Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS

GROMACS is a widely used package for biomolecular simulation, and over the last two decades it has evolved from small-scale efficiency to advanced heterogeneous acceleration and multi-level parallelism targeting some of the largest supercomputers in the world. Here, we describe some of the ways we have been able to realize this through the use of parallelization on all levels, combined with a constant focus on absolute performance. Release 4.6 of GROMACS uses SIMD acceleration on a wide range of architectures, GPU offloading acceleration, and both OpenMP and MPI parallelism within and between nodes, respectively. The recent work on acceleration made it necessary to revisit the fundamental algorithms of molecular simulation, including the concept of neighborsearching, and we discuss the present and future challenges we see for exascale simulation - in particular a very fine-grained task parallelism. We also discuss the software management, code peer review and continuous integration testing required for a project of this complexity.Comment: EASC 2014 conference proceedin

An assessment of food supplementation to chronically sick patients receiving home based care in Bangwe, Malawi : a descriptive study

BACKGROUND: The effect of food supplementation provided by the World Food Programme to patients and their families enrolled in a predominantly HIV/AIDS home based care programme in Bangwe Malawi is assessed. METHODS: The survival and nutritional status of patients and the nutritional status of their families recruited up to six months before a food supplementation programme started are compared to subsequent patients and their families over a further 12 months. RESULTS: 360 patients, of whom 199 died, were studied. Food supplementation did not improve survival but had an effect (not statistically significant) on nutritional status. Additional oil was given to some families; it may have improved survival but not nutritional status. CONCLUSION: Food supplementation to HIV/AIDS home based care patients and their families does not work well. This may be because the intervention is too late to affect the course of disease or insufficiently targeted perhaps due to problems of distribution in an urban setting. The World Food Programme's emphasis on supplementary feeding for these families needs to be reviewed

From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein

Comparisons of observed and modelled lake δ¹⁸O variability

With the substantial number of lake sediment δ¹⁸O records published in recent decades, a quantitative, process-based understanding of these systems can increase our understanding of past climate change. We test mass balance models of lake water δ¹⁸O variability against five years of monthly monitoring data from lakes with different hydrological characteristics, in the East-Midlands region of the UK, and the local isotope composition of precipitation. These mass balance models can explain up to 74% of the measured lake water isotope variability. We investigate the sensitivity of the model to differing calculations of evaporation amount, the amount of groundwater, and to different climatic variables. We show there is only a small range of values for groundwater exchange flux that can produce suitable lake water isotope compositions and that variations in evaporation and precipitation are both required to produce recorded isotope variability in lakes with substantial evaporative water losses. We then discuss the potential for this model to be used in a long-term, palaeo-scenario. This study demonstrates how long term monitoring of a lake system can lead to the development of robust models of lake water isotope compositions. Such systematics-based explanations allow us to move from conceptual, to more quantified reconstructions of past climates and environments

Genome-Wide Studies of Histone Demethylation Catalysed by the Fission Yeast Homologues of Mammalian LSD1

In order to gain a more global view of the activity of histone demethylases, we report here genome-wide studies of the fission yeast SWIRM and polyamine oxidase (PAO) domain homologues of mammalian LSD1. Consistent with previous work we find that the two S. pombe proteins, which we name Swm1 and Swm2 (after SWIRM1 and SWIRM2), associate together in a complex. However, we find that this complex specifically demethylates lysine 9 in histone H3 (H3K9) and both up- and down-regulates expression of different groups of genes. Using chromatin-immunoprecipitation, to isolate fragments of chromatin containing either H3K4me2 or H3K9me2, and DNA microarray analysis (ChIP-chip), we have studied genome-wide changes in patterns of histone methylation, and their correlation with gene expression, upon deletion of the swm1+ gene. Using hyper-geometric probability comparisons we uncover genetic links between lysine-specific demethylases, the histone deacetylase Clr6, and the chromatin remodeller Hrp1. The data presented here demonstrate that in fission yeast the SWIRM/PAO domain proteins Swm1 and Swm2 are associated in complexes that can remove methyl groups from lysine 9 methylated histone H3. In vitro, we show that bacterially expressed Swm1 also possesses lysine 9 demethylase activity. In vivo, loss of Swm1 increases the global levels of both H3K9me2 and H3K4me2. A significant accumulation of H3K4me2 is observed at genes that are up-regulated in a swm1 deletion strain. In addition, H3K9me2 accumulates at some genes known to be direct Swm1/2 targets that are down-regulated in the swm1¿ strain. The in vivo data indicate that Swm1 acts in concert with the HDAC Clr6 and the chromatin remodeller Hrp1 to repress gene expression. In addition, our in vitro analyses suggest that the H3K9 demethylase activity requires an unidentified post-translational modification to allow it to act. Thus, our results highlight complex interactions between histone demethylase, deacetylase and chromatin remodelling activities in the regulation of gene expression

Endomicroscopic and transcriptomic analysis of impaired barrier function and malabsorption in environmental enteropathy

Introduction: Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods: We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results: CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions: Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE

HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis

Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs

Temperature Sensitive Nanocapsule of Complex Structural Form for Methane Storage

The processes of methane adsorption, storage and desorption by the nanocapsule are investigated with molecular-dynamic modeling method. The specific nanocapsule shape defines its functioning uniqueness: methane is adsorbed under 40 MPa and at normal temperature with further blocking of methane molecules the K@C601+ endohedral complex in the nanocapsule by external electric field, the storage is performed under normal external conditions, and methane desorption is performed at 350 K. The methane content in the nanocapsule during storage reaches 11.09 mass%. The nanocapsule consists of tree parts: storage chamber, junction and blocking chamber. The storage chamber comprises the nanotube (20,20). The blocking chamber is a short nanotube (20,20) with three holes. The junction consists of the nanotube (10,10) and nanotube (8,8); moreover, the nanotube (8,8) is connected with the storage chamber and nanotube (10,10) with the blocking chamber. The blocking chamber is opened and closed by the transfer of the K@C601+ endohedral complex under electrostatic field action