Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 523 records · Page 29Linked to original sources

bioRxiv2020

Biogenesis of RNA-containing extracellular vesicles at endoplasmic reticulum membrane contact sites

RNA transferred via extracellular vesicles (EVs) can influence cell and tissue phenotypes; however, the biogenesis of RNA-containing EVs is poorly understood and even controversial. Here, we identify the conserved endoplasmic reticulum membrane contact site (MCS) linker protein VAP-A as a major regulator of the RNA and RNA-binding protein content of small and large EVs. We also identify a unique subpopulation of secreted small EVs that is highly enriched in RNA and regulated by VAP-A. Functional experiments revealed that VAP-A-regulated EVs are critical for the transfer of miR-100 between cells and for in vivo tumor formation. Lipid analysis of VAP-A-knockdown EVs revealed large alterations in lipids known to regulate EV biogenesis, including ceramides and cholesterol. Knockdown of VAP-A-binding ceramide and cholesterol transfer proteins CERT and ORP1L led to similar defects in biogenesis of RNA-containing EVs. We propose that lipid transfer at VAP-A-positive MCS drives biogenesis of a select RNA-containing EV population.

cell biology↗

bioRxiv2020

Graph theoretic analysis reveals intranasal oxytocininduced network changes over frontal regions

In this study, we aim to elucidate how intranasal oxytocin modulates brain network characteristics, especially over the frontal network. As an essential brain hub of social cognition and emotion regulation, we will also explore the association between graphic properties of the frontal network and individual personality traits under oxytocin (OT) administration. 59 male participants administered intranasal OT or placebo were followed by restingstate fMRI scanning. The Correlation-based network model was applied to study OT modulation effects. We performed community detection algorithms and conducted further network analyses, including clustering coefficient, average shortest path and eigenvector centrality. In addition, we conducted a correlation analysis between clustering coefficients and the self-assessed psychological scales. Modular organizations in the OT group reveal integrations of the frontoparietal network (FPN) and the default mode network (DMN) over frontal regions. Results show that frontal nodes within the FPN are characterized by lower clustering coefficients and higher average shortest path values compared to the placebo group. Notably, these modulation effects on frontal network property are associated with Interpersonal Reactivity Index (IRI) fantasy value. Our results suggest that OT elevates integrations between FPN, DMN and limbic system as well as reduces small-worldness within the FPN. Our results support graph theoretic analysis as a potential tool to assess OT induced effects on the information integration in the frontal network.

animal behavior and cognition↗

bioRxiv2020

Identification of a new orthonairovirus associated with human febrile illness in China

The genus Orthonairovirus of the family Nairoviridae includes the important tick-transmitted pathogens, Crimean-Congo hemorrhagic fever virus (CCHFV) and Nairobi sheep disease virus (NSDV), as well as many other poorly characterized viruses isolated from ticks, birds, and mammals1,2. Here we identified a novel orthonairovirus, designated S[o]ngl[i]ng virus (SGLV), from patients who reported being bitten by a tick in China. The genome of SGLV shared similar structural features with orthonairoviruses, with 46.5-65.7% sequence identify. Phylogenetic analysis showed that SGLV belonged to the Tamdy orthonairovirus and formed a unique clade in the Nairoviridae family. Electron microscopy revealed typical morphological characteristics of orthonairoviruses. The isolated SGLVs from the blood samples of patients could induce cytopathic effects in human hepatoma cells. SGLV infection was confirmed in 42 patients in 2017-2018, with the main clinical manifestations of headache, fever, depression, fatigue and dizziness. Serological assays showed that 69% patients generated virus-specific antibody responses in the acute phase. In contrast, neither SGLV viral RNA nor specific antibodies against SGLV were detected in healthy individuals. SGLV was also detected in Ixodes crenulatus, Haemaphysalis longicornis, Haemaphysalis concinna, and Ixodes persulcatus in northeastern China. Collectively, a newly discovered orthonairovirus was shown to be associated with human febrile illness in northeastern China.

microbiology↗

bioRxiv2020

Local adaptation in populations of Mycobacterium tuberculosis endemic to the Indian Ocean Rim

Lineage 1 (L1) and 3 (L3) are two lineages of the Mycobacterium tuberculosis complex (MTBC), causing tuberculosis (TB) in humans. L1 and L3 are endemic to the Rim of the Indian Ocean, the region that accounts for most of the worlds new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Here we analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We show that South Asia played a central role in the dispersion of these two lineages to neighboring regions. Moreover, we found that L1 exhibits signatures of local adaptation at the esxH locus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Our study highlights the importance of genetic diversity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.

genomics↗

bioRxiv2020

Co-infection of influenza A virus enhances SARS-CoV-2 infectivity

The upcoming flu season in the northern hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental co-infection of IAV with either pseudotyped or SARS-CoV-2 live virus, we found that IAV pre-infection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice co-infected with IAV in vivo. Moreover, such enhancement of SARS-CoV-2 infectivity was not seen with several other viruses probably due to a unique IAV segment as an inducer to elevate ACE2 expression. This study illustrates that IAV has a special nature to aggravate SARS-CoV-2 infection, and prevention of IAV is of great significance during the COVID-19 pandemic.

microbiology↗

bioRxiv2020

Spermidine and spermine are the natural substrates of the Acinetobacter baumannii AmvA multidrug efflux pump

Multidrug efflux pumps are important drivers of antibiotic resistance in Acinetobacter baumannii and other pathogens, however their natural roles beyond transport of clinical antimicrobials are poorly described. Polyamines are an ancient class of molecules with broad roles in all three kingdoms of life, and are the likely natural substrate of at least one efflux pump family. We have defined the transcriptome of A. baumannii following treatment with high levels of the polyamines putrescine, cadaverine, spermidine and spermine. These molecules influenced expression of multiple gene classes in A. baumannii including those associated with virulence, and the four polyamines induced distinct but overlapping transcriptional responses. Polyamine shock also induced expression of the MFS-family efflux pump gene amvA and its repressor gene amvR. Loss of amvA dramatically reduced tolerance to the long-chain triaamine spermidine, but caused only modest changes in resistance to known AmvA substrates such as acriflavine. We confirmed reduced accumulation of spermidine in amvA-deficient A. baumannii, and showed that its expression is induced by long-chain polyamines through its cognate regulator AmvR. Our findings suggest that the conserved A. baumannii efflux pump AmvA has evolved to export spermidine from the cell, but that its substrate recognition promiscuity also allows activity against clinically-important biocides and antibiotics. ImportanceAMR genes, including multidrug efflux pumps, evolved long before the ubiquitous use of antimicrobials in medicine and infection control. Multidrug efflux pumps often transport metabolites, signals and host-derived molecules in addition to antibiotics or biocides. Understanding the ancestral physiological roles of multidrug efflux pumps could help to inform the development of strategies to subvert their activity. In this study, we investigated the response of Acinetobacter baumannii to polyamines, a widespread, abundant class of amino acid-derived metabolites, which led us to identify long-chain polyamines as natural substrates of the disinfectant efflux pump AmvA. A second clinically-important efflux pump, AdeABC, also contributed to polyamine tolerance. Our results suggest that the disinfectant resistance capability that allows A. baumannii to survive in hospitals may have evolutionary origins in the transport of polyamine metabolites.

microbiology↗

bioRxiv2020

Heat Stress Interferes with Formation of Double-Strand Breaks and Homology Synapsis in Arabidopsis thaliana

Meiotic recombination (MR) drives novel combination of alleles and contributes to genomic diversity in eukaryotes. In this study, we showed that heat stress (36-38{degrees}C) over fertile threshold fully abolished crossover (CO) formation in Arabidopsis. Cytological and genetic studies in wild-type plants, and the syn1 and rad51 mutants suggested that heat stress reduces generation of SPO11-dependent double-strand breaks (DSBs). In support, the abundance of recombinase DMC1, which is required for MR-specific DSB repair, was significantly reduced under heat stress. In addition, we showed that high temperatures induced disassembly and/or instability of ASY4-but not SYN1-mediated chromosome axis. At the same time, ASY1-associated lateral element of synaptonemal complex (SC) was partially affected, while the ZYP1-dependent central element of SC was disrupted, indicating that heat stress impairs SC formation. Moreover, quantitative RT-PCR revealed that genes involved in DSB formation; e.g. SPO11-1, PRD1, 2 and 3, were not impacted; however, recombinase RAD51 and chromosome axis factors ASY3 and ASY4 were significantly downregulated under heat stress. Taken together, these findings revealed that heat stress inhibits MR via compromised DSB formation and homolog synapsis, which are possible downstream effects of the impacted chromosome axis. Our study thus provides evidence shedding light on how increase of environmental temperature influences MR in Arabidopsis.

plant biology↗

bioRxiv2020

Therapeutic inhibition of keratinocyte TRPV3 sensory channels by local anesthetic dyclonine

The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is selectively targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular docking and mutagenesis, we further uncovered single residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive updated therapeutics for skin inflammation.

biochemistry↗

bioRxiv2020

CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis

Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus of the family Picornaviridae and can cause acute acinar pancreatitis in adults. However, the molecular mechanisms of pathogenesis underlying CVB3-induced acute pancreatitis have remained unclear. In this study, we discovered that CVB3 capsid protein VP1 inhibited pancreatic cell proliferation and exerted strong cytopathic effects on HPAC cells. Through yeast two-hybrid, co-immunoprecipitation, and confocal microscopy, we show that Menage a trois 1 (MAT1), a subunit of the Cdk-Activating Kinase (CAK) complex involved in cell proliferation and transcription, is a novel interaction protein with CVB3 VP1. Moreover, CVB3 VP1 inhibited MAT1 accumulation and localization, thus interfering with its interaction with CDK7. Furthermore, CVB3 VP1 could suppress CAK complex enzymic phosphorylation activity towards RNA Pol II and CDK4/6, direct substrates of CAK. VP1 also suppresses phosphorylation of retinoblastoma protein (pRb), an indirect CAK substrate, especially at phospho-pRb Ser780 and phospho-pRb Ser807/811 residues, which are associated with cell proliferation. Finally, we present evidence using deletion mutants that the C-terminal domain (VP1-D8, 768-859aa) is the minimal VP1 region required for its interaction with MAT1, and furthermore, VP1-D8 alone was sufficient to arrest cells in G1/S phase as observed during CVB3 infection. Taken together, we demonstrate that CVB3 VP1 can inhibit CAK complex assembly and activity through direct interaction with MAT1, to block MAT1-mediated CAK-CDK4/6-Rb signaling, and ultimately suppress cell proliferation in pancreatic cells. These findings substantially extend our basic understanding of CVB3-mediated pancreatitis, providing strong candidates for strategic therapeutic targeting.

microbiology↗

bioRxiv2020

Reduction of neuronal activity mediated by blood-vessel regression in the brain

The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels were found to be widespread in mouse, monkey and human brains. Both brief occlusions of the middle cerebral artery and lipopolysaccharide-mediated inflammation induced an increase of vessel regression. Blockage of leukocyte adhesion to endothelial cells alleviated LPS-induced vessel regression. We further revealed that blood vessel regression caused a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.

neuroscience↗

bioRxiv2020

Many bat species are not potential hosts of SARS-CoV and SARS-CoV-2: Evidence from ACE2 receptor usage

Bats are the suggested natural hosts for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, the latter of which caused the coronavirus disease 2019 (COVID-19) pandemic. The interaction of viral Spike proteins with their host receptor angiotensin-converting enzyme 2 (ACE2) is a critical determinant of potential hosts and cross-species transmission. Here we use virus-host receptor binding and infection assays to show that ACE2 orthologs from 24, 21, and 16 of 46 phylogenetically diverse bat species - including those in close and distant contact with humans - do not support entry of SARS-CoV, SARS-CoV-2, and both of these coronaviruses, respectively. Furthermore, we used genetic and functional analyses to identify genetic changes in bat ACE2 receptors associated with viral entry restrictions. Our study demonstrates that many - if not most - bat species are not potential hosts of SARS-CoV and SARS-CoV-2, and provides important insights into pandemic control and wildlife conservation.

ecology↗

bioRxiv2020

Clustering analysis of single nucleotide polymorphism data reveals population structure of SARS-CoV-2 worldwide

Identifying the population structure of the newly emerged coronavirus SARS-CoV-2 has significant potential to inform public health management and diagnosis. As SARS-CoV-2 sequencing data accrued, grouping them into clusters is important for organizing the landscape of the population structure of the virus. Due to the limited prior information on the newly emerged coronavirus, we utilized four different clustering algorithms to group 16,873 SARS-CoV-2 strains, which automatically enables the identification of spatial structure for SARS-CoV-2. A total of six distinct genomic clusters were identified using mutation profiles as input features. Comparison of the clustering results reveals that the four algorithms produced highly consistent results, but the state-of-the-art unsupervised deep learning clustering algorithm performed best and produced the smallest intra-cluster pairwise genetic distances. The varied proportions of the six clusters within different continents revealed specific geographical distributions. In particular, our analysis found that Oceania was the only continent on which the strains were dispersively distributed into six clusters. In summary, this study provides a concrete framework for the use of clustering methods to study the global population structure of SARS-CoV-2. In addition, clustering methods can be used for future studies of variant population structures in specific regions of these fast-growing viruses.

genetics↗

bioRxiv2020

Integrative proteomic and phosphoproteomic analysis of granulosa cells during follicular atresia in porcine

Ovarian follicular atresia is a natural physiological process; however, the mechanism is not fully understood. In this study, quantitative proteomic and phosphoproteomic analyses of granulosa cells (GC) in healthy (H), slightly atretic (SA), and atretic follicles (A) of porcine were performed by TMT labeling, enrichment of phosphopeptides and LC-MS/MS analysis. In total, 6,201 proteins were quantified and 4,723 phosphorylation sites of 1,760 proteins were quantified. In total, 24 (11 up, 13 down) and 50 (29 up, 21 down) proteins with a fold change (FC) > 5 were identified in H/SA and H/A, respectively. In addition, there were 20 (H/SA, up) and 39 (H/A, up) phosphosites with an FC > 7, that could serve as potential biomarkers for distinguishing different quality categories of follicles. Western blotting and immunofluorescence confirmed the reliability of the proteomic analysis. Some key proteins (e.g., MIF, beta catenin, integrin {beta}2), phosphosites (e.g., S76 of caspase6, S22 and S636 of lamin A/C), pathways (e.g., apoptosis, regulation of actin cytoskeleton pathway), transcription factors (e.g., STAT5A, FOXO1, and BCLAF1), and kinases (e.g., PBK, CDK5, CDK12, AKT3) involved in atresia process were revealed via further analysis of the differentially expressed proteins (DEPs) and phosphorylated proteins (DEPPs). Collectively, the proteomic and phosphoproteomic profiling and functional research in the current study comprehensively analyzed the dynamic changes in protein expression and phosphorylation during follicular atresia and provided some new explanations regarding the regulation of this process.

cell biology↗

bioRxiv2020

Lung Immune Tone Regulation by the Gut-Lung Immune Axis: Short-chain Fatty Acid Receptors FFAR2 and FFAR3, and IL-1β Expression Profiling in Mouse and Human Lung

Microbial metabolites produced by the gut microbiome, such as short-chain fatty acids (SCFA), can influence both local intestinal and distant lung physiology and response to injury. However, how lung immune activity is regulated by SCFAs is unknown. We examined fresh human lung tissue and observed the presence of SCFAs with large inter-individual and even intra-lobe variability. In vitro, SCFAs were capable of modifying the metabolic programming in both resting and LPS-exposed alveolar macrophages (AM). Additionally, since we hypothesized that lung immune tone could be defined through priming of the inflammasome (aka signal 1), we interrogated naive mouse lungs for pro-IL-1{beta} message and localized its presence within the alveolar space in situ, specifically in AM subsets, and in close proximity to alveolar type 2 epithelial (AT2) cells. We established that metabolically active gut microbiota, that produce SCFAs, can transmit LPS and SCFAs to the lung (potential sources of signal 1), and thereby could regulate lung immune tone and metabolic programming. To understand how murine lung cells sensed and upregulated IL-1{beta} in response to gut-microbiome factors, we determined that in vitro, AM and AT2 cells expressed SCFA receptors, FFAR2, FFAR3, and IL-1{beta} but with different expression patterns and LPS-inducibility. Finally, we observed that IL-1{beta}, FFAR2 and FFAR3 were expressed both in isolated human AM and AT2 cells ex-vivo, but in fresh human lung sections in situ, only AM expressed IL-1{beta} at rest and after LPS challenge. Together, this translational study using mouse and human lung tissue and cells supports an important role for the gut microbiome and SCFAs in regulating lung immune tone.

immunology↗

bioRxiv2020

Simultaneous deep generative modeling and clustering of single cell genomic data

Recent advances in single-cell technologies, including single-cell ATAC-seq (scATAC-seq), have enabled large-scale profiling of the chromatin accessibility landscape at the single cell level. However, the characteristics of scATAC-seq data, including high sparsity and high dimensionality, have greatly complicated the computational analysis. Here, we proposed scDEC, a computational tool for single cell ATAC-seq analysis with deep generative neural networks. scDEC is built on a pair of generative adversarial networks (GANs), and is capable of learning the latent representation and inferring the cell labels, simultaneously. In a series of experiments, scDEC demonstrates superior performance over other tools in scATAC-seq analysis across multiple datasets and experimental settings. In the downstream applications, we demonstrated that the generative power of scDEC helps to infer the trajectory and intermediate state of cells during differentiation and the latent features learned by scDEC can potentially reveal both biological cell types and within-cell-type variations.

bioinformatics↗

bioRxiv2020

Frontoparietal dynamics and value accumulation in intertemporal choice

Intertemporal choice requires choosing between a smaller reward available after a shorter time delay and a larger reward available after a longer time delay. Previous studies suggest that intertemporal preferences are formed by generating a subjective value of the monetary rewards that depends on reward amount and the associated time delay. Neuroimaging results indicate that this subjective value is tracked by ventral medial prefrontal cortex (vmPFC) and ventral striatum. Subsequently, an accumulation process, subserved by a network including dorsal medial frontal cortex (dmFC), dorsal lateral prefrontal cortex (dlPFC) and posterior parietal cortex (pPC), selects a choice based on the subjective values. The mechanisms of how value accumulation interacts with subjective valuation to make a choice, and how brain regions communicate during decision making are undetermined. We developed and performed an EEG experiment that parametrically manipulated the probability of preferring delayed larger rewards. A computational model equipped with time and reward information transformation, selective attention, and stochastic value accumulation mechanisms was constructed and fit to choice and response time data using a hierarchical Bayesian approach. Phase-based functional connectivity between putative dmFC and pPC was found to be associated with stimulus processing and to resemble the reconstructed accumulation dynamics from the best performing computational model across experimental conditions. By combining computational modeling and phase-based functional connectivity, our results suggest an association between value accumulation, choice competition, and frontoparietal connectivity in intertemporal choice. Author summaryIntertemporal choice is a prominent experimental assay for impulsivity. Behavior in the task involves several cognitive functions including valuation, action selection and self-control. It is unknown how these different functions are temporally implemented during the course of decision making. In the current study, we combined formal computational models of intertemporal choice with a phase-based EEG measure of activity across brain regions to show that functional connectivity between dmFC and pPC reflects cognitive mechanisms of both visual stimulus processing and choice value accumulation. The result supports the notion that dynamic interaction between frontopatietal regions instantiates the critical value accumulation process in intertemporal choice.

neuroscience↗

bioRxiv2020

A Systematic Review and Meta-analysis of the Protective Effect of FMDV VP1 on Animals

The FMDV VP1 protein has different structures which could decrease or increase the immune response. We undertook a meta-analysis to evaluate the protective effect of VP1 on the FMDV. A systematic search of the PubMed, Embase, CNKI and Wan fang DATA was conducted up to April 2020. Experimental studies involving the VP1 protection effect on FMDV were included. Extracted data were analyzed using Rev-Man 5.3 software. Chi-square tests were used to analyze the heterogeneity among the documents. The fixed-effect model was used for meta-analysis to find the combined effect value and 95% confidence interval. Sensitivity analysis was performed on the differences in the combined values of model effects, and the inverted funnel chart method was used to assess the publication bias of the included literature. A total of 12 articles were included for meta-analysis. The results of showed that VP1 had a protective effect on FMDV [MH = -0.66, 95% CI = (-0.75, -0.56), P < 0.00001]. Sensitivity analysis showed that the results were robust. The funnel graph method showed that the published literature had a small publication bias and met the requirements of this study. It is necessary to study the epitopes of VP1 to produce new vaccines. VP1 could protect animals from FMDV attacks. It is necessary to study the VP1 protein and its epitopes and use it as a new vaccine and diagnostic product.

immunology↗

bioRxiv2020

Cyclin G2 inhibits oral squamous cell carcinoma growth and metastasis by binding to insulin-like growth factor binding protein 3 and regulating the FAK-SRC-STAT signaling pathway

The cell cycle protein cyclin G2 is considered a tumor suppressor. However, its regulatory effects and potential mechanisms in oral cancers are not well understood. This study aimed to investigate the effect of cyclin G2 on oral squamous cell carcinoma (OSCC). The data from 80 patients with OSCC were utilized to predict the abnormal expression of cyclin G2. The proliferation and metastasis were determined by a cell counting Kit-8 assay, flow cytometry, a wound-healing assay and a cell invasion assay. The expression of key proteins and genes associated with the cyclin G2 signaling pathways was determined by western blotting and real-time PCR, respectively. The orthotopic nude mice model was established by a mouth injection of SCC9 cells overexpressing cyclin G2. We showed that the low level of cyclin G2 in OSCC, which is negatively correlated with clinical staging, was a negative prognostic factor for the disease. We also found that cyclin G2 inhibited the proliferation, metastasis and blocked the cell cycle at G1/S of OSCC cells, suggesting that cyclin G2 has an inhibitory effect in OSCC. Mechanistically, cyclin G2 inhibited the growth and metastasis of OSCC by binding to insulin-like growth factor binding protein 3 (IGFBP3) and regulating the focal adhesion kinase (FAK) -SRC-STAT signal transduction pathway. Cyclin G2 competed with integrin to bind to IGFBP3; the binding between integrin and IGFBP3 was reduced after cyclin G2 overexpression, thereby inhibiting the phosphorylation of FAK and SRC. These results showed that cyclin G2 inhibited the progression of OSCC by interacting with IGFBP3 and that it may be a new target for OSCC treatment.

cancer biology↗