Biology subjects

He, Y.

Publications and source records attributed to He, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

The avian colourscape is disproportionately threatened by species extinctions

The impact of projected extinctions on global animal colour diversity remains unknown. Combining citizen science with self-supervised deep learning, we built novel representations of bird plumage colour patterning based on >125,000 museum specimen images covering 9,143 species. We demonstrate that losing currently threatened bird species will drive a disproportionate reduction in avian plumage diversity, with the most severe losses occurring in tropical and subtropical regions. Furthermore, while humans generally find non-typical plumage phenotypes more aesthetically attractive, threatened species are unexpectedly deemed less visually appealing despite their comparatively unusual plumages. Overall, our results highlight severe, imminent threats to the existing avian colourscape and raise critical questions about the future of animal colour diversity in a changing world.

ecology↗

bioRxiv2026

Systematic Quantitative Proteomics Defines Age, Sex, and Region-Dependent Remodeling of Lung Extracellular Matrix

The lung extracellular matrix (ECM) governs tissue architecture, mechanics, and function, yet how it remodels with age across sex and anatomical regions remains poorly understood. Here, we performed a systematic multi-factor proteomic analysis of rat lungs to define age-, sex-, and region-dependent remodeling across the tissue landscape. Age emerged as the dominant source of variation, with a conserved aging signature modified by region- and sex-specific effects. Young lungs showed coordinated ECM assembly, balanced proteolysis, and active biosynthetic programs consistent with structural adaptability and mechanical resilience. In contrast, aged lungs exhibited accumulation of mature collagen crosslinks and a more stabilized matrix architecture, indicating progressive matrix maturation and reduced structural plasticity. These changes were accompanied by proteomic signatures of metabolic stress and immune activation, suggesting coordinated remodeling across ECM, metabolic, and immune pathways during lung aging. Aging effects varied across anatomical regions and were more pronounced in females, highlighting context-dependent trajectories within the broader aging program. Age also partially reshaped spatial proteomic heterogeneity across lung compartments. Together, these findings identify matrix stabilization as a central feature of lung aging that links structural remodeling to metabolic-inflammatory imbalance and increased pulmonary vulnerability.

biochemistry↗

bioRxiv2026

Comprehensive ctDNA Profiling Enables Tissue-of-Origin Prediction and Actionable Biomarker Detection in Cancer of Unknown Primary

Most patients with cancer of unknown primary (CUP) still receive platinum-based chemotherapy and have a poor prognosis, with overall survival of less than one year. Recent studies suggest improved outcomes with molecularly guided or site-specific therapies informed by molecular tissue profiling. Here, we analyzed ctDNA from 190 CUP patients using an integrated genomic and epigenomic assay to identify actionable alterations and predict tissue-of-origin (ToO). Integration of actionable biomarkers, ToO prediction and clinical data yielded diagnostic, prognostic or therapeutic information in 90% of unfavorable CUP cases and 88% of patients analyzed at first diagnosis. High ctDNA tumor fraction was associated with poorer prognosis in both favorable and unfavorable CUP. These findings highlight the clinical utility of ctDNA analysis for therapeutic decision-making in CUP and support its incorporation into the diagnostic work-up, particularly when tissue samples are unavailable or insufficient for molecular testing.

Cancer Biology↗

bioRxiv2026

Region-specific regulation of glucocorticoid and mineralocorticoid receptor signaling in a mouse model of oral contraceptive exposure

Combined oral contraceptives (OCs), containing synthetic estrogen and a progestin such as levonorgestrel (LVNG), are widely used, and up to 10% of users experience adverse mood states and increased depression risk. It is well-established that OCs modulate the hypothalamic-pituitary-adrenal (HPA) axis and blunt the cortisol responses to acute stress. This interaction with stress regulatory pathways is one mechanism by which OCs might impact mood. Here, we used a mouse model of OC exposure (ethinyl estradiol (EE) + LVNG) to investigate how OCs affect regulation of the diurnal CORT cycle and stress-related signaling in the dorsal and ventral hippocampus and paraventricular nucleus of the hypothalamus (PVN). We found that EE+LVNG did not alter basal corticosterone (CORT) levels, but impaired glucocorticoid receptor (GR) - mediated negative feedback in the dexamethasone suppression test. Molecular analyses revealed distinct, region-specific effects. In the dorsal hippocampus, EE+LVNG enhanced glucocorticoid receptor (GR)-dependent gene signaling and prolonged Fkbp5 induction. In the ventral hippocampus, EE+LVNG enhanced mineralocorticoid receptor (MR)-dependent signaling and reduced stress-induced corticotropin-releasing factor expression. In the PVN, EE+LVNG reduced MR expression and modulated MR-dependent signaling. Together, these findings demonstrate that chronic OC exposure disrupts GR- and MR-dependent regulation across stress-related brain regions and impairs glucocorticoid feedback, providing potential mechanisms by which OCs blunt stress responsivity, modify long-term HPA-axis function, and increase susceptibility or resilience to stress and depression.

neuroscience↗

bioRxiv2026

A Tripartite Map of the Ventromedial Prefrontal Cortex

The ventromedial prefrontal cortex (VMPFC) has been repeatedly implicated in affect, valuation, and social cognition, yet how these diverse functions are organized within a single cortical territory has remained unresolved. Here, we integrate large-scale meta-analysis, individual-level task fMRI, artificial neural-network encoding models, and multimodal connectivity analyses to reveal the internal functional architecture of the human VMPFC. Across four complementary studies, we identify a robust tripartite organization along the anterior-posterior axis, comprising posterior affective, middle valuation, and anterior social functional motifs. Connectivity fingerprinting demonstrates that each motif is preferentially embedded within distinct large-scale brain networks, providing a mechanistic account of VMPFC functional specialization. This organization is reproducible at the level of individual subjects, generalizes to naturalistic stimuli, extends across development, and shows cross-species correspondence with non-human primates and multiple neurobiological markers. Together, these findings resolve a long-standing organizational question and establish a biologically grounded framework for interpreting VMPFC function.

neuroscience↗

bioRxiv2026

Spatiotemporal Patterns and Structural Substrates of Individual Functional Variability in Youth

Youth is a period of emerging individuality and extensive neural remodeling, yet how functional brain individuality is organized across development remains unclear. Prior work has often conflated variability in functional topography with variability in functional connectivity, highlighting the need to examine them separately to better understand how functional individuality relates to brain structure and cognition. Here, using individualized functional parcellation in two large multimodal developmental cohorts (total N = 1211), we separately quantified variability in individualized functional parcellation (vIFP) and in functional connectivity (vFC). Both forms of variability were organized along the sensorimotor-association axis and were greatest in the association cortex. During development, vIFP increased significantly with age at both regional and whole-brain level, whereas vFC showed regionally specific age effects but no significant whole-brain increase. Both trajectories exhibited a common mid-adolescent inflection (14-16 years), marking a window of accelerated functional individualization. Despite shared spatial and temporal organization, vIFP and vFC showed dissociable associations with brain structure and cognition. vIFP was more strongly coupled to structural variability, whereas vFC was more strongly associated with cognitive variability. These findings reveal convergent and divergent developmental principles of topographic and connectional functional variability, highlighting their complementary roles in structural constraints and cognitive specialization.

neuroscience↗

bioRxiv2026

Cocaine-Enriched Oral Streptococcus parasanguinis Promotes Neuroimmune Dysfunction and Memory Impairment

Chronic cocaine use is associated with neuroinflammation and cognitive dysfunction, but the underlying mechanisms remain unclear. We previously identified oral enrichment of Streptococcus parasanguinis (SP) and other species in individuals with cocaine use disorder (CUD), and here demonstrate that cocaine selectively enhanced SP growth in vitro. To investigate causality, antibiotic-pretreated wild-type C57BL/6 mice received chronic oral inoculation of SP, S. salivarius, Neisseria flavescens, or vehicle. SP-treated mice exhibited spatial memory impairment, increased brain IL-1{beta}, and non-region-specific microglial activation, without detectable bacterial translocation into the brain. While amyloid-associated signaling changes were observed across all bacterial treatment groups, only SP induced cognitive deficits and neuroinflammation. Untargeted metabolomics identified distinct SP-associated oral-to-brain metabolite signatures, including cysteine S-sulfate (CSS) and altered histamine-associated metabolites. CSS and histamine induced neuroinflammatory and amyloid-associated responses in vitro. Together, these findings identify a cocaine-associated oral pathobiont that promotes neuroinflammation and neurodegeneration, suggesting a novel oral microbiome-brain axis in CUD.

neuroscience↗

bioRxiv2026

Cellfm-datasets: A Unified Data Infrastructure for Single-Cell and Spatial Transcriptomics Foundation Model Pretraining

Large-scale cell foundation models are increasingly limited not only by model architecture, but also by the data infrastructure required to repeatedly sample sparse transcriptomic profiles from out-of-core cohorts. AnnData/H5AD has become a standard exchange format for single-cell and spatial omics analysis, yet its HDF5-backed layout is not designed for high-frequency random mini-batch loading under multi-worker and distributed pretraining. We present Cellfm-datasets, a data infrastructure artifact that converts H5AD cohorts into a self-describing compressed sparse row (CSR) memmap layout and exposes the resulting corpus through Hugging Face Dataset and IterableDataset interfaces. The artifact stores a shared gene vocabulary, per-sample metadata, optional spatial coordinates, observation metadata, manifests, and checksums, and reconstructs sparse cell or group records at runtime without dense expansion. A unified sampling abstraction supports random-cell groups, manifest-defined biological regions, and coordinate-based spatial blocks, with deterministic sharding across distributed ranks and data-loader workers. Spatial demonstrations on P14 mouse brain transcriptomics sections illustrate region- and block-level sampling over real anatomical structures. In controlled benchmarks on a public heterogeneous ModelScope scRNA-seq subset, Cellfm-datasets reached 60,571 {+/-} 1,734 samples/s in single-core random loading, scaled to approximately 160,000 samples/s with eight workers, and maintained near-constant process-private memory while reading up to one million cells. By moving sparse single-cell and spatial corpora from model-specific loader code into reusable, validated, and framework-native dataset artifacts, this design may reduce the engineering burden of reproducible cell foundation model pretraining and make repeated training runs, model comparisons, and mixed-modality data reuse easier to standardize. Code availabilityhttps://github.com/PangJiangShuan/cellfm-datasets

bioinformatics↗

bioRxiv2026

HoloCell: A Generative Foundation Model for Holistic Cellular Modeling

Single-cell multi-omics technologies have recently advanced to enable the profiling of epigenomic, transcriptomic, and proteomic layers within individual cells, offering new opportunities to characterize cellular states as integrated biological systems. However, developing a unified framework that can seamlessly integrate diverse omics modalities and remain robust to heterogeneous modality missingness remains challenging. Existing methods are often designed for specific modalities or modality pairs, relying on dataset-specific training or paired measurements. Here we present HoloCell, to our knowledge the first generative foundation model for joint representation learning and generative modeling across all three major single-cell omics modalities, i.e., epigenomics, transcriptomics, and proteomics. HoloCell contains over 860 million parameters and is pretrained on the Human-Multi-Omics-Corpus, which comprises approximately 468 million single-cell profiles across these three omics layers, corresponding to over 425 billion tokens. HoloCell introduces a a simple yet biologically motivated hierarchical tokenization strategy that encodes cis-regulatory elements, genes, and proteins as structured tokens within a shared modeling framework. We evaluated HoloCell across single-omics representation learning, paired multi-omics integration, unpaired multi-omics alignment, and cross-modal generation via iterative diffusion and remasking, demonstrating its superior performance and flexibility across diverse omics tasks. From a representation perspective, HoloCell provides a unified digital mapping of cellular states across multiple omics layers, capturing cell heterogeneity as an integrated system. From a generation perspective, its iterative diffusion and remasking frame-work permits flexible generation orders beyond fixed left-to-right causality, enabling in silico simulation of multi-omics information flow. Together, these capabilities position HoloCell as a versatile foundation model toward the emerging concept of a virtual cell, offering both systematic characterization and generative simulation of cellular systems within a unified framework.

bioinformatics↗

bioRxiv2026

Ignet 2.0 and Vignet: An Ontology-Driven Web Platform for Biomedical Gene Interaction Discovery and Visualization

BackgroundThe expansion of biomedical literature demands systematic ontology-guided discovery of gene interactions, vaccine mechanisms, drug associations, and adverse events. Existing platforms such as STRING, DisGeNET, and PubTator fall short of providing a unified, freely accessible system that integrates ontology-based semantic interaction classification, vaccine-focused heterogeneous network construction, and Artificial Intelligence-assisted evidence retrieval. ResultsIgnet 2.0 and Vignet are freely accessible dual-platform systems that combine PubMed literature mining, BioBERT-based interaction scoring for millions of gene-gene co-occurrence pairs and integrate three biomedical ontologies and one curated drug resource, Interaction Network Ontology (INO), Vaccine Ontology (VO), Human Disease Ontology (HDO), and DrugBank. Ignet 2.0 supports gene interaction discovery, gene set enrichment retrieval of BioBERT-scored GenePair evidence, and AI-assisted summarization through BioSummarAI. Vignet extends these features with VO-guided Vaccine Exploration, VacPair interaction scoring, and the creation of vaccine, gene, drug, and disease networks in VacNet. A public Representational State Transfer Application Programming Interface (REST API) and Model Context Protocol (MCP) endpoint enable real-time integration, fostering trust in biomedical knowledge discovery. ConclusionIgnet 2.0 and Vignet are scalable, ontology-guided biomedical knowledge platforms that facilitate evidence-based gene interaction analysis, vaccine-focused semantic exploration, and AI-assisted knowledge discovery. Their real-time PubMed data integration ensures up-to-date insights; however, users should consider validation processes and potential lags in incorporating the latest experimental data, which may affect the reliability of immediate data. AvailabilityIgnet 2.0: https://ignet.org/ignet; Vignet: https://ignet.org/vignet/

bioinformatics↗

bioRxiv2026

Multiple approaches for CRISPR-based targeting of DNA methylation to promoters of bacterial and viral susceptibility genes in cassava

Targeted epigenetic modifications of specific gene regulatory regions have the potential to confer beneficial traits for crop improvement. Two recently developed CRISPR/Cas9-based epigenome editing tools were tested in transgenic cassava to target cytosine methylation to the promoter region of MeSWEET10a, a necessary gene for infection by the Cassava bacterial blight pathogen, Xanthomonas phaseoli pv. manihotis. The two systems leverage unique methyltransferases, and each induced distinct DNA methylation profiles at the targeted site, decreased effector-triggered MeSWEET10a expression, and attenuated water-soaking symptoms in inoculated leaves. Further, DNA methylation was simultaneously targeted, in addition to MeSWEET10a, to two susceptibility genes for Cassava brown streak virus. Relative levels of de novo DNA methylation at the three loci were inversely correlated with DNA methylation-antagonizing H3K4me3 marks. Finally, an initial assessment of DNA methylation after one generation indicated specific inheritance of CpG methylation that was unstable in the absence of the methyltransferase systems.

plant biology↗

bioRxiv2026

Single-cell spatial transcriptomics and snRNA-seq decoding the organizational principles of functional modules in the mouse amygdala

The amygdala is a functionally heterogeneous nuclear complex comprising multiple subnuclei that orchestrate diverse behaviors, making it essential for survival and reproduction. However, the precise neural mechanisms underlying these heterogeneous functions remain elusive, primarily due to limited knowledge of the amygdalas cellular heterogeneity, developmental origins, spatial organization, and gene expression profiles. Here, we integrate single-cell-resolution spatial transcriptomics with precise anatomical dissection and single-nucleus RNA sequencing to systematically map the subnuclear enrichment patterns of amygdalar cell types. We further demonstrate that developmental origin determines subnuclear positioning and propose a novel functional modular architecture based on cellular composition and gene expression signatures. Furthermore, we reveal that the central amygdala (CEA) exhibits developmental heterogeneity, with Isl1+ neurons in its medial subdivision (CEAm) predominantly originating from hypothalamic progenitors. Our findings establish a spatially resolved cellular and molecular framework for investigating amygdalar functions at cellular type resolution and understanding amygdala-related neuropsychiatric disorders.

neuroscience↗

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

SRC Knockdown Impairs Proliferation, Migration, and Invasion While Promoting Apoptosis in HTR8/SVneo Trophoblast Cells via Activation of the PI3K/Akt/Bcl-2 Signaling Pathway

SRC knockdown inhibits trophoblast cell proliferation, migration, and invasion while inducing apoptosis via activation of the PI3K/Akt/Bcl-2 signaling pathway. Trophoblast dysfunction is central to pregnancy disorders such as preeclampsia and miscarriage, yet the role of SRC, a non-receptor tyrosine kinase, in these cells remains poorly understood. This study aimed to elucidate the functional impact of SRC on trophoblast behavior and its underlying mechanism. Using siRNA-mediated knockdown in HTR8/SVneo cells, we confirmed efficient reduction of SRC mRNA and protein expression via RT-qPCR and Western blot. Functional assays demonstrated that SRC silencing significantly suppressed cell proliferation (CCK-8), migration (wound healing), and invasion (Transwell), while promoting apoptosis, evidenced by increased Annexin V-FITC/PI staining and upregulated Caspase-3 and Caspase-9 protein levels. Mechanistically, Western blot analysis revealed that SRC knockdown upregulated PI3K, Akt1, and Bcl-2 protein expression without altering IRS1 levels, indicating activation of the PI3K/Akt/Bcl-2 pro-survival pathway. This paradoxical activation appears to be a compensatory feedback insufficient to overcome SRC loss-induced dysfunction. Our findings identify SRC as a critical positive regulator of trophoblast proliferation, motility, and survival, acting through a non-canonical, IRS1-independent negative regulation of PI3K/Akt signaling. This study provides novel insights into trophoblast biology and suggests SRC as a potential therapeutic target for pregnancy complications; future in vivo studies are warranted to validate these mechanisms.

molecular biology↗

bioRxiv2026

Cost-Effective Purification of Endotoxin-Free LIF, IL-2, and IL-33

We describe a cost-effective Escherichia coli (E. coli)-based platform for producing endotoxin-free cytokines. As a proof of concept, we applied this protocol to purify four representative human and mouse cytokines - mouse leukemia inhibitory factor (mLIF), human interleukin-2 (hIL-2), and human and mouse interleukin-33 (hIL-33 and mIL-33) - and demonstrated their bioactivity to be equivalent to commercial counterparts for direct use in stem cell culture and immune cell activation, both in vitro and in vivo. Reagent costs for producing these proteins are approximately 5%-10% of commercial list prices. This platform is readily adaptable to other costly cytokines and growth factors, providing a scalable and affordable approach to accelerate research in cell biology, tissue engineering, and biomanufacturing.

bioengineering↗

bioRxiv2026

Alignment-free phylogenetic inference via hyperbolic protein language models

Conventional phylogenetic methods rely on multiple sequence alignments which are computationally intensive and often fail for highly divergent lineages. Here, we introduce LucaPhylo, an alignment-free framework that infers evolutionary relationships directly from unaligned sequences. Through a cascaded learning strategy LucaPhylo integrates protein language models with hyperbolic geometry, a representation space naturally suited to hierarchical branching, to capture deep evolutionary constraints without explicit homology matching. Using highly divergent RNA virosphere as a test case, LucaPhylo places unaligned sequences into phylogenetic trees with an accuracy comparable to leading alignment-based tree construction tools, while retaining divergent sequences that conventional pipelines frequently discard. It further enables the integration of divergent viral lineages into phylogenetic trees, thereby expanding the evolutionary landscape of RNA viruses. Together, LucaPhylo establishes an AI-driven, alignment-free paradigm for phylogenetic inference and provides a robust computational foundation for resolving deep evolutionary relationships among RNA viruses and other biological systems.

evolutionary biology↗

bioRxiv2026

HIPK2 regulates homology-directed DNA repair and PARP inhibitor sensitivity

Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) counteracts genome instability and carcinogenesis. Cancer cells frequently show defects in HR which can be therapeutically exploited by hypersensitivity to poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. Here we identify an unforeseen function of HIPK2 in HR repair and PARPi sensitivity. HIPK2 accumulates at DSBs and associates with DSB repair factors at DNA damage foci. DSB recruitment of HIPK2 requires checkpoint kinase ATM activity. DNA repair pathway analysis revealed that HIPK2 depletion specifically impairs HR. Mechanistically, we found that HIPK2 binds BRCA1 and phosphorylates BRCA1 at Ser1191, a site that regulates damage-induced BRCA1 protein stability. Consistently, HIPK2 depletion or pharmacological inhibition of HIPK2 results in reduced BRCA1 protein levels, and sensitizes BRCA1-proficient cancer cells to IR damage and PARPi treatment. In sum, our results identify a role for HIPK2 in HR through regulating BRCA1 protein levels, and propose HIPK2 inhibition as a novel strategy to sensitize BRCA1-proficient cancer cells to PARPi treatment.

cell biology↗

bioRxiv2026

BMSC-Laden PEGDA/HAMA Dual-Crosslinked Hydrogels with Distinct Stiffness Profiles for Osteochondral Defect Repair

This study aimed to develop a BMSC-laden polyethylene glycol diacrylate/methacrylated hyaluronic acid (PEGDA/HAMA) dual-crosslinked hydrogel and evaluate its effects on osteochondral defect repair. Two PEGDA concentrations, 3.75% and 7.5% (w/v), were used to prepare representative soft and stiff hydrogel formulations, respectively. The hydrogels were characterized in terms of morphology, cytocompatibility, and compressive behavior, and their ability to support BMSC-associated matrix deposition was evaluated in vitro. Repair outcomes were further assessed in a rat osteochondral defect model at 4 and 8 weeks. The 7.5% PEGDA/HAMA hydrogel exhibited higher stiffness than the 3.75% formulation and supported BMSC viability and matrix deposition in vitro. In vivo, the stiff hydrogel group showed improved defect filling and subchondral bone remodeling compared with the soft hydrogel and defect groups. However, histological and immunohistochemical analyses revealed predominant collagen type I deposition and limited collagen type II expression in the repair region, indicating fibrocartilaginous rather than hyaline-like cartilage repair. These findings suggest that BMSC-laden PEGDA/HAMA hydrogels may provide a useful platform for osteochondral defect repair, while further optimization of degradation behavior, matrix maturation, and collagen type II deposition is required to improve hyaline cartilage-oriented repair.

bioengineering↗