Biology subjects

Lyu, Q.

Publications and source records attributed to Lyu, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

A hypothalamic dynorphin-KOR pathway that orchestrates male sexual behavior under sexual competition

In nature, males often attack rivals before mating, yet how aggression shapes mating strategies remains unclear. Using a laboratory sexual competition model with optogenetics, calcium imaging, and pharmacology, we found that aggressive male mice attack competitors before mating, whereas social males mate promptly. This delay is mediated by Gi-coupled kappa-opioid receptor-expressing GABAergic interneurons in the medial preoptic area (MPOAKOR), recruited by estrogen receptor 1-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvlEsr1), which inhibit MPOAEsr1 mating neurons. VMHvlEsr1 neurons activate MPOAKOR neurons through direct glutamatergic transmission and indirect disinhibition by suppressing dynorphin release from prodynorphin-expressing arcuate nucleus terminals (ArcPdyn). During rival encounters, aggressive males show a greater MPOA dynorphin decline and stronger MPOAKOR activity than social males. Thus, a VMHvlEsr1/ArcPdyn[->]MPOAKOR[->]MPOAEsr1 circuit gates mating according to prior aggressive experience, explaining how social competition shapes reproductive strategies.

neuroscience↗

bioRxiv2026

PCC1 treatment reshapes ribosomal, lysosomal and membrane-lipid transcriptional programs in therapy-induced senescent human stromal cells

Cellular senescence combines stable proliferative arrest with extensive changes in secretory, metabolic and organelle programs. Procyanidin C1 (PCC1) has dose-dependent senomorphic and senolytic activity, but the structure of its transcriptome-wide response is not well defined. We reanalyzed published RNA-sequencing counts from bleomycin-induced senescent PSC27 human stromal cells treated with 50 {micro}M PCC1. The primary contrast contained three independent biological replicates per condition. PCC1 altered 8,420 genes at adjusted P<0.05 and absolute log2 fold change[≥]1. Ribosomal genes showed the clearest coordinated response, followed by lysosomal genes. Analysis across the full ontologies also identified lysosomal-membrane, proton-transport, late-endosome, lipid-localization, cholesterol and fatty-acid programs. Prespecified analyses revealed two trajectories relative to senescence. Lipid-transport, lipid-binding and plasma-membrane programs decreased during senescence and increased after PCC1, whereas lysosomal-membrane, mitochondrial-membrane, cholesterol and ion-transport programs increased in both contrasts. Senescence-associated outputs were more selective. A prespecified SASP-effector score decreased, but a broad Reactome SASP set did not pass false-discovery correction. AP-1-family expression shifted, and an HSP90/HSF1/proteostasis panel increased. Together, these data support a model in which PCC1 induces coordinated transcriptomic remodeling in senescent stromal cells, encompassing membrane-lipid remodeling, changes in cellular infrastructure, and selective modulation of senescence-associated outputs.

bioinformatics↗

bioRxiv2026

Atherosclerosis destabilizes regulatory T cells (Tregs) resulting in multiple families of exTregs

How regulatory T cells (Tregs) lose lineage identity during chronic inflammation remains poorly understood. Here, using inducible Foxp3 lineage tracing together with single-cell transcriptomic, proteomic and T cell receptor (TCR) profiling in atherosclerosis-prone mice, we identify Treg destabilization as a staged and branching differentiation process rather than an abrupt loss of lineage identity. Conventional Tregs (cTregs) first transition through an effector Treg (eTreg) intermediate characterized by attenuation of the CD25-STAT5 axis while retaining core Treg features, before diversifying into eight transcriptionally distinct exTreg states, including Tfh-like, cytotoxic, Th1-like inflammatory, Th1-like cytotoxic and proliferative populations. Trajectory inference, TCR clonotype analysis and experimental Treg-to-exTreg conversion independently converged on this developmental framework, revealing that clonally related exTregs acquire distinct effector programs. Mechanistically, we identify Treg-intrinsic IL-6R signaling as an important driver of this process. IL-6 accelerated exTreg generation in vitro, whereas Treg-specific deletion of Il6ra reduced inflammatory exTreg differentiation and attenuated atherosclerosis in vivo. Together, these findings establish a framework for Treg destabilization during atherosclerosis and provide a conceptual basis for preserving Treg lineage stability in chronic inflammatory disease.

immunology↗

bioRxiv2026

Talin-1 determines the direction of primary mouse neutrophils migrating in vivo

Talin-1 is essential for {beta}2 integrin activation in neutrophils, yet its dynamic behavior during neutrophil trafficking in vivo remains poorly understood. Here, we generated EGFP-talin1 knock-in mice, enabling real-time visualization of talin-1 dynamics under physiological conditions. EGFP-talin1 is robustly expressed and preserves without altering {beta}2 integrin expression and activation. Using total internal reflection fluorescence (TIRF) microscopy under flow, we found that talin-1 was rapidly recruited to the plasma membrane during rolling and accumulates further during neutrophil arrest. Intravital microscopy revealed highly dynamic and stage-specific talin-1 redistribution during luminal crawling, transendothelial migration, and interstitial migration. Talin-1 preferentially accumulated at endothelial contact sites during crawling and polarized toward the leading edge during directional migration. These findings establish EGFP-talin1 knock-in mice as platform for visualizing integrin-associated cytoskeletal dynamics in vivo and identify dynamic talin-1 polarization as a feature of neutrophil trafficking.

immunology↗

bioRxiv2026

Immunometabolic Remodeling of Perivascular Adipose Tissue in Murine Lupus: Implications for Lupus Vasculopathy

BackgroundPatients with systemic lupus erythematosus (SLE) face markedly increased cardiovascular disease (CVD) risk driven by mechanisms beyond traditional risk factors. Thoracic aortic perivascular adipose tissue (tPVAT) is dysfunctional in lupus and exacerbates endothelial dysfunction, yet the molecular basis of this dysfunction remains poorly defined. MethodsIntegrated multi-omics profiling, including bulk RNA-seq, untargeted proteomics, lipidomics, and high-dimensional spectral flow cytometry, was performed on tPVAT from 15-week-old MRL/lpr mice (active lupus, n = 4-6) and MRL control mice (n = 5-6). Adipogenic differentiation capacity of tPVAT adipose stromal and progenitor cells (ASPCs) from MRL/lpr was assessed by Oil Red O staining at 5 (pre-dieasea) and 15 weeks (active disease), with subcutaneous ASPCs used as depot controls. ResultsTranscriptomic profiling of tPVAT from MRL/lpr mice identified 2,742 upregulated and 1,494 downregulated genes (adjusted p < 0.001, |log2FC| > 1), with strong activation of interferon, IL6-JAK-STAT3, and TNFA signaling pathways together with suppression of fatty acid metabolism, oxidative phosphorylation, and adipogenic pathways. Proteomic and lipidomic analyses were concordant, revealing broad downregulation of mitochondrial bioenergetic machinery, depletion of cardiolipin and acylcarnitines, and enrichment of ceramide phosphoinositols and lysophosphatidylcholines. Cardiolipin strongly correlated with the mitochondrial/metabolic protein module (r = 0.95) and inversely with the immune/inflammatory protein module (r = -0.92). Spectral flow cytometry confirmed marked CD45+ leukocyte infiltration dominated by T cells, together with a significantly reduced Treg/CD4+ ratio indicating loss of local immunoregulatory balance. ASPCs derived from PVAT of 15-week-old MRL/lpr mice exhibited impaired white and beige adipogenic differentiation, while APCs from PVAT of 5-week-old MRL/lpr mice, and from subcutaneous adipose tissues of 15-week-old MRL/lpr mice, had normal white and beige differentiation, consistent with an acquired, depot-specific, disease-stage-dependent progenitor defect in PVAT of MRL/lpr mice. ConclusionsLupus tPVAT undergoes a concordant cross-platform molecular reprogramming of mitochondrial bioenergetic genes coupled with establishment of an interferon-dominant immune niche and acquired loss of ASPC adipogenic capacity. These findings provide a molecular framework for lupus PVAT dysfunction and identify restoration of mitochondrial function, suppression of interferon-driven inflammation, and renewal of progenitor differentiation as potential therapeutic strategies for lupus vasculopathy.

molecular biology↗

bioRxiv2026

Retinoic acid resolves the conflict between X-chromosome inactivation and pluripotency program in female cleavage-stage embryos

The tight coupling of X-chromosome inactivation (XCI) and pluripotency is a paradigm of holistic developmental regulation, and their inverse correlation enables XCI establishment during implantation. In contrast, the co-establishment of imprinted XCI (iXCI) and pluripotency program in female preimplantation embryos challenges the holistic pattern, but how embryos coordinate the two remains unknown. Here, we find that Nanog during the cleavage stage strongly represses the co-upregulated Rnf12-Xist axis, the triggering signaling of iXCI, creating a conflict that threatens iXCI. We identify retinoic acid (RA) as the coordinator that resolves the conflict and safeguards iXCI. RA activates its receptor RARG to evict NANOG from Rnf12 5region, avoiding NANOGs threat. In vivo, either maternal vitamin A deficiency or embryonic RA synthesis defects results in impaired iXCI and female-biased embryonic lethality. Thus, we highlight RA as a master regulator to holistically balance iXCI and pluripotency during cleavage stages, thereby ensuring proper female embryogenesis.

developmental biology↗

bioRxiv2026

Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia

The central apparatus of motile cilia, consisting of central microtubules and various protein projections, is essential for dictating the ciliary movement. Although three proteins (FAP65, FAP147, and FAP70) have been localized to the C2a projection in Chlamydomonas reinhardtii, the full protein composition and functional roles of the vertebrate C2a remain inadequately defined. Here, we use three knockout mouse models corresponding to their respective homologs (Ccdc108, Mycbpap, and Cfap70) to systematically investigate their functions in vertebrates. Notably, all three knockout strains exhibit distinct phenotypes related to primary ciliary dyskinesia (PCD), including hydrocephalus and sinusitis. The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one anothers stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules and ultimately alters the ciliary movement pattern. Furthermore, we significantly expand the vertebrate C2a proteome by identifying ARMC3 and MYCBP as additional C2a components. Collectively, our findings illuminate the proteomic composition and strict physiological requirements of the vertebrate C2a projection, providing new insights into the molecular pathogenesis of PCD. Impact StatementDeficiency in any of the interdependent C2a proteins (CCDC108, MYCBPAP, and CFAP70) collapses this central pair microtubule-associated projection, disrupting vertebrate ciliary movement and causing primary ciliary dyskinesia phenotypes in mice.

cell biology↗

bioRxiv2025

Fast and slow architectures of cortical dynamics in human brain

The human brain operates across a vast temporal range, from fast perception and action to slow physiological regulation. The capacity has attributed to a unitary cortical gradient of intrinsic timescales, yet such a unidimensional model cannot explain how local circuits simulateously support both rapid external behavior and slow internal body-coupled dynamics. Using SPLIT (spectral piecewise-linear inference of timescales) on a large-scale intracranial stereo-electroencephalography (8,619 contacts, 185 individuals), we identified dissociable fast (~10-100 Hz) and slow (~1-10 Hz) temporal components. Only the fast-component timescales followed the canonical sensorimotor-to-association cortical hierarchy. Slow-component timescales showed no hierarchical gradient, but were instead covaried with heart rate and enriched at site with heart-related neural responses. This dual temporal architecture persisted across wakefulness, rest, sleep, and anesthesia, challenging the unitary view of brain timescales and revealing an intrinsic bipartite organization that is associated with cortical hierarchy or neurophysiology.

neuroscience↗

bioRxiv2025

High-throughput in silico screen uncovers key regulators of 3D genome architecture

The vertebrate genome is spatially organized into topologically associating domains (TADs), primarily via cohesin-mediated loop extrusion which typically halts at convergent CTCF binding sites to establish domain boundaries. However, despite the essential roles of CTCF and cohesin in establishing TADs, a long-standing paradox persists: CTCF and cohesin binding sites dramatically outnumber observed TAD boundaries, suggesting the existence of undiscovered architectural factors. To identify such missing factors, we conducted high-resolution in silico screens using C.Origami, a multi-modal AI model for predicting chromatin interactions. Remarkably, we identified ZNF654 and JMJD6 as novel factors uniquely defining TAD boundaries. Experimental validation confirmed that ZNF654, an uncharacterized vertebrate-specific zinc-finger protein, interacts with CTCF to form an architectural protein complex that demarcates chromatin domains. Genetic knockout of ZNF654 weakens TAD boundary strength without influencing other CTCF or cohesin binding sites. JMJD6, a deeply conserved jmjC-family dioxygenase, marks the anchors of the strongest chromatin stripes at both TAD boundaries and enhancer-promoter sites, while deleting JMJD6 weakens or diminishes such interaction signature. These results revealed the long-sought factors that uniquely mark TAD boundary and chromatin interaction anchors which, together with CTCF and cohesin, demarcate chromatin domains during 3D genome organization. Last, the evolutionary trajectory of ZNF654 and JMJD6 offers key insight into the evolutionary origins of 3D genome organization across metazoan species.

genomics↗

bioRxiv2025

Sexually Dimorphic Transdifferentiation of Endothelial Cells in Atherosclerosis

ObjectiveTo elucidate the sex-specific trajectories of endothelial cell (EC) transdifferentiation and their contribution to distinct atherosclerotic plaque phenotypes in males and females. Approach and ResultsWe utilized Cdh5-CreERT2/Apoe-/-/Rosa26-mTmG lineage-tracing mice to perform single-nucleus RNA sequencing (snRNA-seq) of aortic tissues from male, female, and ovariectomized female mice following 12 weeks of high-fat diet. We mapped high-resolution EC fates, identifying distinct transdifferentiation routes into smooth muscle cell (SMC)-like, adipocyte-like, macrophage-like, and fibroblast-like cells. Females exhibited higher overall EC plasticity with a preference for SMC-like and metabolically active adipocyte-like trajectories, contributing to plaque stability. Conversely, male ECs favored inflammatory macrophage-like and stress-responsive fates. Trajectory analysis revealed a novel direct EC-to-adipocyte-like transition that bypasses the canonical endothelial-to-mesenchymal transition (EndoMT). Gene regulatory network analysis, validated by in vitro knockdown assays, identified KLF2 as a homeostatic brake on transdifferentiation, while CREB5 and ESRRG emerged as critical molecular switches governing the bifurcation between adipogenic and myogenic fates. Ovariectomy in females shifted the transcriptomic landscape toward a male-like, lipid-anabolic phenotype. ConclusionsEC plasticity is a sex-dimorphic process driving differential plaque composition. We identify a novel, direct EC-to-adipocyte trajectory and pinpoint KLF2 and CREB5 as key regulators, offering new mechanistic insights into why premenopausal women develop more stable atherosclerotic lesions than men.

pathology↗

bioRxiv2025

Stage-resolved Spatial Multi-omics Reveals Myeloid Niches in Human Atherosclerotic Plaques

BackgroundAtherosclerosis, a leading cause of heart attack and stroke, involves intricate immune cell dynamics within arterial plaques, yet their spatial organization and functional roles remain elusive. MethodsWe combined Visium HD spatial transcriptomics, imaging mass cytometry, and single-cell RNA-seq across fatty-streak, advanced, and restenotic plaques to map myeloid architectures and relate them to lesion geography and extracellular matrix features. Slingshot trajectory analysis resolved macrophages differentiation path. In vitro, we tested microenvironmental and lipid cues separately: fibronectin (FN) exposure during PMA-driven THP-1 differentiation and oxidized LDL (oxLDL)-induced foam cell formation in murine bone-marrow derived macrophages (BMDMs). ResultsOur analysis identified seven macrophage subsets and two neutrophil populations with distinct spatial distribution and functional roles. In early lesions, neutrophils expressing MMP9, MPO, p47phox, TGF-{beta}1 and arachidonate 5-lipoxygenase (ALOX5), aligned with proteolysis, inflammatory processes, and endothelial-mesenchymal transition features. In advanced plaques, macrophage subsets exhibit specialized functions: Ki67+ proliferative macrophages localized near necrotic cores, sustaining local population; SPP1+ macrophages, enriched in lipid handling and tissue remodeling, are prone to apoptosis/ferroptosis, potentially promoting necrotic core expansion; and C3aR+ macrophages form antigen-presenting niches with elevated HLA-DR and CD74, engaging T cells possibly through CXCL12-CXCR4 signaling. Slingshot trajectories indicated progression from C3aR toward SPP1 remodeling states concentrated at fibronectin-rich rims. In vitro, FN increased MMP9 and TIMP1 in THP-1-derived macrophages, consistent with FN imprinting remodeling features characteristic of SPP1 macrophages in situ. Concurrently, oxLDL-treated BMDMs showed enhanced lipid-handling and remodeling modules consistent with the SPP1 program. ConclusionsThese findings define conserved myeloid niches and support a microenvironment-imprinting model that links ECM composition and lipid loading to macrophage state transitions, providing a framework for microenvironment-targeted therapies to stabilize plaques and mitigate cardiovascular risk.

pathology↗

bioRxiv2025

Tree species shape ectomycorrhizal fungal traits and community composition through litter quality and resultant soil properties

Ectomycorrhizal (ECM) fungi are key components of the nitrogen (N) and carbon (C) cycles in temperate and boreal forests soils. However, it is still unclear how differences in soil properties driven by litter quality shape ECM fungal diversity and composition. To test this, we used a unique common garden experiment in Denmark which included three common European tree species, lime, beech, and Norway spruce, each associated with contrasting litter quality from fast-to slow-turnover respectively. We found that soil physicochemical properties varied significantly among tree species, with spruce soils having higher soil organic matter (SOM), phosphorus (P), inorganic N and lower pH, than beech and lime. A total of 1,248 ECM root tips were selected for Sanger sequencing and individually assessed for the presence of hyphae and/or rhizomorphs protruding from the fungal mantle. Sequencing revealed 133 fungal amplicon sequence variants (ASVs), clustered in 86 fungal operational taxonomic units (OTUs), from which 61 corresponded to ECM fungi. Compared to spruce, lime and beech supported a higher ECM fungal richness and diversity in lime and beech compared to spruce. The ECM fungal community composition differed significantly between broadleaved species and spruce, with Russula dominating in lime and beech. Regarding fungal traits, in addition to the direct observations of hyphae and rhizomorphs, species were also scored based on literature for exploration types and hyphae hydrophobicity. Tree species had a specific association with ECM fungal exploration types, with broadleaved species favoring contact and short-distance types and spruce associating with long-distance types. The results suggest that tree species via foliar litter quality have a direct impact on soil properties and indirect to the ECM fungal community, where broadleaved tree species with nutrient-rich and rapid decomposing litter support a more diverse ECM community with limited soil exploration capabilities, while spruce supports an ECM fungal community more adapted to soil exploration.

ecology↗

bioRxiv2025

Rapid and accurate protein structure database search using inverse folding model and contrastive learning

Protein structure database search has become increasingly challenging due to the growing number of experimental and computational structures. We introduce mTM-align2, a novel two-step approach for rapid and accurate protein structure database search. In the first step, protein structures are first transformed into embeddings using a pre-trained inverse folding model (ESM-IF) and 3D Zernike polynomials. The ESM-IF embeddings are further optimized through a contrastive learning network, which is trained on [~]7 million structure pairs. Structures with similar embeddings are returned on the fly in this step. The second step employs a rapid structure alignment program to refine top candidates, ensuring high precision and producing high-quality alignments. Extensive benchmarks reveal that mTM-align2 performs competitively compared to other leading methods, completing monomeric structure search in seconds with over 90% precision for the top 10 hits. The t-SNE visualization of the mTM-align2 embeddings for thousands of structures demonstrates that our embeddings are structurally informed, capturing the global structural features. It uncovers insights such as structure misclassifications and ambiguous structural class boundaries. A web server for mTM-align2 is accessible at https://yanglab.qd.sdu.edu.cn/mTM-align/.

bioinformatics↗

bioRxiv2025

Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis

Mutations in mitochondrial DNA (mtDNA) can lead to mitochondrial and cellular dysfunction. However, recent studies suggest that there is purifying selection against mutant mtDNAs during transgenerational transmission. We investigated the mtDNA dynamics during ovarian follicle development. Using base-editing, we generated mice harboring a 3177 G>A mutation corresponding to the human Leber hereditary optic neuropathy (LHON)-related mtDNA mutation and confirmed the transgenerational reduction of mutant mtDNA. Using a mouse follicle culture system in which pathogenic mtDNA mutations were introduced in vitro followed by mtDNA sequencing and digital PCR, we found this germline heteroplasmy shift during early folliculogenesis was induced by the decrease of mutant mtDNA together with compensatory replication of wild-type mtDNA. In contrast, synonymous mtDNA mutations did not impact the mtDNA dynamics. These findings show that mice can eliminate certain pathogenic mtDNA mutations in the germline during early folliculogenesis, maintaining mitochondrial integrity across generations.

genetics↗

bioRxiv2023

A wave of minor de novo DNA methylation initiates in mouse 8-cell embryos and co-regulates imprinted X- chromosome inactivation

DNA methylation is extensively reprogrammed during early stage of mammalian development and is essential for normal embryogenesis. It is well established that mouse embryos acquire genome-wide DNA methylation during implantation, referred to as de novo DNA methylation, from globally hypomethylated blastocysts. However, the fact that the main de novo DNA methyltransferase 3B (DNMT3B) is initially expressed as early as the 8-cell stage, contradicts the current knowledge about timing of initiation of de novo DNA methylation. Here, we reported that a previously overlooked minor wave of de novo DNA methylation initially occurs during the transition from the 8-cell to blastocyst stage, before the well-known large-scale de novo DNA methylation during implantation. Functional analyses indicated that minor de novo DNA methylation regulates proliferation, lineage differentiation and metabolic homeostasis of preimplantation embryos, and is critical for embryonic developmental potential and pregnancy outcomes. Furthermore, bioinformatic and functional analyses indicated that minor de novo DNA methylation preferentially occurs on the X chromosome and co-regulates imprinted X-chromosome inactivation via the interaction between DNMT3B and polycomb repressive complexes 2 core components during blastocyst formation. Thus, our study updates the current knowledge of embryonic de novo DNA methylation, thereby providing a novel insight of early embryonic epigenetic reprogramming. Summary statementA minor wave of de novo DNA methylation has been initiated prior to blastocyst formation, but not during the implantation period, and co-regulates imprinted X-chromosome inactivation.

developmental biology↗

bioRxiv2023

INKILN is a novel long noncoding RNA promoting vascular smooth muscle inflammation

BackgroundActivation of vascular smooth muscle cells (VSMCs) inflammation is vital to initiate vascular disease. However, the role of human-specific long noncoding RNAs (lncRNAs) in VSMC inflammation is poorly understood. MethodsBulk RNA-seq in differentiated human VSMCs revealed a novel human-specific lncRNA called INflammatory MKL1 Interacting Long Noncoding RNA (INKILN). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation and human atherosclerosis and abdominal aortic aneurysm (AAA) samples. The transcriptional regulation of INKILN was determined through luciferase reporter system and chromatin immunoprecipitation assay. Both loss- and gain-of-function approaches and multiple RNA-protein and protein-protein interaction assays were utilized to uncover the role of INKILN in VSMC proinflammatory gene program and underlying mechanisms. Bacterial Artificial Chromosome (BAC) transgenic (Tg) mice were utilized to study INKLIN expression and function in ligation injury-induced neointimal formation. ResultsINKILN expression is downregulated in contractile VSMCs and induced by human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-{kappa}B site within its proximal promoter. INKILN activates the proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. Mechanistically, INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-{kappa}B pathway. INKILN depletion blocks ILI{beta}-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1, and the luciferase activity of an NF-{kappa}B reporter. Further, INKILN knockdown enhances MKL1 ubiquitination, likely through the reduced physical interaction with the deubiquitinating enzyme, USP10. INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in BAC Tg mice. ConclusionsThese findings elucidate an important pathway of VSMC inflammation involving an INKILN/MKL1/USP10 regulatory axis. Human BAC Tg mice offer a novel and physiologically relevant approach for investigating human-specific lncRNAs under vascular disease conditions.

molecular biology↗

bioRxiv2022

An Inducible Cre Mouse with Preferential Activity in Vascular Smooth Muscle Evades a Previously Lethal Intestinal Phenotype

All smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a new tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed limited activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice displayed high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains, including Myh11-CreERT2, where SMC gene loss results in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.

genetics↗

bioRxiv2021

Dietary Exposure to Antibiotic Residues Facilitates Metabolic Disorder by Altering the Gut Microbiota and Bile Acid Composition

Antibiotics used as growth promoters in livestock and animal husbandry can be detected in animal-derived food. Epidemiological studies have implicated that exposure to these antibiotic residues in food may be associated to childhood obesity. Herein, the effect of exposure to residual dose of tylosin--an antibiotic growth promoter--on host metabolism and gut microbiota was explored in vivo. Theoretical maximal daily intake (TMDI) doses of tylosin were found to facilitate high-fat diet-induced obesity, induce insulin resistance, and perturb the composition of gut microbiota in mice. The obesity-related phenotypes were transferrable to germ-free recipient mice, indicating that the effects of TMDI dose of tylosin on obesity and insulin resistance occurred mainly via alteration of the gut microbiota. Tylosin TMDI exposure restricted to early life, which is the critical period of gut microbiota development, altered the abundance of specific bacteria related to host metabolic homeostasis later in life. Moreover, early-life exposure to tylosin TMDI was sufficient to modify the ratio of primary to secondary bile acids, thereby inducing lasting metabolic consequences via the downstream FGF15 signaling pathway. Altogether, these findings demonstrate that exposure to very low dose of antibiotic residues, whether continuously or in early life, can exert long-lasting effects on host metabolism by altering gut microbiota and its metabolites. ImportanceEvidence has indicated that chronic exposure to antibiotic residues in food could contribute to obesity. However, few studies have investigated the effect of chronic exposure to very low-dose antibiotic residue in food (~1000-fold lower than the therapeutic dose) on gut microbiota and host metabolism. Our study demonstrates that even with limited exposure in early life, a residual dose of tylosin causes lasting metabolic disturbances through altering gut microbiota and its metabolites. Our findings reveal that the gut microbiota is susceptible to previously ignored environmental factors.

microbiology↗