Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 1. Generalized Born

We present an implementation of generalized Born implicit solvent all-atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA enabled NVIDIA graphics processing units (GPUs). We discuss the algorithms that are used to exploit the processing power of the GPUs and show the performance that can be achieved in comparison to simulations on conventional CPU clusters. The implementation supports three different precision models in which the contributions to the forces are calculated in single precision floating point arithmetic but accumulated in double precision (SPDP), or everything is computed in single precision (SPSP) or double precision (DPDP). In addition to performance, we have focused on understanding the implications of the different precision models on the outcome of implicit solvent MD simulations. We show results for a range of tests including the accuracy of single point force evaluations and energy conservation as well as structural properties pertainining to protein dynamics. The numerical noise due to rounding errors within the SPSP precision model is sufficiently large to lead to an accumulation of errors which can result in unphysical trajectories for long time scale simulations. We recommend the use of the mixed-precision SPDP model since the numerical results obtained are comparable with those of the full double precision DPDP model and the reference double precision CPU implementation but at significantly reduced computational cost. Our implementation provides performance for GB simulations on a single desktop that is on par with, and in some cases exceeds, that of traditional supercomputers

Elevated circulating Sclerostin concentrations in individuals with high bone mass, with and without LRP5 mutations.

CONTEXT: The role and importance of circulating sclerostin is poorly understood. High bone mass (HBM) caused by activating LRP5 mutations has been reported to be associated with increased plasma sclerostin concentrations; whether the same applies to HBM due to other causes is unknown. OBJECTIVE: Our objective was to determine circulating sclerostin concentrations in HBM. DESIGN AND PARTICIPANTS: In this case-control study, 406 HBM index cases were identified by screening dual-energy x-ray absorptiometry (DXA) databases from 4 United Kingdom centers (n = 219 088), excluding significant osteoarthritis/artifact. Controls comprised unaffected relatives and spouses. MAIN MEASURES: Plasma sclerostin; lumbar spine L1, total hip, and total body DXA; and radial and tibial peripheral quantitative computed tomography (subgroup only) were evaluated. RESULTS: Sclerostin concentrations were significantly higher in both LRP5 HBM and non-LRP5 HBM cases compared with controls: mean (SD) 130.1 (61.7) and 88.0 (39.3) vs 66.4 (32.3) pmol/L (both P < .001, which persisted after adjustment for a priori confounders). In combined adjusted analyses of cases and controls, sclerostin concentrations were positively related to all bone parameters found to be increased in HBM cases (ie, L1, total hip, and total body DXA bone mineral density and radial/tibial cortical area, cortical bone mineral density, and trabecular density). Although these relationships were broadly equivalent in HBM cases and controls, there was some evidence that associations between sclerostin and trabecular phenotypes were stronger in HBM cases, particularly for radial trabecular density (interaction P < .01). CONCLUSIONS: Circulating plasma sclerostin concentrations are increased in both LRP5 and non-LRP5 HBM compared with controls. In addition to the general positive relationship between sclerostin and DXA/peripheral quantitative computed tomography parameters, genetic factors predisposing to HBM may contribute to increased sclerostin levels.This study was supported by The Wellcome Trust NIHR Clinical Research Network (portfolio number 5163); and the supporting Comprehensive Local Research Networks included Birmingham and the Black Country, North and East Yorkshire and Northern Lincolnshire, South Yorkshire, West Anglia, and Western. C.L.G. was funded through a Wellcome Trust Clinical Research Training Fellowship (080280/Z/06/Z) and is now funded by Arthritis Research UK (Grant 20000). K.E.S.P. acknowledges the support of Cambridge NIHR Biomedical Research Centre and the Medical Research Council Human Nutrition Research Unit, Cambridge.This is the author accepted manuscript. The final version is available from the Endocrine Society via http://dx.doi.org/10.1210/jc.2013-395

To swim or not to swim: an interpretation of farmed mink's motivation for a water bath

How an animal’s behavioural (ethological) needs can be met is a pivotal issue in the assessment of welfare for captive animals. The value of swimming water for farmed mink is an example how scientific and societal questions relating to animal welfare can be answered. A number of studies have addressed the issue of the indispensability of swimming water for mink; however, so far with inconclusive evidence. In this paper, the results of these studies and related literature are reviewed. First, the biological definition of need is discussed. Subsequently, attention is paid to the effects of the presence, absence and the removal of swimming water on behavioural and physiological correlates of well-being including stereotypic and anticipatory behaviour and urinary cortisol. Thereafter we discuss individual differences in the use of swimming water, the price animals pay for access to a water bath, and the effect of access to swimming water on juvenile play. The main conclusions of the literature review are that 1) the use of a water bath for mink is most likely related to foraging behaviour (foraging areas: land and water); 2) absence of swimming water, without prior experience, does not lead to consistent changes in level of stereotypic behaviour, or anticipatory responses; 3) removal of a previously experienced water bath may induce short-term stress as indicated by behavioural parameters and elevated cortisol responses; 4) mink work hard for access to a swimming bath and running wheel in consumer demand studies. Other cage modifications such as tunnels and biting objects, may also provide environmental enrichment, if they are added to otherwise impoverished conditions; 5) There are individual differences in the use of swimming water: these are related in part to variation in prior experience of aquatic resources.; 6) As prior experience is important both with respect to individual use of swimming water and the response to deprivation, swimming water can not be described as biological need in the sense of a fixed requirement for survival. As swimming water appears to act as an incentive that induces its own motivation a more accurate term may be an “incentive induced or environmentally facilitated need”. Given the available evidence, it is not possible to conclude whether mink that have never experienced swimming water, suffer as a consequence of its absence. However, it is possible to predict that mink with access to water have improved quality of life, due to increased behavioural opportunities, in comparison to farmed mink without access to swimming water. In practical terms, it is still open to debate whether mink should be provided with swimming water, or if alternative, less valued, but easier to install and maintain forms of environmental enrichment, should be provided in mink housing. To clarify these issues a number of future studies would be valuable. These include; 1) whether specific environmental cues affect motivation to swim, such as the form of drinking water delivery systems ; 2) whether prior experience of swimming water affects its incentive value; in other words “can you miss what you never experienced?”; 3) do behavioural parameters such as stereotypic behaviour; rebound effects and vacuum activity have any general utility in assessing the value of absent resources; 4) what are preferences for and the value of alternative resources which may act as substitutes for swimming water. In addition we would recommend further work investigating: relationship between access to swimming water and positive indicators of welfare such as play and/or anticipatory behaviour; the effects of preventing the performance of rewarding behaviours and deprivation of a previous experienced resource; and health and hygeine issues related to provision of a water bath. In future work, it would be desirable to present be the actual percentages of animals using a water bath during the experiment and the use of power analyses, to aid their interpretation

Isotropic soft-core potentials with two characteristic length scales and anomalous behaviour

Isotropic soft-core potentials with two characteristic length scales have been used since 40 years to describe systems with polymorphism. In the recent years intense research is showing that these potentials also display polyamorphism and several anomalies, including structural, diffusion and density anomaly. These anomalies occur in a hierarchy that resembles the anomalies of water. However, the absence of directional bonding in these isotropic potentials makes them different from water. Other systems, such as colloidal suspensions, protein solutions or liquid metals, can be well described by these family of potentials, opening the possibility of studying the mechanism generating the polyamorphism and anomalies in these complex liquids

The WiggleZ Dark Energy Survey: small-scale clustering of Lyman-break galaxies at z < 1

The WiggleZ Dark Energy Survey is a large-scale structure survey of intermediate-redshift ultraviolet-selected (UV-selected) emission-line galaxies scheduled to cover 1000 deg^2, spanning a broad redshift range 0.2 < z < 1.0 . The main scientific goal of the survey is the measurement of baryon acoustic oscillations (BAO) in the galaxy clustering pattern at a significantly higher redshift than previous studies. The BAO may be applied as a standard cosmological ruler to constrain dark energy models. Based on the first 20 per cent of the data set, we present initial results concerning the small-scale clustering of the WiggleZ targets, together with survey forecasts. The WiggleZ galaxy population possesses a clustering length r_0 = 4.40 ± 0.12 h^(−1) Mpc, which is significantly larger than z = 0 UV-selected samples, with a slope γ = 1.92 ± 0.08 . This clustering length is comparable to z = 3 Lyman-break galaxies with similar UV luminosities. The clustering strength of the sample increases with optical luminosity, UV luminosity and reddening rest-frame colour. The full survey, scheduled for completion in 2010, will map an effective volume V_eff ≈ 1 Gpc^3 (evaluated at a scale k = 0.15 h Mpc^(−1)) and will measure the angular diameter distance and Hubble expansion rates in three redshift bins with accuracies of ≈5 per cent. We will determine the value of a constant dark energy equation-of-state parameter, wcons, with a higher precision than existing supernovae observations using an entirely independent technique. The WiggleZ and supernova measurements lie in highly complementary directions in the plane of w_(cons) and the matter density Ω_m. The forecast using the full combination of WiggleZ, supernova and cosmic microwave background (CMB) data sets is a marginalized error Δw_(cons) = 0.07 , providing a robust and precise measurement of the properties of dark energy including cross-checking of systematic errors

Flexible, actin-based ridges colocalise with the β1 integrin on the surface of melanoma cells

Using a combination of laser-scanning confocal microscopy and atomic force microscopy, we have identified flexible, actin-based structures on the surface of cells derived from the vertical growth phase of melanoma progression. These flexible structures, lacking on the surface of mature melanocytes, were observed on the surface of all four melanoma cell lines tested. Further investigation revealed that the β1 integrin colocalises with these actin-based ridges on the cell surface, whereas β1 integrin distribution in melanocytes did not correlate with actin-based structures. Fibronectin staining on the surface of melanoma cells was partially codistributed with the ridges. The combination of structural information derived from atomic force microscopy images and fluorescent imaging of the distribution of labelled proteins involved in invasion and metastasis has allowed us to identify a common feature that may be involved in disease progression, at the surface of vertical growth phase melanoma cells, despite the known variation in genetic composition of melanoma

The WiggleZ Dark Energy Survey: Survey Design and First Data Release

The WiggleZ Dark Energy Survey is a survey of 240,000 emission line galaxies in the distant universe, measured with the AAOmega spectrograph on the 3.9-m Anglo-Australian Telescope (AAT). The target galaxies are selected using ultraviolet photometry from the GALEX satellite, with a flux limit of NUV<22.8 mag. The redshift range containing 90% of the galaxies is 0.2<z<1.0. The primary aim of the survey is to precisely measure the scale of baryon acoustic oscillations (BAO) imprinted on the spatial distribution of these galaxies at look-back times of 4-8 Gyrs. Detailed forecasts indicate the survey will measure the BAO scale to better than 2% and the tangential and radial acoustic wave scales to approximately 3% and 5%, respectively. This paper provides a detailed description of the survey and its design, as well as the spectroscopic observations, data reduction, and redshift measurement techniques employed. It also presents an analysis of the properties of the target galaxies, including emission line diagnostics which show that they are mostly extreme starburst galaxies, and Hubble Space Telescope images, which show they contain a high fraction of interacting or distorted systems. In conjunction with this paper, we make a public data release of data for the first 100,000 galaxies measured for the project.Comment: Accepted by MNRAS; this has some figures in low resolution format. Full resolution PDF version (7MB) available at http://www.physics.uq.edu.au/people/mjd/pub/wigglez1.pdf The WiggleZ home page is at http://wigglez.swin.edu.au

ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study

PURPOSE: The development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer. METHODS: This phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an "AI-sensitive/naïve" group who received anastrozole and "prior-AI" group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity. RESULTS: 140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in "AI-sensitive/naive" and "prior-AI" sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash. CONCLUSION: Saracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases. CRUKE/11/023, ISRCTN23804370