Essential but partially redundant roles for POU4F1/Brn-3a and POU4F2/Brn-3b transcription factors in the developing heart

Congenital heart defects contribute to embryonic or neonatal lethality but due to the complexity of cardiac development, the molecular changes associated with such defects are not fully understood. Here, we report that transcription factors (TFs) Brn-3a (POU4F1) and Brn-3b (POU4F2) are important for normal cardiac development. Brn-3a directly represses Brn-3b promoter in cardiomyocytes and consequently Brn-3a knockout (KO) mutant hearts express increased Brn-3b mRNA during mid-gestation, which is linked to hyperplastic growth associated with elevated cyclin D1, a known Brn-3b target gene. However, during late gestation, Brn-3b can cooperate with p53 to enhance transcription of pro-apoptotic genes e.g. Bax, thereby increasing apoptosis and contribute to morphological defects such as non-compaction, ventricular wall/septal thinning and increased crypts/fissures, which may cause lethality of Brn-3a KO mutants soon after birth. Despite this, early embryonic lethality in e9.5 double KO (Brn-3a(-/-) : Brn-3b(-/-)) mutants indicate essential functions with partial redundancy during early embryogenesis. High conservation between mammals and zebrafish (ZF) Brn-3b (87%) or Brn-3a (76%) facilitated use of ZF embryos to study potential roles in developing heart. Double morphant embryos targeted with morpholino oligonucleotides to both TFs develop significant cardiac defects (looping abnormalities and valve defects) suggesting essential roles for Brn-3a and Brn-3b in developing hearts

Halal dating: changing relationship attitudes and experiences among young British Muslims

Young Muslims in the UK are making space to gain greater control over their personal lives through the diction of ‘halal’ and ‘haram’ when reflecting on and negotiating personal relationships. This article explores the significance of ‘halal dating’ within the lived experiences and sexual relationships of young British Muslims. It draws upon 56 in-depth interviews conducted with young (16–30 years) British Muslims of Pakistani heritage. This research shows that, contrary to popular stereotype and widespread expectations, many young British Muslims do date, or have dated. By entertaining the idea that certain forms of dating may be halal, these young Muslims are finding and claiming agency to make relationship choices of their own

Predictors of esophageal varices in patients with HBV-related cirrhosis: a retrospective study

<p>Abstract</p> <p>Background</p> <p>All patients with liver cirrhosis are recommended to undergo an evaluation of esophageal varices (EV) to assess their risk of bleeding. Predicting the presence of EV through non-invasive means may reduce a large number of unnecessary endoscopies. This study was designed to develop a predictive model for varices in patients with Hepatitis B virus-related cirrhosis.</p> <p>Methods</p> <p>The retrospective analysis was performed in 146 patients with Hepatitis B virus-related cirrhosis. The data were assessed by univariate analysis and a multivariate logistic regression analysis. In addition, the receiver operating characteristic curves were also applied to calculate and compare the accuracy of the model and other single parameters for the diagnosis of esophageal varices.</p> <p>Results</p> <p>We found the prevalence of EV in patients with Hepatitis B virus-related cirrhosis to be 74.7%. In addition, platelet count, spleen width, portal vein diameter and platelet count/spleen width ratio were significantly associated with the presence of esophageal varices on univariate analysis. A multivariate analysis revealed that only the spleen width and portal vein diameter were independent risk factors. The area under the receiver operating characteristic curve of regression function (RF) model, which was composed of the spleen width and portal vein diameter, was higher than that of the platelet count. With a cut-off value of 0.3631, the RF model had an excellent sensitivity of 87.2% and an acceptable specificity of 59.5% with an overall accuracy of 80.1%.</p> <p>Conclusion</p> <p>Our data suggest that portal vein diameter and spleen width rather than platelet count may predict the presence of varices in patients with Hepatitis B virus-related cirrhosis, and that the RF model may help physicians to identify patients who would most likely benefit from screenings for EV.</p

16S rRNA Gene-based Analysis of Fecal Microbiota from Preterm Infants with and without Necrotizing Enterocolitis

Neonatal necrotizing enterocolitis (NEC) is an inflammatory intestinal disorder affecting preterm infants. Intestinal bacteria play a key role; however no causative pathogen has been identified. The purpose of this study was to determine if there are differences in microbial patterns which may be critical to the development of this disease. Fecal samples from twenty preterm infants, ten with NEC and ten matched controls (including four twin pairs) were obtained from patients in a single site Level III neonatal intensive care unit. Bacterial DNA from individual fecal samples were PCR amplified and subjected to terminal restriction fragment length polymorphism analysis and library sequencing of the 16S rRNA gene to characterize diversity and structure of the enteric microbiota. The distribution of samples from NEC patients distinctly clustered separately from controls. Intestinal bacterial colonization in all preterm infants was notable for low diversity. Patients with NEC had even less diversity, an increase in abundance of Gammaproteobacteria, a decrease in other bacteria species, and had received a higher mean number of previous days of antibiotics. Our results suggest that NEC is associated with severe lack of microbiota diversity which may accentuate the impact of single dominant microorganisms favored by empiric and wide-spread use of antibiotics

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

An essential role for the baseplate protein Gp45 in phage adsorption to Staphylococcus aureus

Despite the importance of phages in driving horizontal gene transfer (HGT) among pathogenic bacteria, the underlying molecular mechanisms mediating phage adsorption to S. aureus are still unclear. Phage φ11 is a siphovirus with a high transducing efficiency. Here, we show that the tail protein Gp45 localized within the φ11 baseplate. Phage φ11 was efficiently neutralized by anti-Gp45 serum, and its adsorption to host cells was inhibited by recombinant Gp45 in a dose-dependent manner. Flow cytometry analysis demonstrated that biotin-labelled Gp45 efficiently stained the wild-type S. aureus cell but not the double knockout mutant ΔtarM/S, which lacks both α- and β-O-GlcNAc residues on its wall teichoic acids (WTAs). Additionally, adsorption assays indicate that GlcNAc residues on WTAs and O-acetyl groups at the 6-position of muramic acid residues in peptidoglycan are essential components of the φ11 receptor. The elucidation of Gp45-involved molecular interactions not only broadens our understanding of siphovirus-mediated HGT, but also lays the groundwork for the development of sensitive affinity-based diagnostics and therapeutics for S. aureus infection