Biology subjects

Zhou, Z.

Publications and source records attributed to Zhou, Z..

At least 433 records · Page 24Linked to original sources

bioRxiv2020

Single-cell atlas of human developing and azoospermia patients' testicles reveals the roadmap and defects in somatic microenvironment

Non-obstructive azoospermia (NOA) affects 1% of men. However, the unknowns of NOA pathogenesis and even normal spermatogenic microenvironment establishment severely limit the clinical efficacy of NOA treatment. We profiled > 80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. Sertoli cells, which form the scaffold in the testicular microenvironment, exhibited the most obvious damages in NOA patients. We identified the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature but with abnormal immune response, while the cells in idiopathic NOA (iNOA) are basically physiologically immature. Furthermore, inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.

developmental biology↗

bioRxiv2020

Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells

Prohibitin is an evolutionarily conserved and ubiquitously expressed protein in eukaryocyte. It mediate many important roles in cell survival, apoptosis, autophagy and senescence. In the present study, we aimed to explore the role of prohibitin in cigarette smoke extract (CSE)-induced apoptosis of human pulmonary microvascular endothelial cells (HPMECs). For this purpose, HPMECs were trasfected with prohibitin and challenged with CSE. Our results showed that CSE exposure inhibited prohibitin expression in a dose-dependent manner in HPMECs. Overexpression of prohibitin could protect cell from CSE-induced injury by inhibiting CSE-induced cell apoptosis, inhibiting reactive oxygen species (ROS) production, increase mitochondrial membrane potential, increase the content of mitochondrial transcription factor A (mtTFA), IKK/{beta} phosphorylation and I{kappa}B- degradation. CSE decreases prohibitin expression in endothelial cells and restoration of prohibitin expression in these cells can protect against the deleterious effects of CSE on mitochondrial and cells. We identified prohibitin is a novel regulator of endothelial cell apoptosis and survival in the context of cigarette smoke exposure.

pharmacology and toxicology↗

bioRxiv2020

Single-cell transcriptomic analysis identifies neocortical developmental differences between human and mouse

BackgroundThe specification and differentiation of neocortical projection neurons is a complex process under precise molecular regulation; however, little is known about the similarities and differences in cerebral cortex development between human and mouse at single-cell resolution. ResultsHere, using single-cell RNA-seq (scRNA-seq) data we explore the divergence and conservation of human and mouse cerebral cortex development using 18,446 and 7,610 neocortical cells. Systematic cross-species comparison reveals that the overall transcriptome profile in human cerebral cortex is similar to that in mouse such as cell types and their markers genes. By single-cell trajectories analysis we find human and mouse excitatory neurons have different developmental trajectories of neocortical projection neurons, ligand-receptor interactions and gene expression patterns. Further analysis reveals a refinement of neuron differentiation that occurred in human but not in mouse, suggesting that excitatory neurons in human undergo refined transcriptional states in later development stage. By contrast, for glial cells and inhibitory neurons we detected conserved developmental trajectories in human and mouse. ConclusionsTaken together, our study integrates scRNA-seq data of cerebral cortex development in human and mouse, and uncovers distinct developing models in neocortical projection neurons. The earlier activation of cognition -related genes in human may explain the differences in behavior, learning or memory abilities between the two species.

bioinformatics↗

bioRxiv2020

Microbial dark matter driven degradation of carbon fiber polymer composites

Polymer composites have become attractive for structural applications in the built environment due to their lightweight and high strength properties but can suffer from degradation due to environmental factors. While impacts of abiotic factors like temperature and moisture are well studied, little is known about the influence of naturally occurring microbial communities on their structural integrity. Here we apply complementary time-series multi-omics of biofilms growing on polymer composites and materials characterization to elucidate, for the first time, the processes driving their degradation. We measured a reduction in mechanical properties due to molecular chain breakage and reconstructed 121 microbial genomes to describe microbial diversity and pathways associated with their degradation. The composite microbiome is dominated by four bacterial groups including the Candidate Phyla Radiation that possess pathways for breakdown of acrylate, esters, and bisphenol, abundant in composites. Overall, we provide a foundation for understanding interactions of next-generation structural materials with their natural environment that can predict their durability and drive future designs.

microbiology↗

bioRxiv2020

Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo

BackgroundThe outbreak of SARS CoV-2 has caused ever-increasing attention and public panic all over the world. Currently, there is no specific treatment against the SARS CoV-2. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. Previous studies found that indomethacin has the ability to inhibit the replication of several unrelated DNA and RNA viruses, including SARS-CoV. MethodsSARS CoV-2 pseudovirus-infected African green monkey kidney VERO E6 cells treated with different concentrations of indomethacin or aspirin at 48 hours post infection (p.i). The level of cell infection was determined by luciferase activity. Anti-coronavirus efficacy in vivo was confirmed by evaluating the time of recovery in canine coronavirus (CCV) infected dogs treated orally with 1mg/kg body weight indomethacin. ResultsWe found that indomethacin has a directly and potently antiviral activity against the SARS CoV-2 pseudovirus (reduce relative light unit to zero). In CCV-infected dogs, recovery occurred significantly sooner with symptomatic treatment + oral indomethacin (1 mg/kg body weight) daily treatments than with symptomatic treatment + ribavirin (10-15 mg/kg body weight) daily treatments (P =0.0031), but was not significantly different from that with symptomatic treatment + anti-canine coronavirus serum + canine hemoglobin + canine blood immunoglobulin + interferon treatments (P =0.7784). ConclusionThe results identify indomethacin as a potent inhibitor of SARS CoV-2.

microbiology↗

bioRxiv2020

Computational analysis suggests putative intermediate animal hosts of the SARS-CoV-2

The recent emerged SARS-CoV-2 may first transmit to intermediate animal host from bats before the spread to humans. The receptor recognition of ACE2 protein by SARS-CoVs or bat-originated coronaviruses is one of the most important determinant factors for the cross-species transmission and human-to-human transmission. To explore the hypothesis of possible intermediate animal host, we employed molecular dynamics simulation and free energy calculation to examine the binding of bat coronavirus with ACE2 proteins of 47 representing animal species collected from public databases. Our results suggest that intermediate animal host may exist for the zoonotic transmission of SARS-CoV-2. Furthermore, we found that tree shrew and ferret may be two putative intermediate hosts for the zoonotic spread of SARS-CoV-2. Collectively, the continuous surveillance of pneumonia in human and suspicious animal hosts are crucial to control the zoonotic transmission events caused by SARS-CoV-2.

bioinformatics↗

bioRxiv2020

Transcriptome Analysis in Yeast Reveals the Externality of Position Effect

When a gene is integrated into the chromosome, its activity depends on the genomic context. Although this phenomenon of "position effect" was widely reported, how the integration event affects the local environment, or the "externality" of position effect, remained largely unexplored, let alone the mechanism or phenotypic consequence of such externality. Here, we examined the transcriptome profiles of [~]250 Saccharomyces cerevisiae strains, each with GFP inserted into a different locus of the wild-type strain. We found that the GFP expression level and the change of expression of genes near the integration site decreases in genomic regions with high density of essential genes. This observation was found associated with H3K4me2 by further joint-analysis with public genome-wide histone modification profiles. More importantly, we found that the expression changes of neighboring genes, but not the GFP expression, exerted a significant impact on cellular growth rate. As a result, genomic loci that grant higher GFP expression immediately after the integration will have lower total yield of GFP in the long run. Our results, which were consistent with the competition for transcriptional resources among neighboring genes, revealed a previously unappreciated facet of the position effect, and highlighted its impact on the fate of genomic integration of exogenous genes, which has profound implications for biological engineering and pathology of virus integrative to host genome.

genomics↗

bioRxiv2020

RBD mutations from circulating SARS-CoV-2 strains enhance the structure stability and infectivity of the spike protein

The current global pandemic of COVID-19 is caused by a novel coronavirus SARS-CoV-2. The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring mutations in the RBD during the early transmission phase have altered the receptor binding affinity and infectivity, firstly we analyzed in silico the binding dynamics between mutated SARS-CoV-2 RBDs and the human ACE2 receptor. Among 32,123 genomes of SARS-CoV-2 isolates (January through March, 2020), 302 non-synonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations. The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding ELISA, surface plasmon resonance, and pseudotyped virus assays. Genome phylogenetic analysis of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F + D614G) which emerged later and formed a distinct sub-cluster. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of SARS-CoV-2 under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. ImportanceA novel coronavirus SARS-CoV-2 has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether the mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and caused them more infectious, should be paid more attentions to. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase that have increased human ACE2 receptor binding affinity and infectivity. The RBD mutation analysis provides insights into SARS-CoV-2 evolution. The continuous surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is important and necessary, particularly when the direct correlation between the virus variations and vaccine effectiveness is underdetermined during the sustained COVID-19 pandemic.

microbiology↗

bioRxiv2020

O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

Viruses hijack the host cell machinery to promote viral replication; however, the mechanism by which metabolic reprogramming regulates innate antiviral immunity in the host remains elusive. Herein, we found that Hepatitis B virus (HBV) infection upregulates glucose transporter 1expression, promotes hexosamine biosynthesis pathway (HBP) activity, and enhances O-linked {beta}-N-acetylglucosamine (O-GlcNAc) modification of downstream proteins. HBP-mediated O-GlcNAcylation positively regulates host antiviral response against HBV in vitro and in vivo. Mechanistically, O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) on Ser93 stabilizes SAMHD1 and enhances its antiviral activity. In addition, O-GlcNAcylation of SAMHD1 promoted its antiviral activity against human immunodeficiency virus-1 in vitro. In conclusion, the results of our study reveal a link between HBP, O-GlcNAc modification, and innate antiviral immunity by targeting SAMHD1. Therefore, the results of this study demonstrate a strategy for the potential treatment of HBV infection by modulating HBP activity.

microbiology↗

bioRxiv2020

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

The outbreak of coronavirus disease (COVID-19) in China caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. It is currently no specific viral protein targeted therapeutics yet. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein is yet to be clear. Herein, we have determined the 2.7 [A] crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although overall structure is similar with other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the {beta}-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.

molecular biology↗

bioRxiv2020

Ecological stoichiometric characteristics of Carbon (C), Nitrogen (N) and Phosphorus (P) in leaf, root, stem, and soil in four wetland plants communities in Shengjin Lake, China,

Ecological stoichiometric should be incorporated into management and nutrient impacted ecosystems dynamic to understand the status of ecosystems and ecological interaction. The present study focused on ecological stoichiometric characteristics of different macrophyte plants soil, leave, stem and root after the removal of seine fishing since 2000 from Shengjin Lake. For C, N and P analysis from leaves, stems, roots and soil to explore their stoichiometric ratio and deriving environmental forces here four dominant plant communities (Zizania caduciflora, Vallisineria natans, Trapa quadrispinosa and Carex schmidtii) were collected. C, N, P and C: N: P ratio in leafs, stems, roots and soil among the plant communities vary and the studied plant communities had significant effect on the measured variables. There was high C: N in C.schmidtii soil (7.08{+/-}1.504) but not vary significantly (P >0.05), and N: P ratio measured high in V. natans (13.7{+/-}4.05) and C: P in T.quadrispinosa soil (81.14{+/-}43.88) and showed significant variation (P<0.05) respectively. High leaf C: N and N: P ratio was measured in C. schmidtii and V. natans respectively. Nevertheless, high leaf C: P ratio was measured in Z.caduciflora. From the three studied organs leafs C: N, N: P ratio showed high values compared to root and stems. The correlation analysis result showed that, at 0-10cm depth ranges SOC correlated negatively with stem total phosphorus (STP), and RTN (P<0.05) but positively strongly with LTP and LTN (P<0.01) respectively. Soil total nitrogen at 0-10cm strongly positively correlated with LTP (P<0.01) and positively with RN: P and LTC (P<0.05). Soil basic properties such as SMC.BD and pH positively correlated with soil ecological stoichiometric characteristics. Redundancy analysis (RDA) result showed pH and available phosphorus were the potential determinant of soil stoichiometry.

ecology↗

bioRxiv2020

MS-DIAL 4: accelerating lipidomics using an MS/MS, CCS, and retention time atlas

To the EditorWe formulated mass spectral fragmentations of lipids across 117 lipid subclasses and included ion mobility tandem mass spectrometry (MS/MS) to provide a comprehensive lipidome atlas with retention time, collision cross section, and MS/MS information. The all-in-one solution from import of raw MS data to export of a common output format (mztab-M) was packaged in MS-DIAL 4 (http://prime.psc.riken.jp/) providing an enhanced standardized untargeted lipidomics procedure following lipidomics standards initiative (LSI) semi-quantitative definitions and shorthand notation system of lipid structures with a 1-2% estimated false discovery rate, which will contribute to harmonizing lipidomics data across laboratories to accelerate lipids research.

bioinformatics↗

bioRxiv2020

Tracing Evolutionary Ages of Cancer-Driving Sites by Cancer Somatic Mutations

Evolutionary understanding of cancer genes may provide insights on the nature and evolution of complex life and the origin of multicellularity. In this study, we focus on the evolutionary ages of cancer-driving sites, and try to explore to what extent the amino acids of cancer-driving sites can be traced back to the most recent common ancestor (MRCA) of the gene. According to gene phylostraigraphy analysis, we use the definition of gene age (tg) by the most ancient phylogenetic position that can be traced back, in most cases based on the large-scale homology search of protein sequences. Our results are shown that the site-age profile of cancer-driving sites of TP53 is correlated with the number of cancer types the somatic mutations may affect. In general, those amino acid sites mutated in most cancer types are much ancient. These sites frequently mutated in cancerous cells are possibly responsible for carcinogenesis; some may be very important for basic growth of single-cell organisms, and others may contribute to complex cell regulation of multicellular organisms. The further cancer genomics analysis also indicates that ages of cancer-driving sites are ancient but may have a broad range in early stages of metazoans.

evolutionary biology↗

bioRxiv2020

Diversity and Structural Variability of Bacterial Microbial Communities in Rhizocompartments of Desert Leguminous Plants

By assessing diversity variations of bacterial communities under different rhizocompartment types (i.e., roots, rhizosphere soil, root zone soil, and inter-shrub bulk soil), we explore the structural variability of bacterial communities in different root microenvironments under desert leguminous plant shrubs. Results will enable the influence of niche differentiation of plant roots and root soil on the structural stability of bacterial communities under three desert leguminous plant shrubs to be examined. High-throughput 16S rRNA genome sequencing was used to characterize diversity and structural differences of bacterial microbes in the rhizocompartments of three xeric leguminous plants. Results from this study confirm previous findings relating to niche differentiation in rhizocompartments under related shrubs, and they demonstrate that diversity and structural composition of bacterial communities have significant hierarchical differences across four rhizocompartment types under leguminous plant shrubs. Desert leguminous plants had significant effects on the enrichment and filtration of specific bacterial microbiomes across different rhizocompartments (P<0.05). The core bacterial microbiomes causing structure and composition variability of bacterial communities across different niches of desert leguminous plants are also identified. By investigating the influence of niches on the structural variability of soil bacterial communities with the differentiation of rhizocompartments under desert leguminous plant shrubs, we provide data support for the identification of dominant bacteria and future preparation of inocula, and provide a foundation for further study of the host plants-microbial interactions. IMPORTANCEColonization by plant communities make valued contribution to sand-fixing in poor ecological desert environments, thereby reducing the effects of wind erosion in these areas. Our study revealed that specific core bacterial microbiomes in under-shrub soil microbial communities had a significant hierarchical enrichment effect among rhizocompartments, and were filtered into roots. The root endophyte microbiomes thus formed had low abundance and diversity, but their structural variability was the highest. In addition, our data also verified that the rhizocompartments of under desert leguminous plant shrubs had a significant differentiation effect for the core bacterial microbiomes enriched and filtered by host plants, and that each rhizocompartment represented a unique niche of bacterial communities. Understanding the interactions between xeric shrubs and soil microbial communities is a fundamental step for describing desert soil ecosystems, which in turn can offer a microbe-associated reference for evaluating the restoration of desert vegetation.

ecology↗

bioRxiv2020

SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic beta-cells

SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we show that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of {beta}-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets from sparc -/- mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS in sparc -/- mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic {beta} cells.

cell biology↗

bioRxiv2020

Accurate reconstruction of the pan- and core- genomes of bacteria with PEPPA

Bacterial genomes can contain traces of a complex evolutionary history, including extensive homologous recombination, gene loss, gene duplications and horizontal gene transfer. In order to reconstruct the phylogenetic and population history of a set of multiple bacteria, it is necessary to examine their pan-genome, the composite of all the genes in the set. Here we introduce PEPPAN, a novel pipeline that can reliably construct pan-genomes from thousands of genetically diverse bacterial genomes that represent the diversity of an entire genus. PEPPAN outperforms existing pan-genome methods by providing consistent gene and pseudogene annotations extended by similarity-based gene predictions, and identifying and excluding paralogs by combining tree- and synteny-based approaches. The PEPPAN package additionally includes PEPPAN_parser, which implements additional downstream analyses including the calculation of trees based on accessory gene content or allelic differences between core genes. In order to test the accuracy of PEPPAN, we implemented SimPan, a novel pipeline for simulating the evolution of bacterial pan-genomes. We compared the accuracy and speed of PEPPAN with four state-of-the-art pan-genome pipelines using both empirical and simulated datasets. PEPPAN was more accurate and more specific than any of the other pipelines and was almost as fast as any of them. As a case study, we used PEPPAN to construct a pan-genome of ~40,000 genes from 3052 representative genomes spanning at least 80 species of Streptococcus. The resulting gene and allelic trees provide an unprecedented overview of the genomic diversity of the entire Streptococcus genus.

bioinformatics↗

bioRxiv2019

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells

Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency, and delay growth of human prostate cancer xenografts by reducing the number of cancer propagating cells. In sum, our study provides a definitive proof of tumor suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer propagating cells in prostate cancers with MME downregulation.

cancer biology↗

bioRxiv2019

Highly diverse Asgard archaea participate in organic matter degradation in coastal sediments

Asgard is an archaeal superphylum that might hold the key to understand the origin of eukaryotes, but its diversity and ecological roles remain poorly understood. Here, we reconstructed 15 metagenomic-assembled genomes (MAGs) from coastal sediments covering most known Asgard archaea and a novel group, which is proposed as a new Asgard phylum named as the "Gerdarchaeota". Genomic analyses predict that Gerdarchaeota are facultative anaerobes in utilizing both organic and inorganic carbon. Unlike their closest relatives Heimdallarchaeota, Gerdarchaeota have genes encoding for cellulase and enzymes involving in the tetrahydromethanopterin-based Wood-Ljungdahl pathway. Transcriptomic evidence showed that all known Asgard archaea are capable of degrading organic matter, including peptides, amino acids and fatty acids, in different ecological niches in sediments. Overall, this study broadens the diversity of the mysterious Asgard archaea and provides evidence for their ecological roles in coastal sediments.

microbiology↗