Gene-Environment Interactions for Cardiovascular Disease

Purpose of reviewWe provide an overview of recent findings with respect to gene-environment (GxE) interactions for cardiovascular disease (CVD) risk and discuss future opportunities for advancing the field.Recent findingsOver the last several years, GxE interactions for CVD have mostly been identified for smoking and coronary artery disease (CAD) or related risk factors. By comparison, there is more limited evidence for GxE interactions between CVD outcomes and other exposures, such as physical activity, air pollution, diet, and sex. The establishment of large consortia and population-based cohorts, in combination with new computational tools and mouse genetics platforms, can potentially overcome some of the limitations that have hindered human GxE interaction studies and reveal additional association signals for CVD-related traits. The identification of novel GxE interactions is likely to provide a better understanding of the pathogenesis and genetic liability of CVD, with significant implications for healthy lifestyles and therapeutic strategies

Quantifying the Pressure-dependence of Work of Adhesion in Silicon-Diamond Contacts

Continuum mechanics models for contacting surfaces assume a constant interfacial energy, or work of adhesion, between materials. Recent studies have challenged this assumption, instead demonstrating that stress-dependent chemical reactions across the interface modify the work of adhesion. Here, we perform 77 adhesion tests on diamond-silicon contacts using in situ TEM and atomistic simulations to quantify how the adhesion changes as a function of applied pressure. The results show a 7-fold increase in work of adhesion (from approximately 1 to 7 J/m2) with an increase in mean applied pressure from 0 to 11 GPa, where the most significant increase occurs above 5 GPa. We rule out alternative explanations for the changing work of adhesion, such as electron-beam artifacts, bulk shape change by inelastic deformation, and time-dependent processes such as creep. Therefore, these results confirm the presence of stress-driven chemical reactions in the contact and quantify the resulting change in adhesion of these materials with applied pressure

DOXORUBICIN INDUCED COGNITION IMPAIRMENT IN RAT MODEL

 Objective: Doxorubicin (DOX) is a chemotherapeutic agent commonly used to treat a variety of cancers despite having well documented adverse sideeffects in organs like heart, liver, and kidney. The damage caused to brain, if any, and to what extent is, however, still not clear and the present studywas undertaken to estimate the possible role of DOX inducing cognitive impairment in Wistar rats.Methods: The study carried out in two groups of Wistar rats (n=6) with one group receiving DOX, and the other only normal saline used as control.During and after the experimentation period cognitive level of each rat was measured using Barnes maze (BM) till 8 weeks. At the end of theobservation period (after 8th week), a series of biochemical and histopathological studies were carried out after sacrificing the animals.Results: Errors to reach target and time taken to reach the target was found in BM experiment, elevated levels of antioxidants and hemoglobin wasfound reduced significantly in the DOX treated group when compared to the controls while histopathology of brain cells of DOX treated group alsoshowed reduction in hippocampal cellularity and cell death in hippocampal area suggesting evidence of oxidative damage caused by DOX treatment.Conclusion: Parameters in this study which not only conclusively show the damage caused to brain by DOX, but also estimates the changes caused toeach indicator by this drug.Keywords: Chemotherapy, Brain, Hippocampus, Oxidative stress

A Method for Quantitative Real-Time Evaluation of Measurement Reliability When Using Atomic Force Microscopy-Based Metrology

In atomic force microscopy (AFM) and metrology, it is known that the radius of the scanning tip affects the accuracy of the measurement. However, most techniques for ascertaining tip radius require interruption of the measurement technique to insert a reference standard or to otherwise image the tip. Here we propose an inline technique based on analysis of the power spectral density (PSD) of the topography that is being collected during measurement. By identifying and quantifying artifacts that are known to arise in the power spectrum due to tip blunting, the PSD itself can be used to determine progressive shifts in the radius of the tip. Specifically, using AFM images of an ultrananocrystalline diamond, various trends in measured PSD are demonstrated. First, using more than 200 different measurements of the same material, the variability in the measured PSD is demonstrated. Second, using progressive scans under the same conditions, a systematic shifting of the mid-to-high-frequency data is visible. Third, using three different PSDs, the changes in radii between them were quantitatively determined and compared to transmission electron microscopy (TEM) images of the tips taken immediately after use. The fractional changes in tip radii were detected; the absolute values of the tip radii could be matched between the two techniques, but only with careful selection of a fitting constant. Further work is required to determine the generalizability of the value of this constant. Overall, the proposed approach represents a step towards quantitative and inline determination of the radius of the scanning tip and thus of the reliability of AFM-based measurements

Identifying the sources of intestinal colonization with extended-spectrum β-lactamase-producing Escherichia coli in healthy infants in the community

The prevalence of fecal colonization with extended-spectrum β-lactamase-producing Escherichia coli (ESBL-Ec) among children in low- and middle-income countries is alarmingly high. This study aimed to identify the sources of ESBL-Ec colonization in children < 1 year old through comparative analysis of E. coli isolates from child stool, child’s mother stool, and point-of-use drinking water from 46 rural households in Bangladesh. The pairwise similarity in antibiotic susceptibility of E. coli from all three sources was evaluated, followed by phylogenetic clustering using enterobacterial repetitive intergenic consensus polymerase chain reaction and whole-genome sequence analysis of the isolates. Matching antibiotic susceptibility and enterobacterial repetitive intergenic consensus polymerase chain reaction patterns were found among ESBL-Ec isolates from child–mother dyads of 24 and 11 households, respectively, from child–water dyads of 5 and 4 households, respectively, and from child–mother–water triads of 3 and 4 households, respectively. Whole-genome sequence analysis of 30 isolates from 10 households revealed that ESBL-Ec from children in five households (50%) was clonally related to ESBL-Ec either from their mothers (2 households), drinking water sources (2 households), or both mother and drinking-water sources (1 household) based on serotype, phylogroup, sequence type, antibiotic resistance genes, mobile genetic elements, core single-nucleotide polymorphisms, and whole-genome multilocus sequence typing. Overall, this study provides empirical evidence that ESBL-Ec colonization in children is linked to the colonization status of mothers and exposure to the household environments contaminated with ESBL-Ec. Interventions such as improved hygiene practices and a safe drinking water supply may help reduce the transmission of ESBL-Ec at the household level

Genotypic and Phenotypic Characterization of Escherichia coli Isolates from Feces, Hands, and Soils in Rural Bangladesh via the Colilert Quanti-Tray System

The increased awareness of the role of environmental matrices in enteric disease transmission has resulted in the need for rapid, field-based methods for fecal indicator bacteria and pathogen detection. Evidence of the specificity of β-glucuronidase-based assays for detection of Escherichia coli from environmental matrices relevant to enteric pathogen transmission in developing countries, such as hands, soils, and surfaces, is limited. In this study, we quantify the false-positive rate of a β-glucuronidase-based E. coli detection assay (Colilert) for two environmental reservoirs in Bangladeshi households (hands and soils) and three fecal composite sources (cattle, chicken, and humans). We investigate whether or not the isolation source of E. coli influences phenotypic and genotypic characteristics. Phenotypic characteristics include results of biochemical assays provided by the API-20E test; genotypic characteristics include the Clermont phylogroup and the presence of enteric and/or environmental indicator genes sfmH, rfaI, and fucK. Our findings demonstrate no statistically significant difference in the false-positive rate of Colilert for environmental compared to enteric samples. E. coli isolates from all source types are genetically diverse, representing six of the seven phylogroups, and there is no difference in relative frequency of phylogroups between enteric and environmental samples. We conclude that Colilert, and likely other β-glucuronidase-based assays, is appropriate for detection of E. coli on hands and in soils with low false-positive rates. Furthermore, E. coli isolated from hands and soils in Bangladeshi households are diverse and indistinguishable from cattle, chicken, and human fecal isolates, using traditional biochemical assays and phylogrouping

High genomic diversity and heterogenous origins of pathogenic and antibiotic-resistant Escherichia coli in household settings represent a challenge to reducing transmission in low-income settings

Escherichia coli; is present in multiple hosts and environmental compartments as a normal inhabitant, temporary or persistent colonizer, and as a pathogen. Transmission of; E. coli; between hosts and with the environment is considered to occur more often in areas with poor sanitation. We performed whole-genome comparative analyses on 60; E. coli; isolates from soils and fecal sources (cattle, chickens, and humans) in households in rural Bangladesh. Isolates from household soils were in multiple branches of the reconstructed phylogeny, intermixed with isolates from fecal sources. Pairwise differences between all strain pairs were large (minimum, 189 single nucleotide polymorphisms [SNPs]), suggesting high diversity and heterogeneous origins of the isolates. The presence of multiple virulence and antibiotic resistance genes is indicative of the risk that; E. coli; from soil and feces represent for the transmission of variants that pose potential harm to people. Analysis of the accessory genomes of the Bangladeshi; E. coli; relative to; E. coli; genomes available in NCBI identified a common pool of accessory genes shared among; E. coli; isolates in this geographic area. Together, these findings indicate that in rural Bangladesh, a high level of; E. coli; in soil is likely driven by contributions from multiple and diverse; E. coli; sources (human and animal) that share an accessory gene pool relatively unique to previously published; E. coli; genomes. Thus, interventions to reduce environmental pathogen or antimicrobial resistance transmission should adopt integrated One Health approaches that consider heterogeneous origins and high diversity to improve effectiveness and reduce prevalence and transmission.; IMPORTANCE; Escherichia coli; is reported in high levels in household soil in low-income settings. When; E. coli; reaches a soil environment, different mechanisms, including survival, clonal expansion, and genetic exchange, have the potential to either maintain or generate; E. coli; variants with capabilities of causing harm to people. In this study, we used whole-genome sequencing to identify that; E. coli; isolates collected from rural Bangladeshi household soils, including pathogenic and antibiotic-resistant variants, are diverse and likely originated from multiple diverse sources. In addition, we observed specialization of the accessory genome of this Bangladeshi; E. coli; compared to; E. coli; genomes available in current sequence databases. Thus, to address the high level of pathogenic and antibiotic-resistant; E. coli; transmission in low-income settings, interventions should focus on addressing the heterogeneous origins and high diversity

Antimicrobial activity of leaf and root methanolic extracts from Vinca pusilla Murr.

Vinca pusilla Murr. is a traditional medicinal plant used to treat several diseases. To substantiate the traditional medicinal utility of the plant, the present study aims at screening the antimicrobial activity of methanolic extracts of leaves and roots against five Gram positive, five Gram negative bacterial and four fungal strains. The minimum inhibitory concentration (MIC) were determined by two fold dilution assay. The results indicated that, leaf and root extracts were more effective on Bacillus subtilis and Staphylococcus aureus strains (MIC &lt; 1 mg/mL). The tested organisms were sensitive to root extract compared to leaf extract. Fungal strains were resistant than the bacterial strains to both the extracts. Thus the present study illustrates the antimicrobial potential of the plant.

Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection

Individuals with features of metabolic syndrome are particularly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus associated with the severe respiratory disease, coronavirus disease 2019 (COVID-19). Despite considerable attention dedicated to COVID-19, the link between metabolic syndrome and SARS-CoV-2 infection remains unclear. Using data from the UK Biobank, we investigated the relationship between severity of COVID-19 and metabolic syndrome-related serum biomarkers measured prior to SARS-CoV-2 infection. Logistic regression analyses were used to test biomarker levels and biomarker-associated genetic variants with SARS-CoV-2-related outcomes. Among SARS-CoV-2-positive cases and negative controls, a 10&nbsp;mg/dl increase in serum HDL-cholesterol or apolipoprotein A1 levels was associated with ∼10% reduced risk of SARS-CoV-2 infection, after adjustment for age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. Evaluation of known genetic variants for HDL-cholesterol revealed that individuals homozygous for apolipoprotein E4 alleles had ∼2- to 3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared with apolipoprotein E3 homozygotes, even after adjustment for HDL-cholesterol levels. However, cumulative effects of all evaluated HDL-cholesterol-raising alleles and Mendelian randomization analyses did not reveal association of genetically higher HDL-cholesterol levels with decreased risk of SARS-CoV-2 infection. These results implicate serum HDL-cholesterol and apolipoprotein A1 levels measured prior to SAR-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL-cholesterol levels are associated with SAR-CoV-2 infection

Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: An in vitro and in silico approach

Introduction: Adipose tissue functions as a key endocrine organ which releases multiple bioactive substances and regulate obesity-linked complications. Dysregulation of adipocyte differentiation, triglyceride metabolism, adipokines production and lipid transport contributes to impaired lipid metabolism resulting in obesity, insulin resistance and type 2 diabetes. Gymnema sylvestre plant is frequently used in Ayurveda for treatment of diabetes and obesity. Gymnemagenin is a major bioactive compound of Gymnema sylvestre. The present study was undertaken to elucidate the role of gymnemagenin in lipid metabolism by in vitro and computational approaches.Methods: A panel of twelve genes viz., Fasn, Lipe, Lpl, Pparg, Plin2, Cidea, Scd1, Adipoq, Lep, Ccl2, Fabp4, and Slc2a4, essential in lipid metabolism were selected and gene expression pattern and triglyceride content were checked in adipocytes (3T3L1 cells) with/without treatment of gymnemagenin by Real time PCR and colorimetric estimation, respectively. Mode of action of gymnemagenin on Pparg and Fabp4 was accomplished by computational studies. Gene set enrichment and network pharmacology were performed by STRING and Cytoscape. Molecular docking was performed by AutoDock vina by POAP pipeline. Molecular dynamics, MM-PBSA were done by Gromacs tool.Results:In vitro study showed that gymnemagenin improved triglyceride metabolism by up regulating the expression of lipase genes viz., Lipe and Lpl which hydrolyse triglyceride. Gymnemagenin also up regulated the expression of anti-inflammatory gene Adipoq. Importantly, gymnemagenin treatment up regulated the expression of Pparg gene and the downstream target genes (Plin2, Cidea, and Scd1) which are associated with adipogenesis. However, gymnemagenin has no effect on expression of Fabp4, codes for a lipid transport protein. In silico study revealed that gymnemagenin targeted 12 genes were modulating 6 molecular pathways involved in diabetes and obesity. Molecular docking and dynamics revealed that gymnemagenin stably bind to active site residue of Pparg and failed to bind to Fabp4 active site compared to its standard molecules throughout 100 ns MD production run. Gymnemagenin scored binding free energy of −177.94 and −25.406 kJ/mol with Pparg and Fabp4, respectively.Conclusion: Gymnemagenin improved lipid metabolism by increasing triglyceride hydrolysis (lipolysis), up regulating the crucial gene of adipogenesis and increasing the expression of anti-inflammatory adipokine proving its therapeutic importance as anti-obesity and anti-diabetic phytocompound