The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies

On the impact of the Bristol ChemLabS’ outreach programme on admissions to the School of Chemistry

Analysis of the average number of applicants received from schools that engaged in the Bristol ChemLabS Outreach program prior to a student‟s application with those that did not engage, shows a significant increase in applicants from engaged schools. The significance is weaker when just Post 16 students are considered but this is almost certainly due to a smaller sample size. When this analysis was inspected in terms of the distance of the school from the University of Bristol, there was an increase in the number of applicants from engaged schools irrespective of distance. However, a statistically significant increase was observed for schools within 50 miles of the University from an analysis of just Post 16 students. Students who applied to the department from an engaged school were more likely to accept an offer and also to make the department their firm acceptance. A slightly higher number of applications that were rejected came from engaged schools too. There are two possible reasons; first, the engagement may have encouraged more students who did not have the required entry qualifications. Second, during the period of analysis, the overall entry grades went up by one grade each year. Such a dramatic rise was probably the reason for the slightly elevated numbers

Use of standardized body composition measurements and malnutrition screening tools to detect malnutrition risk and predict clinical outcomes in children with chronic conditions

Background: Better tools are needed to diagnose and identify children at risk of clinical malnutrition. / Objectives: We aimed to compare body composition (BC) and malnutrition screening tools (MSTs) for detecting malnutrition on admission; and examine their ability to predict adverse clinical outcomes [increased length of stay (LOS) and complications] in complex pediatric patients. / Methods: This was a prospective study in children 5–18 y old admitted to a tertiary pediatric hospital (n = 152). MSTs [Pediatric Yorkhill Malnutrition Score (PYMS), Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP), and Screening Tool for Risk of Impaired Nutritional Status and Growth (STRONGkids)] were completed on admission. Weight, height, and BC [fat mass (FM) and lean mass (LM) by DXA] were measured (n = 118). Anthropometry/BC and MSTs were compared with each other and with clinical outcomes. / Results: Subjects were significantly shorter with low LM compared to reference data. Depending on the diagnostic criteria used, 3%–17% were classified as malnourished. Agreement between BC/anthropometric parameters and MSTs was poor. STAMP and STRONGkids identified children with low weight, LM, and height. PYMS, and to a lesser degree STRONGkids, identified children with increased LOS, as did LM compared with weight or height. Patients with complications had lower mean ± SD LM SD scores (−1.38 ± 1.03 compared with −0.74 ± 1.40, P < 0.05). In multivariable models, PYMS high risk and low LM were independent predictors of increased LOS (OR: 3.76; 95% CI: 1.36, 10.35 and OR: 3.69; 95% CI: 1.24, 10.98, respectively). BMI did not predict increased LOS or complications. / Conclusions: LM appears better than weight and height for predicting adverse clinical outcomes in this population. BMI was a poor diagnostic parameter. MSTs performed differently in associations to BC/anthropometry and clinical outcomes. PYMS and LM provided complementary information regarding LOS. Studies on specific patient populations may further clarify the use of these tools and measurements

Discovery of a bright eclipsing cataclysmic variable

We report on the discovery of J0644+3344, a bright deeply eclipsing cataclysmic variable (CV) binary. Spectral signatures of both binary components and an accretion disk can be seen at optical wavelengths. The optical spectrum shows broad H I, He I, and He II accretion disk emission lines with deep narrow absorption components from H I, He I, Mg II and Ca II. The absorption lines are seen throughout the orbital period, disappearing only during primary eclipse. These absorption lines are either the the result of an optically-thick inner accretion disk or from the photosphere of the primary star. Radial velocity measurements show that the H I, He I, and Mg II absorption lines phase with the the primary star, while weak absorption features in the continuum phase with the secondary star. Radial velocity solutions give a 150+/-4 km/s semi-amplitude for the primary star and 192.8+/-5.6 km/s for the secondary. The individual stellar masses are 0.63-0.69 Mdot for the primary and 0.49-0.54 Mdot for the secondary. The bright eclipsing nature of this binary has helped provide masses for both components with an accuracy rarely achieved for CVs. This binary most closely resembles a nova-like UX UMa or SW Sex type of CV. J0644+3344, however, has a longer orbital period than most UX UMa or SW Sex stars. Assuming an evolution toward shorter orbital periods, J0644+3344 is therefore likely to be a young interacting binary. The secondary star is consistent with the size and spectral type of a K8 star, but has an M0 mass.Comment: 10 pages, 13 figure, accepted for publication in A&

Ability of enteroaggregative Escherichia coli strains to adhere in vitro to human intestinal mucosa

A collection of 44 enteroaggregative Escherichia coli (EAggEC) strains isolated from infants with diarrhea in India and the United Kingdom were examined for their ability to adhere in vitro to human intestinal mucosa and by electron microscopy for production of putative adherence factors. None of the strains adhered to human duodenal mucosa, and six strains tested did not adhere to ileal mucosa; all 44 strains, however, adhered to human colonic mucosa in localized aggregates. Electron microscopy of infected colonic mucosa indicated fimbrially mediated adhesion of the EAggEC strains. Four morphologically distinct kinds of fimbriae, including a new morphological type of E. coli fimbriae consisting of bundles of fine filaments, were identified among the EAggEC strains; this new type of fimbria was observed in 43 of the 44 EAggEC strains. Forty-three of the 44 EAggEC strains were positive with a DNA probe developed to identify EAggEC, and most of the strains belonged to serotypes unrelated to the other major classes of diarrheic E. coli. These results suggest that EAggEC may be a large-bowel pathogen and colonize the colon by a fimbrially mediated adhesion mechanism

Women, anger, and aggression an interpretative phenomenological analysis

This study reports a qualitative phenomenological investigation of anger and anger-related aggression in the context of the lives of individual women. Semistructured interviews with five women are analyzed using interpretative phenomenological analysis. This inductive approach aims to capture the richness and complexity of the lived experience of emotional life. In particular, it draws attention to the context-dependent and relational dimension of angry feelings and aggressive behavior. Three analytic themes are presented here: the subjective experience of anger, which includes the perceptual confusion and bodily change felt by the women when angry, crying, and the presence of multiple emotions; the forms and contexts of aggression, paying particular attention to the range of aggressive strategies used; and anger as moral judgment, in particular perceptions of injustice and unfairness. The authors conclude by examining the analytic observations in light of phenomenological thinking

Defining critical factors in multi-country studies of assisted reproductive technologies (ART): data from the US and UK health systems

As the worldwide use of assisted reproductive technologies (ART) continues to grow, there is a critical need to assess the safety of these treatment parameters and the potential adverse health effects of their use in adults and their offspring. While key elements remain similar across nations, geographic variations both in treatments and populations make generalizability challenging. We describe and compare the demographic factors between the USA and the UK related to ART use and discuss implications for research. The USA and the UK share some common elements of ART practice and in how data are collected regarding long-term outcomes. However, the monitoring of ART in these two countries each brings strengths that complement each other’s limitations

Pain psychology in the 21st century: lessons learned and moving forward

Background and aims In the spring of 2019, Professor Steven J. Linton, the founder of the Center for Health and Medical Psychology (CHAMP) at Örebro University, Sweden, formally retired. As a tribute to his scholarly work covering decades of influence and inspiration to the field of pain psychology, the research center organized a topical conference titled “Pain in the 21st century: Where do we come from and where are we going?”, which resulted in this state-of the-art synthesis. The aim of this declaration is to highlight lessons learned but not in the least is meant to inspire and guide our continued journey forward, developing pain psychology into the 21st century. Methods Several collaborators of Professor Linton have summarized and reflected on the current state-of-the-art of pain psychology from the perspective of his input to the field, as well as on developments from the last years of advancements in pain psychology. Results The topics have been divided into six themed sections covering the fear avoidance model, transdiagnostics, secondary prevention, risk- and protective factors, communication and contextual factors. The sections cover a broad spectrum, from basic experimental studies, integrating emotion and motivational theories into current theoretical models, to applied research on the effect of early interventions as well as sophisticated emotion-focused treatment models for pain patients with concurrent emotional ill-health. Conclusions There have been major advancements within pain psychology research during the last decades, moving the field towards a more comprehensive picture, taking emotional and motivational aspects into account to understand pain sufferers. Although psychologically informed interventions in general mainly focus on the individual, it has been put forward that pain management is highly influenced by the surrounding environment, including communication with health care providers, and the occupational and social context. Implications Professor Steven J. Linton has been at the forefront of pain psychology research during the last decades, and inspired by his work this journey will continue into the 21st century, with the ultimate goal of enhancing the understanding and treatment for all people suffering from persistent and disabling pain

Association between monosodium glutamate intake and sleep-disordered breathing among Chinese adults with normal body weight

ObjectiveTo assess whether monosodium glutamate (MSG) intake is associated with sleep-disordered breathing (SDB).MethodsData from 1227 Chinese subjects who participated in the Jiangsu Nutrition Study were analyzed. All the participants were examined at two time points (baseline in 2002 and follow-up in 2007). The MSG intake was assessed quantitatively in 2002 and a sleep questionnaire was used to assess snoring and to construct an SDB probability score in 2007. Those within the fifth quintile of the score (highest) were defined as having a high probability of SDB.ResultsThe MSG intake was positively associated with snoring and a high probability of SDB in participants who had a normal body weight but in those who were overweight. A comparison of the extreme quartiles of MSG intake in subjects with a body mass index lower than 23 kg/m² showed an odds ratio of 2.02 (95% confidence interval 1.02-4.00) for snoring and an odds ratio of 3.11 (95% confidence interval 1.10-8.84) for a high probability of SDB. There was a joint effect between MSG and overweight in relation to SDB.ConclusionThe intake of MSG may increase the risk of SDB in Chinese adults with a normal body weight.Zumin Shi, Gary A. Wittert, Baojun Yuan, Yue Dai, Tiffany K. Gill, Gang Hu, Robert Adams, Hui Zuo, Anne W. Taylo

Supercritical water oxidation of dioxins and furans in waste incinerator fly ash, sewage sludge and industrial soil

Three environmental samples containing dioxins and furans have been oxidized in the presence of hydrogen peroxide under supercritical water oxidation conditions. The samples consisted of a waste incinerator fly ash, sewage sludge and contaminated industrial soil. The reactor system was a batch, autoclave reactor operated at temperatures between 350°C and 450°C, corresponding to pressures of ~20-33.5 MPa and with hydrogen peroxide concentrations from 0.0 to 11.25 vol%. Hydrogen peroxide concentration and temperature/pressure had a strong positive effect on the oxidation of dioxins and furans. At the highest temperatures and pressure of supercritical water oxidation of 450°C and 33.5 MPa and with 11.25 vol% of hydrogen peroxide, the destruction efficiencies of the individual polychlorinated dibenzo-ρ-dioxins/polychlorinated dibenzofurans (PCDD/PCDF) isomers were between 90% and 99%. There did not appear to be any significant differences in the PCDD/PCDF destruction efficiencies in relation to the different sample matrices of the waste incinerator fly ash, sewage sludge and contaminated industrial soil