Biology subjects

Yan, H.

Publications and source records attributed to Yan, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome

The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. While mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 co-regulates divergent cell fates remains only partially characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome and Down Syndrome associated acute megakaryoblastic leukemia, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Hence, we hypothesized that chromatin accessibility facilitates lineage specificity of GATA1, thereby permitting efficient cellular differentiation. To understand the connection between chromatin accessibility and GATA1, we performed comprehensive studies of erythropoiesis in Stag2{Delta} mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid maturation, increased number of MkPs, and increased megakaryocytes. RNA- and ATAC-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Gata1 occupancy was lost at erythroid targets, while occupancy increased at megakaryocyte targets. Functionally, we observed that Stag2-deficient EryPs have diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays. Human models and primary MDS patients recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study advances the understanding of the interplay between TF function and chromatin accessibility. Moreover, these data suggest a novel conceptual paradigm of dyserythropoiesis in MDS. Key Pointsxxxxx

molecular biology↗

bioRxiv2025

Segmentation Matters: Recognizing the Cell Segmentation Challenge in Spatial Transcriptomics

Probe-based in situ hybridization spatial transcriptomics has emerged as a state-of-the-art for neuroscience research. Accurate segmentation of neurons and non-neuronal cells, a critical step for downstream analysis, remains a big challenge. Using human sensory ganglia neurons as an example, we systematically explore this problem. We evaluated multiple automatic segmentation approaches using quantitative performance metrics and downstream results. We show that careful parameter tuning is essential for achieving accurate segmentation; however, even with optimized parameters, different models still yield distinct classes of errors. To mitigate these errors, we propose a manual quality check, which can validate and refine automated segmentation results. As a future direction, integrating multi-modal imaging data with tailored neural networks may further improve segmentation accuracy. In summary, our results argue that each automated segmentation method has distinct strengths, weaknesses, and characteristic error patterns; and that a manual review is necessary.

neuroscience↗

bioRxiv2025

Rewired NAD+ metabolism promotes NF-κB-mediated oxidative stress and disrupts lipid homeostasis in liver fibrosis progression

Chronic liver fibrosis significantly increases the risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths. However, the molecular mechanisms linking fibrosis to inflammation-associated HCC development remain unclear, complicating early diagnosis and intervention. In this study, we employ multi-omics analyses, including untargeted and targeted metabolomics, lipidomics, and transcriptomics, in a mouse model of chemically induced liver fibrosis and HCC, integrating publicly available transcriptome data from LX-2 human hepatic stellate cell (HSC) line. Our results reveal a profound rewiring of NAD+ metabolism as a central driver of metabolic disturbance. Analysis of bulk liver tissue shows increased activity of the kynurenine pathway of tryptophan metabolism, enhancing NAD+ precursor production. Hepatic nicotinamide (NAM) levels decrease due to elevated expression of NAM N-methyltransferase (Nnmt) in HSCs. Despite reduced hepatic NAM, serum NAD+ level rise and is compartmentalized, triggering a disruption in NAD+ homeostasis and activating NF-{kappa}B-mediated oxidative stress pathways. Moreover, lipid dysregulation occurs, with NF-{kappa}B dominating the regulation of SIRT1/SREBP-controlled lipogenic and cholesterogenic genes, leading to imbalances in hepatic and serum lipids. These insights elucidate connections between NAD+ metabolism, inflammation, and lipid dysregulation, potentially aiding in developing diagnostic biomarkers and therapeutic targets for non-viral HCC. Key PointsO_LIThe integration of untargeted and targeted metabolomics identifies the metabolic pathways that are associated with the development of hepatocellular carcinoma (HCC) and the potential role of disturbances in NAD+ metabolism as a central driver of metabolic dysregulation in hepatic fibrosis, validated across transcriptomics. C_LIO_LIFibrosis-associated HCC is linked to the depletion of nicotinamide and a cascade of metabolic disturbances that promote inflammation and oxidative stress in hepatic stellate cells. C_LIO_LITargeted analysis of the metabolites in the discriminative pathways along a continuum of fibrosis-cirrhosis-HCC discovers several potential tissue and serum biomarkers for monitoring disease progression. C_LIO_LIMulti-omics analysis (i.e., metabolomics, lipidomics, and transcriptomics) reveals complex interplay between NAD+ metabolism, NF-{kappa}B-mediated oxidative stress, and lipid homeostasis in fibrosis-associated HCC development. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/668888v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@e39d72org.highwire.dtl.DTLVardef@175cdc7org.highwire.dtl.DTLVardef@118d707org.highwire.dtl.DTLVardef@1cd3a43_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

A Novel 'Three-in-one' Mucosal Vaccine Elicits Broad Protection against Three Distinct Clusters of ACE2-using Sarbecoviruseses

With the persistent risk of coronavirus epidemics, the development of universal vaccines is urgently needed and challenging to achieve. In this study, we aimed to design a multivalent immunogen to provide broad protection against diverse ACE2-using sarbecoviruses, which pose a significant threat to global health. Our analysis revealed that the receptor-binding domains (RBDs) of ACE2-using sarbecoviruses segregate into three antigenically distinct clusters, including one cluster that encompasses viruses related to SARS-CoV-2. Based on these findings, we engineered a three-in-one immunogen, designated as 3Rs-NC, which incorporates representative RBDs from all three clusters. 3Rs-NC preserved the natural epitope configuration of each monomeric RBD component, and efficiently elicited high levels of neutralizing antibodies against representative viruses and closely related sarbecoviruses. When administered intranasally with flagellin-based mucosal adjuvant KFD, 3Rs-NC induced robust and durable RBD-specific serum IgG and mucosal IgA responses in mice. Furthermore, KFD-adjuvanted 3Rs-NC conferred sustained protection in both the upper and lower respiratory tracts against SARS-CoV-2 Omicron BA.1 and SARS-like coronavirus WIV1. Additionally, 3Rs-NC immunization protected mice from lethal challenge of SARS-like coronavirus rRsSHC014S, with more efficient protection observed in female mice than male mice. This needle-free three-in-one vaccine represents a promising candidate for a universal mucosal vaccine against ACE2-using sarbecoviruses and could serve as a foundational component of three-in-one vaccine series to form a comprehensive coronavirus vaccine package. HighlightO_LInovel three-in-one immunogen 3Rs-NC induced a high level of neutralizing antibodies against three distinct ACE2-using Sabecovirus clusters. C_LIO_LIadministration of 3Rs-NC plus KFD adjuvant (3Rs-NC+KFDi.n) generated potent and long-lasting RBD-specific serum IgG and mucosal IgA. C_LIO_LI3Rs-NC+KFDi.n provided long-term protection in both upper- and lower-respiratory tracts in mice. C_LIO_LI3Rs-NC+KFDi.n could serve as a foundational component for next-generation coronavirus vaccine strategies. C_LI

immunology↗

bioRxiv2025

Comprehensive Multimodal Profiling of Atherosclerosis Reveals Bhlhe40 as a Potential Regulator of Vascular Smooth Muscle Cell Phenotypic Modulation

BackgroundVascular smooth muscle cells (VSMCs) play a central role in atherosclerosis by undergoing phenotypic modulation from a quiescent, contractile state to a range of synthetic phenotypes, including fibroblast-like, macrophage-like, and lipid-laden foam cell-like states. However, a comprehensive multimodal characterization and understanding of the transcriptional programs driving these transitions remain incomplete. MethodsTo comprehensively define the phenotypic diversity of VSMCs during atherosclerosis progression, we performed in-depth profiling using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and bulk RNA sequencing in a VSMC lineage-tracing atherosclerotic mouse model. Insights from these datasets guided the design of targeted in vitro experiments to investigate candidate regulatory mechanisms. ResultsSingle-cell multi-omics revealed extensive cellular heterogeneity within atherosclerotic plaques, including a rare population of VSMC-derived macrophage-like cells, whose presence was confirmed by histological analysis. These studies also identified a substantial population of VSMC-derived foam cells, comprising approximately 70% of all foam cells in the lesions. These cells exhibited activation of gene programs associated with lipid metabolism, proliferation, and tumor-like features. The transcription factor Bhlhe40 emerged as a key regulator of this phenotypic transition, with elevated expression in VSMC-derived foam cells during disease progression. Functional knockdown of Bhlhe40 suppressed VSMC phenotypic switching and foam cell characteristics, underscoring its potential role as a driver of VSMC modulation. ConclusionsThese findings advance our understanding of VSMC phenotypic modulation in atherosclerosis and highlight Bhlhe40 as a key regulator of this process. Elucidating the mechanisms governing VSMC plasticity may offer new therapeutic opportunities to reduce cardiovascular risk by targeting disease-driving cellular transitions.

molecular biology↗

bioRxiv2025

TidyMass2: Advancing LC-MS Untargeted Metabolomics Through Metabolite Origin Inference and Metabolic Feature-based Functional Module Analysis

Untargeted metabolomics provides a direct window into biochemical activities but faces critical challenges in determining metabolite origins and interpreting unannotated metabolic features. Here, we present TidyMass2, an enhanced computational framework for Liquid Chromatography-Mass Spectrometry (LC-MS) untargeted metabolomics that addresses these limitations. TidyMass2 introduces three major innovations compared its predecessor, TidyMass: (1) a comprehensive metabolite origin inference capability that traces metabolites to human, microbial, dietary, pharmaceutical, and environmental sources through integration of 11 metabolite databases containing 532,488 metabolites with source information; (2) a metabolic feature-based functional module analysis approach that bypasses the annotation bottleneck by leveraging metabolic network topology to extract biological insights from unannotated metabolic features; and (3) an intuitive graphical interface that makes advanced metabolomics analyses accessible to researchers without programming expertise. Applied to longitudinal urine metabolomics data from human pregnancy, TidyMass2 identified diverse metabolites originating from human, microbiome, and environment, and uncovered 27 dysregulated metabolic modules. It increased the proportion of biologically interpretable metabolic features from 5.8% to 58.8%, revealing coordinated changes in steroid hormone biosynthesis, carbohydrate metabolism, and amino acid processing. By expanding biological interpretation beyond conventionally MS2 spectra-based annotated metabolites, TidyMass2 enables more comprehensive metabolic phenotyping while upholding strict open-source principles of reproducibility, traceability, and transparency.

bioinformatics↗

bioRxiv2025

Dual MYC and GSPT1 Protein Degrader for MYC-Driven Cancers

Direct targeting of the oncoprotein MYC has long been attempted in cancer therapy, with limited success. We here identify a novel co-regulatory feedback loop of MYC and G1 to S phase transition protein 1 (GSPT1), where MYC promotes transcription of GSPT1, and GSPT1 senses stop codon of MYC to promote its translation. We report on the first-in-class dual MYC/GSPT1 protein degrader, GT19630. GT19630 significantly induced integrated stress response, abrogated oxidative phosphorylation through inhibition of the TCA cycle and induced cell death. Protein degradation of MYC was critical for efficacy of GT19630. GT19630 induced profound anti-proliferative effects and apoptosis agnostic to TP53 in a broad range of cancer cells, and is highly active in vivo in multiple, therapy-resistant hematologic and solid tumor models. Dual MYC/GSPT1 degradation was well tolerated in humanized CrbnI391V mice. In conclusion, we propose a novel treatment approach by directly targeting the MYC-GSPT1 axis in MYC-driven cancers. Statement of significanceMYC has been considered an undruggable protein. We found a targetable, novel positive co-regulatory feedback of MYC and GSPT1, a key translation terminator. The dual MYC/GSPT1 degrader GT19630 is highly active in MYC-driven tumors, with moderate effects on humanized Crbn mice, providing opportunities to improve treatment outcome of MYC-driven cancers.

cancer biology↗

bioRxiv2025

Spatially aligned random partition models on spatially resolved transcriptomics data

We propose spatially aligned random partition (SARP) models for clustering multiple types of experimental units, incorporating dependence in a subvector of the cluster-specific parameters, e.g., a subvector of spatial information, as in the motivating application. The approach is developed for inference about co-localization of immune, stromal, and tumor cell sub-populations. The aim is to understand the recruitment of immune and stromal cell subtypes by tumor cells, formalized as spatial dependence of the corresponding homogeneous cell subpopulations. This is achieved by constructing Bayesian nonparametric random partition models for the different types of cells, with a hierarchically structured prior introducing the desired dependence. Specifically, we use Pitman-Yor priors and add dependence in the base measure for spatial features, while leaving the base measure corresponding to gene expression features a priori independent across different types of cells. Details of the model construction are designed to lead to a convenient MCMC algorithm for posterior inference. Simulation studies show favorable performance in identifying co-localization between types of cells. We apply the proposed approach with colorectal cancer (CRC) data and discover subtypes of immune and stromal cells that are spatially aligned with specific tumor regions.

bioinformatics↗

bioRxiv2025

MKFGO: Integrating Multi-Source Knowledge Fusion with Pre-Trained Language Model for High-Accuracy Protein Function Prediction

Accurately identifying protein functions is essential to understand life mechanisms and thus advance drug discovery. Although biochemical experiments are the gold standard for determining protein functions, they are often time-consuming and labor-intensive. Here, we proposed a novel composite deep-learning method, MKFGO, to infer Gene Ontology (GO) attributes through integrating five complementary pipelines built on multi-source biological data. MKFGO was rigorously benchmarked on 1522 non-redundant proteins, demonstrating superior performance over 11 state-of-the-art function prediction methods. Comprehensive data analyses revealed that the major advantage of MKFGO lies in its two deep-learning components, HFRGO and PLMGO, which derive handcraft features and protein large language model (PLM)-based features, respectively, from protein sequences in different biological views, with effective knowledge fusion at the decision-level. HFRGO leverages an LSTM-attention network embedded with handcraft features, in which the triplet loss-based guilt-by-association strategy is designed to enhance the correlation between feature similarity and function similarity. PLMGO employs the PLM to capture feature embeddings with discriminative functional patterns from sequences. Meanwhile, another three components provide complementary insights for further improving prediction accuracy, driven by protein-protein interaction, GO term probability, and protein-coding gene sequence, respectively. The source codes and models of MKFGO are freely available at https://github.com/yiheng-zhu/MKFGO.

bioinformatics↗

bioRxiv2025

Construction of Complete Telomere-to-Telomere Genome Assembly of the Rabbit Using Haploid Embryonic Stem Cells

The rabbit owns commercial importance in meat and fur production, and also has long served as a valuable animal model in biomedical research. Yet, the complete assembly of a high-quality rabbit reference genome has not been established. Here, we present a telomere-to-telomere (T2T) genome assembly of the New Zealand White (NZW) rabbit, the most complete and accurate rabbit genome to date. Using a haploid embryonic stem cells (haESCs) to overcame the challenges of homologous sequence interference and structural variation, we generate a genome with a contig N50 of 137.71 Mb, anchoring all chromosomes with only three gaps, through integrating long-read sequencing (PacBio HiFi, Oxford Nanopore), Hi-C, and Illumina data. Quality assessments reveal near-complete coverage of the BUSCO mammalian gene set, with 99.61% completeness. Notably, this complete assembly allowed for the first comprehensive annotation of the rabbit immunoglobulin loci and major histocompatibility complex region, which were previously unresolved in earlier genome versions. The NZW-T2T assembly based on haESCs not only provides a critical resource for advancing rabbit-based research, but also set a new benchmark for de novo genome assembly for other animals with complex genome.

genomics↗

bioRxiv2025

Hyper-responsiveness of cancer stem cells to microenvironmental cues controls metastasis and therapy response through YAP/TAZ/TEAD

Cancer stem cells (CSCs) are key drivers of metastasis and therapy resistance but have been challenging to visualize and study in situ. Using a fluorescent CSC reporter, we observed very different population dynamics for CSCs and nonCSCs during metastatic lung colonization in breast cancer models. CSC expansive self-renewal drives early lesion formation before switching to a maintenance mode of balanced self-renewal and differentiation, whereupon nonCSC proliferation takes over as the main driver of metastatic expansion. Mechanistic analyses showed that CSCs are hyper-responsive to microenvironmental cues such as cell crowding and nutrient availability, suggesting a novel role for CSCs as sensors and early responders to fluctuating local conditions in the tumor. Incoming signals converge on YAP/TAZ/TEAD, with heightened CSC sensitivity and response supported by elevated receptor expression and increased chromatin accessibility around enhancers with TEAD binding sites. Targeting inputs to the YAP/TAZ/TEAD node reversed chemotherapy-induced enrichment of CSCs in lung metastases. HighlightsO_LIDifferent population dynamics for breast cancer stem cells (CSCs) and their differentiated progeny in early metastatic colonization C_LIO_LICSCs are hyper-responsive to microenvironmental cues and serve as sensors of local conditions for the tumor C_LIO_LIMany microenvironmental inputs converge on YAP/TAZ to regulate self-renewal vs differentiation fate decisions in the CSC C_LIO_LITargeting YAP/TAZ input pathways blocks chemotherapy-induced enrichment of CSCs C_LI

cancer biology↗

bioRxiv2025

Physical Activity and Depressive Mood Shared the Structural Connectivity between Motor and Reward Network: a population-based study from the UK Biobank

BackgroundExercise has been revealed to leave a positive effect on alleviating depressive symptoms by various existing studies. However, the neural basis behind this phenomenon remains unknown, as well as its underlying biological mechanism.AimsUsing a large neuroimaging cohort from UK Biobank, this study aimed to identify structural connectivity (SC) patterns simultaneously linked with physical activity and depression, as well as its biological interpretation.Method492 participants with major depression disorder (MDD) and 535 healthy controls (HC) were extracted from the UK Biobank dataset. Partial least squares regression was first utilized to explore a replicable SC pattern simultaneously associated with physical activity and depressive mood. The neuromaps toolbox was applied to interpret the biological ontologies of the identified SC pattern. Neuroimaging-transcriptome association and enrichment analyses were conducted to explore its underlying genetic basis, pathways and cell types. The reproducibility and generalizability were tested on another independent MDD dataset (N=3,496) and bipolar disorder (BD) dataset (N=81).ResultsA SC pattern linked with exercise was identified to be both significantly correlated with depressive mood and group discriminative between MDDs and HCs, which primarily located between the motor-related regions and reward-related regions. This pattern was associated with multiple neurotransmitter receptors, such as serotonin and GABA receptors, and enriched in pathways like synaptic signaling and astrocytes cell type. The SC pattern and genetic results were also replicated in another independent MDD dataset and present commonalities with BD.ConclusionsThis study not only initially identified a reproducible shared SC pattern between physical activity and depressive mood, but also elucidated the underlying biological mechanisms, which enhanced our understanding of how exercise helps alleviate depression and may inform the development of novel neuromodulation targets.

neuroscience↗

bioRxiv2025

Scaling up spatial transcriptomics for large-sized tissues: uncovering cellular-level tissue architecture beyond conventional platforms with iSCALE

Recent advances in spatial transcriptomics (ST) technologies have transformed our ability to profile gene expression while retaining the crucial spatial context within tissues. However, existing ST platforms suffer from high costs, long turnaround times, low resolution, limited gene coverage, and small tissue capture areas, which hinder their broad applications. Here we present iSCALE, a method that predicts super-resolution gene expression and automatically annotates cellular-level tissue architecture for large-sized tissues that exceed the capture areas of standard ST platforms. The accuracy of iSCALE were validated by comprehensive evaluations, involving benchmarking experiments, immunohistochemistry staining, and manual annotation by pathologists. When applied to multiple sclerosis human brain samples, iSCALE uncovered lesion associated cellular characteristics that were undetectable by conventional ST experiments. Our results demonstrate iSCALEs utility in analyzing large-sized tissues with automatic and unbiased tissue annotation, inferring cell type composition, and pinpointing regions of interest for features not discernible through human visual assessment.

genomics↗

bioRxiv2025

scWGBS-GPT: A Foundation Model for Capturing Long-Range CpG Dependencies in Single-Cell Whole-Genome Bisulfite Sequencing to Enhance Epigenetic Analysis

Single-cell DNA methylomes are challenging to interpret because of sparse CpG coverage and the complexity of genome-wide sequences. We present scDNAm-GPT, a universal foundation model that uses context-aware CpG tokenization, a Mamba backbone, and cross-attention to capture both local and global DNA methylation patterns. Trained on over one million single cells from 35 human and mouse tissues, scDNAm-GPT enables accurate cell clustering, zero-shot prediction of CpG effects on gene expression, improved trajectory inference, and reference-free deconvolution of cell types from cell-free DNA. The model hierarchically learns regulatory features, and its attention maps highlight functionally relevant regions, demonstrating high biological interpretability. These results establish scDNAm-GPT as a scalable and generalizable framework for single-cell epigenomic analysis, offering new opportunities to dissect epigenetic regulation in health and disease. Code is available at GitHub (https://github.com/ChaoqiLiang/scDNAm-GPT).

bioinformatics↗

bioRxiv2025

ACE2 utilization of HKU25 clade MERS-related coronaviruses with broad geographic distribution

Dipeptidyl peptidase-4 (DPP4) is a well-established receptor for several MERS-related coronaviruses (MERSr-CoVs) isolated from humans, camels, pangolins, and bats (1-6). However, the receptor usage of many genetically diverse bat MERSr-CoVs with broad geographical distributions remains poorly understood. Recent studies have identified angiotensin-converting enzyme 2 (ACE2) as an entry receptor for multiple merbecovirus clades. Here, using viral antigen and pseudovirus-based functional assays, we demonstrate that several bat merbecoviruses from the HKU25 clade previously thought to utilize DPP4 (7), employ ACE2 as their functional receptor. Cryo-electron microscopy analysis revealed that HsItaly2011 and VsCoV-a7 recognize ACE2 with a binding mode sharing similarity with that of HKU5 but involving remodeled interfaces and distinct ortholog selectivity, suggesting a common evolutionary origin of ACE2 utilization for these two clades of viruses. EjCoV-3, a strain closely related to the DPP4-using MERSr-CoV BtCoV-422, exhibited relatively broad ACE2 ortholog tropism and could utilize human ACE2 albeit suboptimally. Despite differences in entry mechanisms and spike proteolytic activation compared to MERS-CoV, these viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors. These findings redefine our understanding of the evolution of receptor usage among MERSr-CoVs and highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses. SignificanceRecent studies unexpectedly revealed that several merbecoviruses convergently evolved ACE2 receptor usage with distinct binding modes across three continents, challenging the dogma that DPP4 is their primary receptor. Here, we demonstrate that HKU25 clade MERS-related coronaviruses broadly distributed across Eurasia utilize ACE2 as host receptor through a binding mode shared with HKU5, challenging prior findings. These findings reveal a prevalence of ACE2 usage in diverse MERS-related coronaviruses in bats and show that EjCoV-3 is preadapted to use human ACE2, suggesting a potential for spillover. Our data provide a blueprint of host receptor barrier determinants which will facilitate global surveillance and development of countermeasures against these poorly characterized merbecoviruses.

microbiology↗

bioRxiv2025

Plat safeguards maternally aged oocytes against programmed cell death through activating the Erk1/2 pathway

The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice, morphologically defective aged oocytes are identified with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is downregulated with oocyte aging, and Plat knockdown increases oocytes susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through programmed cell death. Supplementing exogenous tPA in in vitro oocyte maturation cultures reduces defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from programmed cell death, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.

developmental biology↗

bioRxiv2024

Neural Circuit Mechanisms Underlying Dominance Traits and Social Competition

The survival of animals often hinges on their dominance status, established through repeated social competitions. The dorsomedial prefrontal cortex (dmPFC) plays a pivotal role in regulating these competitions, yet the formation of intrinsic traits like grit and aggressiveness, crucial for competitive outcomes, remains poorly understood. In this study, we constructed a dmPFC circuit model based on experimental recordings to replicate the characteristic activities of dmPFC neurons during various behavioral patterns observed in the dominance tube test. Our findings reveal that the dmPFC circuit supports bistable behavior states--effortful and passive--depending on external conditions. This bistability is essential for understanding how animals adapt their behaviors in social competitions, thereby influencing the establishment of social hierarchies. Our results indicate that increased self-excitation in pyramidal neurons within the dmPFC enhances the robustness of effortful behaviors, akin to perseverance, but reduces flexibility in responding to rapid external changes. This suggests that dominance status benefits more from perseverance than from increased aggression. Additionally, our study shows that when rapid responses to external signals are necessary, the basal activity in dmPFC neurons can be reconfigured to enhance flexibility, albeit at higher energy costs. This research advances our understanding of the neural basis of social behavior and provides a framework for further exploration into how neural circuits contribute to complex behavioral traits, offering insights into the neural dynamics underlying social dominance. This research also opens avenues for investigating psychiatric and neurological disorders where these mechanisms may be disrupted.

biophysics↗

bioRxiv2024

Mapping Pesticide-Induced Metabolic Alterations in Human Gut Bacteria

Pesticides can modulate gut microbiota (GM) composition, but their specific effects on GM remain largely elusive. Our study demonstrated that pesticides inhibit or promote growth in various GM species, even at low concentrations, and can accumulate in GM to prolong their presence in the host. Meanwhile, the pesticide induced changes in GM composition are associated with significant alterations in gut bacterial metabolism that reflected by the changes of hundreds of metabolites. We generated a pesticide-GM-metabolites (PMM) network that not only reveals pesticide-sensitive gut bacteria species but also report specific metabolic changes in 306 pesticide-GM pairs (PGPs). Using an in vivo mice model, we further demonstrated a PGPs interactions and verified the inflammation-inducing effects of pesticides on the host through dysregulated lipid metabolism of microbes. Taken together, our findings generate a PMM interactions atlas, and shed light on the molecular level of how pesticides impact host health by modulating GM metabolism. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/623895v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@17ed5f5org.highwire.dtl.DTLVardef@10d3e0org.highwire.dtl.DTLVardef@c61b43org.highwire.dtl.DTLVardef@27d035_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗