Biology subjects

Jiang, Z.

Publications and source records attributed to Jiang, Z..

At least 199 records · Page 11Linked to original sources

bioRxiv2020

Antimicrobial emulsifier - glycerol monolaurate impacts gut micobiome inducing distinct effects on metabolic syndrome in low-fat diet fed mice

Previous study demonstrated 150 mg{middle dot}kg-1 glycerol monolaurate (GML) consumption induced gut microbiota dysbiosis and metabolic syndrome (MetS) in low-fat diet fed mice. However, little is known about the dose-effect of dietary GML modulating the gut microbiome alterations and its impacts on the induction of MetS in low-fat diet. Dietary GML-induced effects on MetS and gut microbiota alterations were investigated, combined with antibiotics-treated germ-free experiment and specific gut microbiota transplantation. Our results demonstrated that high-dose (500 mg{middle dot}kg-1) GML alleviated MetS by significantly decreasing the body weight, weight gain, food intake, fat droplet size and percentage of abdominal fat, serum triglycerides (TG), LDL, LPS, TNF- and atherogenic index, compared to the medium-dose (150 mg{middle dot}kg-1) GML. Importantly, high-dose GML significantly increased Lactobacillus reuteri compared to the medium-dose GML. Co-occurrence network analysis revealed Lactobacillus reuteri was positively associated with the metabolic improvement of high-dose GML. Notably, antibiotics-treated germ-free experiment and Lactobacillus reuteri transplantation demonstrated that altered gut microbiota was necessary and sufficient for GML-induced distinct effects on metabolic syndrome. Our results indicate that GML impacts gut microbiome inducing distinct effects on metabolic syndrome, thereby calling for reassessing the safe dosage of GML and other non-specific antibacterial food additives. IMPORTANCEGrowing evidence indicate that the broad use of food emulsifying agents may lead to increase the societal incidence of obesity/ MetS and other chronic inflammatory diseases. GML is widely and regularly consumed as a generally safe food emulsifier and as a potent antimicrobial agent in commonly foods such as meat products, cereals and soft beverage by the general public. Our results indicate that GML impacts gut microbiome inducing distinct effects on metabolic syndrome. Our study provides important and timely evidence supporting the emerging concept that non-specific antibacterial food additives have two-sided effect on gut microbiota contributing to the uncertainties for the incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

microbiology↗

bioRxiv2020

Nanoparticle-mediated microRNA-145 Delivery for Vascular Smooth Muscle Cell Phenotype Modulation and Atherosclerosis Treatment

Vascular smooth muscle cells (VSMCs) change from contractile to the synthetic phenotype during atherogenesis and 30-70% of cells that make up plaques have been elucidated to be of VSMC origin. MicroRNA-145 (miR-145) is responsible for regulating VSMC phenotypic switching, and low miR-145 levels in circulation have been linked with atherosclerosis. Hence, we developed nanoparticles for targeted delivery of miR-145 by synthesizing micelles co-assembled with miR-145 and the CCR2-binding peptides for plaque targeting. The miR cargo was protected in micelles from premature endosomal degradation and rescued contractile markers in synthetic VSMCs and SMCs isolated from patient arteries in vitro. In ApoE-/- mid-stage atherosclerotic mice, miR-145 micelles halted plaque growth and maintained contractile phenotypes similar to baseline levels. In early-stage atherosclerosis, a single dose of miR-145 micelles prevented lesion growth by 49%. We present the potential of miR-145 micelles as a therapeutic that can be applied longitudinally and intervene throughout atherosclerosis pathogenesis.

bioengineering↗

bioRxiv2020

Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer

The extent and function of chromatin state aberrations during colorectal cancer (CRC) progression is not completely understood. Here, by comprehensive epigenomic characterization of 56 tumors, adenomas, and their matched normal tissues, we define the dynamics of chromatin states during the progression of colorectal cancer. H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumor-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was crucial for excessive proliferation. Consistently, combination of MEK plus bromodomain (BET) inhibition was found to have synergistic effects in CRC patient-derived xenograft (PDX) models. Probing inter-tumor heterogeneity, we identified four distinct enhancer subtypes (EpiC), three of which correlate well with previously defined transcriptomic subtypes (CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, and TGF{beta}i) for three EPIC groups. Our data suggest that the dynamics of active enhancer underlies colorectal cancer progression and the patient-specific active enhancer patterns govern their unique gene expression patterns which can be leveraged for precision combination therapy.

cancer biology↗

bioRxiv2020

Profiles of Expression pattern and tissue distribution of host defense peptides genes in different chicken (Gallus gallus) breeds related to body weight

Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomodulatory properties. Selection for increased body weight is suggested to be related to reduced immune response. We studied the relationships among body weight, age, and the HDP expression patterns in intestine and immune organs. We used chickens with marked differences of body sizes. The non-selected Daweishan mini chickens showed the highest indexes of immune organs and the lowest concentrations of the plasma immune parameters C3, C4, IgA, and IgY, while the commercial Avian broiler showed the opposite results. The Daweishan mini chickens showed the highest mRNA expressions of HDP genes in small intestine followed by the semi-selected Wuding chickens. Compared with local breeds, broiler chickens showed higher mRNA expression of HDP genes in spleen, thymus, and bursa. Body weight and HDP expression levels were negatively correlated in the intestine and positively in the immune organs. These results indicated that the HDP immune regulatory roles in small intestine acted as first line of defense in innate immunity in local breeds, and as an adaptive immunity in broiler chickens. Selection was associated with the expression profiles of HDP genes in a chicken, age, and organ-specific manner.

immunology↗

bioRxiv2020

DNN-DTIs: improved drug-target interactions prediction using XGBoost feature selection and deep neural network

Research, analysis, and prediction of drug-target interactions (DTIs) play an important role in understanding drug mechanisms, drug repositioning and design. Machine learning (ML)-based methods for DTIs prediction can mitigate the shortcomings of time-consuming and labor-intensive experimental approaches, providing new ideas and insights for drug design. We propose a novel pipeline for predicting drug-target interactions, called DNN-DTIs. First, the target information is characterized by pseudo-amino acid composition, pseudo position-specific scoring matrix, conjoint triad, composition, transition and distribution, Moreau-Broto autocorrelation, and structure feature. Then, the drug compounds are encoded using substructure fingerprint. Next, we utilize XGBoost to determine nonredundant and important feature subset, then the optimized and balanced sample vectors could be obtained through SMOTE. Finally, a DTIs predictor, DNN-DTIs, is developed based on deep neural network (DNN) via layer-by-layer learning. Experimental results indicate that DNN-DTIs achieves outstanding performance than other predictors with the ACC values of 98.78%, 98.60%, 97.98%, 98.24% and 98.00% on Enzyme, Ion Channels (IC), GPCR, Nuclear Receptors (NR) and Kuang's dataset. Therefore, DNN-DTIs's accurate prediction performance on Network1 and Network2 make it logical choice for contributing to the study of DTIs, especially, the drug repositioning and new usage of old drugs.

bioinformatics↗

bioRxiv2020

Persistent bacterial coinfection of a COVID-19 patient caused by a genetically adapted Pseudomonas aeruginosa chronic colonizer

This study characterized a genetically adapted Pseudomonas aeruginosa small colony variant isolated from a COVID-19 patient who suffered persistent bacterial coinfection and eventually recovered from critical illness. Specification and modification of the isolates discovered at genomic and transcriptomic levels with aligned phenotypic observations indicated that these isolates formed excessive biofilm with elevated quorum sensing systems.

microbiology↗

bioRxiv2020

Insights into the catalytic properties of the mitochondrial rhomboid protease PARL

The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac, which have crucial roles in mitochondrial quality control and apoptosis. To gain insight into the catalytic properties of the PARL protease, we expressed human PARL in yeast and used FRET-based kinetic assays to measure proteolytic activity in vitro. We show PARL activity in detergent is enhanced by cardiolipin. Significantly higher turnover rates are observed for PARL reconstituted in proteoliposomes, with Smac being cleaved most rapidly at a rate of 1 min-1. PGAM5 is cleaved with the highest efficiency compared to PINK1 and Smac. In proteoliposomes, a truncated {beta}-cleavage form of PARL is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5 and Smac. Multiplex substrate profiling reveals a substrate preference for PARL with a bulky side chain Phe in P1, which is distinct from small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences.

biochemistry↗

bioRxiv2020

Integrative Proteomic Analysis of Posttranslational Modification in The Inflammatory Response

The posttranslational modification (PTM) of proteins, particularly acetylation, phosphorylation and ubiquitination, plays a critical role in the host innate immune response. PTMs dynamic changes and the crosstalk among them are complicated. To build a comprehensive dynamic network of inflammation related proteins, we integrated data from the whole cell proteome (WCP), acetylome, phosphoproteome and ubiquitinome of human and mouse macrophages. Our datasets of acetylation, phosphorylation and ubiquitination sites helped identify PTM crosstalk within and across proteins involved in the inflammatory response. Stimulation of macrophages by lipopolysaccharide (LPS) resulted in both degradative and non-degradative ubiquitination. Moreover, this study contributes to the interpretation of the roles of known inflammatory molecules and the discovery of novel inflammatory proteins.

immunology↗

bioRxiv2020

A CRISPR-based genome-wide screen for adipogenesis reveals new insights into mitotic expansion and lipogenesis.

In response to excess nutrients, white adipose tissue expands by both generating new adipocytes and by upregulating lipogenesis in existing adipocytes. Here, we performed a genome-wide functional genomics screen to identify regulators of adipogenesis in the mouse 3T3-L1 preadipocyte model. The pooled screening strategy utilized FACS to isolate populations based on lipid content by gating for fluorescence intensity of the lipophilic, green fluorescent BODIPY dye. Additionally, the approach categorized if genes functioned during mitotic expansion or lipogenesis. Cellular mechanisms regulating the rate of protein translation and protein stability were found critical for adipogenesis and lipogenesis. These protein-directed mechanisms were further supported by proteomic analyses, which demonstrated that essential changes in protein abundance driving 3T3-L1 adipogenesis were not driven by transcription. We exemplify this theme by showing that the hypusination pathway, a conserved regulator of translation initiation, is critical to translate adipogenic inducers of mitotic expansion and that the neddylation/ubiquitin pathway modulates insulin sensitivity to regulate lipogenesis.

molecular biology↗

bioRxiv2020

Numerical Model for Formation and Evolution of the Bleb

ABSTRACTThe bleb morphology and its changes are an important mechanism of cell’s amoeboid migration. By releasing bonds between the membrane and the cortex of a cell, the formation of bleb can be observed experimentally, but the mechanism that affects the size and shape of this kind of bleb is waiting for further study. In this paper, a two-dimensional fluid-solid coupling model is established to describe a cell with membrane, cortex and cytoplasm in a solution, and a numerical solving method for the fluid-solid coupling model is developed to simulate the behaviors of cell bleb. The effects of parameters, such as the number of broken bonds, the viscosity coefficient of the cortex, and the cell’s membrane modulus on the size and the shape of the bleb were investigated. Numerical results show that the model is effective to simulate the formation and evolution of cell’s bleb, and derive the contribution of several affecting factors to the bleb shape and size clearly.SIGNIFICANCE To understand the process of cell migration with bleb pseudopods in the amoeba cell migration, it is necessary to study the formation mechanism of cells protruding bleb. In this paper, we propose a reasonable and reliable cell numerical model. With this model we successfully simulate the bleb phenomenon consistent with the experimental phenomenon by changing the key impact factors. The method in this paper is applicable to the cell model of amoeba cell migration pattern, which helps to understand the important role of blebs in the process of cell migration.View Full Text

cell biology↗

bioRxiv2020

Aminoglycoside antibiotics inhibit mycobacteriophage infection

Antibiotic resistance is becoming the biggest current threat to global health. At the same time, phage therapy is witnessing a return of interest. The therapeutic use of bacteriophages, that infect and kill bacteria, is well suited to be a good strategy to combat antibiotic resistance. Furthermore, bacteriophages are increasingly used in combination with standard antibiotics against the drug-resistant pathogens. Interestingly, we found that the engineered mycobacteriophage phAE159 and natural phage D29 can not infect the Mycobacterium tuberculosis in the presence of kanamycin, hygromycin or streptomycin, but there is no effect on the phage infection in the presence of spectinomycin. Based on a series of studies and structural analysis of the above four aminoglycoside antibiotics, we can speculate as to the mechanism by which amino sugar group of aminoglycoside was able to selectively inhibit mycobacteriophage DNA replication. This is a rare discovery that broad-spectrum antibiotics inhibit phage infection. We envisioned that this study will provide guidance for people to combine phage and antibiotics to treat M. tuberculosis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗

bioRxiv2020

HYD3, a conidial hydrophobin of the fungal entomopathogen Metarhizium acridum induces the immunity of its specialist host locust

Conidial hydrophobins in fungal pathogens of plants1,2, insects3,4, and humans5,6 are required for fungal attachment and are associated with high virulence. They are believed to contribute to the pathogenesis of infection by preventing immune recognition5,6. Here, we refute this generalisation offering a more nuanced analysis. We show that MacHYD3, a hydrophobin located on the conidial surface of the specialist entomopathogenic fungus Metarhizium acridum, activates specifically the humoral and cellular immunity of its own host insect, Locusta migratoria manilensis (Meyen) but not that of other non-host insects. When topically applied to the cuticle, purified MacHYD3 improved the resistance of locusts to both specialist and generalist fungal pathogens but had no effect on the fungal resistance of other insects, including Spodoptera frugiperda and Galleria mellonella. Hydrophobins extracted from the generalist fungal pathogens M. anisopliae and Beauveria bassiana had no effect on the resistance of locusts to fungal infection. Thus, the host locust has evolved to recognize the conidial hydrophobin of its specialist fungal pathogen, whereas conidial hydrophobins from generalist fungi are able to evade recognition. Our results distinguish the immunogenic potential of conidial hydrophobins between specialist and generalist fungi.

microbiology↗

bioRxiv2020

The H3.3 chaperone Hira complex orchestrates oocyte developmental competence

Reproductive success relies on a healthy oocyte competent for fertilisation and capable of sustaining early embryo development. By the end of oogenesis, the oocyte is characterised by a transcriptionally silenced state, but the significance of this state and how it is achieved remains poorly understood. Histone H3.3, one of the H3 variants, has unique functions in chromatin structure and gene expression that are cell cycle-independent. We report here a comprehensive characterisation of the roles of the subunits of the Hira complex (i.e. Hira, Cabin1 and Ubn1), which is primarily responsible for H3.3 deposition during mouse oocyte development. Loss-of-function of any component of the Hira complex led to early embryogenesis failure. Transcriptome and nascent RNA analyses revealed that mutant oocytes fail to silence global transcription. Hira complex mutants are unable to establish the H3K4me3 and H3K9me3 repressive marks, resulting in aberrant chromatin accessibility. Among the misregulated genes in mutant oocytes is Zscan4, a 2-cell specific gene that is involved in zygote genome activation. Overexpression of Zscan4 recapitulates the phenotypes of Hira mutants, illustrating that temporal and spatial expression of Zscan4 is fine-tuned at the oocyte-to-embryo transition. Thus, the H3.3 chaperone Hira complex has a maternal effect function in oocyte developmental competence and early embryogenesis by modulating chromatin condensation and transcriptional quiescence.

developmental biology↗

bioRxiv2020

Role of Inflammasome-independent Activation of IL-1β by the Pseudomonas aeruginosa Protease LasB

Pulmonary damage by Pseudomonas aeruginosa during cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates management of these deep-seated infections. Therefore, preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Pathological inflammation during P. aeruginosa pneumonia is driven by interleukin-1{beta} (IL-1{beta}). This proinflammatory cytokine is canonically regulated by caspase-family inflammasome proteases, but we report that plasticity in IL-1{beta} proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1{beta} activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severe P. aeruginosa pulmonary infection. Discovery of this IL-1{beta} regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such that matrix metalloprotease inhibitors blocking LasB limit inflammation and pathology during P. aeruginosa pulmonary infections. HighlightsO_LIIL-1{beta} drives pathology during pulmonary infection by Pseudomonas aeruginosa. C_LIO_LIThe Pseudomonas protease LasB cleaves and activates IL-1{beta} independent of canonical and noncanonical inflammasomes C_LIO_LIMetalloprotease inhibitors active against LasB limit inflammation and bacterial growth C_LI Research in ContextInflammation is highly damaging during lung infections by the opportunistic pathogen Pseudomonas aeruginosa. Sun et al. demonstrate that the Pseudomonas LasB protease directly activates IL-1{beta} in an inflammasome-independent manner. Inhibition of IL-1{beta} conversion by LasB protects against neutrophilic inflammation and destruction of the lung. Adjunctive therapeutics that limit pathological inflammation induced by infection would be beneficial for the treatment of pulmonary infections when used with conventional antibiotics.

microbiology↗

bioRxiv2020

Mass spectrometry analysis of newly emerging coronavirus HCoV-19 spike S protein and human ACE2 reveals camouflaging glycans and unique post-translational modifications

The pneumonia-causing COVID-19 pandemia has prompt worldwide efforts to understand its biological and clinical traits of newly identified HCoV-19 virus. In this study, post-translational modification (PTM) of recombinant HCoV-19 S and hACE2 were characterized by LC-MSMS. We revealed that both proteins were highly decorated with specific proportions of N-glycan subtypes. Out of 21 possible glycosites in HCoV-19 S protein, 20 were confirmed completely occupied by N-glycans, with oligomannose glycans being the most abundant type. All 7 possible glycosylation sites in hACE2 were completely occupied mainly by complex type N-glycans. However, we showed that glycosylation did not directly contribute to the binding affinity between SARS-CoV spike protein and hACE2. Additionally, we also identified multiple sites methylated in both proteins, and multiple prolines in hACE2 were converted to hydroxylproline. Refined structural models were built by adding N-glycan and PTMs to recently published cryo-EM structure of the HCoV-19 S and hACE2 generated with glycosylation sites in the vicinity of binding surface. The PTM and glycan maps of both HCoV-19 S and hACE2 provide additional structural details to study mechanisms underlying host attachment, immune response mediated by S protein and hACE2, as well as knowledge to develop remedies and vaccines desperately needed nowadays.

molecular biology↗

bioRxiv2020

Cryo-EM structures of inactive and Gi-coupled GABAB heterodimer

Metabotropic GABAB G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane (TM) domain. Here we present cryo-EM structures of human full-length heterodimeric GABAB receptor in the antagonist-bound inactive state and in the active state complexed with agonist and positive allosteric modulator in the presence of Gi1 protein at a resolution range of 2.8-3.0 [A]. Cryo-EM analysis of the activated-GABAB-Gi1 complex revealed that Gi1 couples to the activated receptor primarily in three major conformations, one via GB1 TM and two via GB2 TM, respectively. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, which in turn triggers a rearrangement of TM interfaces between two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistically shifting of TM3, 4 and 5 helices in GB2 TM domain to accommodate the 5-helix of Gi1. These results provide a structural framework for understanding class C GPCR activation and a rational template for allosteric modulator design targeting dimeric interface of GABAB receptor.

molecular biology↗

bioRxiv2020

Pattern-recognition receptors are required for NLR-mediated plant immunity

The plant immune system is fundamental to plant survival in natural ecosystems and productivity in crop fields. Substantial evidence supports the prevailing notion that plants possess a two-tiered innate immune system, called pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). PTI is triggered by microbial patterns via cell surface-localized pattern-recognition receptors (PRRs), whereas ETI is activated by pathogen effector proteins via mostly intracellularly-localized receptors called nucleotide-binding, leucine-rich repeat proteins (NLRs)1-4. PTI and ETI are initiated by dist 30 inct activation mechanisms and are considered to act independently and have evolved sequentially5,6. Here we show that, contrary to the perception of PTI and ETI being separate immune signaling pathways, Arabidopsis PRR/co-receptor mutants, fls2/efr/cerk1 and bak1/bkk1/cerk1 triple mutants, are greatly impaired in ETI responses when challenged with incompatible Pseudomonas syrinage bacteria. We further show that the NADPH oxidase (RBOHD)-mediated production of reactive oxygen species (ROS) is a critical early signaling event connecting PRR and NLR cascades and that PRR-mediated phosphorylation of RBOHD is necessary for full activation of RBOHD during ETI. Furthermore, NLR signaling rapidly augments the transcript and protein levels of key PTI components at an early stage and in a salicylic acid-independent manner. Our study supports an alternative model in which PTI is in fact an indispensable component of ETI during bacterial infection, implying that ETI halts pathogen infection, in part, by directly co-opting the anti-pathogen mechanisms proposed for PTI. This alternative model conceptually unites two major immune signaling pathways in the plant kingdom and mechanistically explains the long-observed similarities in downstream defense outputs between PTI and ETI.

plant biology↗

bioRxiv2020

On the role of transcription in positioning nucleosomes

Nucleosome positioning is crucial for the genomes function. Though the role of DNA sequence in positioning nucleosomes is well understood, a unified framework for studying the impact of transcription remains lacking. Using numerical simulations, we investigated the dependence of nucleosome density profiles on transcription level across multiple species. We found that the low nucleosome affinity of yeast, but not mouse, promoters contributes to the formation of phased nucleosomes arrays for inactive genes. For the active genes, a tug-of-war between two types of remodeling enzymes is essential for reproducing their density profiles. In particular, while ISW2 related enzymes are known to position the +1 nucleosome and align it toward the transcription start site (TSS), enzymes such as ISW1 that use a pair of nucleosomes as their substrate can shift the nucleosome array away from the TSS. Competition between these enzymes results in two types of nucleosome density profiles with well- and ill-positioned +1 nucleosome. Finally, we showed that Pol II assisted histone exchange, if occurring at a fast speed, can abolish the impact of remodeling enzymes. By elucidating the role of individual factors, our study reconciles the seemingly conflicting results on the overall impact of transcription in positioning nucleosomes across species.

biophysics↗