Biology subjects

Hao, Y.

Publications and source records attributed to Hao, Y..

15 recordsLinked to original sources

bioRxiv2018

High stretchability, strength and toughness of living cells enabled by hyperelastic vimentin network

In many normal and abnormal physiological processes, including cellular migration during normal development and invasion in cancer metastasis, cells are required to withstand severe deformations. The structural integrity of eukaryotic cells under small deformations has been known to depend on the cytoskeleton including actin filaments (F-actin), microtubules and intermediate filaments (IFs). However, it remains unclear how cells resist severe deformations since both F-actin and microtubules fluidize or disassemble under moderate strains. Here, we demonstrate that vimentin intermediate filaments (VIFs), a marker of mesenchymal cells, dominate cytoplasmic mechanics at large deformations. Our results show that cytoskeletal VIFs form a stretchable, hyperelastic network. This network works synergistically with other dissipative cytoplasmic components, substantially enhancing the strength, stretchability, resilience and toughness of the living cytoplasm.

biophysics↗

bioRxiv2018

Type 1 Diabetes: an Association Between Autoimmunity the Dynamics of Gut Amyloid-producing E. coli and Their Phages

The etiopathogenesis of type 1 diabetes (T1D), a common autoimmune disorder, is not completely understood. Recent studies suggested the gut microbiome plays a role in T1D. We have used public longitudinal microbiome data from T1D patients to analyze amyloid-producing bacterial composition and found a significant association between initially high amyloid-producing Escherichia coli abundance, subsequent E. coli depletion prior to seroconversion, and T1D development. In children who presented seroconversion or developed T1D, we observed an increase in the E. coli phage/E. coli ratio prior to E. coli depletion, suggesting that the decrease in E. coli was due to prophage activation. Evaluation of the role of phages in amyloid release from E. coli biofilms in vitro suggested an indirect role of the bacterial phages in the modulation of host immunity.\n\nThis study for the first time suggests that amyloid-producing E. coli, their phages, and bacteria-derived amyloid might be involved in pro-diabetic pathway activation in children at risk for T1D.

microbiology↗

bioRxiv2018

Risk Factors Associated with Dengue Virus Infection in Guangdong Province: a Community-based Case-control Study

BackgroundDengue fever is a mosquito-borne infectious disease, and it is now still epidemic in China, especially in Guangdong Province. Owing to the absence of dengue vaccination, effective preventive measure is critical for controlling of dengue fever. This study aimed to explore the individual risk factors of dengue virus infection in Guangdong Province, as well as to provide a scientific basis for prevention and supervision of dengue fever in future.\n\nMethodsA case-control study including 237 cases and 237 controls was performed. The data was collected from the epidemiological questionnaires. Univariate analysis was used for preliminary screening of 28 variables potentially related to dengue virus infection, and an unconditioned logistic regression analysis was used for multivariate analysis to analysis those statistically significant variables.\n\nResultsMultivariate analysis of the result showed three independent risk factors: activities in the park (odd ratio [OR]= 1.70, 95%CI 1.03 to 2.83), outdoor sports (OR= 1.67, 95%CI 1.07 to 2.62), and poor indoor daylight quality (OR= 2.27, 95%CI 1.00 to 5.15); and two protective factors: two persons per room (OR=0.43, 95%CI 0.28 to 0.67), three persons and above per room (OR=0.43, 95%CI 0.22 to 0.86), using air-condition (OR=0.43, 95%CI 0.20 to 0.93).\n\nConclusionThese results are conducive to learn the risk factors for dengue virus infection in Guangdong Province. It is crucial to provide effective and efficient strategy to improve environmental protection and anti-mosquito measures. In addition, more systematic studies are needed to explore the other potential risk factors for dengue fever infection.\n\nAuthor summaryDengue fever, one of the mosquito-borne infectious diseases, is mainly transmitted by Aedes aegypti in Asia and Southeast Asia countries. Since 1978, the incidence of dengue fever has markedly increased in China especially in Guangdong province. In order to formulate the effective prevention and control measures, we explored the risk factors of dengue virus infection in Guangdong Province by conducting a case-control study. In this study, 237 patients with dengue virus infection and 237 participants without dengue virus infection were included. Then through these questionnaires and data analysis, we found that activities in the park, outdoor sports, and poor indoor daylight quality significantly contributed to the residents risk of dengue virus infection. On the other hand, we observed that using air-condition and using anti-mosquito measures were effective personal prevention interventions.

scientific communication and education↗

bioRxiv2018

Dietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain

Exogenous metabolites from microbial and dietary origins have profound effects on host metabolism. Here, we report that a sub-population of lipid droplets (LDs), which are conserved organelles for fat storage, is defined by metabolites-driven targeting of the C. elegans seipin ortholog, SEIP-1. Loss of SEIP-1 function reduced the size of a subset of LDs while over-expression of SEIP-1 had the opposite effect. Ultrastructural analysis revealed SEIP-1 enrichment in an endoplasmic reticulum (ER) subdomain, which co-purified with LDs. Analyses of C. elegans and bacterial genetic mutants indicated a requirement of polyunsaturated fatty acids (PUFAs) and microbial cyclopropane fatty acids (CFAs) for SEIP-1 enrichment, as confirmed by dietary supplementation experiments. In mammalian cells, heterologous expression of SEIP-1 promoted lipid droplet expansion from ER subdomains in a conserved manner. Our results suggest that microbial and polyunsaturated fatty acids serve unexpected roles in regulating cellular fat storage by enforcing LD diversity.

cell biology↗

bioRxiv2018

Predicting negative control drugs to support research in drug safety

The lack of high-quality reference data is a major limitation in drug safety and drug discovery science. Unreliable standards prohibit the use of supervised learning methods and make evaluation of algorithms difficult. While some data is available for positive examples (e.g. which drugs are associated with a side effect), there are no systematic resources of negative controls. To solve this issue, we introduced SIDERctrl, a computational method that ranks drugs based on the likelihood of not causing a side effect. We applied SIDERctrl to predict negative controls from unreported drugs of 890 side effects in SIDER. Our predictions decreased the false negative rate by one-third according to a validation study using AEOLUS data. Three sets of predicted negative controls by different thresholds of precision were provided, and can be accessed at http://tatonettilab.org/resources/negative-drugs.html. This new reference standard will be important in chemical biology, drug development, and pharmacoepidemiology.\n\nKEY POINTSO_LIThe lack of systematic resources providing negative control drugs limits the performance of existing research in drug safety.\nC_LIO_LIWe developed a novel method that integrated chemical and biological properties a drug and the target proteins to calculate the likelihood of the drug being negative control.\nC_LIO_LIWe applied our method to 890 side effects, and showed that our method significantly decreased the false negative rate of predictions.\nC_LI

pharmacology and toxicology↗

bioRxiv2018

Transient DNA Binding Induces RNA Polymerase II Compartmentalization During Herpesviral Infection Distinct From Phase Separation

During lytic infection, Herpes Simplex Virus 1 generates replication compartments (RCs) in host nuclei that efficiently recruit protein factors, including host RNA Polymerase II (Pol II). Pol II and other cellular factors form hubs in uninfected cells that are proposed to phase separate via multivalent protein-protein interactions mediated by their intrinsically disordered regions. Using a battery of live cell microscopic techniques, we show that although RCs superficially exhibit many characteristics of phase separation, the recruitment of Pol II instead derives from nonspecific interactions with the viral DNA. We find that the viral genome remains nucleosome-free, profoundly affecting the way Pol II explores RCs by causing it to repetitively visit nearby binding sites, thereby creating local Pol II accumulations. This mechanism, distinct from phase separation, allows viral DNA to outcompete host DNA for cellular proteins. Our work provides new insights into the strategies used to create local molecular hubs in cells.

bioinformatics↗

bioRxiv2018

Fast and Robust Deconvolution of Tumor Infiltrating Lymphocyte from Expression Profiles using Least Trimmed Squares

Gene-expression deconvolution is used to quantify different types of cells in a mixed population. It provides a highly promising solution to rapidly characterize the tumor-infiltrating immune landscape and identify cold cancers. However, a major challenge is that gene-expression data are frequently contaminated by many outliers that decrease the estimation accuracy. Thus, it is imperative to develop a robust deconvolution method that automatically decontaminates data by reliably detecting and removing outliers. We developed a new machine learning tool, Fast And Robust DEconvolution of Expression Profiles (FARDEEP), to enumerate immune cell subsets from whole tumor tissue samples. To reduce noise in the tumor gene expression datasets, FARDEEP utilizes an adaptive least trimmed square to automatically detect and remove outliers before estimating the cell compositions. We show that FARDEEP is less susceptible to outliers and returns a better estimation of coefficients than the existing methods with both numerical simulations and real datasets. FARDEEP provides the absolute quantitation of each immune cell subset in addition to relative percentages. Hence, FARDEEP represents a novel robust algorithm to complement the existing toolkit for the characterization of tissue-infiltrating immune cell landscape. The source code for FARDEEP as implemented in R is available for download at https://goo.gl/SqGKuo.

bioinformatics↗

bioRxiv2018

Identification of biomarker and HPV strain for Cervical Cancer from pre-existing RNAseq data

Human papillomavirus (HPV) increased the risk of afflicting cervical cancer. Among over a hundred strains, HPV-16 and HPV-18 caused 70% of cervical cancers and precancerous cervical lesions (WHO 2018). To reveal the profile of HPV strains, HPViewer is designed by Hao et al. (2018) for metagenomic or human genomic shotgun sequencing data analysis. The application of HPViewer in detecting HPV strains in RNA sequencing data was assessed and results were communicated in the table. The performance of HPViewer in analyzing RNA sequencing data from multiple sources, demonstrated the potential of enlarging the application of HPViewer to RNA sequencing data. Furthermore, we attempted to verify the capability of a potential biomarker p16INK4a in detecting cervical cancer from precancerous lesions. Considering the protein nature of this biomarker, the experiment was designed to detect the differentially expressed gene, associating with this protein function group, in RNA-seq data from two articles. Compare to the findings from Royse et al. (2014), confirmatory result was reproduced that comparisons between both groups yielded insignificant outcome. Since data from single article was insufficient to provide meaningful clue, final dataset was collected from multiple sources. The results were compromised by batch effect, but they supported p16INK4a to be a prospective biomarker for cervical cancer diagnosis.

bioinformatics↗

bioRxiv2018

The MarR Family Regulator BmrR is involved in Bile Tolerance of Bifidobacterium longum BBMN68 via Controlling the Expression of an ABC-Transporter

In order to colonize the human gastrointestinal tract and exert their beneficial effects, bifidobacteria must effectively cope with the toxic bile salts in the intestine, but the molecular mechanism underlying bile tolerance is poorly understood. In this study, heterologous expression of a MarR family transcriptional regulator BmrR significantly reduced ox-bile resistance of Lactococcus lactis NZ9000, suggesting that it might play a role in bile stress response. In silico analysis combined with RT-PCR assay demonstrated that bmrR was co-transcribed with bmrA and bmrB, which encoded multidrug resistance (MDR) ABC transporters. Promoter prediction and EMSA assay revealed that BmrR could autoregulate the bmrRAB operon by binding to bmr box (ATTGTTG-6nt-CAACAAT) in the promoter region. Moreover, heterologous expression of bmrA and bmrB in L. lactis showed 20.77-fold higher tolerance to 0.10% ox-bile compared to wild type strain. In addition, ox-bile could disrupt the DNA binding activity of BmrR as a ligand. Taken together, our findings indicate that bmrRAB operon is autoregulated by transcriptional regulator BmrR and ox-bile serves as an inducer to activate the bile efflux transporter BmrAB in response to bile stress in B. longum BBMN68.\n\nImportanceBifidobacteria are natural inhabitants of the human intestinal tract. Some bifidobacterial strains are used as probiotics in fermented dairy production because of their health-promoting effects. Following consumption, bifidobacteria finally colonize the lower intestinal tract where the concentration of bile salts remains nearly 0.05% to 2.0%. Bile salts as detergent-like antimicrobial compounds can cause disruption of the cellular membrane, protein misfolding and DNA damage. Therefore, tolerance to physiological bile stress is indeed essential for bifidobacteria to survive and exert the probiotic effects in gastrointestinal tract. In B. longum BBMN68, the MarR-type regulator BmrR was involved in bile stress response by auto-regulating bmrRAB operon and ox-bile as an inducer could increase the expression of BmrAB transporter to enhance the bile tolerance of BBMN68.This is the first report about functional analysis of bmrRAB operon in bile stress response, which will provide new insight into bile tolerance mechanisms in Bifidobacterium and other bacteria.

microbiology↗

bioRxiv2018

Parkinsons disease and bacteriophages as its overlooked contributors

Recent studies suggest that alterations in the gut phagobiota may contribute to pathophysiological processes in mammals; however, the association of bacteriophage community structure with Parkinsons disease (PD) has not been yet characterized. Towards this end, we used a published dataset to analyse bacteriophage composition and determine the phage/bacteria ratio in faecal samples from drug-naive PD patients and healthy participants. Our analyses revealed significant alterations in the representation of certain bacteriophages in the phagobiota of PD patients. We identified shifts of the phage/bacteria ratio in lactic acid bacteria known to produce dopamine and regulate intestinal permeability, which are major factors implicated in PD pathogenesis. Furthermore, we observed the depletion of Lactococcus spp. in the PD group, which was most likely due to the increase of lytic c2-like and 936-like lactococcal phages frequently present in dairy products. Our findings add bacteriophages to the list of possible factors associated with the development of PD, suggesting that gut phagobiota composition may serve as a diagnostic tool as well as a target for therapeutic intervention, which should be confirmed in further studies. Our results open a discussion on the role of environmental phages and phagobiota composition in health and disease.

microbiology↗

bioRxiv2018

C. elegans avoidance of Pseudomonas: thioredoxin shapes the sensory response to bacterially produced nitric oxide

We show that C. elegans avoids a bacterial pathogen Pseudomonas aeruginosa (PA14) by detecting PA14-produced nitric oxide (NO). PA14 mutants deficient for NO production fail to elicit avoidance and NO donors repel worms. PA14 and NO avoidance are mediated by the ASJ chemosensory neurons, which respond to NO with intracellular calcium rises. PA14 avoidance and NO-evoked calcium responses require receptor guanylate cyclases (DAF-11 and GCY-27), and cyclic nucleotide gated ion channels (TAX-2 and -4). ASJ exhibits calcium increases at both the onset and removal of NO. These NO-evoked ON and OFF calcium transients are affected by a redox sensing protein, TRX-1/thioredoxin. TRX-1s trans-nitrosylation activity inhibits the ON transient whereas TRX-1s de-nitrosylation activity promotes the OFF transient. Thus, C. elegans exploits bacterially produced NO as a cue to mediate avoidance and TRX-1 functions as an NO-sensor that endows ASJ with a bi-phasic response to NO exposure.

microbiology↗

bioRxiv2017

The PTPRT pseudo-phosphatase domain is a denitrase

Protein tyrosine nitration occurs under both physiological and pathological conditions1. However, enzymes that remove this protein modification have not yet been identified. Here we report that the pseudo-phosphatase domain of protein tyrosine receptor T (PTPRT) is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer2,3. We demonstrate that some of the tumor-derived mutations located in the pseudophosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. This study uncovers a novel enzymatic activity that is involved in tumor suppression.

cancer biology↗

bioRxiv2017

HPViewer: Sensitive and specific genotyping of human papillomavirus in metagenomic DNA

BackgroundShotgun DNA sequencing provides sensitive detection of all 182 HPV types in tissue and body fluid. However, existing computational methods either produce false positives misidentifying HPV types due to shared sequences among HPV, human, and prokaryotes, or produce false negative since they identify HPV by assembled contigs requiring large abundant of HPV reads.\n\nResultsWe show that HPV shares extensive simple repeats with human and prokaryotes and homologous sequences among different HPV types. The shared sequences caused errors in HPV genotyping and the repeats of human origin caused false positives in HPVDetector. Programs, such as VirusTAP and Vipie, which require de novo assembly of shotgun reads into contigs, eliminated false positives at a cost of substantial reduction in sensitivity. Here, we designed HPViewer with two custom HPV reference databases masking simple repeats and homology sequences respectively and one homology distance matrix to hybridize these two databases. It directly identified HPV from short DNA reads rather than assembled contigs. Using 100,100 simulated samples, we revealed that HPViewer was robust for samples containing either high or low number of HPV reads. Using 12 shotgun sequencing samples from respiratory papillomatosis, HPViewer was equal to VirusTAP, and Vipie and better than HPVDetector with the respect to specificity and was the most sensitive method in the detection of HPV types 6 and 11. We demonstrated that contigs-based approaches had disadvantages of detection of HPV. In 1,573 sets of metagenomic data from 18 human body sites, HPViewer identified 104 types of HPV in a body-site associated pattern and 89 types of HPV co-occurring in one sample with other types of HPV at least once.\n\nConclusionsWe demonstrated HPViewer was sensitive and specific for HPV detection in metagenomic data. It was also suggested that masking shared sequences is an effective approach to avoid false positive detection and identifying HPV from short metagenomic reads is more sensitive than assembled contigs. The innovative homology distance matrix connecting two HPV databases, repeat-mask and homology-mask, optimized the balance of sensitivity and specificity. HPViewer can be accessed at https://github.com/yuhanH/HPViewer/.

bioinformatics↗

bioRxiv2017

Fast functional annotation of metagenomic shotgun data by DNA alignment to a microbial gene catalog

BackgroundMetagenomic shotgun sequencing is becoming increasingly popular to study microbes associated with the human body and in environmental samples. A key goal of shotgun metagenomic sequencing is to identify gene functions and metabolic pathways that differ between samples or conditions. However, current methods to identify function in the large number of reads in a high-throughput sequence data file rely on the computationally intensive and low stringency approach of mapping each read to a generic database of proteins or reference microbial genomes.\n\nResultsWe have developed an alternative analysis approach for shotgun metagenomic sequence data utilizing Bowtie2 DNA-DNA alignment of the reads to a database of well annotated genes compiled from human microbiome data. This method is rapid, and provides high stringency matches (>90% DNA sequence identity) of shotgun metagenomics reads to genes with annotated functions. We demonstrate the use of this method with synthetic data, Human Microbiome Project shotgun metagenomic data sets, and data from a study of liver disease. Differentially abundant KEGG gene functions can be detected in these experiments.\n\nConclusionsFunctional annotation of metagenomic shotgun sequence reads can be accomplished by rapid DNA-DNA matching to a custom database of microbial sequences using the Bowtie2 sequence alignment tool. This method can be used for a variety of microbiome studies and allows functional analysis which is otherwise computationally demanding. This rapid annotation method is freely available as a Galaxy workflow within a Docker image.

bioinformatics↗

bioRxiv2016

Genetic footprint of population fragmentation and contemporary collapse in a freshwater cetacean

Understanding demographic trends and patterns of gene flow in an endangered species is crucial for devising conservation strategies. Here, we examined the extent of population structure and recent evolution of the critically endangered Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis). By analysing genetic variation at the mitochondrial and nuclear microsatellite loci for 148 individuals, we identified three populations along the Yangtze River, each one connected to a group of admixed ancestry. Each population displayed extremely low genetic diversity, consistent with extremely small effective size ([≤]92 individuals). Habitat degradation and distribution gaps correlated with highly asymmetric gene-flow that was inefficient in maintaining connectivity between populations. Genetic inferences of historical demography revealed that the populations in the Yangtze descended from a small number of founders colonizing the river from the sea during the last Ice Age. The colonization was followed by a rapid population split during the last millennium predating the Chinese Modern Economy Development. However, genetic diversity showed a clear footprint of population contraction over the last 50 years leaving only ~2% of the pre-collapsed size, consistent with the population collapses reported from field studies. This genetic perspective provides background information for devising mitigation strategies to prevent this species from extinction.

evolutionary biology↗