Biology subjects

Yuan, Z.

Publications and source records attributed to Yuan, Z..

At least 163 records · Page 9Linked to original sources

bioRxiv2019

Relationship between birth weight and chronic kidney disease: an integrative analysis of observational studies and causal inference through genetic approaches

ObjectiveAlthough many observational studies have shown that there was an inverse association between birth weight and chronic kidney disease (CKD) in adults, whether such association is causal remains largely unclear.\n\nMethodsWe first conducted a systematic review and meta-analysis to investigate the association between birth weight and CKD. Then using a set of valid instrumental variables for birth weight, we performed a two-sample Mendelian randomization (MR) to evaluate its causal effect on CKD based on summary association statistics available from large scale genome-wide association study (GWAS) (up to 143,677 individuals for birth weight and 118,147 individuals for CKD). We further validated the MR results with extensive sensitive analyses.\n\nResultsThe results of meta-analysis showed that individuals with low birth weight have about 76% (95% CI 36[~]126%) higher risk of CKD in late life compared with those with normal birth weight. Depending on 26 instrumental variables, the inverse variance weighted MR showed that the odds ratio per one SD increase of birth weight on CKD was estimated to be 0.91 (95% CI 0.72[~]1.14, p=0.396). The similar null association between birth weight and CKD is also observed using the weighted median method and maximum likelihood method as well as the Egger regression. Such non-significant association is robust against potential instrumental outliers and pleiotropic effects.\n\nConclusionOur study identifies an inverse association between birth weight and adult CKD in observational studies, while it is not supportive of the causal role of birth weight on CKD based on our MR analysis.

genetics↗

bioRxiv2019

Non-antibiotic pharmaceuticals can enhance the spread of antibiotic resistance via conjugation

Antibiotic resistance is a global threat for public health. It is widely acknowledged that antibiotics at sub-inhibitory concentrations are important in disseminating antibiotic resistance via horizontal gene transfer. While there is high use of non-antibiotic human-targeted pharmaceuticals in our societies, the potential contribution of these on the spread of antibiotic resistance has been overlooked so far. Here, we report that commonly consumed non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a {beta}-blocker (propanolol), at clinically and environmentally relevant concentrations, significantly accelerated the conjugation of plasmid-borne antibiotic resistance genes. We looked at the response to these drugs by the bacteria involved in the gene transfer through various analyses that included monitoring reactive oxygen species (ROS) and cell membrane permeability by flow cytometry, cell arrangement, and whole-genome RNA and protein sequencing. We found the enhanced conjugation correlated well with increased production of ROS and cell membrane permeability. We also detected closer cell-to-cell contact and upregulated conjugal genes. Additionally, these non-antibiotic pharmaceuticals caused the bacteria to have responses similar to those detected when exposed to antibiotics, such as inducing the SOS response, and enhancing efflux pumps. The findings advance our understanding of the bacterial transfer of antibiotic resistance genes, and importantly emphasize concerns of non-antibiotic human-targeted pharmaceuticals for enhancing the spread of antibiotic resistance.

microbiology↗

bioRxiv2019

A Single-Cell Immune Atlas of Triple Negative Breast Cancer Reveals Novel Immune Cell Subsets

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, which recently attracts great interest for immune therapeutic development. In this context, in-depth understanding of TNBC immune landscape is highly demanded. Here we report single-cell RNA sequencing results of 9683 tumor-infiltrated immune cells isolated from 14 treatment naive TNBC tumors, where 22 immune cell subsets, including T cells, macrophages, B cells, and DCs have been characterized. We identify a new T cell subset, CD8+CXCL8+ naive T cell, which associates with poor survival. A novel immune cell subset comprised of TCR+ macrophages, is found to be widely distributed in TNBC tumors. Further analyses reveal an up-regulation of molecules associated with TCR signaling and cytotoxicity in these immune cells, indicating TCR signaling activation. Altogether, our study provides a valuable resource to understand the immune ecosystem of TNBC. The novel immune cell subsets reported herein might be functionally important in cancer immunity.\n\nSIGNIFICANCEThis work demonstrates a single-cell transcriptome atlas of immune cells in treatment naive TNBC tumors, revealing novel immune cell subsets. This study provides a valuable resource to understand the immune ecosystem of TNBC, which will be helpful for the immunotherapeutic strategy design of TNBC.

immunology↗

bioRxiv2019

The YdiU Domain Modulates Bacterial Stress Signaling through UMPylation

Sensing stressful conditions and adjusting cellular metabolism to adapt to the environment is essential for bacteria to survive in variable situations. Here, we describe a new stress-related protein YdiU, and characterize YdiU as an enzyme that catalyzes the covalent attachment of uridine 5-monophosphate to a protein tyrosine/histidine residue--a novel modification defined as UMPylation. Mn2+ serves as an essential co-factor for YdiU-mediated UMPylation. UTP and Mn2+-binding converts YdiU to an aggregate-prone state facilitating the recruitment of chaperones. The UMPylation of chaperones prevents them from binding co-factors or clients, thereby impairing their function. Consistent with the recent finding that YdiU acts as an AMPylator, we further demonstrate that the self-AMPylation of YdiU padlocks its chaperone-UMPylation activity. The detailed mechanism is proposed based on Apo-YdiU, YdiU-ATP, YdiU-AMP crystal structures and molecular dynamics simulation models of YdiU-UTP and YdiU-UTP-peptide. In vivo data demonstrate that YdiU effectively protects Salmonella from stress-induced ATP depletion through UMPylation. HighlightsO_LIYdiU involves in stress-resistance of Salmonella. C_LIO_LIYdiU mediates protein UMPylation in a Mn2+-dependent manner. C_LIO_LIStructural insights into YdiU-mediated UMPylation. C_LIO_LIUMPylation of chaperones by YdiU modulates their function. C_LI

biochemistry↗

bioRxiv2019

Testing and controlling for horizontal pleiotropy with the probabilistic Mendelian randomization in transcriptome-wide association studies

Integrating association results from both genome-wide association studies (GWASs) and expression quantitative trait locus (eQTL) mapping studies has the potential to shed light on the molecular mechanisms underlying disease etiology. Several statistical methods have been recently developed to integrate GWASs with eQTL studies in the form of transcriptome-wide association studies (TWASs). These existing methods can all be viewed as a form of two sample Mendelian randomization (MR) analysis, which has been widely applied in various GWASs for inferring the causal relationship among complex traits. Unfortunately, most existing TWAS and MR methods make an unrealistic modeling assumption and assume that instrumental variables do not exhibit horizontal pleiotropic effects. However, horizontal pleiotropic effects have been recently discovered to be wide spread across complex traits, and, as we will show here, are also wide spread across gene expression traits. Therefore, not allowing for horizontal pleiotropic effects can be overly restrictive, and, as we will be show here, can lead to a substantial inflation of test statistics and subsequently false discoveries in TWAS applications. Here, we present a probabilistic MR method, which we refer to as PMR-Egger, for testing and controlling for horizontal pleiotropic effects in TWAS applications. PMR-Egger relies on an MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and, with a newly developed parameter expansion version of the expectation maximization algorithm, is scalable to hundreds of thousands of individuals. With extensive simulations, we show that PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust for various types of horizontal pleiotropic effect mis-specifications, is more powerful than existing MR approaches, and, as a by-product, can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. In these applications, we show how PMR-Egger can lead to new biological discoveries through integrative analysis.

genetics↗

bioRxiv2019

Homoploid hybridization signals due to ancestral subdivision: a case study on the D lineage in wheat

Homoploid hybrid speciation has been reported in a wide range of species since the exploitation of genome sequences in evolutionary studies. However, the interference of ancestral subdivision has not been adequately considered in many such investigations. Using the D lineage in wheat as an example, we showed clearly that ancestral subdivision has led to false detection of homoploid hybridization signals. We develop a novel statistical framework by examining the changes in shared ancestral variations and infer on the likelihood of speciation due to genuine homoploid hybridization or ancestral subdivisions. Applying this to wheat data, we found that homoploid hybridization was not involved in the origin of the D lineage contrary to the now widely held belief. This example indicates that the significance of homoploid hybrid speciation is likely exaggerated. The underlying methodology developed in this study should be valuable for clarifying whether homoploid hybridization has contributed to the speciation of many other species.

evolutionary biology↗

bioRxiv2019

A new immunotherapeutic concept for pancreatic cancer using childhood vaccine recall antigens and Listeria

Pancreatic ductal adenocarcinoma is highly metastatic, poorly immunogenic, and immune suppression prevents T cell activation in the tumor microenvironment. We developed a microbial-based immunotherapeutic concept for selective delivery of a highly immunogenic tetanus toxoid protein (TT856-1313), into tumor cells by attenuated Listeria monocytogenes, and reactivation of pre-existing TT-specific memory T cells (generated during childhood) to kill infected tumor cells. Thus, TT here functions as an alternative for neoantigens. Treatment of KPC mice with Listeria-TT resulted in TT accumulation in tumors and inside tumor cells, and attraction of predominantly TT-specific memory CD4 T cells. Moreover, gemcitabine (GEM) combined with Listeria-TT significantly improved the migration of CD4 T cells into tumors and the production of perforin and granzyme B, turning cold tumors into immunological hot tumors. In vivo depletion of T cells in Listeria-TT+GEM-treated mice demonstrated CD4 T cell-mediated eradication of tumors and metastases (Mann-Whitney p<0.05). In addition, peritumoral lymph node like structures (LNS) were observed in close contact with the pancreatic tumors displaying CD4 T cells and CD8 T cells of KPC mice treated with Listeria-TT or Listeria-TT+GEM. The production of perforin and granzyme B was observed in LNS of KPC mice that received Listeria-TT+GEM. This combination not only reduced tumor burden (80%) and metastases (87%) significantly (p<0.05, Mann-Whitney), but also improved the survival time of KPC mice with advanced pancreatic cancer substantially (Mantel-Cox p<0.0001). Our results unveil new mechanisms of Listeria and GEM improving immunotherapy for PDAC.

immunology↗

bioRxiv2019

An Array of 60,000 Antibodies for Proteome-Scale Antibody Generation and Target Discovery

Antibodies are essential for elucidating the roles of genes decoded by genome sequencing. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed the Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 mAbs against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic feature of an antibody. Distinctive combinations of 10,000-20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-target pairs were discovered for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for human membrane proteins and ChIP-seq mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues discovered internalizing tumor antigens for antibody-drug conjugates. By discovering high affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.

systems biology↗

bioRxiv2019

Epigenetic Profiling Provides Insights into AIDS Resistance in African Green Monkey

As a natural host of simian immunodeficiency virus (SIV), African green monkeys (AGM) do not develop AIDS although high levels of SIV replication were maintained. Low frequencies of CD4+ T cells and high frequencies of CD8dim T cells were observed in healthy adult AGM, which may partially explain the absence of SIV-induced disease progression. Elucidating the mechanisms that allow this natural host co-exist with SIV without progressive disease may facilitate knowledge of AIDS pathogenesis. Here we show: (1) Compared with junior AGM, 3 miRNA were up-regulated in adult AGM in which hsa-miR-151a-3p was shown to target both CD4 and MAZR; 15 miRNAs were down-regulated in adult AGM in which hsa-miR-140-5p, hsa-miR-126-3p and hsa-miR-194-5p were shown to target CD8; (2) MeDIP sequencing analysis of adult AGM samples revealed that hypermethylation exists in the promoter region of CD4, CXCR6, CCR5, while hypomethylation exists in the promoter region of RUNX3, ICAM2; (3) Hypomethylation in the promoter region of PTK2 contributes to up-regulated expression of hsa-miR-151a-3p in adult AGM, while hypermethylation in the promoter region of WWP2 contributes to down-regulated expression of hsa-miR-140-5p. Our data for the first time demonstrates the link between miRNA and DNA methylation expression profile, which may together contribute to the phenotype of AIDS resistance in AGM. Author SummaryAfrican green monkeys (AGM) do not develop AIDS although high levels of SIV replication were maintained. Elucidating the mechanisms that allow this natural host co-exist with SIV without progressive disease may facilitate knowledge of AIDS pathogenesis. In this study, the miRNA expression patterns were found to be associated with the switch from CD4+ to CD4-CD8adim in adult AGM. The up-regulated hsa-miR-151a-3p was shown to target both AGM CD4 and MAZR, while the down-regulated hsa-miR-140-5p, hsa-miR-126-3p and hsa-miR-194-5p were shown to target AGM CD8. And none of these miRNAs possess target sites in cynomolgus macaque (CM) CD4, CD8 and MAZR reflecting differences in AIDS resistance between these two species. Our data also demonstrates the link between miRNA and DNA methylation expression profile, indicating that multiple distinct mechanisms may contribute to AIDS resistance in AGM. Knowledge of the non-pathogenic nature of SIV infection in AGM may provide insight into development of new therapeutic strategies.

microbiology↗

bioRxiv2018

RNA Polymerase II Independent Recruitment of SPT6 at Transcription Start Sites in Arabidopsis

SPT6 is a conserved transcription regulator that is generally viewed as an elongation factor. However, emerging evidence show its potential role in the control of transcription initiation at genic and intragenic promoters. Here we first present the genome-wide occupancy of Arabidopsis SPT6-like (SPT6L) and demonstrate its conserved role in facilitating RNA Polymerase II (RNAPII) occupancy across transcribed genes. Further, we show that SPT6L enrichment is shifted, unexpectedly, from gene body to the transcription starting site (TSS) when its association with RNAPII is disrupted. Finally, we demonstrate that recruitment of SPT6L starts at TSS, and then spreads to the gene body during transcription. These findings refine the mechanisms underlying SPT6L recruitment in transcription and shed light on the role of SPT6L in transcription initiation.

molecular biology↗

bioRxiv2018

Longitudinal Visual Analytics for Unpacking the Cancer Journey

Retrospective cancer research requires identification of patients matching both categorical and temporal inclusion criteria, often based on factors exclusively available in clinical notes. Although natural language processing approaches for inferring higher-level concepts have shown promise for bringing structure to clinical texts, interpreting results is often challenging, involving the need to move between abstracted representations and constituent text elements. We discuss qualitative inquiry into user tasks and goals, data elements and models resulting in an innovative natural language processing pipeline and a visual analytics tool designed to facilitate interpretation of patient summaries and identification of cohorts for retrospective research.

cancer biology↗

bioRxiv2018

Altered microRNA expression profles are involved in Storage Lesions of Apheresis Platelet

Although platelet is anucleate cell, it contains a large amount miRNAs. This study aims to explore the relationship between miRNAs expression profles and platelets function, as well as miRNAs potential roles during platelet storage lesions. Platelets were collected from 15 healthy men with O blood types. MiRNAs profiles in platelets were detected by Agilent Human miRNA Array Differential miRNA levels were studied using human platelets after apheresis and stored for 2, 5 and 8 days using microarray. There were 167 and 230 altered miRNAs during the 5 and 8 day storage, respectively. In addition, the number of reduced miRNAs was much greater than that of increased. And many of them are involved in functions of platelet activation, degranulation, PDGF receptor signaling pathway and cell differentiation. The results of RT-PCR showed that the expression of miR-21-5p, miR-21-3p and miR-155 decreased on the 5th day, while miR-223, miR-3162 and let-7b increased. Flow cytometry results revealed that with increase of storage time, the expression of P2Y12 increased and phosphorylation level of VASP reduced. Meanwhile, the platelet reactivity index (PRI) decreased from 72.7% to 18.2%, while the apoptotic percentage of platelet significantly increased. For the first time, we found altered miRNAs are closely related to platelet aggregation, including P2Y12, VASP and GPb/a. Through KEGG database prediction, we verified there were many miRNAs impacting the pathway of platelet aggregation, such as miR-223, miR-21 and let-7b, which indicated miRNAs might serve as potential biomarkers of storage lesion in platelet. These target miRNAs are related to activation, degranulation and PDGF receptor signaling pathway of platelet.

molecular biology↗

bioRxiv2018

Regulatory networks of gene expression in maize (Zea mays) under drought stress and re-watering

Drought can severely limit plant growth and production. However, few studies have investigated gene expression profiles in maize during drought/re-watering. We compared drought-treated and water-sufficient maize plants by measuring their leaf relative water content, superoxide dismutase and peroxidase activities, proline content, and leaf gas exchange parameters (photosynthetic rates, stomatal conductance, and transpiration rates). We conducted RNA sequencing analyses to elucidate gene expression profiles and identify miRNAs that might be related to drought resistance. A GO enrichment analysis showed that the common DEGs (differently expressed genes) between drought-treated and control plants were involved in response to stimulus, cellular process, metabolic process, cell part, and binding and catalytic activity. Analyses of gene expression profiles revealed that 26 of the DEGs under drought encoded 10 enzymes involved in proline synthesis, suggesting that increased proline synthesis was a key part of the drought response. We also investigated cell wall-related genes and transcription factors regulating abscisic acid-dependent and -independent pathways. The expression profiles of the miRNAs miR6214-3p, miR5072-3p, zma-miR529-5p, zma-miR167e-5p, zma-miR167f-5p, and zma-miR167j-5p and their relevant targets under drought conditions were analyzed. These results provide new insights into the molecular mechanisms of drought tolerance, and may identify new targets for breeding drought-tolerant maize lines.\n\nAbbreviationsleaf relative water content: RWC, superoxide dismutase activity: SOD, peroxidase activity: POD, proline content: Pro, photosynthetic rates: Pn, stomatal conductance: Cond, transpiration rates: Tr.; quantitative real-time polymerase chain reaction: qPCR; abscisic acid; ABA; polyethylene glycol :PEG; Principal component analysis :PCA; polyacrylamide gel electrophoresis :PAGE\n\nHighlightThe study of physiology and molecular mechanism of maize laid a theoretical foundation for drought resistance breeding under drought stress and re-watering.

genomics↗

bioRxiv2018

Hepatitis C virus NS5A inhibitor daclatasvir allosterically impairs NS4B-involved protein-protein interactions within the viral replicase and disrupts the replicase quaternary structure in a replicase assembly surrogate system

Daclatasvir (DCV) is a highly potent direct-acting antiviral that targets the non-structural protein 5A (NS5A) of hepatitis C virus (HCV) and has achieved great clinical successes. Previous studies demonstrate its impact on the viral replication complex assembly. However the precise mechanism by which DCV impairs the replication complex assembly remains elusive. In this study, by using HCV subgenomic replicons and a viral replicase assembly surrogate system that expresses the HCV NS3-5B polyprotein to mimic the viral replicase assembly, we dissected the impacts of DCV on aggregation and tertiary structure of NS5A, the protein-protein interactions within the viral replicase and the quaternary structure of the viral replicase. We found that DCV didnt affect aggregation and tertiary structure of NS5A. DCV induced a quaternary structural change of the viral replicase, evidenced by selectively increasing of the NS4Bs sensitivity to proteinase K digestion. Mechanically, DCV impaired the NS4B-involved protein-protein interactions within the viral replicase. The DCV-resistant mutant Y93H was refractory to the DCV-induced reduction of the NS4B-invoved protein interactions and the quaternary structural change of the viral replicase. In addition, Y93H reduced NS4B-involed protein-protein interactions within the viral replicase and attenuated viral replication. We propose that DCV may induce a position change of NS5A, which allosterically affects the protein interactions within the replicase components and disrupts the replicase assembly.\n\nImportanceThe development of the direct-acting antivirals (DAA) has resulted in great clinical achievements for Hepatitis C Virus (HCV) treatment. Daclatasvir (DCV) is an inhibitor targeting the non-enzymatic NS5A, with the 50% effective concentration values in the picomolar range. Accumulated data suggest that DCV blocks the biogenesis of the HCV replication complex. However the mechanistic actions of DCV are still largely unknown. Insights into the action mechanism of DCV on the viral replication complex assembly of HCV may enlighten the development of next generation of DAAs and new anti-viral strategies for other positive-strand RNA viruses for which there are a scarcity of DAAs. Herein, using HCV subgenomic replicons and a viral replicase assembly surrogate system, we dissected the mechanistic actions of DCV on the viral replicase assembly. We found that DCV allosterically impairs NS4B-involved protein-protein interactions within the viral replicase and disrupts the quaternary structure of the viral replicase.

microbiology↗

bioRxiv2018

Extracellular HBV RNAs are heterogeneous in length and circulate as virions and capsid-antibody-complexes in chronic hepatitis B patients

Extracellular HBV RNA has been detected in both HBV-replicating cell culture media and sera from chronic hepatitis B (CHB) patients, but its exact origin and composition remain controversial. Here, we demonstrated that extracellular HBV RNA species were of heterogeneous lengths, ranging from the length of pregenomic RNA to a few hundred nucleotides. In cell models, these RNAs were predominantly associated with naked capsids although virions also harbored a minority of them. Moreover, HBV RNAs in hepatitis B patients blood circulation were localized in unenveloped capsids in the form of capsid-antibody-complexes (CACs) and in virions. Furthermore, we showed that extracellular HBV RNAs could serve as template for viral DNA synthesis. In conclusion, extracellular HBV RNAs mainly consist of pgRNA or the pgRNA species degraded by the RNase H domain of the polymerase in the process of viral DNA synthesis and circulate as CACs and virions. Their presence in the blood circulation of CHB patients may be exploited to develop novel biomarkers for HBV persistence.

microbiology↗

bioRxiv2018

Structural and functional studies of the RBPJ-SHARP complex reveal conserved corepressor binding site

The Notch pathway is a conserved signaling mechanism that is essential for cell fate decisions during pre and postnatal development. Dysregulated signaling underlies the pathophysiology of numerous human diseases, most notably T-cell acute lymphoblastic leukemia. Receptor-ligand interactions result in changes in gene expression, which are regulated by the transcription factor CSL. CSL forms a complex with the intracellular domain of the Notch receptor and the transcriptional coactivator Mastermind, which is required to activate transcription of all Notch target genes. CSL can also function as repressor by interacting with corepressor proteins, e.g. SHARP in mammals and Hairless in Drosophila melanogaster; however, its role as a transcriptional repressor is not well understood. Here we determine the high-resolution structure of RBPJ, the mouse CSL ortholog, bound to the corepressor SHARP and DNA, which reveals a new mode of corepressor binding to CSL and an interesting example for how ligand binding sites evolve in proteins. Based on the structure, we designed and tested a number of mutants in biophysical, biochemical, and cellular assays to characterize the role of RBPJ as a repressor of Notch target genes. Our cellular studies clearly demonstrate that RBPJ mutants that are deficient for binding SHARP are incapable of repressing transcription from genes responsive to Notch signaling. Altogether, our structure-function studies of the RBPJ-SHARP corepressor complex bound to DNA provide significant insights into the repressor function of RBPJ and identify a new binding pocket on RBPJ that could be targeted for therapeutic benefit.

biochemistry↗

bioRxiv2018

Exosomes exploit the virus entry machinery and pathway to transmit IFN-α-induced antiviral activity.

Interferon- (IFN-) induces the transfer of resistance to hepatitis B virus (HBV) from liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes. However, little is known about the entry machinery and pathway involved in the transmission of IFN--induced antiviral activity. Here, we found that macrophage exosomes depend on T cell immunoglobulin and mucin receptor 1 (TIM-1), a hepatitis A virus (HAV) receptor, to enter hepatocytes for delivering IFN--induced anti-HBV activity. Moreover, two primary endocytic routes for virus infection, clathrin-mediated endocytosis (CME) and macropinocytosis, collaborate to permit exosome entry and anti-HBV activity transfer. Subsequently, lysobisphosphatidic acid (LBPA), an anionic lipid closely related to endosome penetration of virus, facilitates membrane fusion of exosomes in late endosomes/ multivesicular bodies (LEs/MVBs) and the accompanying exosomal cargo uncoating. Together, this study provides comprehensive insights into the transmission route of macrophage exosomes to efficiently deliver IFN--induced anti-HBV activity and highlights the similarities between the entry mechanisms of exosomes and virus.\n\nImportanceOur previous study showed that LNPC-derived exosomes could transmit IFN--induced antiviral activity to HBV replicating hepatocytes, but the concrete transmission mechanisms which include exosome entry and exosomal cargo release remain unclear. In this study, we found that virus entry machinery and pathway were also applied to exosome-mediated cell-to-cell antiviral activity transfer. Macrophage-derived exosomes exploit hepatitis A virus receptor for access to hepatocytes. Later, CME and macropinocytosis are utilized by exosomes which is followed by exosome-endosome fusion for efficient transfer of IFN--induced anti-HBV activity. Dissecting the similarities between exosome and virus entry will be beneficial to designing exosomes as efficient vehicles for antiviral therapy.

microbiology↗

bioRxiv2018

Non-antibiotic antimicrobial triclosan induces multiple antibiotic resistance through genetic mutation

Antibiotic resistance poses a major threat to public health. Overuse and misuse of antibiotics are generally recognised as the key factors contributing to antibiotic resistance. However, whether non-antibiotic, anti-microbial (NAAM) chemicals can directly induce antibiotic resistance is unclear. We aim to investigate whether the exposure to a NAAM chemical triclosan (TCS) has an impact on inducing antibiotic resistance on Escherichia coli. Here, we report that at a concentration of 0.2 mg/L TCS induces multi-drug resistance in wild-type Escherichia coli after 30-day TCS exposure. The oxidative stress induced by TCS caused genetic mutations in genes such as fabI, frdD, marR, acrR and soxR, and subsequent up-regulation of the transcription of genes encoding beta-lactamase and multi-drug efflux pump, together with down-regulation of genes related to membrane permeability. The findings advance our understanding of the potential role of NAAM chemicals in the dissemination of antibiotic resistance in microbes, and highlights the need for controlling biocide applications.

microbiology↗