Deciphering interplay between Salmonella invasion effectors

Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction

Pathological and ecological host consequences of infection by an introduced fish parasite

The infection consequences of the introduced cestode fish parasite Bothriocephalus acheilognathi were studied in a cohort of wild, young-of-the-year common carp Cyprinus carpio that lacked co-evolution with the parasite. Within the cohort, parasite prevalence was 42% and parasite burdens were up to 12% body weight. Pathological changes within the intestinal tract of parasitized carp included distension of the gut wall, epithelial compression and degeneration, pressure necrosis and varied inflammatory changes. These were most pronounced in regions containing the largest proportion of mature proglottids. Although the body lengths of parasitized and non-parasitized fish were not significantly different, parasitized fish were of lower body condition and reduced weight compared to non-parasitized conspecifics. Stable isotope analysis (δ15N and δ13C) revealed trophic impacts associated with infection, particularly for δ15N where values for parasitized fish were significantly reduced as their parasite burden increased. In a controlled aquarium environment where the fish were fed ad libitum on an identical food source, there was no significant difference in values of δ15N and δ13C between parasitized and non-parasitized fish. The growth consequences remained, however, with parasitized fish growing significantly slower than non-parasitized fish, with their feeding rate (items s−1) also significantly lower. Thus, infection by an introduced parasite had multiple pathological, ecological and trophic impacts on a host with no experience of the parasite

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

An observational, cohort, multi-centre, open label phase IV extension study comparing preschool DTAP-IPV booster vaccine responses in children whose mothers were randomised to one of two pertussis-containing vaccines or received no pertussis-containing vaccine in pregnancy in England.

An antenatal pertussis vaccination programme was introduced in 2012 in the UK in the context of a national outbreak of pertussis. It has been shown that a lower antibody response to primary immunisation can be seen for certain pertussis antigens in infants born to women who received pertussis-containing antenatal vaccines, a phenomenon known as blunting. The longer-term impact of this has not been documented previously, and accordingly was evaluated in this study. Children were predominantly recruited from a previous study in which their mothers had received acellular pertussis-containing antenatal vaccines (dTaP3-IPV [diphtheria toxoid, tetanus toxoid, three antigen acellular pertussis and inactivated polio] or dTaP5-IPV [diphtheria toxoid, tetanus toxoid, five antigen acellular pertussis and inactivated polio]), or no pertussis-containing vaccine. Blood samples were obtained prior to and one month after the acellular pertussis-containing preschool booster (dTaP5-IPV) was given at around age 3 years 4 months. Pre- and post-booster immunoglobulin G (IgG) geometric mean concentrations (GMCs) against pertussis toxin, filamentous haemagglutinin, fimbriae 2 & 3, and pertactin, were compared. Prior to the receipt of the preschool booster, there was no difference in the IgG GMCs against pertussis-specific antigens between children born to women vaccinated with dTaP3-IPV and dTaP5-IPV; however, IgG GMCs against pertussis toxin were significantly lower in children born to women vaccinated with dTaP3-IPV compared with children born to unvaccinated women (geometric mean ratio 0.42 [95 % CI 0.22-0.78], p = 0.03). One month after the receipt of the preschool booster there was no differences between the groups. The blunting effect of antenatal pertussis vaccine on pertussis responses in children can persist until preschool age, although it is overcome by the administration of a booster dose. ClinicalTrials.gov registration number: NCT03578120

Mindfulness-based interventions for young offenders: a scoping review

Youth offending is a problem worldwide. Young people in the criminal justice system have frequently experienced adverse childhood circumstances, mental health problems, difficulties regulating emotions and poor quality of life. Mindfulness-based interventions can help people manage problems resulting from these experiences, but their usefulness for youth offending populations is not clear. This review evaluated existing evidence for mindfulness-based interventions among such populations. To be included, each study used an intervention with at least one of the three core components of mindfulness-based stress reduction (breath awareness, body awareness, mindful movement) that was delivered to young people in prison or community rehabilitation programs. No restrictions were placed on methods used. Thirteen studies were included: three randomized controlled trials, one controlled trial, three pre-post study designs, three mixed-methods approaches and three qualitative studies. Pooled numbers (n = 842) comprised 99% males aged between 14 and 23. Interventions varied so it was not possible to identify an optimal approach in terms of content, dose or intensity. Studies found some improvement in various measures of mental health, self-regulation, problematic behaviour, substance use, quality of life and criminal propensity. In those studies measuring mindfulness, changes did not reach statistical significance. Qualitative studies reported participants feeling less stressed, better able to concentrate, manage emotions and behaviour, improved social skills and that the interventions were acceptable. Generally low study quality limits the generalizability of these findings. Greater clarity on intervention components and robust mixed-methods evaluation would improve clarity of reporting and better guide future youth offending prevention programs

Successful treatment of tracheal stenosis by rigid bronchoscopy and topical mitomycin C: a case report

Tracheal stenosis is a known complication of prolonged intubation. It is difficult to treat and traditional surgical approach is associated with significant risk and complications. Recurrent stenosis due to granulation tissue necessitates repeated procedures. We describe a case of short web-like tracheal stenosis (concentric membranous stenosis less than 1 cm in length without associated cartilage damage) managed by a minimally invasive thoracic endoscopic approach. Topical application of Mitomycin C, a potent fibroblast inhibitor reduces granulation tissue formation and prevents recurrence

Using Dried Blood Spots for a Sero-Surveillance Study of Maternally Derived Antibody against Group B Streptococcus.

Vaccination during pregnancy could protect women and their infants from invasive Group B Streptococcus (GBS) disease. To understand if neonatal dried blood spots (DBS) can be used to determine the amount of maternally derived antibody that protects infants against invasive GBS disease, a retrospective case-control study was conducted in England between 1 April 2014 and 30 April 2015. The DBS of cases with invasive GBS disease (n = 61) were matched with healthy controls (n = 125). The haematocrit, DBS storage temperature, freeze-thaw cycle, and paired serum/DBS studies were set up to optimise the antibody assessment. The samples were analysed using a multiplex immunoassay, and the results were assessed using parametric and nonparametric tests. Antibody concentrations were stable at haematocrits of up to 50% but declined at 75%. DBS storage at room temperature was stable for three months compared with storage from collection at -20 °C and rapidly degraded thereafter. Total IgG levels measured in DBS and paired serum showed a good correlation (r2 = 0.99). However, due to suboptimal storage conditions, no difference was found in the GBS IgG levels between DBS samples from cases and controls. We have demonstrated a proof of concept that assays utilising DBS for assessing GBS serotype-specific antibodies in infants is viable. This method could be used to facilitate future large sero-correlate studies, but DBS samples must be stored at -20 °C for long term preservation of antibody