Biology subjects

Zeng, Z.

Publications and source records attributed to Zeng, Z..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

An angiosperm NLR atlas reveals that NLR gene reduction is associated with ecological specialization and signal transduction component deletion

Nucleotide-binding site-leucine-rich repeat receptor (NLR) genes comprise the largest family of plant disease resistance genes. NLR genes are phylogenetically divided into the TNL, CNL, and RNL subclasses. NLR copy numbers and subclass composition vary tremendously across angiosperm genomes. However, the evolutionary associations between genomic NLR content and plant lifestyle, or between NLR content and signal transduction components, are poorly characterized due to limited genome availability. Here, we established an angiosperm NLR atlas (ANNA, http://compbio.nju.edu.cn/app/ANNA/), which includes NLR genes from over 300 angiosperm genomes. Using ANNA, we revealed that NLR copy numbers differ up to 66-fold among closely related species due to rapid gene loss and gain. Interestingly, NLR contraction was associated with adaptations to aquatic, parasitic, and carnivorous lifestyles. The convergent NLR reduction in aquatic plants resembles the long-term evolutionary silence of NLR genes in green algae before the colonization of land. A co-evolutionary pattern between NLR subclasses and plant immune-pathway components was also identified, suggesting that immune pathway deficiencies may drive TNL loss. Finally, we recovered a conserved TNL lineage that may function independently of the RNL pathway. Our findings provide new insights into the evolution of NLR genes in the context of plant lifestyles and genome content variation.

plant biology↗

bioRxiv2021

Self-assembling SARS-CoV-2 nanoparticle vaccines targeting the S protein induces protective immunity in mice

The spike (S), a homotrimer glycoprotein, is the most important antigen target in the research and development of SARS-CoV-2 vaccine. There is no doubt that fully simulating the advanced structure of this homotrimer in the subunit vaccine development strategy is the most likely way to improve the immune protective effect of the vaccine. In this study, the preparation strategies of S protein receptor-binding domain (RBD) trimer, S1 region trimer, and ectodomain (ECD) trimer nanoparticles were designed based on ferritin nanoparticle self-assembly technology. The Bombyx mori baculovirus expression system was used to prepare these three nanoparticle vaccines with high expression levels in the silkworm. The immune results of mice show that the nanoparticle vaccine prepared by this strategy can not only induce an immune response by subcutaneous administration but also effective by oral administration. Given the stability of these ferritin-based nanoparticles vaccine, easy-to-use and low-cost oral immunization strategy can make up for the vaccination blind areas caused by the shortage of ultralow-temperature equipment and medical resources in underdeveloped areas. And the oral vaccine is also a very potential candidate to cut off the spread of SARS-CoV-2 in domestic and farmed animals, especially in stray and wild animals.

immunology↗

bioRxiv2020

Exposure of mammary cells to lipid activates gene expression changes associated with ER-negative breast cancer via chromatin remodeling.

Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A cells and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.

cancer biology↗

bioRxiv2020

Bacterial microcompartments linked to the flavin-based extracellular electron transfer drives anaerobic ethanolamine utilization in Listeria monocytogenes

Ethanolamine (EA) is a valuable microbial carbon and nitrogen source derived from phospholipids present in cell membranes. EA catabolism is suggested to occur in so-called bacterial microcompartments (BMCs) and activation of EA utilization (eut) genes is linked to bacterial pathogenesis. Despite reports showing that activation of eut in Listeria monocytogenes is regulated by a vitamin B12-binding riboswitch and that upregulation of eut genes occurs in mice, it remains unknown whether EA catabolism is BMC dependent. Here, we provide evidence for BMC-dependent anaerobic EA utilization via metabolic analysis, proteomics and electron microscopy. First, we show B12-induced activation of the eut operon in L. monocytogenes coupled to uptake and utilization of EA thereby enabling growth. Next, we demonstrate BMC formation in conjunction to EA catabolism with the production of acetate and ethanol in a molar ratio of 2:1. Flux via the ATP generating acetate branch causes an apparent redox imbalance due to reduced regeneration of NAD+ in the ethanol branch resulting in a surplus of NADH. We hypothesize that the redox imbalance is compensated by linking eut BMC to anaerobic flavin-based extracellular electron transfer (EET). Using L. monocytogenes wild type, a BMC mutant and a EET mutant, we demonstrate an interaction between BMC and EET and provide evidence for a role of Fe3+ as an electron acceptor. Taken together, our results suggest an important role of anaerobic BMC-dependent EA catabolism in the physiology of L. monocytogenes, with a crucial role for the flavin-based EET system in redox balancing. IMPORTANCEListeria monocytogenes is a food-borne pathogen causing severe illness and, as such, it is crucial to understand the molecular mechanisms contributing to pathogenicity. One carbon source that allows L. monocytogenes to grow in humans is ethanolamine (EA), which is derived from phospholipids present in eukaryotic cell membranes. It is hypothesized that EA utilization occurs in bacterial microcompartments (BMCs), self-assembling subcellular proteinaceous structures and analogs of eukaryotic organelles. Here, we demonstrate that BMC-driven utilization of EA in L. monocytogenes results in increased energy production essential for anaerobic growth. However, exploiting BMCs and the encapsulated metabolic pathways also requires balancing of oxidative and reductive pathways. We now provide evidence that L. monocytogenes copes with this by linking BMC activity to flavin-based extracellular electron transfer (EET) using iron as an electron acceptor. Our results shed new light on an important molecular mechanism that enables L. monocytogenes to grow using host-derived phospholipid degradation products.

microbiology↗

bioRxiv2020

Proteomics study of colorectal cancer and adenomatous polyps identifies TFR1, SAHH, and HV307 as potential biomarkers for screening

Colorectal cancer (CRC) is a malignant tumour with high morbidity and mortality worldwide. Efficient screening strategies for CRC and pre-cancerous lesions will promote early medical intervention and treatment, thus reducing morbidity and mortality. Proteins are generally considered key biomarkers of cancer. Herein, we performed a quantitative, tissue-original proteomics study in a cohort of ninety patients from pre-cancerous to cancerous conditions by liquid chromatography-tandem mass spectrometry. A total of 134,812 peptides, 8,697 proteins, 2,355 (27.08%) union differentially expressed proteins (DEPs), and 409 shared DEPs (compared with adjacent tissues) were identified. The number of DEPs showed a positive correlation with increasing severity of illness. The union and shared DEPs were both enriched in the KEGG pathway of focal adhesion, metabolism of xenobiotics by cytochrome P450, and drug metabolism - cytochrome P450. Among the 2,355 union DEPs, 32 were selected for identification and validation by multiple reaction monitoring from twenty plasma specimens. Of these, three proteins, transferrin receptor protein 1 (TFR1), adenosylhomocysteinase (SAHH), and immunoglobulin heavy variable 3-7 (HV307), were significantly differentially expressed and displayed the same expression pattern in plasma as observed in the tissue data. In conclusion, TFR1, SAHH, and HV307 may be considered as potential biomarkers for screening of CRC. SignificanceCRC is a malignant tumour with high morbidity and mortality worldwide. Efficient screening strategies for CRC and pre-cancerous lesions can play an important role in addressing the issue of high morbidity and mortality. Screening of molecular biomarkers provide a non-invasive, cost-effective and effective approach. Proteins are generally considered key molecular biomarkers of cancer. Our study reports a quantitative proteomics analysis of protein biomarkers for colorectal cancer (CRC) and adenomatous polyps and identifies TFR1, SAHH, and HV307 as potential biomarkers for screening. The research makes a significant contribution to the literature because whereas mass spectrometry-based proteomics research has been widely used for clinical research, its application to clinical translation is lacking as parallel specimens ranging from pre-cancerous to cancerous tissues, according to the degree of disease progression, have not been readily assessed.

biochemistry↗

bioRxiv2020

An Engineered Genetic Circuit for Lactose Intolerance Alleviation Coupled with Gut Microbiota Recovery

BackgroundLactose malabsorption occurs in around 68% of the world populations, causing lactose intolerance (LI) symptoms such as abdominal pain, bloating and diarrhoea. To alleviate LI, previous studies mainly focused on strengthening intestinal {beta}-galactosidase activity but neglected the inconspicuous colon pH drop caused by gut microbes fermentation on non-hydrolysed lactose. The colon pH drop will reduce intestinal {beta}-galactosidase activity and influence the intestinal homeostasis. ResultsHere, we synthesized a tri-stable-switch circuit equipped with high {beta}-galactosidase activity and pH rescue ability. This circuit can switch in functionality between expression of {beta}-galactosidase and expression of l-lactate dehydrogenase in respond to intestinal lactose signal and intestinal pH signal. We confirmed the circuit functionality was efficient using 12-hrs in vitro culture at a range of pH levels, as well as 6-hrs in vivo simulations in mice colon. Moreover, another 21-days mice trial indicated that this circuit can recover lactose-effected gut microbiota of mice to the status (enterotypes) similar to that of mice without lactose intake. ConclusionsTaken together, the tri-stable-switch circuit can serve as a promising prototype for LI symptoms relief, especially by flexibly adapting to environmental variation, stabilizing colon pH and restoring gut microbiota.

bioengineering↗

bioRxiv2020

High-Fiber Diet Restores Maternal Obesity-Induced Cognitive and Social Behavioral Deficits in Offspring via Regulating Gut Microbiota-Metabolites-Brain Axis

Maternal obesity has been reported to be related to the neurodevelopmental disorders in offspring. However, the underlying mechanisms and effective interventions remain unclear. Here, a cross-sectional study on 778 children aged 7-14 years in two cities of China indicates that the maternal obesity is highly associated with the poorer cognition and sociality of their children. Moreover, we also find that the maternal obesity in mice disrupts the behavior and the gut microbiome in the offspring, which are alleviated by a high-fiber diet in either dams or offspring. Co-housing and feces microbiota transplantation experiments reveal a causal relationship between the reshaped microbiota and the behavioral changes. Moreover, treatment of the microbiota-derived short-chain fatty acids exhibits a similar beneficial effect on alleviating the behavioral deficits in offspring. Together, our study purports the microbiota-metabolites-brain axis as a mechanism, and high-dietary fiber intake is a promising intervention against maternal obesity-induced cognitive and social dysfunctions.

neuroscience↗

bioRxiv2020

Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS

RATIONALEA history of chronic cigarette smoking is known to increase risk for ARDS, but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures, and thus an interesting candidate gene for the study of exposure-related lung disease. METHODS AND RESULTSLungs harvested from current versus former/never smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle treated controls. In separate studies, endothelial (EC)-specific WWOX KO versus wild type mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31+CD45- cells. These were grown in culture, confirmed to be WWOX-deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing (ECIS) as well as a FITC dextran transwell assay for their barrier properties during MRSA or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to wild type cells during either MRSA or LPS treatment as measured by both ECIS and the transwell assay. CONCLUSIONThe increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.

molecular biology↗

bioRxiv2020

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger Cyclin K degradation

Molecular glues are small molecules that exert their biologic or therapeutic activities by inducing gain-of-function interactions between pairs of proteins. In particular, molecular-glue degraders, which mediate interactions between target proteins and components of the ubiquitin proteasome system to cause targeted protein degradation, hold great promise as a unique modality for therapeutic targeting of proteins that are currently intractable. Here, we report a new molecular glue HQ461 discovered by high-throughput screening of small molecules that inhibited NRF2 activity. Using unbiased loss-of-function and gain-of-function genetic screening followed by biochemical reconstitution, we show that HQ461 acts by promoting interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of CDK12s interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that engages its target protein directly with DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.

biochemistry↗

bioRxiv2020

Molecular epidemiology and clone transmission of carbapenem-resistant Acinetobacter baumannii in ICU rooms

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a major cause of nosocomial infections and hospital outbreaks worldwide, remaining a critical clinical concern. Here we characterized and investigated the phylogenetic relationships of 105 CRAB isolates on intensive care unit surfaces from one hospital in China collected over six years. All strains carried blaOXA-23, blaOXA-66 genes for carbapenem resistance, also had high resistance gene, virulence factor and insertion sequences burdens. Whole-genome sequencing revealed all strains belonged to ST2, the global clone CC2. The phylogenetic analysis based on the core genome showed all isolates was dominated by a single lineage of three clusters and eight different clones. Two clones were popular during the collection time. Using chi-square test to identify the epidemiologically meaningful groupings, we found the significant difference in community structure only present in strains from separation time. The haplotype and median-joining network analysis revealed genetic differences among clusters and changes occurred overtime in the dominating cluster. Our results highlighted substantial multidrug-resistant CRAB burden in hospital ICU environment, demonstrated potential clone outbreak in hospital.

bioinformatics↗

bioRxiv2020

Precise detection of Acrs in prokaryotes using only six features

Anti-CRISPR proteins (Acrs) can suppress the activity of CRISPR-Cas systems. Some viruses depend on Acrs to expand their genetic materials into the host genome which can promote species diversity. Therefore, the identification and determination of Acrs are of vital importance. In this work we developed a random forest tree-based tool, AcrDetector, to identify Acrs in the whole genomescale using merely six features. AcrDetector can achieve a mean accuracy of 99.65%, a mean recall of 75.84%, a mean precision of 99.24% and a mean F1 score of 85.97%; in multi-round, 5-fold cross-validation (30 different random states). To demonstrate that AcrDetector can identify real Acrs precisely at the whole genome-scale we performed a cross-species validation which resulted in 71.43% of real Acrs being ranked in the top 10. We applied AcrDetector to detect Acrs in the latest data. It can accurately identify 3 Acrs, which have previously been verified experimentally. A standalone version of AcrDetector is available at https://github.com/RiversDong/AcrDetector. Additionally, our result showed that most of the Acrs are transferred into their host genomes in a recent stage rather than early.

bioinformatics↗

bioRxiv2020

Generation of kidney ureteric bud and collecting duct organoids that recapitulate kidney branching morphogenesis

Kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidneys collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from pluripotent human stem cells. UB organoids differentiate into CD organoids in vitro, with differentiated cell types adopting spatial assemblies reflective of the adult kidney collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Combining efficient gene editing with the UB organoid model will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting system. One sentence summaryCollecting duct organoids derived from primary mouse and human ureteric bud progenitor cells and human pluripotent stem cells provide an in vitro platform for genetic dissection of development, regeneration and diseases of the mammalian collecting system.

developmental biology↗

bioRxiv2020

Isopropoxy benzene guanidine kills Staphylococcus aureus without detectable resistance

Antibiotic resistance is a serious public health crisis. The challenge caused by Staphylococcus aureus infections clearly urges the development of novel antimicrobial therapy. Drug repurposing has emerged as an alternative approach to rapidly identify effective drugs against multidrug-resistant bacteria. Recently, substituted benzene guanidine compounds have been used as leading structures to discover new promising drugs in both synthetic and medicinal chemistry. We investigated the antimicrobial activity of an analog of substituted benzene guanidine compounds (isopropoxy benzene guanidine) and further explored its antibacterial mechanism against S. aureus. Isopropoxy benzene guanidine had a MIC of 0.125-4g/ml against S. aureus and displayed potent activity against S. aureus by disrupting cell membrane. Unlike conventional antibiotics, repeated use of isopropoxy benzene guanidine had a low probability of resistance section. The most substantial isopropoxy benzene guanidine-induced changes occurred in transcript levels of membrane transport functions-regulated genes, and genes involved in purine- and pyrimidine-synthesis pathway and virulence factors. Furthermore, in vivo studies demonstrated that isopropoxy benzene guanidine is capable of treating invasive MRSA infections. These findings provided strong evidence that isopropoxy benzene guanidine represents a new chemical lead for novel antibacterial agent against multidrug-resistant S. aureus infections.

microbiology↗

bioRxiv2020

Predictions for the binding domain and potential new drug targets of 2019-nCoV

An outbreak of new SARS-like viral in Wuhan, China has been named 2019-nCoV. The current state of the epidemic is increasingly serious, and there has been the urgent necessity to develop an effective new drug. In previous studies, it was found that the conformation change in CTD1 was the region where SARS-CoV bound to human ACE2. Although there are mutations of the 2019-nCoV, the binding energy of ACE2 remains high. The surface glycoprotein of 2019-nCoV was coincident with the CTD1 region of the S-protein by comparing the I-TASSER prediction model with the actual SARS model, which suggests that 2019-nCoV may bind to the ACE2 receptor through conformational changes. Furthermore, site prediction on the surface glycoprotein of 2019-nCoV suggests some core amino acid area may be a novel drug target against 2019-nCoV.

bioinformatics↗

bioRxiv2019

Single-cell transcriptomics reveals diverse and complex gene expression alterations in human trisomy 18

Trisomy 18, commonly known as Edwards syndrome, is the second most common autosomal trisomy among live born neonates. Multiple tissues including cardiac, abdominal, and nervous systems are affected by an extra chromosome 18. To delineate the complexity of anomalies of trisomy 18, we analyzed amniotic fluid cells from two normal and three trisomy 18 samples using single-cell transcriptomics. We identified six cell groups, which function in major tissue development such as kidney, vasculature, and smooth muscle, and display significant alterations in gene expression detected by single-cell RNA-sequencing. Moreover, we demonstrated significant gene expression changes in previously proposed trisomy 18 critical regions, and identified three new regions such as 18p11.32, 18q11, 18q21.32, which are likely associated with trisomy 18 phenotypes. Our results indicate complexity of trisomy 18 at the gene expression level and reveal genetic reasoning of diverse phenotypes in trisomy 18 patients.

genetics↗

bioRxiv2019

Expert Curation of the Human and Mouse Olfactory Receptor Gene Repertoires Identifies Conserved Coding Regions Split Across Two Exons

Olfactory receptor (OR) genes are the largest multi-gene family in the mammalian genome, with over 850 in human and nearly 1500 genes in mouse. The expansion of the OR gene repertoire has occurred through numerous duplication events followed by diversification, resulting in a large number of highly similar paralogous genes. These characteristics have made the annotation of the complete OR gene repertoire a complex task. Most OR genes have been predicted in silico and are typically annotated as intronless coding sequences. Here we have developed an expert curation pipeline to analyse and annotate every OR gene in the human and mouse reference genomes. By combining evidence from structural features, evolutionary conservation and experimental data, we have unified the annotation of these gene families, and have systematically determined the protein-coding potential of each locus. We have defined the non-coding regions of many OR genes, enabling us to generate full-length transcript models. We found that 13 human and 41 mouse OR loci have coding sequences that are split across two exons. These split OR genes are conserved across mammals, and are expressed at the same level as protein-coding OR genes with an intronless coding region. Our findings challenge the long-standing and widespread notion that the coding region of a vertebrate OR gene is contained within a single exon.

genomics↗

bioRxiv2019

Single-cell transcriptomic landscape of cardiac neural crest cell derivatives during embryonic and neonatal development

RationaleCardiac neural crest cells (CNCCs) contribute greatly to cardiovascular development. A thorough understanding of the cell lineages, transcriptomic states and regulatory networks of CNCC derivatives during normal development is essential for deciphering the pathogenesis of CNCC-associated congenital anomalies. However, the transcriptomic landscape of CNCC derivatives during development has not yet been examined at a single-cell resolution.\n\nObjectiveWe sought to systematically characterize the cell lineages, define the developmental chronology and elucidate the transcriptomic dynamics of CNCC derivatives during embryonic and neonatal development.\n\nMethods and ResultsWe performed single-cell transcriptomic sequencing of 34,131 CNCC-derived cells in mouse hearts from eight developmental stages between E10.5 and P7. Through single-cell analyses and single-molecule fluorescence in situ hybridization, we confirmed the presence of CNCC-derived mural cells. Furthermore, we found the transition from CNCC-derived pericytes to microvascular smooth muscle cells, and identified the genes that were significantly regulated during this transition through pseudo-temporal analysis. CNCC-derived neurons first appeared at E10.5, which was earlier than previously recognized. In addition, the CNCC derivatives switched from a proliferative to a quiescent state with the progression of development. Gradual loss of the neural crest molecular signature with development was also observed in the CNCC derivatives. Our data suggested that many CNCC-derivatives had already committed or differentiated to a specific lineage when migrating to the heart. Finally, we characterized some previously unknown subpopulations of CNCC derivatives during development. For example, we found that Penk+ cells, which were mainly localized in outflow tract cushions, were all derived from CNCCs.\n\nConclusionsOur study provides novel insights into the cell lineages, molecular signatures, developmental chronology and state change dynamics of CNCC derivatives during embryonic and neonatal development. Our dataset constitutes a valuable resource that will facilitate future efforts in exploring the role of CNCC derivatives in development and disease.

developmental biology↗

bioRxiv2019

Liquid-liquid phase separation and fibrillization of tau are independent processes with overlapping conditions

Amyloid aggregation of the microtubule binding protein tau is a hallmark of Alzheimers disease and many other neurodegenerative diseases. Recently, tau has been found to undergo liquid-liquid phase separation (LLPS) near physiological conditions. Although LLPS and aggregation have been shown to simultaneously occur under certain common conditions, it remains to be seen whether tau LLPS promotes aggregation, or if they are two independent processes. In this study, we address this question by combining multiple biochemical and biophysical assays in vitro. We investigated the impacts of LLPS on tau aggregation at three stages: conformation of tau, kinetics of aggregation and fibril quantity. We showed that none of these properties are influenced directly by LLPS, while amyloid aggregation propensity of tau can be altered without affecting its LLPS behavior. LLPS and amyloid aggregation of tau occur under overlapping conditions of enhanced intermolecular interactions and localization, but are two independent processes.

biophysics↗