Biology subjects

Wang, M.

Publications and source records attributed to Wang, M..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

Cross-Species Insights from ART-D to Uncover Evolutionarily Conserved Oncogenic Mechanisms

Cancer arises from oncogenic clones, yet the dynamic mechanisms governing their stepwise evolution toward malignancy remain incompletely understood. Here, we establish the Atlas of Ras-driven Tumors in Drosophila (ART-D), a systematic, cross-species platform that dissects the molecular and phenotypic trajectories of tumorigenesis through ten genetically defined RasV12-driven models. By integrating longitudinal phenotypic profiling, we define three conserved stages of tumor development--initiation, promotion, and progression--distinguished by dynamic changes in tumor burden and tumor-induced cachexia. Transcriptomic dynamics reveal stage-specific signaling rewiring: early tumorigenesis is marked by co-activation of JAK/STAT, NF-{kappa}B/Toll, and MAPK pathways, whereas malignant progression is driven by Notch hyperactivation and Hippo pathway inactivation. Through integrative multi-omics and machine learning, we uncover an evolutionarily conserved pathogenic network involving coordinated JNK, NF-{kappa}B/Toll, Notch, and Hippo signaling that is functionally validated across species. ART-D provides a transformative resource that bridges Drosophila genetics and human cancer biology, offering a framework for decoding conserved oncogenic principles and enabling precision targeting of stage-specific vulnerabilities in RAS-driven cancers.

genetics↗

bioRxiv2025

LabOS: The AI Co-Scientist That Sees and Works With Humans

Modern science advances fastest when thought meets action. LabOS represents the first AI co-scientist that unites computational reasoning with physical experimentation through multimodal perception, self-evolving agents, and XR-enabled, embodied human-AI collaboration. To empower agentic AI with embodied intelligence, we built LabSuperVision, the first vision-language-model (VLM) benchmark spanning biomedical and materials science laboratories, designed to evaluate scientific perception and reasoning. This endowed LabOS with visual reasoning capabilities that surpass those of general-purpose models on laboratory-specific tasks. By connecting multi-model AI agents, smart glasses, and human-AI-robot collaboration, LabOS allows AI to see what scientists see, understand experimental context, and participate in real-time execution through immersive XR interaction and robotic autonomation. Across applications-from cancer immunotherapy target discovery to cell engineering-LabOS shows that AI can move beyond computational design to participation, turning the laboratory into an intelligent, collaborative environment where human and machine discovery evolve together.

bioengineering↗

bioRxiv2025

Uterine stromal Erbb3-Igf1 signaling is critical to functional gland development conducive to implantation

Preimplantation uterine gland differentiation, involving glandular branching, is a prerequisite for secretion of leukemia inhibitory factor (LIF), thereby establishing uterine receptivity to embryo implantation. This differentiation process is disrupted by the absence of FOXA2, a transcription factor specifically present in uterine glands. It remains unclear whether preimplantation glandular differentiation is regulated exclusively by gland-intrinsic mechanisms or is influenced by the surrounding microenvironment through mesenchymal-epithelial interactions. We show here that uterine deletion of Erbb3 leads to impaired gland branching and FOXA2 expression, as well as reduced female fertility. In contrast, females with uterine epithelial-specific deletion of Erbb3 show normal fertility, suggesting a critical role of stromal ERBB3 signaling. A transcriptomic profiling of day 3 stromal cells identified Igf1 as a candidate paracrine factor mediating the stromal-epithelial interaction. Thus, the uterine deletion of Igf1r leads to a reduced gland branching phenotype similar to that observed in Erbb3d/d uteri. These results demonstrate that ERBB3 regulates glandular branching and embryo implantation via the ERBB3-IGF1-IGF1R signaling pathway.

developmental biology↗

bioRxiv2025

Antiviral reverse transcriptases reveal the evolutionary origin of telomerase

Defense-associated reverse transcriptases (DRTs) employ diverse and distinctive mechanisms of cDNA synthesis to protect bacteria against viral infection. However, much of DRT family diversity remains unstudied. Here we identify a new antiviral defense system, DRT10, that associates with a non-coding RNA (ncRNA) to catalyze processive, protein-primed synthesis of tandem-repeat DNA. Repeat addition is dictated by sequence and structural features of the ncRNA that have direct parallels in the RNA component of telomerase. Remarkably, a phylogenetic analysis of RTs across domains of life reveals an unexpected link between DRT10 and telomerase that is further supported by structural comparisons and mechanistic evidence. These findings expand the repertoire of reverse transcription mechanisms in antiviral defense and point to a bacterial origin for telomerase. One-Sentence SummaryInsights from antiviral defense systems reveal an unexpected bacterial origin for the mechanism of chromosome maintenance by eukaryotic telomerase.

molecular biology↗

bioRxiv2025

A Population-scale Single-cell Spatial Transcriptomic Atlas of the Human Cortex

The genetic and spatial determinants of cell type diversity in human cerebral cortices remain poorly defined. Here, we present a population-level single-cell spatial transcriptomic atlas of human cortices from 71 donors across the lifespan. We identified 906 layer-specific genes showing conserved and divergent laminar expression patterns between humans and other species. Spatial analysis revealed neuronal vulnerability and glial activation during aging, together with a decline in the proportion of superficial SST neurons and their interactions with other cells. Disease-associated genes exhibited high cell-type and layer-specific expression, implicating the pathogenic role of spatially specific gene expression. Spatial cis-eQTL analysis identified regulatory variants linked to genes related to diseases like Tourette syndrome. Cross-species comparison demonstrated glial expansion in the human cortex, accompanied by enhanced neuron-glia communication via the neuregulin signaling. Together, we provide a comprehensive single-cell atlas of the human cortex that is essential for understanding aging, evolution, and disease pathogenesis.

neuroscience↗

bioRxiv2025

Clinical profile impacts the replicability of multivariate brain-behavioural associations

Recent work suggests that thousands of individuals are required in multivariate brain-behaviour analyses to obtain consistently replicable results. Some believe, however, that smaller sample sizes may be sufficient if specific subpopulations are targeted. We investigate how sample size and cohort composition influence the replicability of Canonical Correlation Analysis (CCA) results using the UK Biobank (N=40,514). We apply CCA to diffusion-weighted magnetic resonance imaging (dMRI) phenotypes and cognitive assessment test scores. We define four participant cohorts based on clinical profile and find that, across all cohorts, sample sizes of {approx}500 are needed to obtain replicable canonical correlations and variable loadings. The most targeted cohort (comprising individuals with a history of psychoactive substance use) requires much fewer samples to achieve similar or greater correlations than the other cohorts. Our findings support the idea that moderate sample sizes from targeted cohorts can be sufficient for obtaining replicable brain-behaviour associations.

neuroscience↗

bioRxiv2025

EPAS1 regulates host antibacterial defense in response to bacterial quorum sensing

Hypoxia-inducible factors (HIFs) are a family of transcription factors that function as sensors of hypoxia. However, it remains unclear whether and how HIFs modulate host immunity by responding to other ligands. Here, we describe an immune regulatory function of HIF-2 (also known as EPAS1) in response to cis-2-dodecenoic acid (BDSF), a quorum sensing (QS) signal, secreted by Burkholderia cenocepacia. Upon ligand binding, EPAS1 activation leads to the production of inflammatory cytokines and the initiation of antibacterial defense. Inoculation with diffusible BDSF or liposome-encapsulated BDSF improves survival in mice infected with B. cenocepacia or Acinetobacter baumannii by preconditioning the immune system. Our findings reveal a previously unidentified role of EPAS1 as an intracellular pattern recognition receptor (PRR) for bacterial QS signal to control host antibacterial defense.

microbiology↗

bioRxiv2025

CSCN: Inference of Cell-Specific Causal Networks Using Single-Cell RNA-Seq Data

Understanding gene regulation is fundamental to deciphering the coordinated activity of genes within cells. Although single-cell RNA sequencing (scRNA-seq) enables gene expression profiling at cellular resolution, most gene network inference methods operate at the tissue or population level, thereby overlooking regulatory heterogeneity across individual cells. Recent approaches, such as Cell-Specific Network (CSN) and its extension c-CSN, attempt to construct gene networks at single-cell resolution, providing a more detailed view of the regulatory logic underlying individual cellular states. However, these methods remain limited by high false positive rates due to indirect associations and lack of directionality or causal interpretability. To address these issues, we propose the Cell-Specific Causal Network (CSCN) framework, which infers directed, cell-specific gene regulatory relationships by explicitly modeling causality. CSCN combines causal discovery techniques with efficient computation using kd-trees and bitmap indexing to perform conditional independence testing, yielding sparse and interpretable causal graphs for each cell that effectively suppress indirect and spurious associations. We demonstrate through simulations that CSCN significantly reduces false positives compared to existing methods. Furthermore, we evaluate the quality of the inferred causal networks via clustering on the Causal Katz Matrix (CKM), and CSCN outperforms CSN and c-CSN in distinguishing cellular states.

bioinformatics↗

bioRxiv2025

Human brains construct individualized global rankings from identical few-shot local learning

Ranking--a ubiquitous relational structure--enables humans to organize complex information and overcome cognitive load, yet in real-world settings it is often inferred from sparse, few-shot learning of local pairwise relationships. How the human brain performs relational inference under such limited evidence remains unknown. We hypothesized that under few-shot learning, relational inference is shaped by inductive biases, such that individuals actively impose structured global relationships--often idiosyncratic--to constrain and unify limited local information. In a preregistered behavioral study combined with magnetoencephalography (MEG) recordings, we show that even after identical few-shot local pair learning, individuals construct stable and self-consistent, yet idiosyncratic, global rankings that diverge from the ground-truth order--a phenomenon not readily explained by classical computational models of transitive inference. MEG recordings further reveal that frontoparietal neural representations are reorganized to reflect each individuals subjective ranking rather than those of others. Together, these findings highlight the constructive and generative nature of human cognition: under sparse samples and limited computational resources, the human brain actively infers and imposes relational structure.

neuroscience↗

bioRxiv2025

NR0B1 alters the 9-cis-retinoic acid response in Ewing Sarcoma cells

Pediatric cancers are often characterized by relatively low DNA mutation rates and are frequently driven instead by alterations in gene expression programs. In Ewing Sarcoma (EwS), these changes result from the activity of an oncogenic fusion transcription factor, EWS::FLI1, which alters the enhancer landscape and rewires transcriptional programs to promote oncogenic transformation. Among the targets directly activated by EWS::FLI1, NR0B1 has emerged as a potentially targetable transcription co-regulator and as a manifold for widespread alterations in downstream gene expression programs mediated by members of the ligand-inducible nuclear receptor superfamily of transcription factors. We have dissected the gene regulatory activity of NR0B1 in EwS models, showing its role in altering the basal gene expression programs of nuclear receptors COUP-TFII, EAR2, RXRa, and TR4. Additionally, we show that NR0B1 impacts the EwS response to retinoids, particularly 9-cis-retinoic acid signaling in part through RXRa. Our findings suggest NR0B1 silencing or inhibition offer a means of achieving a more potent response to retinoids, which may activate differentiation programs, decrease EwS gene expression signatures, and limit in vitro transformation phenotypes. Taken together, our study presents evidence of NR0B1 acting canonically as a nuclear receptor co-regulator in EwS, revealing a potential pathway to treatment of this aggressive cancer by combining NR0B1 inhibition with therapeutic nuclear receptor ligands.

cancer biology↗

bioRxiv2025

Beyond the straight path: high-density laminar recordings in the ventral hippocampus with curved microprobes

Neural circuits are organized within complex three-dimensional architectures. Most neural interfaces follow linear insertion trajectories, limiting their ability to achieve laminar recording in brain regions where neuronal layers lie approximately parallel to the insertion path. Here, we introduce a curved flexible neural interface that enables near-perpendicular alignment of the recording sites with the targeted neuronal layers. The device consists of a flexible Parylene-C neural probe, integrating 16 PEDOT:BF4-coated Au microelectrodes and a transient silk fibroin stiffener for controlled implantation. The electrodes exhibit low impedance at 1 kHz (29.2 {+/-} 2.5 k{Omega}) and were accurately positioned across the layers of the ventral hippocampus using a rotational implantation strategy. Chronic in vivo recordings demonstrate stable electrochemical performance and reliable acquisition of local field potentials over four weeks. This work establishes a strategy for anatomically matched neural interfacing, enabling high-resolution investigation of neural circuits that are challenging to study with conventional linear probes.

neuroscience↗

bioRxiv2025

NQO1 phase condensation promotes stress granule assembly to facilitate pancreatic carcinogenesis

G3BP1 promotes pancreatic ductal adenocarcinoma (PDAC) tumorigenesis driven by oncogenic KRAS mutations through liquid-liquid phase separation (LLPS)-mediated assembly of stress granules (SGs). However, the regulatory mechanisms remain elusive. We identify the antioxidant enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) as a novel SG regulator that enhances SG assembly in pancreatic cancer cells independently of reactive oxygen species (ROS). Mechanistic studies reveal that NQO1 does not regulate the expression of G3BP1 or other SG-associated genes. Instead, NQO1 undergoes LLPS dependent on its RNA-binding K homology (KH) like domain. Further analysis demonstrates that residues 121-131 of NQO1 directly interact with G3BP1s RNA-binding domain (RBD), enhancing the multivalency of G3BP1 complexes to potentiate LLPS-driven SG assembly. This interaction accelerates cell proliferation, KRAS mutation-induced acinar-to-ductal metaplasia (ADM), and pancreatic carcinogenesis. Notably, the interaction between NQO1 residues 121-131 and G3BP1s RBD is essential for NQO1 phase condensation under stress condition. Integrative analysis of human PDAC transcriptomic datasets reveals a weak association between NQO1 and G3BP1 levels. Importantly, both NQO1 and G3BP1 formed biological condensates and co-localized in the lesions of human PDAC tissue sections. Our study uncovers a novel KRAS mutation-driven mechanism of pancreatic carcinogenesis through the lens of phase separation, transcending conventional gene expression regulation and offering new insights into non-canonical KRAS-NQO1-G3BP1-SG regulatory networks in PDAC initiation.

cancer biology↗

bioRxiv2025

Programmable Aptamer-Embedded Circular RNAs for Targeted Antigen-Presenting Cells Immunotherapy

The targeted delivery of mRNA to specific cell types in vivo remains a major unmet need in mRNA-based therapeutics. Conventional strategies rely on nanocarriers engineered with various modifications. However, these exogenous materials could cause adverse reactions, and their complex manufacturing processes often hinder clinical application. By leveraging the innate programmability of RNA sequences, we herein report a carrier-free, scalable, and programmable aptamer-embedded circular RNAs (Apt-circRNAs) design that confers targeting capability through the strategic incorporation of different aptamers at varying densities, while retaining circular RNA stability and protein production capability. Experimental results show that antigen-loaded Apt-circRNAs enable targeted delivery to antigen-presenting cells (APCs), drive endogenous antigen expression, activate antigen-specific T cells, and elicit potent immune responses that mediate clearance of both early-and late-stage tumors in mouse models. In humanized models of colorectal cancer, the combination of Apt-circRNA and PD-1 blockade produced synergistic antitumor effects and significantly reshaped the tumor microenvironment. In a first-in-human (FIH) clinical trial, Apt-circRNA vaccine encoding KRAS G12D/G12V neoantigens exhibited a favorable safety profile and induced robust immune activation, T cell mobilization, and neoantigen-specific immune responses. With this study, we have established a new paradigm in carrier-free, APC-targeted RNA vaccine design, offering a safe and effective platform for next-generation cancer immunotherapy.

bioengineering↗

bioRxiv2025

Reactivation-coupled brain stimulation enables complete learning generalization

Generalization of learned knowledge to new contexts is essential for adaptive behavior. Despite extensive research on the brain plasticity mechanisms underlying learning specificity, the mechanisms that facilitate generalization remain poorly understood. Here, we investigate whether using brain stimulation to disrupt offline consolidation in visual cortex promotes learning generalization. Separate groups of participants (N = 144) were trained on visual detection tasks using either a reactivation-based protocol or conventional full-practice, combined with anodal or sham transcranial direct current stimulation (tDCS) over the visual cortex. Strikingly, only combination of reactivation-based learning with anodal tDCS produced complete generalization from trained to untrained stimuli, an effect consistently replicated across features (orientation, motion direction). In contrast, reactivation-based learning alone and conventional full-practice - whether with or without brain stimulation - yielded stimulus-specific learning. Importantly, reactivation-coupled brain stimulation achieved generalization with an 80% reduction in training trials while maintaining learning gains comparable to full-practice. These findings demonstrate that reactivation and neuromodulation interact to unlock learning generalization, revealing a key brain plasticity mechanism and offering a rapid, translatable strategy for sensory rehabilitation.

neuroscience↗

bioRxiv2025

PI-FC: Pre-training Individual-specific Functional Connectome through State-invariant Contrastive Learning

Functional MRI enables non-invasive mapping of brain connectivity, yet its clinical translation remains hindered by uncontrolled state-dependent variability that obscures individual-specific signatures during routine scanning. Here we introduce PI-FC -- a deep learning framework leveraging state-invariant contrastive learning to extract stable individual brain signatures across diverse arousal levels, cognitive states, and temporal scales spanning tens of seconds to hours. PI-FC achieves equivalent phenotypic prediction accuracy using substantially reduced scanning time, and eliminates state-dependent effects varying task demands and brain states. Trained on 36,119 subjects across 8 independent datasets, our model demonstrates superior cross-site generalization and outperforms traditional functional connectome (FC) in predicting neuropsychiatric conditions including schizophrenia, autism, depression, and anxiety. Furthermore, PI-FC enables zero-shot inference of brain age, biological sex, and cognitive ability without site-specific retraining. Overall, PI-FC represents a robust, clinically scalable framework that overcomes fundamental barriers to real-world deployment of precision functional neuroimaging.

neuroscience↗

bioRxiv2025

Probing the genomic and proteomic basis of encystment in Oxytricha granulifera

Protozoan encystment is a crucial survival strategy for resisting environmental stresses, yet its molecular mechanisms remain poorly understood due to limited genomic resources and lack of integrated multi-omics analyses in model ciliates. In this study, we aimed to elucidate the molecular mechanisms underlying the encystment process in Oxytricha granulifera by sequencing and assembled its genome, and by conducting comprehensive transcriptome, proteome and morphology analyses to reveal gene expression and morphologic changes between vegetative and cyst stages. Morphological observation revealed ciliary dedifferentiation and cyst-wall formation during encystment, events respectively supported by the downregulation of microtubule dynamics related genes and the upregulation of vesicle transport related genes in cyst stage. Expanded gene families for carbohydrate metabolism, autophagy and cellular acidification align with the species mucocyst signature and their observed autophagic clearance, hinting at previously unrecognized mechanisms underlying cyst formation. Elevated expression of the ubiquitin-proteasome system and autophagy pathways facilitates protein turnover, and upregulation of antioxidant enzymes genes helps mitigate oxidative damage, while a rewired post-transcriptional regulation that increases spliceosome activity and alternative splicing frequency--each trend validated at the protein level. Concurrently, the methyltransferases responsible for DNA N6-adenine methylation (6mA), with homologous genes of AMT1 and AMT6/7 significantly downregulated. These results suggesting a multilayered regulation of ciliate encystment and the first integrated evidence that alternative splicing modulates dormancy. Our findings establish the first multi-omics framework for O. granulifera encystment, offering baseline data and tentative clues to the dormancy mechanism that will inform future inquiries into how single-celled eukaryotes endure adverse environments. IMPORTANCEOxytricha species are widely distributed in freshwater and terrestrial ecosystems, playing significant ecological roles in microbial communities. Their ability to undergo encystment provides a powerful model for studying cellular differentiation and stress adaptation in microbial eukaryotes. This study presents the first multi-omics analysis of encystment in Oxytricha granulifera, revealing microbial survival strategies through enhanced protein turnover, autophagy, alternative splicing, and DNA methylation reprogramming. These findings offer fundamental insights into dormancy mechanisms and environmental adaptation in protists, advancing our understanding of microbial resilience, evolutionary innovation, and ecological success in fluctuating environments.

genomics↗

bioRxiv2025

What Could Go Wrong? Promoting Success by Planning for Failure in Label-Free Biosensor Assay Development

Label-free biosensors offer powerful platforms for detecting molecular interactions, but developing robust assays on these systems presents several challenges due to the complexity of the testing systems and intersection of disciplines. In this work, we describe a lightweight, 3-step experimental workflow supporting troubleshooting and root cause analysis that we developed during the design and optimization of silicon photonic biosensor assays in an academic research setting. Because such environments often lack the resources and formal quality-management infrastructure available in industry, our approach emphasizes practicality and ease of adoption. Drawing from our own assay failures and successes, we identify common failure modes, propose structured troubleshooting workflows, and provide case studies illustrating the application of established frameworks, including the Five Whys, the Plan-Do-Check-Act cycle, Open-Narrow-Close and the Ishikawa (fishbone) diagram. By applying this framework to our research, we increased our assay yield by a factor of 2, from ~45% to ~90%. This paper aims to support other teams engaged in label-free assay development by equipping them with practical tools and experimental best practices. HighlightsO_LIWe doubled assay yield from ~45% to ~90% by planning for failure, not just success. C_LIO_LITailored troubleshooting frameworks help pinpoint and solve various assay failures. C_LIO_LIApplying innovative problem-solving to workflows accelerates biosensor development. C_LIO_LISystematic troubleshooting improves assay development across a range of lab settings. C_LIO_LIA 3-step workflow highlighting what could go wrong supports continuous improvement. C_LI

bioengineering↗

bioRxiv2025

Dual checkpoint blockade of glioblastoma with Anti-PD-1 and Anti-LAG-3 promotes expansion of tumor-reactive T cell clones along a unique pathway of differentiation

IDH-wildtype grade IV glioblastoma is the most aggressive adult primary brain tumor and remains refractory to anti-PD-1 monotherapy despite evidence of limited tumor-specific T cell induction. To determine the impact of immune checkpoint inhibitors (ICIs) on glioblastoma T cell transcriptional landscape and repertoire, we conducted paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) of tumor-infiltrating lymphocytes (TILs) from patients with untreated, newly diagnosed glioblastoma and from recurrent glioblastoma treated with dual checkpoint blockade targeting PD-1 and LAG-3. Using a validated transcriptional signature, we found that predicted tumor-reactive T cells (TRC) in untreated glioblastomas reside almost exclusively in a clonally expanded GZMKhi population with developmental plasticity, affording them the potential to differentiate into both tissue-resident and terminal effector T cells. Dual ICI therapy induced substantial clonal remodeling, characterized by the recruitment of new TRC from the periphery into the tumor microenvironment (TME) and differentiation into transitional effectors and ultimately terminal effectors along a gradient characterized by simultaneous acquisition of cytotoxic and exhaustion genes, regulated by specific transcriptional, metabolic, and epigenetic programs. Longitudinal clonal tracking in peripheral blood confirmed that with ICI treatment, most TRC expand transiently in circulation prior to tumor infiltration, with peripherally derived clones becoming the major contributor to the GZMKhi TRC that further expand in the tumor. Our study provides the first comprehensive map of T cell clonal dynamics and differentiation in glioblastoma following dual ICIs and highlights a potential mechanism of immune activation and peripheral recruitment of TRC in glioblastoma not previously described. Our results suggest that therapeutic strategies to sustain these GZMKhi early effector and transitional effector T cells may further enhance ICI therapeutic efficacy in glioblastoma.

immunology↗