Boron-Based Inhibitors of the NLRP3 Inflammasome.

NLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Accounting for centre-effects in multicentre trials with a binary outcome - when, why, and how?

BACKGROUND: It is often desirable to account for centre-effects in the analysis of multicentre randomised trials, however it is unclear which analysis methods are best in trials with a binary outcome. METHODS: We compared the performance of four methods of analysis (fixed-effects models, random-effects models, generalised estimating equations (GEE), and Mantel-Haenszel) using a re-analysis of a previously reported randomised trial (MIST2) and a large simulation study. RESULTS: The re-analysis of MIST2 found that fixed-effects and Mantel-Haenszel led to many patients being dropped from the analysis due to over-stratification (up to 69% dropped for Mantel-Haenszel, and up to 33% dropped for fixed-effects). Conversely, random-effects and GEE included all patients in the analysis, however GEE did not reach convergence. Estimated treatment effects and p-values were highly variable across different analysis methods. The simulation study found that most methods of analysis performed well with a small number of centres. With a large number of centres, fixed-effects led to biased estimates and inflated type I error rates in many situations, and Mantel-Haenszel lost power compared to other analysis methods in some situations. Conversely, both random-effects and GEE gave nominal type I error rates and good power across all scenarios, and were usually as good as or better than either fixed-effects or Mantel-Haenszel. However, this was only true for GEEs with non-robust standard errors (SEs); using a robust ‘sandwich’ estimator led to inflated type I error rates across most scenarios. CONCLUSIONS: With a small number of centres, we recommend the use of fixed-effects, random-effects, or GEE with non-robust SEs. Random-effects and GEE with non-robust SEs should be used with a moderate or large number of centres

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Corporate tax: what do stakeholders expect?

Motivated by the ongoing controversy surrounding corporate tax, this article presents a study that explores stakeholder expectations of corporate tax in the context of UK business. We conduct a qualitative analysis of in-depth interviews with representatives of community groups (NGOs/think tanks and special interest groups), as well as interviews with those representing business groups (business leaders and industry representatives). We then identify eight themes that together describe “what” companies need to do, “how” they need to do it, and “why” they need to do it, if they wish to appeal to a wide group of interested parties. We discuss our findings based on the corporate social responsibility literature and propose novel ways for community groups and business groups to connect on the topic of corporate tax, suggesting opportunities and themes for dialogue and potential steps to co-create solutions in a stakeholder society

Impact of technology-based interventions for children and young people with type 1 diabetes on key diabetes self-management behaviours and prerequisites: A systematic review

Background The role of technology in the self-management of type 1 diabetes mellitus (T1DM) among children and young people is not well understood. Interventions should aim to improve key diabetes self-management behaviours (self-management of blood glucose, insulin administration, physical activity and dietary behaviours) and prerequisites (psychological outcomes and HbA1c) highlighted in the UK guidelines of the National Institute for Health and Care Excellence (NICE) for management of T1DM. The purpose was to identify evidence to assess the effectiveness of technological tools in promoting aspects of these guidelines amongst children and young people. Methods A systematic review of English language articles was conducted using the following databases: Web of Science, PubMed, Scopus, NUSearch, SAGE Journals, SpringerLink, Google Scholar, Science Direct, Sport Discus, Embase, Psychinfo and Cochrane Trials. Search terms included paediatric, type one diabetes, technology, intervention and various synonyms. Included studies examined interventions which supplemented usual care with a health care strategy primarily delivered through a technology-based medium (e.g. mobile phone, website, activity monitor) with the aim of engaging children and young people with T1DM directly in their diabetes healthcare. Studies did not need to include a comparator condition and could be randomised, non-randomised or cohort studies but not single-case studies. Results Of 30 included studies (21 RCTs), the majority measured self-monitoring of blood glucose monitoring (SMBG) frequency, clinical indicators of diabetes self-management (e.g. HbA1c) and/or psychological or cognitive outcomes. The most positive findings were associated with technology-based health interventions targeting SMBG as a behavioural outcome, with some benefits found for clinical and/or psychological diabetes self-management outcomes. Technological interventions were well accepted by children and young people. For the majority of included outcomes, clinical relevance was deemed to be little or none. Conclusions More research is required to assess which elements of interventions are most likely to produce beneficial behavioural outcomes. To produce clinically relevant outcomes, interventions may need to be delivered for at least 1 year and should consider targeting individuals with poorly managed diabetes. It is not possible to determine the impact of technology-based interventions on insulin administration, dietary habits and/or physical activity behaviour due to lack of evidence

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201