A self-optimised approach to synthesising DEHiBA for advanced nuclear reprocessing, exploiting the power of machine-learning

In an effort to advance the development of hydrometallurgical reprocessing of used nuclear fuel across the globe, this work sets out to explore and identify an optimised, cost effective pathway to synthesise the ligand DEHiBA (N,N-di-(2-ethylhexyl)isobutyramide). Currently, very few chemical suppliers stock and distribute this specialist ligand, designed for selective uranium chelation and extraction from nuclear fuel. The current high cost of DEHiBA therefore restricts access to essential large-scale testing of this promising ligand designed to advance nuclear reprocessing. This work utilises an automated flow reactor platform for the efficient optimisation of four synthetic routes to DEHiBA. These optimisations focus on optimising cost, reagent efficiency, yield, and productivity target functions by exploiting the power of machine-learning algorithms for rapid process development. Ultimately, we have identified an efficient and cost-effective solvent-free route to DEHiBA from isobutyric anhydride and di-2-ethylhexylamine for 99%, at a purity of 76%, and a process mass intensity of 1.29 g g−1, whilst alternative conditions demonstrated productivities >75 kg L−1 h−1, all whilst maintaining a high level of process control with outlet temperatures not exceeding 35 °C

EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling

Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements

IC 4663: the first unambiguous [WN] Wolf-Rayet central star of a planetary nebula

We report on the serendipitous discovery of the first central star of a planetary nebula (PN) that mimics the helium- and nitrogen-rich WN sequence of massive Wolf–Rayet (WR) stars. The central star of IC 4663 (PN G346.2−08.2) is dominated by broad He II and N V emission lines which correspond to a [WN3] spectral type. Unlike previous [WN] candidates, the surrounding nebula is unambiguously a PN. At an assumed distance of 3.5 kpc, corresponding to a stellar luminosity of 4000 L⊙, the V= 16.9 mag central star remains 4–6 mag fainter than the average luminosity of massive WN3 stars even out to an improbable d= 8 kpc. The nebula is typical of PNe with an elliptical morphology, a newly discovered asymptotic giant branch (AGB) halo, a relatively low expansion velocity (vexp= 30 km s−1) and a highly ionized spectrum with an approximately solar chemical abundance pattern. The [WN3] star is hot enough to show Ne VII emission (T*= 140 ± 20 kK) and exhibits a fast wind (v∞= 1900 km s−1), which at d= 3.5 kpc would yield a clumped mass-loss rate of forumla= 1.8 × 10−8 M⊙ yr−1 with a small stellar radius (R*= 0.11 R⊙). Its atmosphere consists of helium (95 per cent), hydrogen (<2 per cent), nitrogen (0.8 per cent), neon (0.2 per cent) and oxygen (0.05 per cent) by mass. Such an unusual helium-dominated composition cannot be produced by any extant scenario used to explain the H-deficiency of post-AGB stars. The O(He) central stars share a similar composition and the discovery of IC 4663 provides the first evidence for a second He-rich/H-deficient post-AGB evolutionary sequence [WN] →O(He). This suggests that there is an alternative mechanism responsible for producing the majority of H-deficient post-AGB stars that may possibly be expanded to include other He-rich/H-deficient stars such as R Coronae Borealis stars and AM Canum Venaticorum stars. The origin of the unusual composition of [WN] and O(He) central stars remains unexplained

Geographical Perspectives on Transport and Ageing

In terms of ageing, we are living in unprecedented times. People across the globe are living longer than ever before and societies are ageing at increasing rates. In low to middle income countries reductions in mortality at young ages have fuelled this growth. A person born today in Brazil, for example, can expect to live 20 years longer than someone born 50 years ago (WHO, 2015). For the first time life expectancy across the globe is over 60 years of age. In high Income countries, someone born now can expect to live up to around 80 years of age on average (ONS, 2015). There are not simply a growing number of older people, but also a growing number of older people as a total percentage of the population due to people living longer and declining birth rates in many countries. Across Europe, for example, people aged over 65 years will account for 29.5% of the population in 2060 compared to around 19% now (EUROSTAT, 2017). The share of those aged 80 years or above across Europe will almost triple by 2060 (EUROSTAT, 2017)The macro level demographics and associated trends mask big differences within the ageing populations. There can be as much as 10 years difference in life expectancy within high income countries, for example in the UK someone born a baby boy born in Kensington and Chelsea has a life expectancy of 83.3 years, compared with a boy born in Glasgow who has a life expectancy of 10 years lower (73.0 years) (ONS, 2015). For newborn baby girls, life expectancy is highest in Chiltern at 86.7 years and 8 years lower Glasgow at 78.5 years (ONS, 2015; NRS, 2016). There is also considerable variation within cities, spatially and socially.This volume brings together contributions from a broad range of human geographers, with different disciplinary perspectives of transport and ageing. This chapter outlines some of the key contemporary issues for an ageing society in terms of transport and mobility, highlights the importance of considering transport and mobility for ageing populations and outlines the contribution that a geographical approach can offer to studies of transport and ageing

Autonomous vehicle interactions in the urban street environment: A research agenda

© ICE Publishing 2018. All rights reserved. The Venturer project is trialling an autonomous vehicle (AV) in the context of use on urban roads. This paper summarises a literature review undertaken to assist in developing a research agenda for the trialling. The first contribution of the paper is a framework of four use scenarios for AVs as follows: (1) fully segregated AV network, (2) motorway or expressway network, (3) typical urban network, (4) shared space. The paper then focuses on a review of the social interactions in the street environment and discusses issues concerning human behaviour in relation to autonomy. The second contribution of the paper is a set of research questions for AV trialling in relation to other road users, including, pedestrians and cyclists, which have emerged from the literature review.

Bayesian Diallel analysis reveals MX1-dependent and MX1-independent effects on response to influenza a virus in mice

Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but the host genetic architecture is not well understood. Here, we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8 × 8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 d postinfection. Heritable effects in aggregate explained ∼57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 postinfection and was consistent with previous reports of antiinfluenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; these additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC, and are also replicated here in a CC recombinant intercross population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies of origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for ∼34% of the phenotypic variance. Implications for future mapping studies are discussed

Propranolol in the treatment of infantile haemangiomas:lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey

Oral propranolol is widely prescribed as first line treatment for infantile haemangiomas (IHs) and anecdotally prescribing practice differs widely between centres