Biology subjects

Bai, L.

Publications and source records attributed to Bai, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

PPARγ controls ESCRT-dependent fibroblast-like synoviocyte exosome biogenesis and Alleviates Chondrocyte Osteoarthritis Mediated by Exosomal ANXA1

Osteoarthritis (OA) is characterized by synovitis, cartilage degeneration and exercise therapy has been recognized as first line therapy. The exercise related exosome involved in the interaction between fibroblast-like synoviocytes (FLSs) and chondrocytes could be a novel promising strategy for treating OA. In this study, PPAR{gamma} was upregulated in FLSs under exercise by single cell transcriptome sequencing. Then, we investigated the underlying mechanisms of PPAR{gamma}-treated FLSs derived exosome on OA in vivo and vitro. Our data revealed that overexpression PPAR{gamma} FLSs derived exosome could ameliorate the OA severity in vivo and vitro. But knockdown PPAR{gamma} FLSs derived exosome aggravate OA. Moreover, we found PPAR{gamma} controls the endosomal sorting complex required for the transport (ESCRT)-dependent exosome biogenesis pathway. Annexin A1 (ANXA1) was enriched in OE-PPAR{gamma} exosome by quantitative proteomics. By Chip-qPCR and Co-IP methods, PPAR{gamma} and its coactivator -1 (PGC-1) acts with ESCRT subunits including HRS, STAM1, TSG101, CHMP7 and promotes their association to cargo ANXA1. As a therapeutic cargo, exosomal ANXA1 was confirmed be internalization by chondrocyte via exosome labeled experiment and ANXA1 could inhibit the phospharylation of ERK to activate the autophagy and decrease chondrocyte apoptosis. While the ANXA1 receptor blocker BOC-2 could reverse the therapic effect. In conclusion, PPAR{gamma}/ESCRT - FLSs exosomal ANXA1 - ERK axis provides a deeper theoretical basis for exercise therapy of OA and a new idea for the clinical transformation of exosomes into OA therapy.

cell biology↗

bioRxiv2023

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1

Despite the unique ability of pioneer transcription factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called ChIP-ISO to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1. Combining ChIP-ISO with in vitro and neural network analyses, we find that 1) FOXA1 binding is strongly affected by co-binding TFs AP-1 and CEBPB, 2) FOXA1 and AP-1 show binding cooperativity in vitro, 3) FOXA1s binding is determined more by local sequences than chromatin context, including eu-/heterochromatin, and 4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.

genetics↗

bioRxiv2023

Super-Resolution Imaging of Fast Morphological Dynamics of Neurons in Behaving Animals

Neurons are best studied in their native working states in which their functional and morphological dynamics support animals natural behaviors. Super-resolution microscopy can potentially reveal these dynamics in much higher details but has been challenging in behaving animals due to severe motion artifacts. Here, we report multiplexed line-scanning structured illumination microscopy, which could tolerate motions of up to 50 m/s while achieving 150 and 100 nm lateral resolutions in its linear and nonlinear forms respectively over large fields-of-view. We continuously imaged the dynamics of spinules in dendritic spines and axonal boutons volumetrically over thousands of frames and tens of minutes in mouse brains during sleep-wake cycles. Super-resolution imaging of axonal boutons revealed their prevalent spinule dynamics on a scale of seconds. Simultaneous two-color imaging further enabled analyses of the correlation between the spatial distributions of diverse PSD-95 clusters and the structural dynamics of dendrites in the brains of awake mice.

neuroscience↗

bioRxiv2023

Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig.

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression of UGT2B31 in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.

genetics↗

bioRxiv2023

Synergistic effects of multiple pesticides on the flight ability of honey bees (Apis cerana F.)

Pesticides cause risks in the environment for Asian honey bees (Apis cerana). Imidacloprid (I), chlorpyrifos (C) and glyphosate (G) are among the most-widely used pesticides in the world. It is not clear on how these pesticides and combination of them affect the flight ability of A. cerana. Here we utilized flight mills to show new results that acute treatment of individual pesticides, such as 0.2 ng/bees imidacloprid (20 L, 10 ng/g), 0.6 ng/bees chlorpyrifos (20 L, 30 ng/g) and 1.2 ng/bees glyphosate (20 L, 60 ng/g), had no effect on the flight ability of bees. However, forager bees showed a significantly decrease in the flying duration and flying distance when oral exposed to two or three these pesticides. This evidence indicated that two or three pesticides can produce synergistic changes in the flight ability and behavior of honeybees. Results showed a light on new understandings of complex effects and potential risks of these three pesticide on bee behavior including homing ability and food-collecting ability. Our results are key information to understand new synergistic potential among pesticide formulations and how they impair bee behavior. Table of Contents Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/541595v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@70e24dorg.highwire.dtl.DTLVardef@1195fb8org.highwire.dtl.DTLVardef@db5ad5org.highwire.dtl.DTLVardef@1287b51_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2023

Structure of a fungal 1,3-β-glucan synthase

1,3-{beta}-Glucan is the major component of the fungal cell wall and is synthesized by 1,3-{beta}-glucan synthase located in the plasma membrane, which is a molecular target of anti-fungal drugs echinocandins and the triterpenoid ibrexafungerp. In this study, we report the 3.0-[A] resolution cryo-EM structure of Saccharomyces cerevisiae 1,3-{beta}-glucan synthase, Fks1. The structure reveals a central catalytic region adopting a cellulose synthase fold with a cytosolic conserved GT-A type glycosyltransferase domain and a closed transmembrane glucan-transporting channel. We found that two extracellular disulfide bonds are crucial for Fks1 enzymatic activity. Structural comparison between Fks1 and cellulose synthases and structure-guided mutagenesis studies provided novel insights into the molecular mechanisms of the fungal 1,3-{beta}-glucan synthase.

biophysics↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

Molecular characters and phylogenetic analysis of Clostridium perfringens from different regions in China, from 2013 to 2021

Clostridium perfringens (C. perfringens) is a significant foodborne pathogen and a common cause of intestinal diseases in both animals and humans. Altogether, 186 isolates were obtained from humans (n = 147), animals (n = 25), and food (n = 14), comprising 174 type A strains (93.55%), 11 type F strains (5.91%), and one type D strain (0.54%); and were analyzed by multilocus sequence typing (MLST) and antimicrobial susceptibility testing. Additionally, some specific ST complexes were analyzed by cgMLST and cgSNP to investigate genetic relatedness. MLST indicated the most prevalent STs of C. perfringens of human and animal origin were as follows: ST221 (5/147), ST62 (4/147), ST408 (4/147), and ST493 (4/147) were predominant in humans, while ST479 (5/25) was the major type in animals. Within the same ST complex, genetically unrelated relationships or potential clustering/transmission events were further recognized by cgMLST and cgSNP, illustrating that these two methods are valuable in defining outbreaks and transmission events. All tested isolates were susceptible to vancomycin and meropenem. The rates of resistance to metronidazole, penicillin, cefoxitin, moxifloxacin, and clindamycin were low (metronidazole: 1.08%; penicillin: 9.68%; cefoxitin: 0.54%; moxifloxacin: 6.45%; and chloramphenicol: 3.76%). Interestingly, 49.66% of human origin were clindamycin-resistant, and 18.2% were penicillin-insensitive. Importantly, the portion of MDR isolates was significantly lower than in previous reports. The study provides an overview of the epidemiological characteristics of C. perfringens with different origins and hosts in China. C. perfringens demonstrated remarkable genetic diversity and distinct molecular features compared to antibiotic-resistance profiles from other studies. IMPORTANCEC. perfringens is one of the most common bacterial causes of foodborne illness globally, responsible for several food-poisoning outbreaks each year. This study provides an overview of C. perfringens isolates from different hosts and regions in China according to MLST, antibiotic-resistance characters, cgMLST, and cgSNP analyses, showing high genetic diversity and identifying potential clustering and transmission events. The antimicrobial profile in this study was distinct from that of a previous report with a much lower MDR rate, indicating that C. perfringens in China needs further investigation.

molecular biology↗

bioRxiv2022

Study on the mechanism of HE4 in hyperoxia-induced alveolar damage in rats

ObjectiveThis study investigated the mechanism of human epididymis protein 4 (HE4) in hyperoxia-induced alveolar damage in rats. MethodsThe pathological changes of SD rat lung tissue were detected by hematoxylin-eosin staining. Plasma protein levels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of mRNA was detected by real-time RT-PCR. ResultsHyperoxia intervention within 7 days could induce acute lung injury in neonatal SD rats. Hyperoxia induction can increase HE4, MMP9 and TIMP1 in plasma and tissue of neonatal SD rats. By overexpressing and silencing HE4 gene in neonatal rat primary alveolar type II epithelial cells, we found that HE4 protein activates the phosphorylation of ERK and p65, activates the downstream MMP9 signaling pathway, inhibits MMP9 mRNA expression, inhibits protein activity, and reduces COLI degradation, increases collagen secretion, promoting matrix remodeling and fibrosis. ConclusionHE4 mediates the pathophysiological process of hyperoxia-induced lung injury in rats through ERK, MMP9 and TIMP1 signaling pathways. HE4 overexpression mediates lung basal remodeling and lung injury.

zoology↗

bioRxiv2022

Apolipoprotein E genotype modulates longitudinal atrophy at the temporal lobe after mild traumatic brain injury

BackgroundsModerate or severe traumatic brain injury (TBI) is one of the strongest environmental risks for late-life dementia, especially Alzheimers disease (AD). However, the interaction between genetic factors and environmental exposure to mild TBI triggering neurodegenerative processes is still unclear. We used longitudinal imaging to differentiate spatial patterns of progressive brain volume loss in individual patients with and without carrying apolipoprotein E (APOE) {varepsilon}4 carriers. MethodsFor 59 patients with acute mild TBI (mTBI, age: 36.92 {+/-} 11.91 years; 14 APOE {varepsilon}4 carriers) and 48 matched healthy controls (HCs, age: 37.92 {+/-} 11.72 years; 10 APOE {varepsilon}4 carriers), longitudinal (6-12 months follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal volume changes in the temporal lobe were characterized by the Jacobian determinant (JD) metric, reflecting spatial warping between the baseline and follow-up scans. JD values were regionally calculated and correlated with neuropsychological measures. ResultsMTBI patients lost a mean of 0.27% (SD = 0.43) of GM and 0.27% (SD = 0.50) of WM volume in the temporal lobe over the 6-12 month follow-up. Patients with a high genetic risk for AD (APOE {varepsilon}4 allele carries) were associated with severer atrophy in the left superior temporal gyrus and middle temporal gyrus regions than the controls (P < 0.05). Furthermore, atrophy in these regions of gray matter could predict the performance change ratio of the language fluency in mTBI APOE {varepsilon}4 carriers ({beta} = 0.570, P < 0.05). While, compared with HC APOE {varepsilon}4 non-carriers, mTBI non-carriers exhibited volume loss in the medial temporal lobe. ConclusionsThis prospective study provided evidence that the APOE {varepsilon}4 allele interacting with mTBI increased the risk of AD phenotype development with language dysfunction. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/503827v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@39af96org.highwire.dtl.DTLVardef@136a0f7org.highwire.dtl.DTLVardef@181deb4org.highwire.dtl.DTLVardef@144349d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

A Unified Catalog of 19,251 Non-human Reference Species Genomes Provides New Insights into the Mammalian Gut Microbiomes

The gut microbiota is essential for host health and survival. Here, using samples from animals living in the Qinghai-Tibetan Plateau, we recovered 119,568 metagenome-assembled genomes (MAGs) that were clustered into 19,251 species-level genome bins (SGBs) of which most represent novel species. We present a novel mechanism shaping mammalian gut microbiomes using ancestral founder bacteria (AFB) as a core skeleton and recurring lineage-specific gains of microbial species that are transferred frequently among multiple hosts, not strictly limited by host phylogeny. Such lineage specific gains are responsible for increasing gut microbial diversity, maintaining functional stability, and endowing specific functions for host adaptions. Our analyses did not support the existence of co-phylogeny or co-speciation events between mammal hosts and their individual gut symbionts. The results presented in this study not only reveal novel unique gut microbial species and offer insight of value for understanding the diversity, stability, functionality of the mammalian gut microbiomes, and the co-evolution with their hosts, but also emphasize that animals living in extreme environments are a promising resource for the discovery of novel biological functions.

microbiology↗

bioRxiv2022

Basic helix-loop-helix pioneer factors interact with the histone octamer to invade nucleosomes and generate nucleosome depleted regions

Nucleosomes drastically limit transcription factor (TF) occupancy, while pioneer transcription factors (PFs) somehow circumvent this nucleosome barrier. In this study, we compare nucleosome binding of two conserved S. cerevisiae basic helix-loop-helix (bHLH) TFs, Cbf1 and Pho4. A Cryo-EM structure of Cbf1 in complex with the nucleosome reveals that the Cbf1 HLH region can electrostatically interact with exposed histone residues within a partially unwrapped nucleosome. Single molecule fluorescence studies show that the Cbf1 but not the Pho4 HLH region facilitates efficient nucleosome invasion by slowing its dissociation rate relative to DNA through interactions with histones. In vivo studies show that this enhanced binding provided by the Cbf1 HLH region enables nucleosome invasion and ensuing repositioning. These structural, single molecule, and in vivo studies reveal the mechanistic basis of dissociation rate compensation by pioneer factors and how this translates to facilitating chromatin opening inside cells.

biophysics↗

bioRxiv2021

Structure and dynamics of human disease-complication network

A complication is an unanticipated disease arisen following, induced by a disease, a treatment or a procedure. We compile the Human Disease-Complication Network from the medical data and investigate the characteristics of the network. It is observed that the modules of the network are dominated by the classes of diseases. The relations between modules are unveiled in detail. Three nontrivial motifs are identified from the network. We further simulate the dynamics of motifs with the Boolean dynamic model. Each motif represents a specific dynamic behavior, which is potentially functional in the disease system, such as generating temporal progressions and governing the responses to fluctuating external stimuli. Author summaryAdvances in molecular biology lead to a new discipline of network medicine, investigating human diseases in a networked structure perspective. Recently, clinical records have been introduced to the research of complex networks of diseases. An important available medical dataset that has been overlooked so far is the complications of diseases, which are vital for human beings. We compile the Human Disease-Complication Network, representing the causality between the upstream diseases and their downstream complications. This work not only helps us to comprehend why certain groups of diseases appear collectively, but also provides a new paradigm to investigate the dynamics of disease progression. For clinical applications, the investigation of complications may yield new approaches to disease prevention, diagnosis and treatment.

bioinformatics↗

bioRxiv2021

Selective YAP activation in Procr cells is essential for ovarian stem/progenitor expansion and epithelium repair

Ovarian surface epithelium (OSE) undergoes recurring ovulatory rupture and OSE stem cells rapidly generate new cells for the repair. How the stem cell senses the rupture and promptly turns on proliferation is unclear. Our previous study has identified that Protein C Receptor (Procr) marks OSE progenitors. In this study, we observed decreased adherent junction and selective activation of YAP signaling in Procr progenitors at OSE rupture site. OSE repair is impeded upon deletion of Yap in these progenitors. Interestingly, Procr+ progenitors show lower expression of Vgll4, an antagonist of YAP signaling. Overexpression of Vgll4 in Procr+ cells hampers OSE repair and progenitor proliferation, indicating that selective low Vgll4 expression in Procr+ progenitors is critical for OSE repair. In addition, YAP activation promotes transcription of the OSE stemness gene Procr. The combination of increased cell division and Procr expression leads to expansion of Procr+ progenitors surrounding the rupture site. These results illustrate a YAP- dependent mechanism by which the stem/progenitor cells recognize the ovulatory rupture, and rapidly multiply their numbers, highlighting a YAP- induced stem cell expansion strategy.

developmental biology↗

bioRxiv2021

Enteroendocrine cell types that drive food reward and aversion

Animals must learn through experience which foods are nutritious and should be consumed, and which are toxic and should be avoided. Enteroendocrine cells (EECs) are the principal chemosensors in the GI tract, but investigation of their role in behavior has been limited by the difficulty of selectively targeting these cells in vivo. Here we describe an intersectional genetic approach for manipulating EEC subtypes in behaving mice. We show that multiple EEC subtypes inhibit food intake but have different effects on learning. Conditioned flavor preference is driven by release of cholecystokinin whereas conditioned taste aversion is mediated by serotonin and substance P. These positive and negative valence signals are transmitted by vagal and spinal afferents, respectively. These findings establish a cellular basis for how chemosensing in the gut drives learning about food.

physiology↗

bioRxiv2021

Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

ObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformins participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota. MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies. ResultsFirst, METH addicts exhibited higher diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice. DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms. Study HighlightsO_ST_ABSWhat is known?C_ST_ABSO_LIThere are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates. C_LIO_LIMetformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei. C_LI What is new here?O_LIMETH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. C_LIO_LIThe therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites. C_LIO_LIInosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours. C_LI

animal behavior and cognition↗

bioRxiv2021

ORC binds and remodels nucleosomes to specify MCM loading onto DNA

The numerous enzymes and cofactors involved in eukaryotic DNA replication are conserved from yeast to human, and the budding yeast Saccharomyces cerevisiae (S.c.) has been a useful model organism for these studies. However, there is a gap in our knowledge of why replication origins in higher eukaryotes do not use a consensus DNA sequence as found in S.c.. Using in vitro reconstitution and single-molecule visualization, we show here that S.c. origin recognition complex (ORC) stably binds nucleosomes and that ORC-nucleosome complexes have the intrinsic ability to load the replicative helicase MCM double hexamers onto adjacent nucleosome-free DNA regardless of sequence. Furthermore, we find that Xenopus laevis nucleosomes can substitute for yeast ones in engaging with ORC. Combined with new analysis of genome-wide ORC binding, our results lead us to propose that the yeast origin recognition machinery contains the cryptic capacity to bind nucleosomes near a nucleosome-free region and license origins, and that this nucleosome-directed origin licensing paradigm generalizes to all eukaryotes.

biophysics↗

bioRxiv2021

EOMES is responsible for WNT memory and can substitute for WNT in mesendoderm specification

Embryogenesis is guided by a limited set of signaling pathways dynamically expressed in different places. How a context dependent signaling response is generated has been a central question of developmental biology, which can now be addressed with in vitro models of human embryos that are derived from embryonic stem cells (hESCs) called gastruloids. Our previous work demonstrated that during early self-organization of gastruloids, cells chronicle signaling hierarchy. Only cells that have been exposed (primed) by WNT signaling can respond to subsequent Activin exposure and differentiate to mesendodermal (ME) fates. Here, we show that WNT priming does not alter SMAD2 binding nor its chromatin opening, but rather, acts by inducing the expression of the SMAD2 co-factor, EOMES. Expression of EOMES is sufficient to replace WNT upstream of Activin-mediated ME differentiation, thus unveiling the mechanistic basis for priming and cellular memory in early development.

developmental biology↗