Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field

International audienceAll-atom molecular dynamics (MD) simulations were used to predict water-cyclohexane distribution coefficients D cw of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the trans-ferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error (RMSE) in log D cw of almost 4 log units and an overall signed error of −3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NV T and NPT ensembles. The signed error suggests a systematic error but the experimental D cw data on their own are insufficient to Manuscript Click here to download Manuscript sampl5-manuscript.pdf Click here to view linked References 2 Ian M. Kenney et al. uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations

SAMPL6: calculation of macroscopic pKa values from ab initio quantum mechanical free energies

International audienceMacroscopic pKa values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pKa values were derived from the gas-phase free energy difference between protonated and deprotonated forms together with the Conductor-like Polarizable Continuum Solvation Model and the experimental solvation free energy of the proton. pH-dependent microstate free energies were obtained from the microscopic pKas with a maximum likelihood estimator and appropriately summed to yield macroscopic pKa values or microstate populations as function of pH. We assessed the accuracy of three approaches to calculate the microscopic pKas: direct use of the quantum mechanical free energy differences and correction of the direct values for short-comings in the QM solvation model with two different linear models that we independently derived from a small training set of 38 compounds with known pKa. The predictions that were corrected with the linear models had much better accuracy [root-mean-square error (RMSE) 2.04 and 1.95 pKa units] than the direct calculation (RMSE 3.74). Statistical measures indicate that some systematic errors remain, likely due to differences in the SAMPL6 data set and the small training set with respect to their interactions with water. Overall, the current approach provides a viable physics-based route to estimate macroscopic pKa values for novel compounds with reasonable accuracy

Soil and crop response to stover removal from rainfed and irrigated corn

Excessive corn (Zea mays L.) stover removal for biofuel and other uses may adversely impact soil and crop production. We assessed the effects of stover removal at 0, 25, 50, 75, and 100% from continuous corn on water erosion, corn yield, and related soil properties during a 3-year study under irrigated and no-tillage management practice on a Ulysses silt loam at Colby, irrigated and strip till management practice on a Hugoton loam at Hugoton, and rainfed and no-tillage management practice on a Woodson silt loam at Ottawa in Kansas, USA. The slope of each soil was \u3c1%. One year after removal, complete (100%) stover removal resulted in increased losses of sediment by 0.36–0.47 Mg ha-1 at the irrigated sites, but, at the rainfed site, removal at rates as low as 50% resulted in increased sediment loss by 0.30 Mg ha-1 and sediment-associated carbon (C) by 0.29 kg ha-1. Complete stover removal reduced wet aggregate stability of the soil at the irrigated sites in the first year after removal, but, at the rainfed site, wet aggregate stability was reduced in all years. Stover removal at rates ≥ 50%resulted in reduced soil water content, increased soil temperature in summer by 3.5–6.8 °C, and reduced tem-perature in winter by about 0.5 °C. Soil C pool tended to decrease and crop yields tended to increase with an increase in stover removal, but 3 years after removal, differences were not significant. Overall, stover removal at rates ≥50% may enhance grain yield but may increase risks of water erosion and negatively affect soil water and temperature regimes in this region

Ram-pressure stripped radio tail and two ULXs in the spiral galaxy HCG 97b

We report LOFAR and VLA detections of extended radio emission in the spiral galaxy HCG 97b, hosted by an X-ray bright galaxy group. The extended radio emission detected at 144 MHz, 1.4 GHz and 4.8 GHz is elongated along the optical disk and has a tail that extends 27 kpc in projection towards the centre of the group at GHz frequencies or 60 kpc at 144 MHz. Chandra X-ray data show two off-nuclear ultra-luminous X-ray sources (ULXs) with the more distant one being a suitable candidate for an accreting intermediate-mass black hole (IMBH) embedded in an environment with an increased density of molecular gas. Given the observed morphology in optical, CO, and radio continuum, we propose that the galaxy is undergoing ram-pressure stripping and the relativistic plasma accelerated in star-forming regions is transported from the galactic disc by galaxy-intragroup medium interaction. Finally, we also demonstrate that the formation of the radio tail could, in principle, be the result of putative IMBH-induced activity, which could facilitate the stripping or inject the radio plasma via jets.Comment: 15 pages, 11 figures, submitted to MNRAS, comments are welcom

Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing.

The strict exchange of protons for sodium ions across cell membranes by Na+/H+ exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+ exchange can be modelled as competition between H+ and Na+ to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+ antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+ to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter

Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization

Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23 degrees C. inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport. (C) 2011 Elsevier B.V. All rights reserved

Bringing 'place' back in: regional clusters, project governance, and new product outcomes

We examine new product outcomes in the context of regional clusters. Based on past research on marketing relationships, clusters, and social networks, we propose that the overall configuration of a cluster helps promote particular governance practices among its members. These practices have distinct value-creating properties, and when they are brought to bear on a specific new product development project within a cluster, they promote performance outcomes like product novelty and speed to market. Ultimately, these performance effects are reinforced by the configuration of the cluster itself. In general, we propose that new product outcomes follow from complex interactions between a cluster's macro-level configuration and its micro-level governance processes. More broadly, our framework points to the importance of geographical variables and to the role of “place” in marketing decision-making

Skin Vaccination against Cervical Cancer Associated Human Papillomavirus with a Novel Micro-Projection Array in a Mouse Model

Background: Better delivery systems are needed for routinely used vaccines, to improve vaccine uptake. Many vaccines contain alum or alum based adjuvants. Here we investigate a novel dry-coated densely-packed micro-projection array skin patch (Nanopatch (TM)) as an alternate delivery system to intramuscular injection for delivering an alum adjuvanted human papillomavirus (HPV) vaccine (Gardasil (R)) commonly used as a prophylactic vaccine against cervical cancer

The new enclosures: critical perspectives on corporate land deals

The contributions to this collection use the tools of agrarian political economy to explore the rapid growth and complex dynamics of large-scale land deals in recent years, with a special focus on the implications of big land deals for property and labour regimes, labour processes and structures of accumulation. The first part of this introductory essay examines the implications of this agrarian political economy perspective. First we explore the continuities and contrasts between historical and contemporary land grabs, before examining the core underlying debate around large- versus small-scale farming futures. Next, we unpack the diverse contexts and causes of land grabbing today, highlighting six overlapping mechanisms. The following section turns to assessing the crisis narratives that frame the justifications for land deals, and the flaws in the argument around there being excess, empty or idle land available. Next the paper turns to an examination of the impacts of land deals, and the processes of inclusion and exclusion at play, before looking at patterns of resistance and constructions of alternatives. The final section introduces the papers in the collection.ESR

Participatory modelling for stakeholder involvement in the development of flood risk management intervention options

Advancing stakeholder participation beyond consultation offers a range of benefits for local flood risk management, particularly as responsibilities are increasingly devolved to local levels. This paper details the design and implementation of a participatory approach to identify intervention options for managing local flood risk. Within this approach, Bayesian networks were used to generate a conceptual model of the local flood risk system, with a particular focus on how different interventions might achieve each of nine participant objectives. The model was co-constructed by flood risk experts and local stakeholders. The study employs a novel evaluative framework, examining both the process and its outcomes (short-term substantive and longer-term social benefits). It concludes that participatory modelling techniques can facilitate the identification of intervention options by a wide range of stakeholders, and prioritise a subset for further investigation. They can help support a broader move towards active stakeholder participation in local flood risk management