Selectivity of pyoverdine recognition by the FpvA receptor of Pseudomonas aeruginosa from molecular dynamics simulations

International audienceThe Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism

Racecadotril for acute diarrhoea in children: systematic review and meta-analyses

OBJECTIVE Racecadotril is an antisecretory agent that can prevent fluid/electrolyte depletion from the bowel as a result of acute diarrhoea, without affecting intestinal motility. An up-to-date systematic review is indicated to summarise the evidence on Racecadotril for the treatment of acute diarrhoea in children. DESIGN A Cochrane format systematic review of Randomised controlled trials (RCTs). Data extraction and assessment of methodological quality were performed independently by two reviewers. Methodological quality was assessed using the Cochrane risk of bias tool. PATIENTS Children with acute diarrhoea, as defined by the primary studies. INTERVENTIONS RCTs comparing racecadotril to placebo or other interventions. MAIN OUTCOME MEASURS Duration of illness, stool output/volume and adverse events. RESULTS Seven RCTs were included. Five comparing racecadotril with placebo or no intervention, one with pectin / caolin and one with loperamide. Moderate to high risk of bias was present in all studies. There was no significant difference in efficacy or adverse events between racecadotril to loperamide. Meta-analysis of 3 studies with 642 participants showed significantly shorter duration of symptoms with racecadotril compared to placebo (Mean Difference (MD) -53.48 hours, 95% CI -65.64 to -41.33,). Meta-analysis of 5 studies with 949 participants showed no significant difference in adverse events between racecadotril and placebo (Risk Ratio (RR) 0.99, 95% CI 0.73 to 1.34). CONCLUSIONS There is some evidence that racecadotril is more effective than placebo or no intervention in reducing the duration of illness and stool output in children with acute diarrhoea. However, the overall quality of the evidence is limited due to sparse data, heterogeneity and risk of bias. Racecadotril appears safe and well tolerate

Complex differences in infection rates between ethnic groups in Scotland: a retrospective, national census-linked cohort study of 1.65 million cases

Background Ethnicity can influence susceptibility to infection, as COVID-19 has shown. Few countries have systematically investigated ethnic variations in infection. Methods We linked the Scotland 2001 Census, including ethnic group, to national databases of hospitalizations/deaths and serological diagnoses of bloodborne viruses for 2001–2013. We calculated age-adjusted rate ratios (RRs) in 12 ethnic groups for all infections combined, 15 infection categories, and human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses. Results We analysed over 1.65 million infection-related hospitalisations/deaths. Compared with White Scottish, RRs for all infections combined were 0.8 or lower for Other White British, Other White and Chinese males and females, and 1.2–1.4 for Pakistani and African males and females. Adjustment for socioeconomic status or birthplace had little effect. RRs for specific infection categories followed similar patterns with striking exceptions. For HIV, RRs were 136 in African females and 14 in males; for HBV, 125 in Chinese females and 59 in males, 55 in African females and 24 in males; and for HCV, 2.3–3.1 in Pakistanis and Africans. Conclusions Ethnic differences were found in overall rates and many infection categories, suggesting multiple causative pathways. We recommend census linkage as a powerful method for studying the disproportionate impact of COVID-19

Pilot study linking primary care records to Census, cardiovascular hospitalization and mortality data in Scotland: feasibility, utility and potential

Background There are substantial ethnic variations in the risk of cardiovascular disease (CVD)-related hospitalization and mortality in Scotland. We piloted extracting and linking primary care risk factors to Scottish Census and health data, to test the feasibility of further investigating these variations.Methods Data extracted from 10 general practices were linked at individual level to Census and hospitalization/death records. Linkage rates, reasons for non-linkage and completeness of primary care data were examined. CVD relative risks were calculated, adjusting for age, socioeconomic status and primary care-derived risk factors.Results Practice enrolment and data extraction proved challenging. Primary care records for 52 975 (55.2%) people were linked to Census data. Completeness and validity of risk variables were similar across ethnic groups. A total of 48 325 (91.2%) records had a valid smoking status recorded and 2900 (5.5%) people had a primary care record of diabetes. Ethnic-specific adjusted estimates of CVD risk were plausible and consistent with previous work.Conclusions Risk factor data extracted from primary care were of good quality and successfully linked to national Census records. Given further methodological refinement, this method illustrates the potential value of linkage using national primary care datasets to contribute to public health surveillance and research.<br/

A newly developed genetic sex marker and its application to understanding chemically induced feminisation in roach (Rutilus rutilus )

This is the final version. Available on open access from Wiley via the DOI in this record.Oestrogenic wastewater treatment works (WwTW) effluents discharged into UK rivers have been shown to affect sexual development, including inducing intersex, in wild roach (Rutilus rutilus). This can result in a reduced breeding capability with potential population level impacts. In the absence of a sex probe for roach it has not been possible to confirm whether intersex fish in the wild arise from genetic males or females, or whether sex reversal occurs in the wild, as this condition can be induced experimentally in controlled exposures to WwTW effluents and a steroidal oestrogen. Using restriction site‐associated DNA sequencing (RAD‐seq), we identified a candidate for a genetic sex marker and validated this marker as a sex probe through PCR analyses of samples from wild roach populations from non‐polluted rivers. We also applied the sex marker to samples from roach exposed experimentally to oestrogen and oestrogenic effluents to confirm suspected phenotypic sex reversal from males to females in some treatments, and also that sex‐reversed males are able to breed as females. We then show, unequivocally, that intersex in wild roach populations results from feminisation of males, but find no strong evidence for complete sex reversal in wild roach at river sites contaminated with oestrogens. The discovered marker has utility for studies in roach on chemical effects, wild stock assessments, and reducing the number of fish used where only one sex is required for experimentation. Furthermore, we show that the marker can be applied non‐destructively using a fin clip or skin swab, with animal welfare benefits.Natural Environmental Research Council (NERC)Department for the Environmental Food and Rural AffairsUniversity of Exete

Life expectancy of different ethnic groups using death records linked to population census data for 4.62 million people in Scotland

Background: Few countries record the data needed to estimate life expectancy by ethnic group. Such information is helpful in assessing the extent of health inequality. Method: Life tables were created using 3 years of deaths (May 2001–April 2004) linked to Scottish 2001 Census data for 4.62 million individuals with self-reported ethnicity. We created 8 ethnic groups based on the census definitions, each with at least 5000 individuals and 40 deaths. Life expectancy at birth was calculated using the revised Chiang method. Results: The life expectancy of White Scottish males at birth was 74.7 years (95% CI 74.6 to 74.8), similar to Mixed Background (73.0; 70.2 to 75.8) and White Irish (75.0; 74.0 to 75.9), but shorter than Indian (80.9; 78.4 to 83.4), Pakistani (79.3; 76.9 to 81.6), Chinese (79.0; 76.5 to 81.5), Other White British (78.9; 78.6 to 79.2) and Other White (77.2; 76.4 to 78.1). The life expectancy of White Scottish females was 79.4 years (79.3 to 79.5), similar to mixed background (79.3; 76.6 to 82.0), but shorter than Pakistani (84.6; 82.0 to 87.3), Chinese (83.4; 81.1 to 85.7), Indian (83.3; 80.7 to 85.9), Other White British (82.6; 82.3 to 82.9), other White (82.0; 81.3 to 82.8) and White Irish (81; 80.2 to 81.8). Conclusions: Males and females in most of the larger ethnic minority groups in Scotland have longer life expectancies than the majority White Scottish population

Ether bond cleavage of a phenylcoumaran beta-5 lignin model compound and polymeric lignin catalysed by a LigE-type etherase from Agrobacterium sp

A LigE-type beta-etherase enzyme from lignin-degrading Agrobacterium sp. has been identified, which assists degradation of polymeric lignins. Testing against lignin dimer model compounds revealed that it does not catalyse the previously reported reaction of Sphingobium SYK-6 LigE, but instead shows activity for a β-5 phenylcoumaran lignin dimer. The reaction products did not contain glutathione, indicating a catalytic role for reduced glutathione in this enzyme. Three reaction products were identified: the major product was a cis-stilbene arising from C−C fragmentation involving loss of formaldehyde; two minor products were an alkene arising from elimination of glutathione, and an oxidised ketone, proposed to arise from reaction of an intermediate with molecular oxygen. Testing of the recombinant enzyme against a soda lignin revealed the formation of new signals by two-dimensional NMR analysis, whose chemical shifts are consistent with the formation of a stilbene unit in polymeric lignin

Syndromic (phenotypic) diarrhea in early infancy

Syndromic diarrhea (SD), also known as phenotypic diarrhea (PD) or tricho-hepato-enteric syndrome (THE), is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN). To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000–400,000 live births in Western Europe. Ethnic origin does not appear to be associated with SD. Infants are born small for gestational age and present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hairs are woolly, easily removed and poorly pigmented. Severe and persistent diarrhea starts within the first 6 months of life (≤ 1 month in most cases) and is accompanied by severe malabsorption leading to early and relentless protein energy malnutrition with failure to thrive. Liver disease affects about half of patients with extensive fibrosis or cirrhosis. There is currently no specific biochemical profile, though a functional T-cell immune deficiency with defective antibody production was reported. Microscopic analysis of the hair show twisted hair (pili torti), aniso- and poilkilotrichosis, and trichorrhexis nodosa. Histopathological analysis of small intestine biopsy shows non-specific villous atrophy with low or no mononuclear cell infiltration of the lamina propria, and no specific histological abnormalities involving the epithelium. The etiology remains unknown. The frequent association of the disorder with parental consanguinity and/or affected siblings suggests a genetic origin with an autosomal recessive mode of transmission. Early management consists of total PN. Some infants have a rather milder phenotype with partial PN dependency or require only enteral feeding. Prognosis of this syndrome is poor, but most patients now survive, and about half of the patients may be weaned from PN at adolescence, but experience failure to thrive and final short stature

Transcriptome profiling during a natural host-parasite interaction

BACKGROUND: Infection outcome in some coevolving host-pathogens is characterised by host-pathogen genetic interactions, where particular host genotypes are susceptible only to a subset of pathogen genotypes. To identify candidate genes responsible for the infection status of the host, we exposed a Daphnia magna host genotype to two bacterial strains of Pasteuria ramosa, one of which results in infection, while the other does not. At three time points (four, eight and 12 h) post pathogen exposure, we sequenced the complete transcriptome of the hosts using RNA-Seq (Illumina). RESULTS: We observed a rapid and transient response to pathogen treatment. Specifically, at the four-hour time point, eight genes were differentially expressed. At the eight-hour time point, a single gene was differentially expressed in the resistant combination only, and no genes were differentially expressed at the 12-h time point. CONCLUSIONS: We found that pathogen-associated transcriptional activity is greatest soon after exposure. Genome-wide resistant combinations were more likely to show upregulation of genes, while susceptible combinations were more likely to be downregulated, relative to controls. Our results also provide several novel candidate genes that may play a pivotal role in determining infection outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1838-0) contains supplementary material, which is available to authorized users