Wide variation in susceptibility of transmitted/founder HIV-1 subtype C Isolates to protease inhibitors and association with in vitro replication efficiency

© 2016 The Author(s).The gag gene is highly polymorphic across HIV-1 subtypes and contributes to susceptibility to protease inhibitors (PI), a critical class of antiretrovirals that will be used in up to 2 million individuals as second-line therapy in sub Saharan Africa by 2020. Given subtype C represents around half of all HIV-1 infections globally, we examined PI susceptibility in subtype C viruses from treatment-naïve individuals. PI susceptibility was measured in a single round infection assay of full-length, replication competent MJ4/gag chimeric viruses, encoding the gag gene and 142 nucleotides of pro derived from viruses in 20 patients in the Zambia-Emory HIV Research Project acute infection cohort. Ten-fold variation in susceptibility to PIs atazanavir and lopinavir was observed across 20 viruses, with EC50 s ranging 0.71-6.95 nM for atazanvir and 0.64-8.54 nM for lopinavir. Ten amino acid residues in Gag correlated with lopinavir EC50 (p < 0.01), of which 380 K and 389I showed modest impacts on in vitro drug susceptibility. Finally a significant relationship between drug susceptibility and replication capacity was observed for atazanavir and lopinavir but not darunavir. Our findings demonstrate large variation in susceptibility of PI-naïve subtype C viruses that appears to correlate with replication efficiency and could impact clinical outcomes

Evaluation of growth methods for the heteroepitaxy of non-polar (1120) GAN on sapphire by MOVPE

Non-polar a-plane gallium nitride (GaN) lms have been grown on r-plane (1102) sapphire by metal organic vapour phase epitaxy (MOVPE). A total of ve in-situ defect reduction techniques for a-plane GaN are compared, including two variants with a low temperature GaN nucleation layer (LTNL) and three variants without LTNL, in which the high- temperature growth of GaN is performed directly on the sapphire using various crystallite sizes. The material quality is investigated by photoluminescence (PL), x-ray di raction, cathodoluminescence, atomic force and optical microscopy. It is found that all layers are anisotropically strained with threading dislocation densities over 109 cm2. The PL spectrum is typically dominated by emission from basal plane stacking faults. Overall, growth techniques without LTNL do not yield any particular improvement and even result in the creation of new defects, ie. inversion domains, which are seldom observed if a low temperature GaN nucleation layer is used. The best growth method uses a LTNL combined with a single silicon nitride interlayer.This work is supported by the Engineering and Physical Sciences Research Council (United Kingdom) under EP/J003603/1 and EP/H0495331. The European Research Council has also provided nancial support under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 279361 (MACONS).This is the final published version, also available from Elsevier at: http://dx.doi.org/10.1016/j.jcrysgro.2014.09.00

Quantum oscillations in the anomalous phase in Sr3Ru2O7

This is the final version. Available from American Physical Society via the DOI in this recordWe report measurements of quantum oscillations detected in the putative nematic phase of Sr3Ru2O7. Improvements in sample purity enabled the resolution of small amplitude de Haas-van Alphen (dHvA) oscillations between two first order metamagnetic transitions delimiting the phase. Two distinct frequencies were observed, whose amplitudes follow the normal Lifshitz-Kosevich profile. Variations of the dHvA frequencies are explained in terms of a chemical potential shift produced by reaching a peak in the density of states, and an anomalous field dependence of the oscillatory amplitude provides information on domains. © 2009 The American Physical Society.Engineering and Physical Sciences Research Council (EPSRC

Quantum oscillations near the metamagnetic transition in Sr3Ru2O7

This is the final version. Available from American Physical Society via the DOI in this recordWe report a detailed investigation of quantum oscillations in Sr 3 Ru2 O7, observed inductively (the de Haas-van Alphen effect) and thermally (the magnetocaloric effect). Working at fields from 3 to 18 T allowed us to straddle the metamagnetic transition region and probe the low- and high-field Fermi liquids. The observed frequencies are strongly field dependent in the vicinity of the metamagnetic transition, and there is evidence for magnetic breakdown. We also present the results of a comprehensive rotation study. The most surprising result concerns the field dependence of the measured quasiparticle masses. Contrary to conclusions previously drawn by some of us as a result of a study performed with a much poorer signal-to-noise ratio, none of the five Fermi-surface branches for which we have good field-dependent data gives evidence for a strong-field dependence of the mass. The implications of these experimental findings are discussed. © 2010 The American Physical Society.Engineering and Physical Sciences Research Council (EPSRC

Tailoring Three-Point Functions and Integrability III. Classical Tunneling

We compute three-point functions between one large classical operator and two large BPS operators at weak coupling. We consider operators made out of the scalars of N=4 SYM, dual to strings moving in the sphere. The three-point function exponentiates and can be thought of as a classical tunneling process in which the classical string-like operator decays into two classical BPS states. From an Integrability/Condensed Matter point of view, we simplified inner products of spin chain Bethe states in a classical limit corresponding to long wavelength excitations above the ferromagnetic vacuum. As a by-product we solved a new long-range Ising model in the thermodynamic limit.Comment: 37 pages, 10 figure

Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20–37 kg/m2). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min−1.m−2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR

Theoretical and experimental analysis of the photoluminescence and photoluminescence excitation spectroscopy spectra of m\textit{m}-plane InGaN/GaN quantum wells

We present a combined theoretical and experimental analysis of the optical properties of $\textit{m}$-plane InGaN/GaN quantum wells. The sample was studied by photoluminescence and photoluminescence excitation spectroscopy at low temperature. The spectra show a large Stokes shift between the lowest exciton peak in the excitation spectra and the peak of the photoluminescence spectrum. This behavior is indicative of strong carrier localization effects. These experimental results are complemented by tight-binding calculations, accounting for random alloy fluctuations and Coulomb effects. The theoretical data explain the main features of the experimental spectra. Moreover, by comparison with calculations based on a virtual crystal approximation, the importance of carrier localization effects due to random alloy fluctuations is explicitly shown.This work was supported by Science Foundation Ireland (Project No. 13/SIRG/2210) and the United Kingdom Engineering and Physical Sciences Research Council (Grant Agreement Nos. EP\J001627\1 and EP\J003603\1). S.S. acknowledges computing resources provided by the SFI/HEA Irish Centre for High-End Computing. R.A.O. and F.T. acknowledge the support of the European Research Council under the European Community's 7th Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 279361 (MACONS)

Defining the key wintering habitats in the Sahel for declining African-Eurasian migrants using expert assessment

SummaryThe Sahel in West Africa is a major wintering area for many western Palearctic migrants. The breeding populations of many of these have declined over the past 50 years. However, there have been few intensive field studies on migrant ecology in the Sahel and these were generally within a very restricted area. Consequently our knowledge of the distribution of species within this extensive area and the habitat associations of these species is limited. Understanding these habitat associations is essential for the effective conservation management of populations. We brought together a group of experts and consulted a wider group by email to assess the main Sahelian habitat types used by 68 African-Eurasian migrant bird species. Those species that showed strongest declines during 1970–1990 were associated with more open habitats than those newly declining during 1990–2000, when declining species were associated with habitats with more shrubs and trees. Populations of species that winter in the Sahel are generally stable or increasing now as rainfall has increased and is now near the long-term average for the Sahel. Those which use the Sahel only as a staging area are, in many cases, in rapid decline at present.We would like to thank Andy Clements, Paul Donald, Lincoln Fishpool and Mike Mortimore for contributing to the workshop and Peter Jones, Ian Newton, Volker Salewski, Tim Wacher, Eddy Wymenga and Leo Zwarts for useful comments by email on draft habitat importance scores. This study was funded by the Newton Trust and the Cambridge Conservation Initiative Collaborative Fund, supported by Arcadia. WJS is funded by Arcadia.This is the accepted manuscript of a paper published in Bird Conservation International, Volume 24, Issue 04, December 2014, pp 477-491, DOI: http://dx.doi.org/10.1017/S0959270913000531, Published online: 24 February 201

Decreasing intensity of open-ocean convection in the Greenland and Iceland seas

The air–sea transfer of heat and fresh water plays a critical role in the global climate system. This is particularly true for the Greenland and Iceland seas, where these fluxes drive ocean convection that contributes to Denmark Strait overflow water, the densest component of the lower limb of the Atlantic Meridional Overturning Circulation (AMOC). Here we show that the wintertime retreat of sea ice in the region, combined with different rates of warming for the atmosphere and sea surface of the Greenland and Iceland seas, has resulted in statistically significant reductions of approximately 20% in the magnitude of the winter air–sea heat fluxes since 1979. We also show that modes of climate variability other than the North Atlantic Oscillation (NAO) are required to fully characterize the regional air–sea interaction. Mixed-layer model simulations imply that further decreases in atmospheric forcing will exceed a threshold for the Greenland Sea whereby convection will become depth limited, reducing the ventilation of mid-depth waters in the Nordic seas. In the Iceland Sea, further reductions have the potential to decrease the supply of the densest overflow waters to the AMOC

Emergent Properties of Tumor Microenvironment in a Real-life Model of Multicell Tumor Spheroids

Multicellular tumor spheroids are an important {\it in vitro} model of the pre-vascular phase of solid tumors, for sizes well below the diagnostic limit: therefore a biophysical model of spheroids has the ability to shed light on the internal workings and organization of tumors at a critical phase of their development. To this end, we have developed a computer program that integrates the behavior of individual cells and their interactions with other cells and the surrounding environment. It is based on a quantitative description of metabolism, growth, proliferation and death of single tumor cells, and on equations that model biochemical and mechanical cell-cell and cell-environment interactions. The program reproduces existing experimental data on spheroids, and yields unique views of their microenvironment. Simulations show complex internal flows and motions of nutrients, metabolites and cells, that are otherwise unobservable with current experimental techniques, and give novel clues on tumor development and strong hints for future therapies.Comment: 20 pages, 10 figures. Accepted for publication in PLOS One. The published version contains links to a supplementary text and three video file