Multiple mantle upwellings in the transition zone beneath the northern East-African Rift system from relative P-wave travel-time tomography

Mantle plumes and consequent plate extension have been invoked as the likely cause of East African Rift volcanism. However, the nature of mantle upwelling is debated, with proposed configurations ranging from a single broad plume connected to the large low-shear-velocity province beneath Southern Africa, the so-called African Superplume, to multiple lower-mantle sources along the rift. We present a new P-wave travel-time tomography model below the northern East-African, Red Sea, and Gulf of Aden rifts and surrounding areas. Data are from stations that span an area from Madagascar to Saudi Arabia. The aperture of the integrated data set allows us to image structures of 100 km length-scale down to depths of 700– 800 km beneath the study region. Our images provide evidence of two clusters of low-velocity structures consisting of features with diameter of 100–200 km that extend through the transition zone, the first beneath Afar and a second just west of the Main Ethiopian Rift, a region with off-rift volcanism. Considering seismic sensitivity to temperature, we interpret these features as upwellings with excess temperatures of 100 6 50 K. The scale of the upwellings is smaller than expected for lower mantle plume sources. This, together with the change in pattern of the low-velocity anomalies across the base of the transition zone, suggests that ponding or flow of deep-plume material below the transition zone may be spawning these upper mantle upwellings

A qualitative evidence synthesis of employees' views of workplace smoking reduction or cessation interventions

Background The need to reduce smoking rates is a recognised public health policy issue in many countries. The workplace offers a potential context for offering smokers’ programmes and interventions to assist smoking cessation or reduction. A qualitative evidence synthesis of employees’ views about such programmes might explain why some interventions appear effective and others not, and can be used to develop evidence-based interventions for this population and setting. Methods A qualitative evidence synthesis of primary research exploring employees’ views about workplace interventions to encourage smoking cessation, including both voluntary programmes and passive interventions, such as restrictions or bans. The method used was theory-based “best fit” framework synthesis. Results Five relevant theories on workplace smoking cessation were identified and used as the basis for an a priori framework. A comprehensive literature search, including interrogation of eight databases, retrieved 747 unique citations for the review. Fifteen primary research studies of qualitative evidence were found to satisfy the inclusion criteria. The synthesis produced an evidence-based conceptual model explaining employees’ experiences of, and preferences regarding, workplace smoking interventions. Conclusion The synthesis suggests that workplace interventions should employ a range of different elements if they are to prove effective in reducing smoking among employees. This is because an employee who feels ready and able to change their behaviour has different needs and preferences from an employee who is not at that stage. Only a multi-faceted intervention can satisfy the requirements of all employees

Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design

β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer’s disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites

"Best fit" framework synthesis: refining the method

Background Following publication of the first worked example of the “best fit” method of evidence synthesis for the systematic review of qualitative evidence in this journal, the originators of the method identified a need to specify more fully some aspects of this particular derivative of framework synthesis. Methods and Results We therefore present a second such worked example in which all techniques are defined and explained, and their appropriateness is assessed. Specified features of the method include the development of new techniques to identify theories in a systematic manner; the creation of an a priori framework for the synthesis; and the “testing” of the synthesis. An innovative combination of existing methods of quality assessment, analysis and synthesis is used to complete the process. This second worked example was a qualitative evidence synthesis of employees’ views of workplace smoking cessation interventions, in which the “best fit” method was found to be practical and fit for purpose. Conclusions The method is suited to producing context-specific conceptual models for describing or explaining the decision-making and health behaviours of patients and other groups. It offers a pragmatic means of conducting rapid qualitative evidence synthesis and generating programme theories relating to intervention effectiveness, which might be of relevance both to researchers and policy-makers

Author Correction: New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

Correction to: Scientific Reports https://doi.org/10.1038/srep29179, published online 14 July 201

Assay platform for clinically relevant metallo-beta-lactamases

Metallo-β-lactamases (MBLs) are a growing threat to the use of almost all clinically used β-lactam antibiotics. The identification of broad-spectrum MBL inhibitors is hampered by the lack of a suitable screening platform, consisting of appropriate substrates and a set of clinically relevant MBLs. We report procedures for the preparation of a set of clinically relevant metallo-β-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (São Paulo MBL), and VIM-2 (Verona integron-encoded MBL)) and the identification of suitable fluorogenic substrates (umbelliferone-derived cephalosporins). The fluorogenic substrates were compared to chromogenic substrates (CENTA, nitrocefin, and imipenem), showing improved sensitivity and kinetic parameters. The efficiency of the fluorogenic substrates was exemplified by inhibitor screening, identifying 4-chloroisoquinolinols as potential pan MBL inhibitors

Delivering NEET policy packages? A decade of NEET policy in England

This article explores the way in which government policy shapes the lives of young people who are not in education, employment or training (NEET). In particular it examines how the concept of NEETs is set within a specific infrastructure and discourse for managing and supporting young people. The article provides a brief history of the NEET concept and NEET initiatives, before moving on to scrutinise the policies of the Coalition Government. A key distinction is made between those policies and practices that seek to prevent young people becoming NEET from those that seek to re-engage those who are NEET. It is argued that the Coalition has drawn on a similar active labour market toolkit to the previous Labour administration, but that this has been implemented with fewer resources and less co-ordination. It concludes that there is little reason to believe that Coalition policy will be any more successful than that of the previous government, and some reason to be concerned that it will lead to young people becoming more entrenched within NEET

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis

Methodology: We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-Angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-Angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis