Biology subjects

Ge, J.

Publications and source records attributed to Ge, J..

65 records · Page 4Linked to original sources

bioRxiv2020

TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors, but also posed computational challenges on how to integrate and utilize the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly two million cells from 76 high-quality tumor datasets across 28 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, malignant cell classification, cell clustering, cell-type annotation, differential expression analysis, and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching, and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.

bioinformatics↗

bioRxiv2020

Impaired learning and memory ability induced by a bilaterally hippocampal injection of streptozotocin in mice: involved with the adaptive changes of synaptic plasticity

BackgroundAlzheimers disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability and loss of self-sufficiency. ObjectiveTo establish an AD mice model, investigate the behavioral performance, and explore the potential mechanism. MethodsStreptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL /6 mice to establish the AD model. Behavioral changes (anhedonia and despair, balance and motor coordination, locomotion, and learning and memory) were examined and the serum concentrations of insulin and nesfatin-1 were measured by ELISA. The activation of hippocampal microglia was assessed by immunohistochemistry and the protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the prefrontal cortex (PFC) was detected via western blotting. ResultsThe STZ model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-{beta}-catenin/{beta}-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3{beta} (ser9)/GSK-3{beta} were reduced in the hippocampus. ConclusionA bilateral hippocampal microinjection of STZ could successfully duplicate an AD mice model, as indicated by the impaired learning and memory and the alternated synaptic plasticity, together with the hyperactive inflammatory response in the hippocampus and the imbalanced abundance of serum insulin and nesfatin-1. Apart from these, the mechanism might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/235481v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@181c9a9org.highwire.dtl.DTLVardef@1deaa4forg.highwire.dtl.DTLVardef@17f3f09org.highwire.dtl.DTLVardef@1037c21_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Myofibroblast Forms Atherosclerotic Plaques

For decades, smooth muscle cells (SMCs) and macrophages are considered as the main contributors to atherosclerotic plaques. However, we found that in the human coronary atherosclerotic plaques, SMCs were few, while lots of myofibroblasts infiltrated in the intima near the lumen (fibrous cap) and their distribution was highly positive related to intimal thickness. In addition to lots of foam cells formation, collagen fibers were forming in the thickening intima near the lumen (fibrous cap), and denaturing or calcifying gradually far from the lumen, which evolved into various complex plaques. In vitro, myofibroblasts could actively take lots of low-density lipoprotein (LDL) to enhance proliferation. Lots of collagen fibers, foam cells and extracellular lipids accumulation emerged in myofibroblasts cultured with 5% FBS high glucose DMEM without adding modified LDL. It is consistent with the characteristics of human coronary atherosclerotic plaques. It is the first time that lipid rich plaques with lots of foam cells, extracellular lipids and collagen fibers formed in vitro. It demonstrated that myofibroblast should be the direct and main source of collagen fibers, foam cells and extracellular lipids. This suggests that atherosclerosis is not as complicated as previously considered, and it might be mainly a process of myofibroblast remodeling to vascular injury caused by various risk factors. This study made the pathogenesis of atherosclerosis clearer. It would provide a target cell for future treatments of atherosclerotic diseases. In vitro atherosclerotic plaques model formed by human myofibroblasts would be an efficient and convenient way to study atherosclerosis.

cell biology↗

bioRxiv2020

Potent human neutralizing antibodies elicited by SARS-CoV-2 infection

The pandemic caused by emerging coronavirus SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. SARS-CoV-2 cellular entry depends on binding between the viral Spike protein receptor-binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) target cell receptor. Here, we report on the isolation and characterization of 206 RBD-specific monoclonal antibodies (mAbs) derived from single B cells of eight SARS-CoV-2 infected individuals. These mAbs come from diverse families of antibody heavy and light chains without apparent enrichment for particular families in the repertoire. In samples from one patient selected for further analyses, we found coexistence of germline and germline divergent clones. Both clone types demonstrated impressive binding and neutralizing activity against pseudovirus and live SARS-CoV-2. However, the antibody neutralizing potency is determined by competition with ACE2 receptor for RBD binding. Surprisingly, none of the SARS-CoV-2 antibodies nor the infected plasma cross-reacted with RBDs from either SARS-CoV or MERS-CoV although substantial plasma cross-reactivity to the trimeric Spike proteins from SARS-CoV and MERS-CoV was found. These results suggest that antibody response to RBDs is viral species-specific while that cross-recognition target regions outside the RBD. The specificity and neutralizing characteristics of this plasma cross-reactivity requires further investigation. Nevertheless, the diverse and potent neutralizing antibodies identified here are promising candidates for prophylactic and therapeutic SARS-CoV-2 interventions.

immunology↗

bioRxiv2020

Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-[A]. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified {beta}-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp. One Sentence SummaryStructure of 2019-nCov RNA polymerase.

biochemistry↗

bioRxiv2020

Crystal structure of the 2019-nCoV spike receptor-binding domain bound with the ACE2 receptor

A novel and highly pathogenic coronavirus (2019-nCoV) has caused an outbreak in Wuhan city, Hubei province of China since December 2019, and soon spread nationwide and spilled over to other countries around the world. To better understand the initial step of infection at atomic-level, we determined the crystal structure of the 2019-nCoV spike receptor-binding domain (RBD) bound with the cell receptor ACE2 at 2.45 [A] resolution. The overall ACE2-binding mode of the 2019-nCoV RBD is nearly identical to that of the SARS-CoV RBD, which also utilizes ACE2 as the cell receptor. Structural analysis identified residues in 2019-nCoV RBD critical for ACE2 binding, and majority of which are either highly conserved or shared similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly argue for a convergent evolution between 2019-nCoV and SARS-CoV RBD for improved binding to ACE2 despite of being segregated in different genetic lineages in the betacoronavirus genus. The epitopes of two SARS-CoV antibodies targeting the RBD are also analyzed with the 2019-nCoV RBD, providing insights into future identification of cross-reactive antibodies.

biophysics↗

bioRxiv2019

Chromosome-level genome assembly of the greenfin horse-faced filefish (Thamnaconus septentrionalis) using Oxford Nanopore PromethION sequencing and Hi-C technology

The greenfin horse-faced filefish, Thamnaconus septentrionalis, is a valuable commercial fish species that is widely distributed in the Indo-West Pacific Ocean. It has characteristic blue-green fins, rough skin and spine-like first dorsal fin. T. septentrionalis is of a conservation concern as a result of sharply population decline, and it is an important marine aquaculture fish species in China. The genomic resources of this filefish are lacking and no reference genome has been released. In this study, the first chromosome-level genome of T. septentrionalis was constructed using Nanopore sequencing and Hi-C technology. A total of 50.95 Gb polished Nanopore sequence were generated and were assembled to 474.31 Mb genome, accounting for 96.45% of the estimated genome size of this filefish. The assembled genome contained only 242 contigs, and the achieved contig N50 was 22.46 Mb, reaching a surprising high level among all the sequenced fish species. Hi-C scaffolding of the genome resulted in 20 pseudo-chromosomes containing 99.44% of the total assembled sequences. The genome contained 67.35 Mb repeat sequences, accounting for 14.2% of the assembly. A total of 22,067 protein-coding genes were predicted, of which 94.82% were successfully annotated with putative functions. Furthermore, a phylogenetic tree was constructed using 1,872 single-copy gene families and 67 unique gene families were identified in the filefish genome. This high quality assembled genome will be a valuable genomic resource for understanding the biological characteristics and for facilitating breeding of T. septentrionalis.

genomics↗

bioRxiv2019

CaATP prolongs strong actomyosin binding and promotes futile myosin stroke

Calcium plays an essential role in muscle contraction, regulating actomyosin interaction by binding troponin of thin filaments. There are several buffers for calcium in muscle, and those buffers play a crucial role in the formation of the transient calcium wave in sarcomere upon muscle activation. One such calcium buffer in muscle is ATP. ATP is a fuel molecule, and the important role of MgATP in muscle is to bind myosin and supply energy for the power stroke. Myosin is not a specific ATPase, and CaATP also supports myosin ATPase activity. The concentration of CaATP in sarcomeres reaches 1% of all ATP available. Since 294 myosin molecules form a thick filament, naive estimation gives three heads per filament with CaATP bound, instead of MgATP. We found that CaATP dissociates actomyosin slower than MgATP, thus increasing the time of the strong actomyosin binding. The rate of the basal CaATPase is faster than that of MgATPase, myosin readily produces futile stroke with CaATP. When calcium is upregulated, as in malignant hyperthermia, kinetics of myosin and actomyosin interaction with CaATP suggest that myosin CaATPase activity may contribute to observed muscle rigidity and enhanced muscle thermogenesis.

biochemistry↗

bioRxiv2019

Allicin regulates energy homeostasis through brown adipose tissue

Background/objectivesDisorder of energy homeostasis can lead to a variety of metabolic diseases, especially obesity. Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a main bioactive ingredient in garlic, has multiple biology and pharmacological function. However, the role of Allicin, in the regulation of metabolic organ, especially the role of activation of BAT, has not been well studied. Here, we analyzed the role of Allicin in whole-body metabolism and the activation of BAT.\n\nResultsAllicin had a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in diet-introduced obesity (DIO) mice. Then we find that Allicin can strongly activate brown adipose tissue (BAT). The activation of brown adipocyte treated with Allicin was also confirmed in mouse primary brown adipocytes.\n\nConclusionAllicin can ameliorate obesity through activating brown adipose tissue. Our findings provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.

molecular biology↗

bioRxiv2019

Prognostic Role of c-Met Overexpression in High Grade Glioma: a Meta-analysis

ObjectivesThis study aims to assess the relationship between the expression of c-Met and the prognosis of high grade glioma patients.\n\nMethodThe MET proto-oncogene encoded c-Met protein. The gene expression data of 325 patients were downloaded from CGGA. The Oncomine database analysis and the prognosis analysis were conducted. Besides, meta-analysis was also performed to confirm the conclusion.\n\nResultOncomine database was identified and analyzed and results showed that the MET copy number was obviously higher in glioblastoma than normal tissue consistently (p<0.001). The prognostic analysis of 325 high grade glioma samples showed that high c-Met expression patients had poor overall survival (OS) and progression free survival (PFS) than the low c-Met expression patients dramatically (HR, 2.223; 95% CI: 1.662 to 2.974; P<0.0001 and HR, 2.089; 95% CI: 1.578 to 2.770; P<0.0001). 6 studies involving 503 patients were included in the meta-analysis. The pooled results indicated that the high expression of c-Met was not significantly associated with OS (HR =1.01, 95% CI:0.93-1.09), but strongly connected with shorter PFS (HR =1.92, 95% CI:1.42-2.58, p<0.01).\n\nConclusionc-Met overexpression has correlation with poor prognosis of high grade glioma patients.

cancer biology↗

bioRxiv2019

Knowledge-guided analysis of ‘omics’ data using the KnowEnG cloud platform

We present KnowEnG, a free-to-use computational system for analysis of genomics data sets, designed to accelerate biomedical discovery. It includes tools for popular bioinformatics tasks such as gene prioritization, sample clustering, gene set analysis and expression signature analysis. The system offers knowledge-guided data-mining and machine learning algorithms, where user-provided data are analyzed in light of prior information about genes, aggregated from numerous knowledge-bases and encoded in a massive Knowledge Network. KnowEnG adheres to FAIR principles: its tools are easily portable to diverse computing environments, run on the cloud for scalable and cost-effective execution of compute-intensive and data-intensive algorithms, and are interoperable with other computing platforms. They are made available through multiple access modes including a web-portal, and include specialized visualization modules. We present use cases and re-analysis of published cancer data sets using KnowEnG tools and demonstrate its potential value in democratization of advanced tools for the modern genomics era.

cancer biology↗