Characterisation of the effects of salicylidene acylhydrazide compounds on type three secretion in Escherichia coli O157:H7

Recent work has highlighted a number of compounds that target bacterial virulence by affecting gene regulation. In this work, we show that small-molecule inhibitors affect the expression of the type III secretion system (T3SS) of <i>Escherichia coli</i> O157:H7 in liquid culture and when the bacteria are attached to bovine epithelial cells. The inhibition of T3SS expression resulted in a reduction in the capacity of the bacteria to form attaching and effacing lesions. Our results show a marked variation in the ability of four structurally-related compounds to inhibit the T3SS of a panel of isolates. Using transcriptomics, we provide a comprehensive analysis of the conserved- and inhibitor-specific transcriptional responses to the four compounds. These analyses of gene expression show that numerous virulence genes, located on horizontally-acquired DNA elements, are affected by the compounds but the number of genes significantly affected varied markedly between the compounds. Overall, we highlight the importance of assessing the effect of such "anti-virulence" agents on a range of isolates and discuss the possible mechanisms which may lead to the co-ordinate down-regulation of horizontally acquired virulence genes

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease

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Workshop on Managing Agriculture in Changing Climate organized by CAZRI, Jodhpur.Not AvailableNot Availabl

Behavioural interventions to address rational use of antibiotics in outpatient settings of low-income and lower-middle-income countries

Objectives To explore the current evidence on interventions to influence antibiotic prescribing behaviour of health professionals in outpatient settings in low-income and lower-middle-income countries, an underrepresented area in the literature.Methods The systematic review protocol for this study was registered in PROSPERO (CRD42020170504). We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies relating to antibiotic prescribing of health professionals in outpatient settings in low-income and lower-middle-income countries. Behavioural interventions were classified as persuasive, enabling, restrictive, structural or bundle (mix of different interventions). In total, 3,514 abstracts were screened and 42 studies were selected for full-text review, with 13 studies included in the final narrative synthesis.Results Of the 13 included studies, five were conducted in Vietnam, two in Sudan, two in Tanzania, two in India and two in Kenya. All studies were conducted in the outpatient or ambulatory setting: eight took place in primary health centres, two in private clinics and three in pharmacies. Our review found that enabling or educational interventions alone may not be sufficient to overcome the ingrained incentives to link revenue generation to sales of antibiotics, and hence, their inappropriate prescription or misuse. Bundle interventions appear to be very effective at changing prescription behaviour among healthcare providers, including drug sellers and pharmacists.Conclusions Multi-faceted bundle interventions that combine regulation enforcement with face-to-face education and peer influence may be more effective than educational interventions alone at curbing inappropriate antibiotic use

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Not AvailableTechnical bulletin on Sewan grass (Lasiurus scindicus)Not Availabl