Biology subjects

Zeng, Z.

Publications and source records attributed to Zeng, Z..

117 records · Page 7Linked to original sources

bioRxiv2019

Novel immune and stromal subtype classification system of lung adenocarcinoma based on tumor microenvironment

BackgroundTumor microenvironment has complex effects on tumorigenesis and metastasis in lung adenocarcinoma (LUAD). However, there is still a lack of comprehensive understanding of the relationship between immune and non-immune stromal characteristics in tumor microenvironment.\n\nPatients and methodsEight cohort of 1681 lung caner patients were included in this study. The immune and non-immune stromal signatures of tumor microenvironment were identified by eigendecomposition and extraction algorithms. We developed a novel immune and stromal scoring system to quantify anti-tumor immune and promote-metastasis stromal activation, namely PMBT (prognostic model based on tumor microenvironment) as an R package. Tumors were classified into 4 subtypes according to PMBT system. Comprehensive analysis was performed in different subtypes.\n\nResultsThe 4 subgroups had different mutation landscape, molecular, cellular characteristics and prognosis, which validated by 7 data sets containing 1175 patients. 19% patients was characterized by highly active anti-tumor reaction with high production of immunoactive mediators, immunocyte, low fibroblasts infiltration, low TGF-{beta}, VEGFA, collagen and glucose catabolic, low immune checkpoint per T cell, tumor mutation burden, and favourable overall survival (all, P < 0.05) named high-immune and low-stromal activation subgroup (HL). Cellular paracrine network showed both high humoral and cellular immune interaction in HL group. The low-immune and high-stromal activation group (19%) had opposite characteristics with HL group. Moreover, the PMBT system showed the value to predict overall survival and immunotherapy responses (all, P < 0.05).\n\nConclusionsDifferent molecular, cellular characteristics, mutation landscape and prognosis were discovered in the 4 subgroups. Our classification, PMBT system provided novel insight for clinical monitoring and treatment in LUAD.

bioinformatics↗

bioRxiv2019

Inducible Plasmid Self-Destruction (IPSD) assisted genome engineering in lactobacilli and bifidobacteria

Genome engineering is essential for application of synthetic biology in probiotics including lactobacilli and bifidobacteria. Several homologous recombination system-based mutagenesis tools have been developed for these bacteria but still, have many limitations in different species or strains. Here we developed a genome engineering method based on an inducible self-destruction plasmid delivering homologous DNA into bacteria. Excision of the replicon by induced recombinase facilitates selection of homologous recombination events. This new genome editing tool called Inducible Plasmid Self-Destruction (IPSD) was successfully used to perform gene knock-out and knock-in in lactobacilli and bifidobacteria. Due to its simplicity and universality, the IPSD strategy may provide a general approach for genetic engineering of various bacterial species.

bioengineering↗

bioRxiv2019

MRGPRX4 is a novel bile acid receptor in cholestatic itch

Patients with liver diseases often suffer from chronic itch or pruritus, yet the itch-causing pruritogen(s) and their cognate receptor(s) remain largely elusive. Using transcriptomics and GPCR activation assays, we found that an orphan, primate specific MRGPRX4 is expressed in human dorsal root ganglia (hDRG) and selectively activated by bile acids. In situ hybridization and immunohistochemistry revealed that MRGPRX4 is expressed in [~]7% of hDRG neurons and co-localizes with HRH1, a known itch-inducing GPCR. Bile acids elicited a robust Ca2+ response in a subset of cultured hDRG neurons, and intradermal injection of bile acids and an MRGPRX4 specific agonist induced significant itch in healthy human subjects. Surprisingly, application of agonist for TGR5, a known sequence conserved bile acid receptor previously implicated in cholestatic itch, failed to elicit Ca2+ response in cultured hDRG neurons, nor did it induce pruritus in human subjects. In situ hybridization and immunostaining results revealed that hTGR5 is selectively expressed in satellite glial cells, unlike mTGR5 (in mouse DRG neurons), likely accounting for the inter-species difference functionally. Finally, we found that patients with cholestatic itch have significantly higher plasma bile acid levels compared to non-itchy patients and the bile acid levels significantly decreased after itch relief. This elevated bile acid level in itchy patients is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch, providing a promising new drug target for anti-itch therapies.

neuroscience↗

bioRxiv2019

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

It is largely unknown how the risk of development of breast cancer is transduced by somatic genetic alterations. To address this lacuna of knowledge and acknowledging that benign breast disease (BBD) is an established risk factor for breast cancer, we established a case-control study: The Benign Breast & Cancer Risk (BBCAR) Study. Cases are women with BBD who developed subsequent invasive breast cancer (IBC) at least 3 years after the biopsy and controls are women with BBD who did not develop IBC (median follow-up 16.6 years). We selected 135 cases and individually matched controls (1:2) to cases based on age and type of benign disease: non-proliferative or proliferation without atypia. Whole exome sequencing was performed on DNA from the benign lesions and from subsets with available germline DNA or tumor DNA. Although the number of cases and controls with copy number variation data is limited, several amplifications and deletions are exclusive to the cases. In addition to two known mutational signatures, a novel signature was identified that is significantly (p=0.007) associated with triple negative breast cancer. The somatic mutation rate in benign lesions is similar to that of invasive breast cancer and does not differ between cases and controls. Two mutated genes are significantly associated with time to the diagnosis of breast cancer, and mutations shared between the benign biopsy tissue and the breast malignancy for the ten cases for which we had matched pairs were identified. BBD tissue is a rich source of clues to breast oncogenesis.\n\nOne Sentence SummaryGenetic aberrations in benign breast lesions distinguish breast cancer cases from controls and predict cancer risk.

genetics↗

bioRxiv2019

Deep learning for cancer type classification

Genetic information is becoming more readily available and is increasingly being used to predict patient cancer types as well as their subtypes. Most classification methods thus far utilize somatic mutations as independent features for classification and are limited by study power. To address these limitations, we propose DeepCues, a deep learning model that utilizes convolutional neural networks to derive features from DNA sequencing data for disease classification and relevant gene discovery. Using whole-exome sequencing, germline variants and somatic mutations, including insertions and deletions, are interactively amalgamated as features. In this study, we applied DeepCues to a dataset from TCGA to classify seven different types of major cancers and obtained an overall accuracy of 77.6%. We compared DeepCues to conventional methods and demonstrated a significant overall improvement (p=8.8E-25). Using DeepCues, we found that the top 20 genes associated with breast cancer have a 40% overlap with the top 20 breast cancer genes in the COSMIC database. These data support DeepCues as a novel method to improve the representational resolution of both germline variants and somatic mutations interactively and their power in predicting cancer types, as well the genes involved in each cancer.

cancer biology↗

bioRxiv2018

CasLocusAnno: a web-based server for annotating Cas loci and their corresponding (sub)types

CRISPR-Cas systems are prevalent in bacterial and archaeal genomes, and these systems provide a powerful adaptive immune system against predation by phages and other mobile genetic elements (MGEs). They also contribute to other functions, such as gene regulation in prokaryotic organisms. Determining Cas proteins and Cas loci can help mine Cas proteins and facilitate the identification of Cas-associated accessory proteins. Therefore, the purpose of this work is to develop a web-based server, CasLocusAnno, to annotate Cas proteins and Cas loci and to classify them according to (sub)type based on a previous study. CasLocusAnno can annotate Cas proteins and Cas loci and assign their (sub)types within {bsim}28 seconds for whole protein sequence submissions, with protein sequence numbers ranging from {bsim}30 to {bsim}10500. Comparison with Makarova et al.s benchmark data demonstrates that CasLocusAnno can accurately identify Cas loci and (sub)types. In addition, CasLocusAnno can identify Cas proteins with higher accuracy and a lower additional prediction rate (APR) than two excellent software programs, CRISPRCasFinder and MacSyFinder. The domain alignment of a Cas protein can be easily browsed in the annotation results. Our server can be freely accessed at http://cefg.uestc.edu.cn/CasLocusAnno/.

bioinformatics↗

bioRxiv2017

Predicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features

The CCCTC-binding zinc finger protein (CTCF)-mediated network of long-range chromatin interactions is important for genome organization and function. Although this network has been considered largely invariant, we found that it exhibits extensive cell-type-specific interactions that contribute to cell identity. Here we present Lollipop--a machine-learning framework--which predicts CTCF-mediated long-range interactions using genomic and epigenomic features. Using ChIA-PET data as benchmark, we demonstrated that Lollipop accurately predicts CTCF-mediated chromatin interactions both within and across cell-types, and outperforms other methods based only on CTCF motif orientation. Predictions were confirmed computationally and experimentally by Chromatin Conformation Capture (3C). Moreover, our approach reveals novel determinants of CTCF-mediated chromatin wiring, such as gene expression within the loops. Our study contributes to a better understanding about the underlying principles of CTCF-mediated chromatin interactions and their impact on gene expression.

systems biology↗

bioRxiv2017

Separating an allele associated with late flowering and slow maturation of Arabidopsis thaliana from population structure

Genome-wide association analysis is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset of Arabidopsis thaliana. We demonstrate the efficiency of double-phenotype analysisto uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, acommon allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate gene AT1G11560 that potentially causes this association. Further analysis indicates that this locusis co-selected with flowering-time-related genes. The discovered pleiotropic genotypephenotype map provides new insights into understanding the genetic correlation of complex traits.

genetics↗

bioRxiv2017

Wilms Tumor 1b defines a wound-specific sheath cell subpopulation associated with notochord repair

Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify a novel and unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury. Using live imaging in zebrafish, we show that localized damage leads to Wt1b expression in the sheath, and that wt1b+ cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. At the wound wt1b+ and entpd5+ cells constitute distinct subpopulations, and mark the site of an extra vertebra that forms in an untypical manner via a cartilage intermediate. Surprisingly, wt1b+ cells become closely associated with the chordacentra and sustain wt1b expression for over 35 days during vertebra formation. Given that remnants of notochord cells remain in the adult intervertebral disc, the identification of novel subpopulations may have important implications for regenerative treatments for spine disorders.\n\nHighlightsO_LINotochord injury triggers wound-specific expression of wt1b in novel sheath subpopulation\nC_LIO_LIWT1b notochord sheath cells fill injury site and form stopper-like structure\nC_LIO_LIWT1b subpopulation marks site of a new vertebra that forms via a cartilage intermediate\nC_LIO_LIWT1b wound-specific subpopulation perdures throughout and after vertebra repair\nC_LI

developmental biology↗