Tissue dyslipidemia in salmonella-infected rats treatTissue dyslipidemia in salmonella-infected rats treated with amoxillin and pefloxac

Background: This study investigated the effects of salmonella infection and its chemotherapy on lipid metabolism in tissues of rats infected orally with Salmonella typhimurium and treated intraperitoneally with pefloxacin and amoxillin. Methods: Animals were infected with Salmonella enterica serovar Typhimurium strain TA 98. After salmonellosis was confirmed, they were divided into 7 groups of 5 animals each. While one group served as infected control group, three groups were treated with amoxillin (7.14 mg/kg body weight, 8 hourly) and the remaining three groups with pefloxacin (5.71mg/kg body weight, 12 hourly) for 5 and 10 days respectively. Uninfected control animals received 0.1ml of vehicle. Rats were sacrificed 24h after 5 and 10 days of antibiotic treatment and 5 days after discontinuation of antibiotic treatment. Their corresponding controls were also sacrificed at the same time point. Blood and tissue lipids were then evaluated. Results: Salmonella infection resulted in dyslipidemia characterised by increased concentrations of free fatty acids (FFA) in plasma and erythrocyte, as well as enhanced cholesterogenesis, hypertriglyceridemia and phospholipidosis in plasma, low density lipoprotein-very low density lipoprotein (LDL-VLDL), erythrocytes, erythrocyte ghost and the organs. The antibiotics reversed the dyslipidemia but not totally. A significant correlation was observed between fecal bacterial load and plasma cholesterol (r=0.456, p<0.01), plasma triacyglycerols (r=0.485, p<0.01), plasma phospholipid (r=0.414, p<0.05), plasma free fatty acids (r=0.485, p<0.01), liver phospholipid (r=0.459, p<0.01) and brain phospholipid (r=0.343, p<0.05). Conclusion: The findings of this study suggest that salmonella infection in rats and its therapy with pefloxacin and amoxillin perturb lipid metabolism and this perturbation is characterised by cholesterogenesis

A field-deployable reverse transcription recombinase polymerase amplification assay for rapid detection of the Chikungunya virus

Background&nbsp; Chikungunya virus (CHIKV) is a mosquito-borne virus currently transmitted in about 60 countries. CHIKV causes acute flu-like symptoms and in many cases prolonged musculoskeletal and joint pain. Detection of the infection is mostly done using RT-RCR or ELISA, which are not suitable for point-of-care diagnosis.&nbsp; Methodology/Principal Findings&nbsp; In this study, a reverse transcription recombinase polymerase amplification (RT-RPA) assay for the detection of the CHIKV was developed. The assay sensitivity, specificity, and cross-reactivity were tested. CHIKV RT-RPA assay detected down to 80 genome copies/reaction in a maximum of 15 minutes. It successfully identified 18 isolates representing the three CHIKV genotypes. No cross-reactivity was detected to other alphaviruses and arboviruses except O'nyong'nyong virus, which could be differentiated by a modified RPA primer pair. Seventy-eight samples were screened both by RT-RPA and real-time RT-PCR. The diagnostic sensitivity and specificity of the CHIKV RT-RPA assay were determined at 100%.&nbsp; Conclusions/Significance&nbsp; &nbsp;The developed RT-RPA assay represents a promising method for the molecular detection of CHIKV at point of need

Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS.The research leading to these results has received funding from the European Commission Seventh Framework Programme [FP7/2007-2013] for the DENFREE project under Grant Agreement no. 282378. MO has a PhD grant from FCT (The Portuguese Foundation for Science and Technology - SFRH/BD/95626/2013). I3S is financed by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Competitiveness and Internationalization Operational Programme (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of the project "Institute for Research and Innovation in Health Sciences" (POCI-01-0145-FEDER-007274). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

CD209 in inflammatory bowel disease: a case-control study in the Spanish population

<p>Abstract</p> <p>Background</p> <p>The etiology of Ulcerative Colitis (UC) and Crohn's Disease (CD), considered together as Inflammatory Bowel Diseases (IBD), involves environmental and genetic factors. Although some genes are already known, the genetics underlying these diseases is complex and new candidates are continuously emerging. The <it>CD209 </it>gene is located in a region linked previously to IBD and a <it>CD209 </it>functional polymorphism (rs4804803) has been associated to other inflammatory conditions. Our aim was to study the potential involvement of this <it>CD209 </it>variant in IBD susceptibility.</p> <p>Methods</p> <p>We performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the <it>CD209 </it>single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using χ²tests.</p> <p>Results</p> <p>No association between <it>CD209 </it>and UC or CD was observed initially. However, stratification of UC patients by <it>HLA-DR3 </it>status, a strong protective allele, showed that carriage of the <it>CD209</it>_G allele could increase susceptibility in the subgroup of <it>HLA-DR3</it>-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04–3.02, <it>vs. </it>controls).</p> <p>Conclusion</p> <p>A functional variant in the <it>CD209 </it>gene, rs4804803, does not seem to be influencing Crohn's disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in <it>HLA-DR3</it>-positive individuals but further studies are necessary.</p

Human adaptation of Ebola virus during the West African outbreak

The 2013–2016 outbreak of Ebola virus (EBOV) in West Africa was the largest recorded. It began following the cross-species transmission of EBOV from an animal reservoir, most likely bats, into humans, with phylogenetic analysis revealing the cocirculation of several viral lineages. We hypothesized that this prolonged human circulation led to genomic changes that increased viral transmissibility in humans. We generated a synthetic glycoprotein (GP) construct based on the earliest reported isolate and introduced amino acid substitutions that defined viral lineages. Mutant GPs were used to generate a panel of pseudoviruses, which were used to infect different human and bat cell lines. These data revealed that specific amino acid substitutions in the EBOV GP have increased tropism for human cells, while reducing tropism for bat cells. Such increased infectivity may have enhanced the ability of EBOV to transmit among humans and contributed to the wide geographic distribution of some viral lineages

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project

Dengue is the most important mosquito-borne viral disease in humans. This disease is now endemic in more than 100 countries and threatens more than 2.5 billion people living in tropical countries. It currently affects about 50 to 100 million people each year. It causes a wide range of symptoms, from an inapparent to mild dengue fever, to severe forms, including dengue hemorrhagic fever. Currently no specific vaccine or antiviral drugs are available. We carried out a prospective clinical study in South-East Asia and Latin America, of virologically confirmed dengue-infected patients attending the hospital, and members of their households. Among 215 febrile dengue subjects, 177 agreed to household investigation. Based on our data, we estimated the proportion of dengue-infected household members to be about 45%. At the time of the home visit, almost three quarters of (29/39) presented an inapparent dengue infection. The proportion of inapparent dengue infection was higher in South-East Asia than in Latin America. These findings confirm the complexity of dengue disease in humans and the need to strengthen multidisciplinary research efforts to improve our understanding of virus transmission and host responses to dengue virus in various human populations

In silico transcriptional regulation and functional analysis of dengue shock syndrome associated SNPs in PLCE1 and MICB genes

YesSingle nucleotide polymorphisms (SNPs) in PLCE1 and MICB genes increase risk for the development of dengue shock syndrome (DSS). We used Bioinformatics tools to predict alterations at the transcriptional and posttranslational levels driven by PLCE1 and MICB SNPs associated with DSS. Functional and phenotypic analysis conducted to determine deleterious SNPs and impact of amino acid substitution on the structure and function of proteins identified rs2274223 (H1619R) as deleterious to protein coding as it induces structural change in the C2 domain of PLCε, with the mutant residue more positively charged than the wild-type residue (RMSD score, 1.75 Å).Moreover, rs2274223 condenses the chromatinrepressing PLCε expression in DSS. Briefly, this study presents the impact of a single nucleotide transition at SNPs associated with DSS on differential protein binding patterns with PLCE1 and MICB genes and on protein structure modification and their possible role in the pathogenesis of DSS