Biology subjects

Li, K.

Publications and source records attributed to Li, K..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

SPCoral: diagonal integration of spatial multi-omics across diverse modalities and technologies

Spatial multi-omics is indispensable for decoding the comprehensive molecular landscape of biological systems. However, the integration of multi-omics remains largely unresolved due to inherent disparities in molecular features, spatial morphology, and resolution. Here we developed SPCoral for diagonal integration of spatial multiomics across adjacent slices. SPCoral extracts spatial covariation patterns via graph attention networks, followed by the use of optimal transport to identify high-confidence anchors in an unsupervised, feature-independent manner. SPCoral utilizes a crossmodality attention network to enable seamless cross-resolution feature integration alongside robust cross-omics prediction. Comprehensive benchmarking demonstrates SPCorals superior performance across different technologies, modalities and varied resolutions. The integrated multi-omics representation further improves spatial domain identification, effectively augments experimental data, enables cross-modal association analysis, and facilitates cell-cell communication. SPCoral exhibits good scalability with data size, reveals biological insights that are not attainable using a single modality. In summary, SPCoral offers a powerful framework for spatial multi-omics integration across various technologies and biological scenarios.

bioinformatics↗

bioRxiv2026

Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia

The basal ganglia play essential roles in motor control, emotion, learning and reward processing. Their dysfunction contributes to many neurological and psychiatric disorders. However, the gene regulatory programs defining basal ganglia cell-type identity and function remain poorly understood, limiting interpretation of disease-associated non-coding variants. Here, we present the first single-cell multiome atlas of histone modifications and transcriptomes across eight basal ganglia regions from neurotypical adult human donors. Joint profiling reveals cell-type-specific deployment of active and repressive cis-regulatory elements and gene regulatory networks, and suggests a combinatorial homeobox transcription factor code underlying cell identity. Integration with matched spatial transcriptomic MERFISH data uncovers regional heterogeneity of epigenomic landscapes. Comparative analysis between human and mouse medium spiny neurons uncovers conservation of core gene regulatory features. This atlas interprets non-coding risk variants of neuropsychiatric disorders and supports the development of a deep learning model to predict gene regulation and functional effects of disease-associated variants. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes and three histone modifications across eight human basal ganglia regions characterizes active and repressive chromatin states at cell-type resolution. C_LIO_LICell-type-specific gene regulatory programs decode combinatorial homeobox TF grammar governing the identity and diversification of basal ganglia neurons. C_LIO_LIIntergrative analyses link noncoding neuropsychiatric risk variants to specific cell types, regulatory elements, and candidate target genes. C_LIO_LIA sequence-to-function deep-learning model predicts gene regulation from DNA sequence and prioritizes functional disease-associated variants. C_LI

genomics↗

bioRxiv2026

Polyploid cardiomyocytes define disease-specific transcriptional states in the mammalian heart

The adult mammalian heart has a limited regenerative capacity. Following injury, cardiomyocytes undergo a hypertrophic response accompanied by polyploidization, which has been described as a barrier to proliferation and regeneration of the heart1,2. However, the unique molecular programs of polyploidy, or genome multiplied cardiomyocytes, and their influence on the disease-related myocardial remodelling process remains unclear. Here, we integrate single-nuclei and high-resolution spatial multi-omics across human, rat, and mouse hearts to define novel cardiac cell states and their tissue niches in ischemic and non-ischemic heart disease. Computational analysis across scales allowed us to generate detailed networks of the cardiac tissue remodelling process as well as tissue and sub-cellular environments uniquely enriched in polyploid cardiomyocytes or their diploid origins. We identify a conserved, dichotomous transcriptional program distinguishing diploid from polyploid cardiomyocytes. Polyploid cardiomyocytes demonstrated rewired metabolic and chromatin-remodeling transcriptional programs and recapitulate the gene signature of immature human fetal cardiomyocytes. Notably, we observe that polyploid cardiomyocytes--rather than the general myocyte population--are the primary sites of enrichment for major heart-failure drug targets, including the mineralocorticoid, {beta}1-adrenergic, and glucagon-like peptide-1 receptors. Based on our cross-species dataset we further identified TNIK, a Wnt-pathway regulator expressed in polyploid cardiomyocytes across species, as a potential therapeutic target and demonstrate that pharmacological TNIK inhibition improves cardiac function after myocardial infarction in rats. Together, this species-spanning, disease-resolved study redefines cardiomyocyte heterogeneity in heart disease and suggests a therapeutic path to heart failure treatment by targeting polyploid cardiomyocytes.

genomics↗

bioRxiv2026

Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain

Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes with active or repressive histone modification in >750,000 nuclei across adult human brain. C_LIO_LIChromatin state annotation of >500,000 candidate cis-regulatory elements distinguishes active enhancers from accessible and Polycomb-repressed regions. C_LIO_LICell-type-resolved regulatory networks and sequence-based deep learning model prioritize functional neuropsychiatric risk variants. C_LIO_LISpatial epigenomic imputation reveals laminar layer-specific Polycomb repression programs. C_LIO_LIIntegration with 3D genome architecture reveals neuron-specific super long-range chromatin loops silencing early developmental genes. C_LIO_LIEvolutionary analysis uncovers conserved active regulatory grammar but divergent repressive landscape. C_LI

genomics↗

bioRxiv2026

An Integrated Single-Cell and Epigenomic Resource for Comparative Analysis of the Basal Ganglia

The basal ganglia regulate motor, cognitive, and affective behaviors, and their dysfunction underlies diverse neurological and psychiatric disorders. Comprehensive, accessible multi-omics resources are needed to understand the regulatory mechanisms governing basal ganglia cell types. Here we present an open, interactive web-based platform for exploring single-cell multi-omics datasets from basal ganglia, generated using 10X Multiome, snm3C-seq, and Paired-Tag technologies from the BICAN (NIH BRAIN Initiative Cell Atlas Network) consortium. The platform is available at https://basalganglia.epigenomes.net/ and enables integrated visualization of gene expression, chromatin accessibility, DNA methylation, histone modifications, and chromatin conformation across cell types and human, macaque, marmoset, and mouse species, with direct genome browser support and comparative epigenomic functionality. Representative analyses demonstrate cell-type-specific regulatory landscapes, conserved and species-specific regulatory elements, and links between epigenomic regulation and transcription. This resource provides a scalable, community-oriented foundation for advancing basal ganglia biology and interpreting regulatory mechanisms relevant to brain function and disease. HighlightsO_LIIntegrated single-cell epigenomic resource for basal ganglia C_LIO_LIInteractive genome browser enables multi-omics and cross-species exploration C_LIO_LIReveals cell-type-specific and species-specific regulatory landscapes C_LIO_LISupports community access to complex brain epigenomic datasets C_LI

genomics↗

bioRxiv2026

Integration of ethologically defined anxiety-related behaviors in the ventral hippocampus

Anxiety is a complex emotional state that unfolds as structured sequences of risk assessment and exploratory behaviors enabling animals to evaluate potential threats in the environment. The ventral hippocampus (vH) regulates anxiety responses, yet the neuronal substrates orchestrating specific ethologically defined anxiety-related behaviors remain unclear. Here, we combined high-resolution 3D behavioral tracking with cell-type specific in vivo calcium imaging and optogenetic manipulations to dissect vH microcircuit dynamics during anxiety. We identified protected and unprotected stretch-attend postures (pSAP and uSAP), along with head dipping, as core anxiety-related risk-assessment behaviors organized along a spatial gradient in the elevated plus maze (EPM). Ventral hippocampal (vH) pyramidal neurons were broadly engaged across all risk-assessment behaviors, consistent with a generalized role in encoding anxiety-related information. In contrast, interneuronal subclasses exhibited striking functional specialization: parvalbumin (PV) interneurons were selectively recruited during uSAP and head dipping, behaviors associated with direct threat exposure, whereas somatostatin (Sst) interneurons were preferentially activated during pSAP, which reflect approach-avoidance conflicts and decision-making processes. Collectively, these findings establish a microcircuit-level framework in which distinct vH neuronal subclasses differentially gate risk-assessment strategies, enabling flexible transitions between avoidance and exploratory behaviors during anxiety.

neuroscience↗

bioRxiv2026

Regulation of spikelet number during wheat spike development

Wheat produces unbranched inflorescences (spikes) composed of smaller inflorescences (spikelets) as their fundamental building units. The spikelet number per spike (SNS) is a major determinant of grain yield and the gene networks that regulate this trait are the focus of this review. Spikelet development starts with the transition of the shoot apical meristem into an inflorescence meristem (IM) that produces lateral spikelet meristems (SMs). The rate at which SMs are produced and the timing of the IM transition into a terminal spikelet (IM[->]TS) determine the final SNS. These two traits are regulated by genes expressed in the IM (e.g. meristem identity genes), as well as by the amount of FLOWERING LOCUS T1 (florigen) transported from leaves to developing spikes. Spikelet number can also be increased by the production of spikes with supernumerary spikelets (SS) or branch-like structures that resemble small spikes. Mutations that promote a reversion from SM to IM identity can induce the formation of SS or branches. Initial efforts to incorporate these mutations into commercial wheat varieties have faced trade-offs in fertility and grain weight, which will require additional research and breeding efforts. Meanwhile, genes and allele combinations that increase SNS without affecting the number of spikelets per node have been identified and are being deployed in wheat breeding programs. Recent spatial transcriptomics, single-cell analyses, and multi-omics studies of wheat spike development are accelerating the discovery of new genes affecting SNS and enhancing our ability to engineer more productive wheat spikes.

plant biology↗

bioRxiv2025

Plasma Ficolins Enable Liver Macrophages to Capture Blood-Borne Bacteria by Recognizing Capsular Polysaccharides

Ficolins are evolutionarily conserved glycan-binding lectins in plasma or on cell membranes of immune cells, yet their physiological functions remain to be defined. Here we demonstrate that plasma ficolins drives the capture of diverse encapsulated bacteria in the blood circulation by the liver resident macrophages (Kupffer cells). Ficolin-activated immunity in the liver sinusoids provides swift and sterilizing immunity in mice. Mice lacking ficolin-A (the only plasma ficolin) became hypersusceptible to the blood infections of the ficolin-A-recognizable bacterial serotypes. Mechanistically, plasma ficolins activate complement C3 on bacterial surfaces by pattern recognition of acetylated monosaccharides on polysaccharide capsules, and thereby deliver the opsonized bacteria to C3 receptors on Kupffer cells for phagocytic elimination. These findings reveal that plasma ficolins serve as pattern-recognition receptors that are essential for maintaining the bloodstream sterile.

microbiology↗

bioRxiv2025

IGHV3-53 antibody abundance drives divergent SARS-CoV-2 immune imprinting

The mechanisms driving divergent SARS-CoV-2 immune imprinting in populations with distinct SARS-CoV-2 exposure histories remain unclear. However, conventional wild-type mouse models fail to recapitulate severe imprinting, even after potent ancestral-strain mRNA immunization, hindering imprinting-related mechanistic investigation and vaccine evaluation. Here, we surprisingly found that V(D)J-humanized mice could faithfully recapitulate human severe imprinting phenotypes. Comprehensive antibody repertoire analysis and deep mutational scanning-based epitope mapping of 583 monoclonal antibodies from these models revealed that the pre-existing IGHV3-53/66 antibody abundance determine imprinting severity through antibody-mediated masking of Omicron-specific epitopes. Both passive IGHV3-53/66 antibody transfer and IGHV3-53 knock-in were sufficient to induce severe imprinting in wild-type mice. Together, these findings demonstrate that the V(D)J germline repertoire--even a single germline-encoded antibody response--can profoundly shape humoral imprinting severity. Accordingly, we established an IGHV3-53 knock-in mouse model that accurately recapitulates the human antibody landscape, providing a valuable tool for guiding future COVID-19 vaccine updates.

immunology↗

bioRxiv2025

p53 preserves genome stability in dividing cells under hypo-osmotic stress

Cells respond to frequent osmotic stress to maintain structural integrity and function. Whereas acute volume regulation is well-known, the cellular response to prolonged osmotic stress and its long-term consequences remain poorly understood. In this study, we investigate how lasting hypo-osmotic stress influences cell growth and division and the associated cellular response. We observe that cells undergoing their first division under hypo-osmotic stress experience delayed mitotic entry, lengthened mitotic duration, elevated mitotic errors and aneuploidy formation. However, continued cell division is halted through a p53/p21-dependent G1 arrest. p53 activation occurs post-mitotically and is associated with hyper-condensed chromatin and impaired nuclear expansion in daughter cells after mitotic exit. We show that the altered nuclear size dynamics lead to nuclear accumulation of p53 and activation of downstream gene expression. These findings uncover a mechanosensitive, p53-mediated mechanism that safeguards genome integrity by suppressing erroneous mitosis under hypo-osmotic stress.

cell biology↗

bioRxiv2025

Dynamic alterations of DNA methylation and transcriptome in adaptation to and recovery from the space environment

Space exploration presents tremendous health challenges. Here, we report time series of multi-omic and phenotypic profiles of seventeen astronauts from six China Manned Space missions with continuous spaceflight durations ranging from 13 to 180 days. We revealed a key role of DNA methylation regulation in reshaping gene expression patterns to adapt to the space environment. Long-duration spaceflight showed more alterations in epigenetic modifications correlated with alternative splicing and protein acetylation. During recovery, an "overrange rebound" phenomenon was observed, furthermore, a mathematical model was established to describe this implying important phenomenon. Moreover, we revealed the correlations between molecular alterations and phenotypic changes such as coagulation activation and bone intensity loss. Additionally, we performed ground-based simulation experiments to estimate the impacts of individual stressors in the space environment on DNA methylation. In summary, our study highlights the importance and complexity of epigenetic regulation in adaptation to and recovery from the space environment.

genomics↗

bioRxiv2025

Energy Landscape Analysis Reveals Thalamic Modulation of Brain State Transitions During Movie Watching

Understanding how large-scale brain networks dynamically coordinate during complex, real-world experiences remains a crucial topic in contemporary neuroscience. Leveraging naturalistic paradigm, this study employed energy landscape modeling to characterize the temporal dynamics of brain state transitions and their functional significance. Using the Sherlock fMRI dataset, we identified two dominant brain states: a perception- and attention-oriented state, and an introspective, integrative state, each associated with distinct canonical brain networks. State transitions were differentially associated with the recruitment of these networks and manifested as either the "easy" or "hard" route, depending on the energy required for the transition. Notably, we demonstrated that the probability of specific state transitions robustly predicted inter-subject correlation within three clusters: subcortical-rich, salience/attention-rich, and DMN-rich regions. This indicates that flexible reorganization of cortical networks underlies shared neural engagement during ecologically valid experiences. Critically, the thalamus emerged as a central modulator, displaying activity changes and dynamic nucleus-specific thalamocortical connectivity changes tied to distinct transition profiles. Together, our findings shed light on the energetic and network mechanisms that orchestrate brain dynamics during naturalistic cognition and underscore the pivotal role of cortico-thalamo-cortical circuits in governing flexible, collective neural responses to richly structured real-life stimuli.

neuroscience↗

bioRxiv2025

OSM-11 modulates salinity-stress tolerance in Caenorhabditis elegans

Most terrestrial animals exhibit narrow salinity tolerance compared to their marine counterparts. Previous studies identified osm-11 (which encodes a Notch co-ligand) mutations as a driver of hyper-saline tolerance in Caenorhabditis elegans, but mechanistic insights remained unclear. This study employs RNA sequencing and CRISPR/Cas-9 genome editing to demonstrate that osm-11 mutations enhance salinity stress resistance through up-regulation of fatty acid metabolism (acdh-12, acs-17) and cytochrome P450 pathways (ugt-15), while suppressing calcium signaling. Furthermore, we demonstrated that acdh-12 mutation impairs salinity-stress tolerance by activating ferroptosis and mitophagy, accompanied by down-regulated oxidative phosphorylation and up-regulated autophagic pathways. Morphological observations show that mitochondrial fragmentation contributes to wild-type nematode mortality under high salinity, while enlarged lipid droplets in wild-types correlate with reduced {beta}-oxidation gene expression (dhs-28, daf-22), whose knockout disrupts tolerance in mutants. These findings unravel the multi-pathway regulatory network of osm-11-mediated salinity tolerance, providing mechanistic insights for developing protective strategies against environmental salinity stressors impacting animal survival.

genetics↗

bioRxiv2025

Differential nucleosome organization in human interphase and metaphase chromosomes

DNA bendability plays a critical role in stabilizing nucleosome assembly, yet its contribution to nucleosome dynamics in vivo remains poorly understood. Here, we applied chemical mapping to generate high-resolution nucleosome positioning maps at single-base-pair resolution from human interphase and metaphase chromosomes, revealing distinct patterns of nucleosome organization between the two states. Notably, we observed a unifying pattern of nucleosome positioning near euchromatic landmarks, including promoters, enhancers, and insulators, during mitosis. Interphase nucleosomes exhibited extensive repositioning, marked by increased nucleosome density, reduced spacing between nucleosomes, and the appearance of additional fragile nucleosomes compared to metaphase. Furthermore, our results show that metaphase nucleosomes display significantly higher DNA cyclizability around the dyad axis, whereas interphase nucleosomes, particularly those near regulatory regions, tend to position DNA with greater cyclizability at the edges of the nucleosome. Together, these findings highlight a dynamic interplay between DNA mechanics and nucleosome organization during the cell cycle.

genomics↗

bioRxiv2025

The scaffold protein PRR14L links the PP2A-TACC3 axis to mitotic fidelity and sensitivity to MPS1 inhibition

Aneuploidy is a hallmark of cancer and is a potential vulnerability that can be selectively targeted. To systematically identify genes that affect the incidence and fitness of aneuploid cells, we conducted a genome-wide CRISPR/Cas9 screen using NMS-P715, an inhibitor of the spindle assembly checkpoint (SAC) kinase MPS1/TTK. In this study, we identified a number of genes known to regulate aneuploidy and mitosis, and subsequently focused on PRR14L, a ubiquitously expressed gene previously implicated in chronic myelomonocytic leukemia (CMML). Proximity labeling of PRR14L using TurboID revealed several cell division proteins, including the PP2A-B56 phosphatase complex and the spindle assembly factor TACC3, as PRR14L-interacting proteins. Loss of PRR14L prolongs SAC-dependent mitotic arrest in response to microtubule depolymerization but, paradoxically, leads to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors. A model derived from our findings provides a rationale for exploiting MPS1 inhibition as a potential vulnerability in cancers containing either PRR14L loss of function mutations or FGFR-TACC3 fusions. Significance StatementO_LIAneuploidy is a hallmark of cancer. Whether aneuploidy can be selectively targeted is not known. C_LIO_LIUtilizing a CRISPR/Cas9 screen, the authors found that loss of the gene PRR14L sensitizes cells to aneuploidy induction. Taking advantage of live cell imaging and proximity labeling, they linked PRR14L to TACC3 and mitosis. C_LIO_LIThese findings suggest that spindle checkpoint inhibitors may have therapeutic potential in cancers with either loss-of-function PRR14L and/or gain of function TACC3 mutations. C_LI

cell biology↗

bioRxiv2025

Modified self-amplifying RNAs mediate robust and prolonged gene expression in the mammalian brain

Facile, non-genomic integrating gene delivery technologies are lacking for rapid onset and prolonged protein expression in the brain. Here we report the protein expression and cell type tropism for an advanced messenger ribonucleic acid (mRNA) technology, modified 5-hydroxymethylcytidine (hm5C) self-amplifying ribonucleic acid (saRNA), when injected into the mouse brain or applied to ex vivo human cortical brain slices. saRNA, encoding fluorescent proteins, encapsulated in an LNP formulation comprising ALC-0315 (present in Comirnaty(R)) efficiently mediates long-lasting protein expression in mouse brain cells beyond five weeks, with detectable expression in some neurons at three months. hm5C saRNA substantially outperforms N1m{Psi} mRNA. In addition to transfecting astrocytes and neurons at the injection site, hm5C saRNA-LNPs label neurons retrogradely. Excitingly, hm5C saRNA-LNPs afford protein expression in human cortical brain slices, with expression emerging within 24 hours and lasting beyond 76 days. Modified saRNA provides new opportunities for mechanistic neuroscience research and therapeutic development.

neuroscience↗

bioRxiv2025

PlantScience.ai: An LLM-Powered Virtual Scientist for Plant Science

The accelerating growth of plant science literature presents a major challenge for researchers seeking to extract accurate, up-to-date knowledge from an increasingly fragmented and domain-specific corpus. General-purpose large language models (LLMs), while powerful, often misinterpret plant science terminology and lack mechanisms for source traceability. We created PlantScience.ai, a virtual plant biology scientist powered by our automated scientific knowledge graph construction pipeline (AutoSKG). PlantScience.ai exhibits expert-level reasoning in plant biology and maintains scholarly rigour in its citations. Through continuous learning, it integrates the latest research, ensuring that its knowledge base remains current and scientifically robust. Apart from providing the answers to the scientific questions, PlantScience.ai can interact with human scientists, follow instructions, and retrieve information with citation awareness, grounding each response in primary sources to ensure accuracy and verifiability. PlantScience.ai marks a pivotal advance toward a collaborative scientific paradigm in which virtual and human plant scientists work synergistically to accelerate discovery while preserving the unique value of human insight. PlantScience.ai is available at https://plantscience.ai.

plant biology↗

bioRxiv2025

XPF mediates 3' flap processing for FEN1-independent Okazaki fragment maturation

Okazaki fragment maturation (OFM), the process that removes RNA-DNA primers, is a major source of DNA replication stress and mutations. It involves Pol{delta}-mediated DNA strand displacement synthesis that produces 5 flaps, FEN1-mediated 5 flap cleavage, and LIG1-catalyzed nick ligation. Recently, we discovered that under stress conditions, yeast cells convert 5 flaps into 3 flaps, which are degraded by 3 flap nucleases to produce ligatable DNA nicks. However, little is known about this stress-induced, 3 flap-based OFM in human cells. Here, we report that 3 flaps frequently form in various human cancer cells, and that FEN1 deficiency significantly enhances 3 flap levels. XPF1 is recruited to the replication forks in FEN1 mutant or FEN1-chemically inhibited cells. Notably, XPF deficiency or inhibition in those defective cells leads to accumulation of 3 flaps, replication-related DNA strand breaks, and unique mutation signatures. Furthermore, XPF and FEN1 inhibitors show synergistic effects in killing human cancer cells. In summary, we demonstrate that 3 flap-based OFM is an important alternative of 5 flap-based OFM in mammalian cells. XPF is a key nuclease to degrade 3 flaps and complete OFM for survival. Targeting this compensatory mechanism could provide new therapeutic strategies to selectively impair cancer cell survival under pre-existed replication stress. HighlightsO_LIXPF is recruited to DNA replication forks in mouse or human cells of functional deficiency of FEN1 due to genetic mutations or chemical inhibition. C_LIO_LIXPF gene deficiency or chemical inhibition results in accumulation of 3 flaps and replicative DNA single-stranded breaks. C_LIO_LIFunctional deficiency of XPF and FEN1 displays a synergy in inducing genome instability and cell death in human cancer cells. C_LI

cell biology↗