Biology subjects

Zhou, J.

Publications and source records attributed to Zhou, J..

At least 631 records · Page 35Linked to original sources

bioRxiv2020

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

A newly identified coronavirus, 2019-nCoV, has been posing significant threats to public health since December 2019. ACE2, the host cell receptor for severe acute respiratory syndrome coronavirus (SARS), has recently been demonstrated in mediating 2019-nCoV infection. Interestingly, besides the respiratory system, substantial proportion of SARS and 2019-nCoV patients showed signs of various degrees of liver damage, the mechanism and implication of which have not yet been determined. Here, we performed an unbiased evaluation of cell type specific expression of ACE2 in healthy liver tissues using single cell RNA-seq data of two independent cohorts, and identified specific expression in cholangiocytes. The results indicated that virus might directly bind to ACE2 positive cholangiocytes but not necessarily hepatocytes. This finding suggested the liver abnormalities of SARS and 2019-nCoV patients may not be due to hepatocyte damage, but cholangiocyte dysfunction and other causes such as drug induced and systemic inflammatory response induced liver injury. Our findings indicate that special care of liver dysfunction should be installed in treating 2019-nCoV patients during the hospitalization and shortly after cure.

genomics↗

bioRxiv2020

Discovery of an evolutionarily conserved smooth muscle cell-specific lncRNA CARMN

Differentiated vascular smooth muscle cells (VSMCs) are critical in maintaining vascular homeostasis by expressing a unique repertoire of contractile genes. Despite the well-defined coding transcriptome in differentiated VSMCs, little is known about the non-coding gene expression signature. Herein, by de novo analyzing publicly available RNA-seq and single cell RNA-seq datasets generated from different tissues and cell types, we unambiguously identified CARMN (CARdiac Mesoderm Enhancer-associated Non-coding RNA) as an evolutionarily conserved, SMC-specific lncRNA. CARMN was initially annotated as the host gene of MIR143/145 cluster and recently reported to play roles in cardiac differentiation. Here, we generated a Carmn GFP knock-in reporter mouse model and confirmed its specific expression in SMCs in vivo. In addition, we found Carmn is transcribed independently from Mir143/145 and only expressed transiently in embryonic cardiomyocytes and thereafter becomes restricted to adult SMCs in both human and mouse. Furthermore, we demonstrated that CARMN expression is not only dramatically decreased in human vascular diseases but functionally critical in maintaining VSMC contractile phenotype in vitro. In conclusion, we provided the first evidence showing that CARMN is an evolutionarily conserved SMC-specific lncRNA, down-regulated in different human vascular diseases, and a key lncRNA for maintaining SMC contractile phenotype.

developmental biology↗

bioRxiv2020

Genetic ablation of the mitochondrial ribosome in Plasmodium falciparum sensitizes the human malaria parasite to antimalarial drugs targeting mitochondrial functions

The mitochondrion of malaria parasites contains clinically validated drug targets. Within Plasmodium spp., the mitochondrial DNA (mtDNA) is only 6 kb long, being the smallest mitochondrial genome among all eukaryotes. The mtDNA encodes only three proteins of the mitochondrial electron transport chain and [~] 27 small, fragmented rRNA genes in length of 22-195 nucleotides. The rRNA fragments are thought to form a mitochondrial ribosome (mitoribosome), together with ribosomal proteins imported from the cytosol. The mitoribosome of Plasmodium falciparum has been shown to be essential for maintenance of the mitochondrial membrane potential and parasite viability. However, the role of mitoribosomes in sustaining the metabolic status of the parasite mitochondrion remains unknown. Here, among the 14 annotated mitoribosomal proteins of the small subunit of P. falciparum, we verified the localization and tested the essentiality of three candidates (PfmtRPS12, PfmtRPS17, PfmtRPS18), employing a CRISPR/Cas9 mediated conditional knockdown tool. Using immuno-electron microscopy, we provided evidence that the mitoribosome is closely associated with the mitochondrial inner membrane in the parasite. Upon knockdown of the mitoribosome, the parasites became hypersensitive to inhibitors targeting the bc1 complex, dihydroorotate dehydrogenase and F1Fo ATP synthase complex. Furthermore, knockdown of the mitoribosome blocked the pyrimidine biosynthesis pathway and reduced the pool of pyrimidine nucleotides. Together, our data suggest that disruption of the P. falciparum mitoribosome compromises the metabolic capability of the mitochondrion, rendering the parasite hypersensitive to a panel of inhibitors targeting mitochondrial functions.

biochemistry↗

bioRxiv2019

Single nucleus multi-omics links human cortical cell regulatory genome diversity to disease risk variants

Single-cell technologies enable measure of unique cellular signatures, but are typically limited to a single modality. Computational approaches allow integration of diverse single-cell datasets, but their efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of single cells in tissues, we devised single-nucleus methylCytosine, Chromatin accessibility and Transcriptome sequencing (snmC2T-seq) and applied it to post-mortem human frontal cortex tissue. We developed a computational framework to validate fine-grained cell types using multi-modal information and assessed the effectiveness of computational integration methods. Correlation analysis in individual cells revealed distinct relations between methylation and gene expression. Our integrative approach enabled joint analyses of the methylome, transcriptome, chromatin accessibility and conformation for 63 human cortical cell types. We reconstructed regulatory lineages for cortical cell populations and found specific enrichment of genetic risk for neuropsychiatric traits, enabling prediction of cell types with causal roles in disease.

genomics↗

bioRxiv2019

The Min system disassembles FtsZ foci and inhibits polar peptidoglycan remodeling in Bacillus subtilis

A microfluidic system coupled with fluorescence microscopy is a powerful approach for quantitative analysis of bacterial growth. Here, we measure parameters of growth and dynamic localization of the cell division initiation protein FtsZ in Bacillus subtilis. Consistent with previous reports, we find that after division FtsZ rings remain at the cell pole, and FtsZ ring disassembly coincides with rapid Z-ring accumulation at the midcell. In cells mutated for minD, however, the polar FtsZ rings persist indefinitely, suggesting that the primary function of the Min system is in Z-ring disassembly. The inability to recycle FtsZ monomers in the minD mutant results in maintenance of multiple Z-rings simultaneously, that are restricted by competition for newly synthesized FtsZ. Whereas the parameters of FtsZ dynamics change in the minD mutant, the overall cell cycle remains the same, albeit with elongated cells necessary to accumulate a threshold concentration of FtsZ for promoting medial division. Finally, the minD mutant characteristically produces minicells composed of polar peptidoglycan shown to be inert for remodeling in the wild type. Polar peptidoglycan, however, loses its inert character in the minD mutant suggesting that not only is the Min system important for recycling FtsZ but also may have a secondary role in the regulation of peptidoglycan remodeling. IMPORTANCEMany bacteria grow and divide by binary fission in which a mothercell divides into two identical daughter cells. To produce two equally sized daughters, the division machinery, guided by FtsZ, must dynamically localize to the midcell each cell cycle. Here, we quantitatively analyze FtsZ dynamics during growth and find that the Min system of Bacillus subtilis is essential to disassemble FtsZ rings after division. Moreover, a failure to efficiently recycle FtsZ results in an increase in cell size. Finally, we show that the Min system has an additional role in inhibiting cell wall turnover and contributes to the "inert" property of cell walls at the poles.

microbiology↗

bioRxiv2019

LncRNA and predictive model to improve the diagnosis of clinically diagnosed pulmonary tuberculosis

BackgroundClinically diagnosed pulmonary tuberculosis (PTB) patients lack Mycobacterium tuberculosis (MTB) microbiologic evidence, and misdiagnosis or delayed diagnosis often occurs as a consequence. We investigated the potential of lncRNAs and corresponding predictive models to diagnose these patients. MethodsWe enrolled 1372 subjects, including clinically diagnosed PTB patients, non-TB disease controls and healthy controls, in three cohorts (Screening, Selection and Validation). Candidate lncRNAs differentially expressed in blood samples of the PTB and healthy control groups were identified by microarray and qRT-PCR in the Screening Cohort. Logistic regression models were developed using lncRNAs and/or electronic health records (EHRs) from clinically diagnosed PTB patients and non-TB disease controls in the Selection Cohort. These models were evaluated by AUC and decision curve analysis, and the optimal model was presented as a Web-based nomogram, which was evaluated in the Validation Cohort. The biological function of lncRNAs was interrogated using ELISA, lactate dehydrogenase release analysis and flow cytometry. ResultsThree differentially expressed lncRNAs (ENST00000497872, n333737, n335265) were identified. The optimal model (i.e., nomogram) incorporated these three lncRNAs and six EHR variables (age, hemoglobin, weight loss, low-grade fever, CT calcification and TB-IGRA). The nomogram showed an AUC of 0.89, sensitivity of 0.86 and specificity of 0.82 in the Validation Cohort, which demonstrated better discrimination and clinical net benefit than the EHR model. ENST00000497872 may regulate inflammatory cytokine production, cell death and apoptosis during MTB infection. ConclusionsLncRNAs and the user-friendly nomogram could facilitate the early identification of PTB cases among suspected patients with negative MTB microbiologic evidence.

molecular biology↗

bioRxiv2019

Accurate modeling of replication rates in genome-wide association studies by accounting for winner's curse and study-specific heterogeneity

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in GWAS has been well-studied in the context of Winners Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winners Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes GWAS and replication studies to jointly model Winners Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 GWAS from the Human GWAS Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding.

bioinformatics↗

bioRxiv2019

Nick-seq for single-nucleotide resolution genomic maps of DNA modifications and damage

Here we present the Nick-seq platform for quantitative mapping of DNA modifications and damage at single-nucleotide resolution across genomes. Pre-existing breaks are blocked and DNA structures converted to strand-breaks for 3-extension by nick-translation to produce nuclease-resistant oligonucleotides, and 3-capture by terminal transferase tailing. Libraries from both products are subjected to next-generation sequencing. Nick-seq is a generally applicable method illustrated with quantitative profiling of single-strand-breaks, phosphorothioate modifications, and DNA oxidation.

molecular biology↗

bioRxiv2019

Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype

Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that LDL-C was negatively associated with T2D (OR=0.43[0.41, 0.45] per mmol/L unit of LDL-C), despite positive associations of LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. Finally, two-sample Mendelian randomization analyses suggest that low LDL-C causes T2D, although causal interpretations are challenging due to pleiotropy. Our findings extend our current understanding of the higher T2D risk among individuals with low LDL-C, and of the underlying mechanisms, including those underlying the diabetogenic effect of LDL-C-lowering medications.

genetics↗

bioRxiv2019

A Multimodal and Integrated Approach to Interrogate Human Kidney Biopsies with Rigor and Reproducibility: The Kidney Precision Medicine Project

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3-dimensional (3D) molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3D space is a significant challenge that can be a futile exercise if not well controlled. We describe a "follow the tissue" pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation and harmonization across different OMICS and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis and sharing. We established benchmarks for quality control, rigor, reproducibility and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

scientific communication and education↗

bioRxiv2019

Redefining Interleukin 11 as a regeneration-limiting hepatotoxin

Acetaminophen (APAP) overdose is a leading cause of untreatable liver failure. In the mouse model of APAP-induced liver injury (AILI), the administration of recombinant human interleukin 11 (rhIL11) is protective. Here we show that the beneficial effect of rhIL11 in the mouse is due to its unexpected and paradoxical inhibition of endogenous mouse IL11 activity. Contrary to the accepted paradigm IL11 is a potent hepatotoxin across species, which is secreted from damaged hepatocytes to drive an autocrine loop of NOX4 and JNK-dependent apoptosis. Mice with hepatocyte-specific Il11 expression spontaneously develop liver failure whereas those with Il11ra1 deletion are remarkably protected from AILI. Neutralizing anti-IL11R antibodies administered to moribund mice 10 hours following a lethal APAP overdose results in 90% survival that is associated with very large liver regeneration. Our data overturn a misconception, identify a new disease mechanism and suggest IL11 as a therapeutic target for liver regeneration.

physiology↗

bioRxiv2019

Up-regulation of autophagy by low concentration of salicylic acid delays methyl jasmonate-induced leaf senescence

Crosstalk between salicylic acid (SA) and jasmonic acid (JA) signaling plays an important role in molecular regulation of plant senescence. Our previous works found that SA could delay methyl jasmonate (MeJA)-induced leaf senescence in a concentration-dependent manner. Here, the effect of low concentration of SA (LCSA) application on MeJA-induced leaf senescence was further assessed. High-throughput sequencing (RNA-Seq) results showed that LCSA did not have dominant effects on the genetic regulatory pathways of basal metabolism like nitrogen metabolism, photosynthesis and glycolysis. The ClusterONE was applied to identify discrete gene modules based on protein-protein interaction (PPI) network. Interestingly, an autophagy-related (ATG) module was identified in the differentially expressed genes (DEGs) that exclusively induced by MeJA together with LCSA. RT-qPCR confirmed that the expression of most of the determined ATG genes were upregulated by LCSA. Remarkably, in contrast to wild type (Col-0), LCSA cannot alleviate the leaf yellowing phenotype in autophagy defective mutants (atg5-1 and atg7-2) upon MeJA treatment. Confocal and western blot results showed that LCSA increased the number of autophagic bodies and autophagic flux during MeJA-induced leaf senescence. Collectively, our work revealed up-regulation of autophagy by LCSA as a key regulator to alleviate MeJA-induced leaf senescence.

plant biology↗

bioRxiv2019

Information Enhanced Model Selection for High-Dimensional Gaussian Graphical Model with Application to Metabolomic Data

In light of the low signal-to-noise nature of many large biological data sets, we propose a novel method to learn the structure of association networks using Gaussian graphical models combined with prior knowledge. Our strategy includes two parts. In the first part, we propose a model selection criterion called structural Bayesian information criterion (SBIC), in which the prior structure is modeled and incorporated into Bayesian information criterion (BIC). It is shown that the popular extended BIC (EBIC) is a special case of SBIC. In the second part, we propose a two-step algorithm to construct the candidate model pool. The algorithm is data-driven and the prior structure is embedded into the candidate model automatically. Theoretical investigation shows that under some mild conditions SBIC is a consistent model selection criterion for high-dimensional Gaussian graphical model. Simulation studies validate the superiority of the proposed algorithm over the existing ones and show the robustness to the model misspecification. Application to relative concentration data from infant feces collected from subjects enrolled in a large molecular epidemiological cohort study validates that metabolic pathway involvement is a statistically significant factor for the conditional dependence between metabolites. Furthermore, new relationships among metabolites are discovered which can not be identified by the conventional methods of pathway analysis. Some of them have been widely recognized in biological literature.

bioinformatics↗

bioRxiv2019

P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib

The P16 (CDKN2Aink4a) gene is an endogenous CDK4/6 inhibitor. Palbociclib (PD0332991) is an anti-CDK4/6 chemical for cancer treatment. P16 is most frequently inactivated by copy number deletion and DNA methylation in cancers. It is well known that cancer cells with P16 deletion are more sensitive to palbociclib than those without. However, whether P16 methylation is related to palbociclib sensitivity is not known. By analyzing public pharmacogenomic datasets, we found that the IC50 of palbociclib in cancer cell lines (n=522) was positively correlated with both the P16 expression level and P16 gene copy number. Our experimental results further showed that cancer cell lines with P16 methylation were more sensitive to palbociclib than those without. To determine whether P16 methylation directly increased the sensitivity of cancer cells to palbociclib, we induced P16 methylation in the lung cancer cell lines H661 and HCC827 and the gastric cancer cell line BGC823 via an engineered P16-specific DNA methyltransferase (P16-Dnmt) and found that the sensitivity of these cells to palbociclib was significantly increased. The survival rate of P16-Dnmt cells was significantly lower than that of vector control cells 48 hrs post treatment with palbociclib (10 M). Notably, palbociclib treatment also selectively inhibited the proliferation of the P16-methylated subpopulation of P16-Dnmt cells, further indicating that P16 methylation can increase the sensitivity of cells to this CDK4/6 inhibitor. These results were confirmed in an animal experiment. In conclusion, inactivation of the P16 gene by DNA methylation can increase the sensitivity of cancer cells to palbociclib.

pharmacology and toxicology↗

bioRxiv2019

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

Photoreceptor cell degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become commercially available. Here we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

neuroscience↗

bioRxiv2019

Microbial extracellular polysaccharide production and aggregate stability controlled by Switchgrass (Panicum virgatum) root biomass and soil water potential

Deep-rooting perennial grasses are promising feedstock for biofuel production, especially in marginal soils lacking organic material, nutrients, and/or that experience significant water stress. Perennial grass roots can alter surrounding soil conditions and influence microbial activities, particularly the production of extracellular polymeric substances composed primarily of extracellular polysaccharides (EPS). These polymers can alleviate cellular moisture and nutrient stress, and enhance soil characteristics through improved water retention and aggregate stability, the latter of which may in turn enhance carbon persistence. In this study we used a 13CO2 tracer greenhouse experiment to examine the effect of switchgrass cultivation on the production and origin of EPS in a marginal soil with five fertilization/water treatments (control, +N, +NP, +P, low water). Soils with both added nitrogen and phosphorus had the highest root biomass, EPS and percentage of water-stable soil aggregates. Multiple linear regression analyses revealed root biomass was the most important determinant for soil EPS production, potentially by controlling carbon supply and diurnal changes in soil water potential. Path analysis highlighted the role of soil water potential were and EPS on with water-stable soil aggregates, indicating that EPS concentration and soil aggregation have similar drivers in this soil. High mannose content confirmed the microbial origin of EPS. 13CO2 labeling indicated that 0.18% of newly fixed plant carbon was incorporated into EPS. Analysis of field samples suggests that EPS is significantly enhanced under long-term switchgrass cultivation. Our results demonstrate that switchgrass cultivation can promote microbial production of EPS, providing a mechanism to enhance sustainability of marginal soils.

microbiology↗

bioRxiv2019

JNK-dependent intestinal barrier failure disrupts host-microbe homeostasis during tumorigenesis

In all animals, the intestinal epithelium forms a tight barrier to the environment. The epithelium regulates the absorption of nutrients, mounts immune responses and prevents systemic infections. Here, we investigate the consequences of tumorigenesis on the microbiome using a Drosophila intestinal tumor model. We show that upon loss-of BMP signaling, tumors lead to aberrant activation of JNK signaling, followed by intestinal barrier dysfunction and commensal imbalance. In turn, the dysbiotic microbiome triggers a regenerative response and stimulates tumor growth. We find that inhibiting JNK signaling or depletion of the microbiome restores barrier function of the intestinal epithelium, leading to a reestablishment of host-microbe homeostasis, and organismic lifespan extension. Our experiments identify a JNK-dependent feedback amplification loop between intestinal tumors and the microbiome. They also highlight the importance of controlling the activity level of JNK signaling to maintain epithelial barrier function and host-microbe homeostasis.

developmental biology↗

bioRxiv2019

HeveaDB: a genetic resource database for rubber tree genomic study

With the proceedings in the genome study in rubber tree, more and more data were produced. However, these data are still deposited in public databases as raw format, and the utilization of these NGS data is hindered for the researchers in rubber tree community. HeveaDB was therefore constructed and maintained under the organization of International Rubber Research and Development Board. The HeveaDB 1.0 (http://hevea.catas.cn) mainly stores 4 versions of Hevea draft genome, 99 NGS transcriptomes, 18451annotated EST sequences, 12 curated gene families, 30200 gene annotations, 5049 wild germplasm phenotype data, and 18328 Wickham rubber clonal information. Several bioinformatic tools are integrated in the database to facilitate the utilization of the data for the users who are not skilled in bioinformatics. With the periodical update and functional improvement, the HeveaDB will serve as a potential platform for genomic studies and breeding technology in rubber tree.

bioinformatics↗