Biology subjects

Guo, X.

Publications and source records attributed to Guo, X..

At least 343 records · Page 19Linked to original sources

bioRxiv2019

Heterologous expression of Stlac2, a laccase isozyme of Setosphearia turcica, and the ability of decolorization of malachite green

Laccases can catalyze monoelectronic oxidation and have shown to have an increasing value in industrial application. In this study, as identified by Native-PAGE and ESI-MS/MS, ascomycetous fungus Setosphaeria turcica produced three laccase isozymes: Stlac1, Stlac2, and Stlac6. Stlac2 was heterologously expressed in both eukaryotic and prokaryotic expression systems. The eukaryotic recombinant Stlac2 expressed in Pichia pastoris was inactive, and also showed a higher molecular weight than predicted because of glycosylation. The depression of laccase activity was attributable to the incorrect glycosylation at Asn97. Stlac2 expressed in Escherichia coli and after being renaturated from the inclusion body, the recombinant Stlac2 exhibited activity of 28.23 U/mg with 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) as the substrate. The highest activity was observed at pH of 4.5 and the temperature of 60 {degrees}C. The activity of recombinant Stlac2 was inhibited by 10 mM Na+, Mg2+, Ca2+, Mn2+, and increased by 10 mM of Fe3+ with a relatively activity of 315% compared with no addition. Cu2+ did not affect enzyme activity. Recombinant Stlac2 was capable of decolorizing 67.08% of 20 mg/L malachite green in 15 min without any mediators. It is suggested that Stlac2 has potential industrial applications. ImportanceSetosphaeria turcica, an ascomycetous fungus causes northern corn leaf blight, product three laccase isozymes identified by Native-PAGE and ESI-MS/MS. The major expression laccase gene StLAC2 was expression in both eukaryotic and prokaryotic expression systems, which found incorrect glycosylation at Asn97 may result in the depression of laccase activity. The heterologous laccase Stlac2 decolorize organic dye malachite green, which had a potential industrial application.

bioengineering↗

bioRxiv2018

Anchorene is an endogenous diapocarotenoid required for anchor root formation in Arabidopsis

Arabidopsis root development is predicted to be regulated by yet unidentified carotenoid-derived metabolite(s). In this work, we screened known and putative carotenoid cleavage products and identified anchorene, a predicted carotenoid-derived dialdehyde (diapocarotenoid) that triggers anchor root development. Anchor roots are the least characterized type of root in Arabidopsis. They form at the root-shoot junction, particularly upon damage to the root apical meristem. Using Arabidopsis reporter lines, mutants and chemical inhibitors, we show that anchor roots originate from pericycle cells and that the development of this root type is auxin-dependent and requires carotenoid biosynthesis. Transcriptome analysis and treatment of auxin-reporter lines indicate that anchorene triggers anchor root development by modulating auxin homeostasis. Exogenous application of anchorene restored anchor root development in carotenoid-deficient plants, indicating that this compound is the carotenoid-derived signal required for anchor root development. Chemical modifications of anchorene led to a loss of anchor root promoting activity, suggesting that this compound is highly specific. Furthermore, we demonstrate by LC-MS analysis that anchorene is a natural, endogenous Arabidopsis metabolite. Taken together, our work reveals a new member of the family of carotenoid-derived regulatory metabolites and hormones.\n\nSignificanceUnknown carotenoid-derived compounds are predicted to regulate different aspects of plant development. Here, we characterize the development of anchor roots, the least characterized root type in Arabidopsis, and show that this process depends on auxin and requires a carotenoid-derived metabolite. We identified a presumed carotenoid-derivative, anchorene, as the likely, specific signal involved in anchor root formation. We further show that anchorene is a natural metabolite that occurs in Arabidopsis. Based on the analysis of auxin reporter lines and transcriptome data, we provide evidence that anchorene triggers the growth of anchor roots by modulating auxin homeostasis. Taken together, our work identifies a novel carotenoid-derived growth regulator with a specific developmental function.

plant biology↗

bioRxiv2018

Genome sequencing analysis identifies high-risk Epstein-Barr virus subtypes for nasopharyngeal carcinoma

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and associated with multiple cancers including nasopharyngeal carcinoma (NPC). The role of EBV viral genomic variation in NPC development and its striking endemicity in southern China has been poorly explored. Through large-scale genome sequencing and association study of EBV isolates from China, we identified two non-synonymous EBV variants within BALF2 strongly associated with NPC risk (conditional P value 1.75x10-6 for SNP162476_C and 3.23x10-13 for SNP163364_T), whose cumulative effects contributed to 83% of the overall risk in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in southern China followed by clonal expansion. EBV BALF2 haplotype carrying the risk variants were shown to reduce viral lytic DNA replication, as a result potentially promoting viral latency. Our discovery has not only provided insight to the unique endemic pattern of NPC occurrence in southern China, but also paved the way for the identification of individuals at high risk of NPC and effective intervention program to reduce the disease burden in southern China.

genetics↗

bioRxiv2018

Powerful statistical method to detect disease associated genes using publicly available GWAS summary data

Genome-wide association studies (GWAS) have thus far achieved substantial success. In the last decade a large number of common variants underlying complex diseases have been identified through GWAS. In most existing GWAS, the identified common variants are obtained by single marker based tests, that is, testing one single nucleotide polymorphisms (SNP) at a time. Generally the basic functional unit of inheritance is a gene, rather than a SNP. Thus, results from gene level association test can be more readily integrated with downstream functional and pathogenic investigation. In this paper, we propose a general gene-based p-value adaptive combination approach (GPA) which can integrate association evidence of multiple genetic variants using only GWAS summary statistics (either p-value or other test statistics). The proposed method could be used to test both continuous and binary traits through not only a single but also multiple studies, which helps overcome the limitation of existing methods that only can be applied to specific type of data. We conducted thorough simulation studies to verify that the proposed method controls type I errors well, and performs favorably compared to single-marker analysis and other existing methods. We demonstrated the utility of our proposed method through analysis of GWAS meta-analysis results for fasting glucose and lipids from the international MAGIC consortium and Global Lipids Consortium, respectively. The proposed method identified some novel traits associated genes which can improve our understanding of the mechanisms involved in {beta}-cell function, glucose homeostasis and lipids traits.

genetics↗

bioRxiv2018

Crosstalk between RNA Pol II C-Terminal Domain Acetylation and Phosphorylation via RPRD Proteins

Post-translational modifications of the RNA polymerase II C-terminal domain (CTD) coordinate the transcription cycle. Crosstalk between different modifications is poorly understood. Here, we show how acetylation of lysine residues at position 7 of characteristic heptad repeats (K7ac)--only found in higher eukaryotes--regulates phosphorylation of serines at position 5 (S5p), a conserved mark of polymerases initiating transcription. We identified the regulator of pre-mRNA domain-containing (RPRD) proteins as reader proteins of K7ac. K7ac enhanced CTD peptide binding to the CTD-interacting domain (CID) of RPRD1A and RPRD1B proteins in isothermal calorimetry and molecular modeling experiments. Deacetylase inhibitors increased K7ac- and decreased S5-phosphorylated polymerases, consistent with acetylation-dependent S5 dephosphorylation by an RPRD-associated S5 phosphatase. Consistent with this model, RPRD1B knockdown increased S5p, but enhanced K7ac, indicating RPRD proteins recruit K7 deacetylases, including HDAC1. We also report auto-regulatory crosstalk between K7ac and S5p via RPRD proteins and their interactions with acetyl- and phospho-eraser proteins.

molecular biology↗

bioRxiv2018

Evaluation of the causal effect of fibrinogen on incident coronary heart disease via Mendelian randomization

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.\n\nMethods and FindingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).\n\nIn single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.\n\nConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.\n\nAuthor SummaryInitial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.

genetics↗

bioRxiv2018

SmbHLH37 functions antagonistically with SmMYC2 in regulating jasmonate-mediated biosynthesis of phenolic acids in Salvia miltiorrhiza

Jasmonates (JAs) are integral to various defense responses and induce biosynthesis of many secondary metabolites. MYC2, a basic helix-loop-helix (bHLH) transcription factor (TF), acts as a transcriptional activator of JA signaling. MYC2 is repressed by the JASMONATE ZIM-domain (JAZ) proteins in the absence of JA, but de-repressed by the protein complex SCFCOI1 on perception of JA. We previously reported that overexpression of SmMYC2 promotes the production of salvianolic acid B (Sal B) in Salvia miltiorrhiza. However, the responsible molecular mechanism is unclear. Here, we showed that SmMYC2 binds to and activates the promoters of its target genes SmTAT1, SmPAL1, and SmCYP98A14 to activate Sal B accumulations. SmbHLH37, a novel bHLH gene significantly up-regulated by constitutive expression of SmMYC2, was isolated from S. miltiorrhiza for detailed functional characterization. SmbHLH37 forms a homodimer and interacts with SmJAZ3/8. Overexpression of SmbHLH37 substantially decreased yields of Sal B. SmbHLH37 binds to the promoters of its target genes SmTAT1 and SmPAL1 and blocks their expression to suppress the pathway for Sal B biosynthesis. These results indicate that SmbHLH37 negatively regulates JA signaling and functions antagonistically with SmMYC2 in regulating Sal B biosynthesis in S. miltiorrhiza.

plant biology↗

bioRxiv2018

Red and black: A β-carotene-binding protein carrying a red pigment regulates body-color transition in locusts

Changes of body color have important effects for animals in adapting to variable environments. The migratory locust exhibits body color polyphenism between solitary and gregarious individuals, with the former displaying a uniform green coloration and the latter having a prominent pattern of black dorsal and brown ventral surface. However, the molecular mechanism underlying the density-dependent body color changes of conspecific locusts remain largely unknown. Here, we found that up regulation of {beta}-carotene-binding protein promotes the accumulation of red pigment, which added to the green color palette present in solitary locusts changes it from green to black, and that down regulation of this protein led to the reverse, changing the color of gregarious locusts from black to green. Our results provide insight that color changes of locusts are dependent on variation in the red {beta}-carotene pigment binding to {beta}CBP. This finding of animal coloration corresponds with trichromatic theory of color vision.

evolutionary biology↗

bioRxiv2018

Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

Chronic kidney disease (CKD) affects [~]10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

genetics↗

bioRxiv2018

Efficient variant set mixed model association tests for continuous and binary traits in large-scale whole genome sequencing studies

With advances in Whole Genome Sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and Sequence Kernel Association Test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally-efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-Set Mixed Model Association Tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institutes Trans-Omics for Precision Medicine (TOPMed) program. SMMAT tests share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be only fit once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMAT tests correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

genetics↗

bioRxiv2018

Human cytomegalovirus RNA2.7 regulates host cell cycle and facilitates viral DNA replication by inhibiting RNA polymerase II phosphorylation

Human cytomegalovirus (HCMV) is a ubiquitous pathogen belongs to the beta herpesvirus family. RNA2.7 is a viral long non-coding RNA accounting for more than 20% of total viral transcripts at early time of infection. By construction of RNA2.7 deleted mutant and genome transcriptomic analysis, RNA2.7 is demonstrated to repress host cellular RNA polymerase II (Pol II)-dependent transcription through inhibiting the phosphorylation of RNA polymerase II (Pol II). Co-immunoprecipitation, RNA immunoprecipitation and RNA electrophoretic mobility shift assay are followed to investigate its mechnism. A 145nt-in-length fragment in RNA2.7 is identified to bind to Pol II and block the interaction between Pol II and phosphorylated cyckin-dependent kinase 9 (phospho-CDK9). By inhibiting Pol II phosphorylation, RNA2.7 decreases the transcription and expression levels of chromatin licensing and DNA replication factor 1 (Cdt1) and cell division cycle gene 6 (Cdc6). Through above way, RNA2.7 prevents the entry of cells into S phase and facilitates viral DNA replication. Our results discover the functions of HCMV RNA2.7 in regulation of Pol II phosphorylation and cell cycle control during infection.\n\nAuthor summaryHuman cytomegalovirus (HCMV) RNA2.7 is a viral lncRNA that is most abundant during infection. Here we show that a 145nt-in-length fragment in RNA2.7 binds to RNA polymerase II (Pol II) and blocks the interaction between Pol II and phosphorylated cyckin-dependent kinase 9 (phospho-CDK9). By inhibiting Pol II phosphorylation, RNA2.7 decreases the transcription and expression levels of chromatin licensing and DNA replication factor 1 (Cdt1) and cell division cycle gene 6 (Cdc6), and blocks host cells entering into S phase. RNA2.7 is confirmed to facilitate viral DNA replication through decreasing Cdt1 and Cdc6. Therefore, our results discover the functions of HCMV RNA2.7 in regulation of Pol II phosphorylation and cell cycle control during infection.

microbiology↗

bioRxiv2018

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.\n\nMethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n=15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.\n\nResultsWe identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top association in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was for intronic SNP rs3922344 (P= 8.56x10-26) in SCN5A/SCN10A. Three additional previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.\n\nConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

genetics↗

bioRxiv2018

PROTEIN-CODING VARIANTS IMPLICATE NOVEL GENES RELATED TO LIPID HOMEOSTASIS CONTRIBUTING TO BODY FAT DISTRIBUTION

Body fat distribution is a heritable risk factor for a range of adverse health consequences, including hyperlipidemia and type 2 diabetes. To identify protein-coding variants associated with body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, we analyzed 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries for discovery and 132,177 independent European-ancestry individuals for validation. We identified 15 common (minor allele frequency, MAF[≥]5%) and 9 low frequency or rare (MAF<5%) coding variants that have not been reported previously. Pathway/gene set enrichment analyses of all associated variants highlight lipid particle, adiponectin level, abnormal white adipose tissue physiology, and bone development and morphology as processes affecting fat distribution and body shape. Furthermore, the cross-trait associations and the analyses of variant and gene function highlight a strong connection to lipids, cardiovascular traits, and type 2 diabetes. In functional follow-up analyses, specifically in Drosophila RNAi-knockdown crosses, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). By examining variants often poorly tagged or entirely missed by genome-wide association studies, we implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

genetics↗

bioRxiv2018

Next-Generation Sequencing Could be a Promising Diagnostic Approach for Pathogen Detection: Pathogenic Analysis of Pediatric Bacterial Meningitis by Next-Generation Sequencing Technology Directly from Cerebrospinal Fluid Specimens

BackgroundBacterial meningitis remains one of the major challenges in infectious diseases, leading to sequel in many cases. A prompt diagnosis of the causative microorganism is critical to significantly improve outcome of bacterial meningitis. Although various targeted tests for cerebrospinal fluid (CSF) samples are available, it is a big problem for the identification of etiology of bacterial meningitis.\n\nMethodsHere we describe the use of unbiased sequence analyses by next-generation sequencing (NGS) technology for the identification of infectious microorganisms from CSF samples of pediatric bacterial meningitis patients in the Department of Infectious Diseases from Beijing Childrens Hospital.\n\nResultsIn total, we had 99 bacterial meningitis patients in our study, 55 (55.6%) of these were etiologically confirmed by clinical microbiology methods. Combined with NGS, 68 cases (68.7%) were etiologically confirmed. The main pathogens identified in this study were Streptococcus pneumoniae (n=29), group B streptococcus (n=15), Staphylococcus aureus (n=7), Escherichia coli (n=7). In addition, two cases with cytomegalovirus infection and one with Taenia saginata asiatica were confirmed by NGS.\n\nConclusionsNGS could be a promising alternative diagnostic approach for critically ill patients suffering from bacterial meningitis in pediatric population.\n\nSummaryWe conducted the study for the identification of microorganisms by next-generation sequencing directly from CSF samples of pediatric bacterial meningitis patients. And the study showed that NGS could be a promising alternative diagnostic approach for bacterial meningitis in pediatric population.

microbiology↗

bioRxiv2018

Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Humans and Mice

Aims/hypothesisAging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-related insulin resistance is due to age per se, or increased adiposity associated with advanced age. In the present study, we investigate the impact of aging on insulin sensitivity independent of changes in body composition.\n\nMethodsCohorts of C57BL/6J male mice at 4-8 months of age ( young) and 18-27 mo ( aged) exhibiting similar body composition were characterized with static (plasma glucose and insulin levels) and dynamic (glucose and insulin tolerance tests) measures of glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis. The relationship between aging and insulin resistance in humans was investigated in 1,250 non-diabetic Mexican-American individuals who underwent hyperinsulinemic-euglycemic clamps.\n\nResultsIn mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. However, aged mice demonstrated mildly, but reproducibly, improved glucose tolerance on both chow and high-fat diets due to increased glucose-stimulated insulin secretion. Moreover, hyperinsulinemic-euglycemic clamps revealed impaired insulin sensitivity and reduced insulin clearance in aged mice on both diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican-Americn males. Advanced age was also associated with diminished insulin clearance, but this effect was dependent on increased BMI.\n\nConclusions/interpretationThis study demonstrates for the first time that aging per se impairs insulin sensitivity independent of adiposity in mice and humans. These results raise the possibility that the pathogenetic mechanisms of age-related and obesity-associated insulin resistance are distinct.\n\nAbbreviations

physiology↗

bioRxiv2018

Autophagy Decreases Alveolar Epithelial Cell Injury by Suppressing the NF-κB Signaling Pathway and Regulating the Release of Inflammatory Mediators

To research the impact of autophagy on alveolar epithelial cell inflammation and its possible mechanism in early stages of hypoxia, we established a cell hypoxia-reoxygenation model and orthotopic left lung ischemia-reperfusion model. Rat alveolar epithelial cells stably expressing GFP-LC3 were treated with an autophagy inhibitor (3-methyladenine, 3-MA) or autophagy promoter (rapamycin), followed by hypoxia-reoxygenation treatment at 2, 4 and 6h in vitro. In vivo, twenty-four male Sprague-Dawley rats were randomly divided into four groups (model group: no blocking of hilum in the left lung; control group: blocking of hilum in the left lung for 1h with DMSO lavage; 3-MA group: blocking of hilum in the left lung for 1h with 100ml/kg of 3-MA (5mol/L) solution lavage; rapamycin group: blocking of hilum in the left lung for 1h with 100ml/kg of rapamycin (250nmol/L) solution lavage) to establish an orthotopic left lung ischemia model. This study demonstrated that rapamycin significantly suppressed the NF-{kappa}B signaling pathway, restrained the expression of pro-inflammatory factors. A contrary result was confirmed by 3-MA pretreatment. These findings indicate that autophagy reduces ischemia-reperfusion injury by repressing inflammatory signaling pathways in the early stage of hypoxia in vitro and in vivo. This could be a new protective method for lung ischemia-reperfusion injury.

cell biology↗

bioRxiv2018

Inhibition of EV71 replication by L3HYPDH, a newly identified interferon-stimulated gene product

Enterovirus 71 (EV71) is the common causative agent of hand-foot-mouth disease (HFMD). Despite evidence in mice model suggested that the interferon (IFN) signaling pathways play a role in defending against this virus, knowledge on the IFN-mediated antiviral response is still limited. Here we identified an IFN-stimulated gene (ISG) called L3HYPHD, whose expression inhibits EV71 replication. Mapping assay indicated that amino acids 61-120 and 295-354 are critical for its optimal antiviral activity. Mechanismly, L3HYPDH specifically inhibits protein translation mediated by EV71 internal ribosome entry site (IRES). Our data thus uncovered a new mechanism utilized by the host cell to restrict EV71 replication.

microbiology↗

bioRxiv2018

Membrane proteins with high N-glycosylation, high expression, and multiple interaction partners were preferred by mammalian viruses as receptors

Receptor mediated entry is the first step for viral infection. However, the relationship between viruses and receptors is still obscure. Here, by manually curating a high-quality database of 268 pairs of mammalian virus-host receptor interaction, which included 128 unique viral species or sub-species and 119 virus receptors, we found the viral receptors were structurally and functionally diverse, yet they had several common features when compared to other cell membrane proteins: more protein domains, higher level of N-glycosylation, higher ratio of self-interaction and more interaction partners, and higher expression in most tissues of the host. Additionally, the receptors used by the same virus tended to co-evolve. Further correlation analysis between viral receptors and the tissue and host specificity of the virus shows that the virus receptor similarity was a significant predictor for mammalian virus cross-species. This work could deepen our understanding towards the viral receptor selection and help evaluate the risk of viral zoonotic diseases.

microbiology↗