome-derived metabolites. From the metabolite screen, 4-hydroxyphenylacetic acid (4-HPAA) emerged as a unique immunomodulator: in LPS-challenged cells, 4-HPAA selectively increased IFN signaling with minimal NF-{kappa}B activation. 4-HPAA was evaluated in vivo using a NIAAA-model, with 4-HPAA supplementation (0.4mg/ml) added to the diet. In the NIAAA-model, dietary 4-HPAA did not induce liver injury and was associated with enhanced interferon-stimulated gene expression. Simultaneously, 4-HPAA reduced pro-inflammatory markers such as Il1{beta}, Ly6g and F4/80 compared to the group exposed to ethanol alone. Metabolomic profiling of mouse cecal contents revealed 4-HPAA supplementation counteracted ethanols metabolic effects, selectively reducing triglyceride-associated lipids that had accumulated with ethanol feeding. Conclusions4-HPAA enhances interferon signaling and antiviral gene induction while dampening NF-{kappa}B-driven inflammation in the presence of LPS, both in vitro and in vivo. In an acute-on-chronic alcohol injury model, 4-HPAA attenuated hepatic inflammation, reduced immune cell recruitment, and activated antioxidant defenses, reflecting a shift toward a more hepatoprotective effect. 4-HPAA treatment was associated with reduced pro-inflammatory markers and modest attenuation of ethanol-induced liver injury. Additionally, 4-HPAA reversed ethanol-induced lipid-dysregulation, particularly triglyceride accumulation, highlighting its metabolic benefit in alcohol-fed mice. In conclusion, 4-HPAA rebalances immune and metabolic pathways by enhancing IFN signaling, suppressing NF-{kappa}B inflammation, and reversing alcohol-induced hepatic injury and lipid accumulation.

immunology↗

bioRxiv2026

An Integrated muti-omics cell atlas of the human trabecular meshwork and ciliary body

The trabecular meshwork (TM) and ciliary body (CB) regulate aqueous humor dynamics and intraocular pressure (IOP), and TM/Schlemms canal (SC) dysfunction underlies glaucoma. Here, we present a spatially resolved multi-omics atlas of human TM and CB, integrating snRNA-seq, scRNA-seq, and snATAC-seq from over one million cells and nuclei across 112 donors with Xenium spatial transcriptomics. We identified 9 major cell classes and 21 cell types, revealing heterogeneity, including undercharacterized fibroblast and epithelial subpopulations. Spatial mapping supported TM fibroblast zonation and CB epithelial organization. Regulatory analyses identified cell type-specific programs, including OTX/PAX networks in CB epithelium and SMAD3/TGF-{beta} signaling in fibroblasts. Integration with glaucoma loci showed enrichment of non-coding variants in regulatory elements associated with POAG and PACG. Age- and ancestry-associated remodeling revealed divergent fibroblast aging with increased PIEZO1, suggesting impaired outflow and elevated IOP. Together, this high-resolution atlas links cellular, regulatory, and genetic variation to anterior segment function and glaucoma susceptibility.

genomics↗

bioRxiv2026

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.

cancer biology↗

bioRxiv2026

OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era

Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term "Alzheimers disease", OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery. HighlightO_LIOmicVerse 2.0 consolidates 694 methods spanning 11 omics domains into agent-callable high-level APIs. C_LIO_LIRebuildR automatically reconstructs and evolves R/Bioconductor methods as Python-native implementations under output-equivalence gates. C_LIO_LIOmicOS establishes a state-of-the-art omics agent harness, ranking first on general omics benchmarks across models and substantially improving the analytical capability of local open-source models. C_LIO_LICompositional use of ecosystem modules nominates a colon epithelial axis associated with Alzheimers disease risk. C_LIO_LIExternal algorithm packages supporting automatic iterative evolution can be integrated into the OmicOS ecosystem. C_LI

bioinformatics↗

bioRxiv2026

Spatially organized cancer-associated fibroblast subtypes partition cutaneous carcinomas into immune-active and contracted, immune-repressed niches

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) are the most common keratinocyte-derived malignancies, yet they differ markedly in invasiveness, metastatic potential, and immune contexture. Although cancer-associated fibroblasts (CAFs) are increasingly recognized as key regulators of tumor architecture and tumor immunity, the spatial organization of distinct CAF subtypes in cutaneous carcinomas and their functional relationship with immune cells remains incompletely understood. Using a 33-plex imaging mass cytometry (IMC) panel, we profiled 28 regions of interest (ROIs) from 17 human BCC and SCC specimens, encompassing more than 739,000 single cells, and integrated these data with RNA fluorescence in situ hybridization (RNA-FISH), immunohistochemistry (IHC), multiplex immunofluorescence, and in vitro functional assays. We identified four fibroblast populations, including immunomodulatory CAFs (iCAFs), matrix CAFs (mCAFs), myofibroblast-like CAFs (myoCAFs), and reticular fibroblasts (retFIBs), and found that aggressive tumor subtypes were characterized by increased stromal area, extracellular matrix deposition, and altered CAF composition. CAF composition differed most prominently across BCC subtypes, with nodular BCC enriched for mCAFs and infiltrative BCC showing increased myoCAF density, consistent with a shift toward a contractile stromal program. Spatial analyses revealed distinct CAF-immune niches: iCAFs localized to immune-cell-rich, inflamed niches enriched for activated and/or exhaustion-associated immune-cell marker programs, whereas myoCAFs occupied fibroblast-dense, immune-poor niches with globally reduced immune activation. mCAFs were preferentially associated with immune cell accumulation in the stroma and spatial immune compartmentalization, with limited immune cell presence within tumor nests. At the invasive front, CAF-immune coupling was highly subset-dependent, with iCAFs linked to antigen-experienced T-cell states and myoCAFs linked to immune exclusion. In vitro, patient-derived CAF cultures from myoCAF-rich biopsies showed enhanced collagen-gel contraction, with cultures enriched for MCAM+ CAFs displaying increased contractile capacity. Aggressive tumor variants displayed increased stromal nuclear YAP/TAZ, while complementary single-cell pathway analysis supported a mechanically remodeled stromal microenvironment in which mCAFs contribute ECM/matrix-remodeling programs and RGS5/myoCAF-like populations show enhanced mechanotransduction-associated signaling, rather than a uniform CAF-wide increase in canonical YAP/TAZ transcriptional output. Together, these findings define spatially organized CAF programs in cutaneous carcinomas and identify myoCAF-rich stromal niches as a recurrent feature of aggressive, immune-repressed tumor architecture. These results nominate CAF composition as a biomarker of immune architecture and a potential determinant of therapeutic response.

cancer biology↗

bioRxiv2026

Spatiotemporal Cascade of AP1/CCA1-TOC1 Module Gates Stem Development

Stem development is crucial in plant vertical architecture and overall crop improvement. The molecular mechanisms underlying the initiation and circadian growth of stem remain still enigmatic. Here, we demonstrate that APETALA1 (AP1) spatially initiates circadian stem growth through a noncell-autonomous role of TIMING OF CAB EXPRESSION1 (TOC1) emanating from the floral meristem to inflorescence meristem in Arabidopsis thaliana. Mechanistically, AP1 interacts with and recruits CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) to associate TOC1. Dynamic formation of the AP1-CCA1 complex is crucial for maintaining the circadian rhythmicity and expression of TOC1. Tissue-specific expression of TOC1 in floral meristems rescues the developmental defects of toc1 mutants at both functional and transcriptional levels. Furthermore, TOC1 directly activates the circadian expression of pectin methylesterase gene family, which is critical for its role in stem development. AP1 homologs regulate circadian stem elongation and plant height in wheat and rice, underscoring the conserved mechanism across flowering plants. Our findings uncovered a spatiotemporal regulatory cascade gating stem development and identified candidate genes for crop improvement.

plant biology↗

bioRxiv2026

CA19-9 induces microenvironment remodeling in pancreatic ductal adenocarcinoma

Durable therapeutic efficacy remains a major barrier to improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). An immunosuppressive tumor microenvironment (TME) is a hallmark of PDAC and has been demonstrated to be a dominant driver of therapeutic resistance. The aberrant glycan CA19-9 is prevalent in PDAC and drives tumor progression, but the paracrine mechanisms by which it contributes to TME remodeling are unknown. To address this, we mapped TME changes and performed functional analyses using a genetically engineered mouse model (GEMM) harboring KrasG12D mutation and inducible CA19-9 expression. Elevation of CA19-9 led to expansion of antigen-presenting cancer associated fibroblasts (apCAFs) and regulatory T cells (Tregs), which can drive immunosuppression. Antibody blockade of CA19 -9 resulted in significant restoration of normal histology and decreased apCAF and Treg populations. We dissected the paracrine signaling mechanisms that drive this TME remodeling in vitro using mouse and human organoid mono- and co-culture models as well as in vivo using GEMMs and syngeneic orthotopic transplantation models. CA19-9 induced IL1a and TGFb expression, reprogramming pancreatic mesothelial cells into apCAFs in vitro, which in turn directly ligated naive Cd4+ T cells resulting in Treg differentiation in co-cultures. Antibody blockade of IL1a and TGFb in mice led to reduced apCAF and Treg differentiation. We previously reported that CA19-9 modification of the secreted Fbln3 protein increased Egfr engagement and now find that the induction of IL1a and TGFb expression by CA19-9 is dependent on Fbln3 hyperactivation of EGFR signaling. Genetic depletion of Fbln3 led to reduced tumor progression and increased Cd8+ T cell infiltration in mice. Together these findings identify a previously unknown signaling axis driving immunosuppressive phenotypes in PDAC, uncovering multiple potential nodes to relieve the immunosuppressive pressures within the PDAC TME.

cancer biology↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

Molecular underpinning of Hydra viridissima-algal facultative symbiosis and vertical algal transmission

The symbiosis between algae and animals represents a relatively recent evolutionary innovation, and exemplified by species in the Cnidaria phylum. Cnidaria can harbor algae within a modified cellular organelle called the symbiosome in a process called endosymbiosis. This animal-algal symbiosis can be facultative or obligate. Algae acquisition occurs either by horizontal transmission, where free-swimming planula gain algae through feeding, or by algae deposition into the developing oocyte in vertical transmission[1-5]. Most studies focus on anthozoans that perform obligate endosymbiosis and transmit algae horizontally. How facultative endosymbiosis in combination with vertical algal transmission impacts the evolutionary adaptation between host and symbiont remains unclear. By studying Hydra viridissima, which performs facultative endosymbiosis and transmits its Chlorella algae vertically, we define different cell types and identify the endoderm cell lineage that gives rise to three major cell types hosting algae. Compared to obligate endosymbiosis[6, 7], Hydra viridissima algal host cells exhibit distinct features, including algal uptake, elevated oxidative phosphorylation and redox activities, and express genes that can provide ammonium for their algal symbionts. We further show when and how the developing Hydra oocytes may take up algae and where oocytes may obtain lipids. Since Hydra is amenable to genetic manipulations, our findings should enable mechanistic studies of how facultative endosymbiosis and vertical transmission evolve and adapt in a changing climate.

molecular biology↗

bioRxiv2026

Lamin dosage in cardiomyocytes supports nuclear organization and chromatin gating for transcription

The nuclear lamina contains intermediate filaments, called lamins, which function to maintain nuclear integrity and organize the Lamina-Associated chromatin Domains (LADs). Despite near ubiquitous expression, lamins show cell-type-specific functions. In the heart, they support epicardial cell migration, cardiomyocyte nuclear integrity and maturation. How these functions are integrated with different gene expression programs in these cells during heart development is unknown. We show that cardiomyocytes require lamin-A and -B1 for perinatal mouse survival. Importantly, lamin-B1 facilitates timely cardiomyocyte maturation by maintaining LADs and chromosome territories. By examining changes in cardiomyocyte gene expression and 3D genome organization upon lamin-B1 deletion, we show lamin-B1 maintains chromatin neighborhoods, which can in turn support transcription factors that regulate genes involved in cardiomyocyte structural maturation and gradual cessation of cell division. We propose a genomic logic by which the widely expressed lamins collaborate with transcription factors to specifically promote cardiomyocyte maturation and cell cycle exit during development. HighlightsO_LILamin-A/B1 dose-dependently set cardiomyocyte nuclear order and postnatal survival. C_LIO_LILamin-B1 loss disrupts transcription programs for cardiomyocyte maturation. C_LIO_LILamin-B1 shapes chromatin neighborhoods to support cardiomyocyte maturation programs. C_LI

molecular biology↗

bioRxiv2026

Selective Pyroptosis in NF1-Deficient Cells through PKCδ Agonism

Pyroptosis, a lytic and immunogenic form of cell death, holds broad therapeutic potential, yet its selective induction in specific cell populations remains a fundamental challenge. Loss of the NF1 tumor suppressor, one of the most frequent events across pediatric and adult cancers, elevates RAS-GTP and drives tumorigenesis through hyperactivated RAS signaling. Here we demonstrate that protein kinase C{delta} (PKC{delta}) agonism selectively triggers pyroptosis in NF1-deficient cells by exploiting their dependency on KRAS. PKC{delta} directly phosphorylates KRAS at S39 and S181, inducing KRAS-GDP accumulation and driving endoplasmic reticulum translocation. The dually phosphorylated KRAS-GDP interacts with caspase-8 and competitively displaces inhibitory BCL2, promoting caspase-8/caspase-3/gasdermin-E-mediated pyroptosis. This vulnerability is conserved across multiple NF1-deficient tumor types, and PKC agonism suppresses NF1-deficient neurofibroma and malignant peripheral nerve sheath tumor growth in vivo. These findings establish the inactive KRAS-GDP as a functionally active signaling molecule and PKC{delta} agonism as a selective therapeutic strategy for NF1-deficient cancers.

cancer biology↗

bioRxiv2026

Network Formation Dynamics in Thiol-ene Crosslinked Hyaluronic Acid Hydrogels: Design Principles for In Vitro Tissue Models

Hydrogels are widely used as three-dimensional cell culture systems to understand the impact of cellular mechanotransduction for tissue engineering applications. Photoinitiated thiol-ene click chemistry is a commonly utilized hydrogel crosslinking mechanism that provides spatial and temporal control over hydrogel network formation and resulting mesh size and compressive properties. Despite historically documented efficiency as step-growth reactions, these reactions do not always proceed as predicted. To understand the impact of cell confinement and microenvironmental mechanics on cellular function, thiol-ene network formation must be thoroughly characterized. To this end, the objective of this work was to investigate the crosslinking dynamics to determine hydrogel network formation as assessed via mesh size and mechanical properties using a pentenoate-functionalized hyaluronic acid thiol-ene reaction. Hydrogel parameters including polymer concentration and thiol:-ene crosslinker molar ratio were modulated (4, 6, or 8 polymer weight percent and 0.15:1, 0.5:1, or 1:1 molar ratio of thiol groups to reactive -ene groups) to tune network properties including shear storage modulus and relative mesh size. Molecular Dynamics (MD) simulations were used to simulate the thiol-ene crosslinking reaction and establish a method for predicting thiol-ene reaction efficiency. Lastly, the feasibility of this hydrogel system for in vitro modeling was confirmed via assessment of metabolic activity of encapsulated primary human meniscal cells.

bioengineering↗

bioRxiv2026

BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.

Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimers disease (AD) incidence (12-78%) among Bacillus Calmette-Guerin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature towards that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of the co-stimulatory marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia. One sentence summaryBCG therapy prevents tauopathy in PS19 mouse model.

neuroscience↗

bioRxiv2026

Temporal-deviation-driven community detection uncovers early-warning signals for critical transitions in complex diseases

Early detection of critical transitions in complex diseases is crucial for timely clinical intervention. However, as patients often provide only a single snapshot, identifying sample-specific early-warning signals (EWS) from a dynamical evolution perspective remains challenging, coupled with high-dimensional noise amplification. Here, we present TD-COM, a framework for detecting personalized EWS of critical transitions via single-sample community detection. By constructing a temporal perturbation map STDN, TD-COM captures latent dynamical perturbations inferred from static individual profiles. Synergizing these temporaldeviation signals with static topological features, TD-COM implements a multilevel node filtering strategy during community detection, effectively suppressing single-sample noise. Validated on hour-scale, multi-year, and multi-decade transcriptomic data, TD-COM robustly detects critical states preceding clinical deterioration and uncovers their underlying molecular mechanisms. Comparative experiments demonstrate that TD-COM outperforms existing methods in accuracy and topological robustness. Thus, TD-COM provides a generalizable framework for personalized early warning of complex diseases, particularly when longitudinal sampling is infeasible.

bioinformatics↗

bioRxiv2026

A diagnostic plasma omics-biomarker for Alzheimer's disease informed by microglial single-cell transcriptomics: A pilot study

BackgroundThe current biomarker framework for the diagnosis and staging of Alzheimers disease (AD) relies mainly on neuropathological features; thus, its performance for diagnosis is limited prior to the initiation of neurodegeneration. Here, we leveraged transcriptomic data to develop a new framework for omic-informed blood-based diagnostic biomarkers for AD from early-stage. MethodsMicroglial gene expression from single-nucleus (sn)RNA-seq data was analyzed via 6 statistical methods to identify candidate panels of genes predictive of AD. A total of 78 gene panels, 30-2000 genes in size, were selected and evaluated for their ability to distinguish AD patients from controls. Three top-ranked panels of 300, 50 and 30 genes were transferred to blood (monocyte) transcriptomic data obtained from living subjects via a graph-based mapping approach based on optimal transport statistics. ResultsThe 300-panel method resulted in an AUC of 0.7 and moderate accuracy (75%) in classifying AD; however, the accuracy in predicting cognitively normal patients was lower (53%). While the 300 genes provided high accuracy, inspection of the distribution of p values for the gene set revealed that the panel could be greatly reduced in size to capture the most significant differences between AD patients and cognitively normal individuals. The accuracy and specificity of the 50 and 30 panels demonstrated similar AUC values but improved the balance between the prediction of AD patients and normal controls. Specifically, the 50-gene panel resulted in an AUC of 0.7, with 65% AD accuracy and 71% normal accuracy. ConclusionsIntegrating multiomics datasets into the AD biomarker discovery pipeline offers a powerful modality to increase precision and comprehensiveness in AD research and clinical applications.

genomics↗

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↗