A theoretical study of repeating sequence in HRP II: a combination of molecular dynamics simulations and (17)O quadrupole coupling tensors

Histidine rich protein II derived peptide (HRP II 169-182) was investigated by molecular dynamics, MD, simulation and (17)O electric field gradient, EFG, tensor calculations. MD simulation was performed in water at 300 K with alpha-helix initial structure. It was found that peptide loses its initial alpha-helix structure rapidly and is converted to random coil and bent secondary structures. To understand how peptide structure affects EFG tensors, initial structure and final conformations resulting from MD simulations were used to calculate (17)O EFG tensors of backbone carbonyl oxygens. Calculations were performed using B3LYP method and 6-31+G basis set. Calculated (17)O EFG tensors were used to evaluate quadrupole coupling constants, QCC, and asymmetry parameters, eta(Q). Difference between the calculated QCC and eta(Q) values revealed how hydrogen-bonding interactions affect EFG tensors at the sites of each oxygen nucleus.     

品管圈在PIVAS降低不合理医嘱中的应用

为提高医院PIVAS的医嘱合理性，保证患者用药安全，我院引入品质管理概念，运用品管圈活动的十大步骤，进行计划、执行、确认和处置，完成PDCA循环。结果表明，品管圈活动能显著降低PIVAS不合理用药医嘱数，提升药学服务内涵，有利于药学服务质量的持续改进，值得推广。     

Multiply accelerated ReaxFF molecular dynamics: coupling parallel replica dynamics with collective variable hyper dynamics

ABSTRACT

To tackle the time scales required to study complex chemical reactions, methods performing accelerated molecular dynamics are necessary even with the recent advancement in high-performance computing. A number of different acceleration techniques are available. Here we explore potential synergies between two popular acceleration methods – Parallel Replica Dynamics (PRD) and Collective Variable Hyperdynamics (CVHD), by analysing the speedup obtained for the pyrolysis of n-dodecane. We observe that PRD?+?CVHD provides additional speedup to CVHD by reaching the required time scales for the reaction at an earlier wall-clock time. Although some speedup is obtained with the additional replicas, we found that the effectiveness of the inclusion of PRD is depreciated for systems where there is a dramatic increase in reaction rates induced by CVHD. Similar observations were made in the simulation of ethylene-carbonate/Li system, which is inherently more reactive than pyrolysis, indicate that the speedup obtained via the combination of the two acceleration methods can be generalised to most practical chemical systems.     

Spectroscopic analysis of the intrinsic chromophores within small multidrug resistance protein SugE

Small multidrug resistance (SMR) protein family member, SugE, is an integral inner membrane protein that confers host resistance to antiseptic quaternary cation compounds (QCC). SugE studies generally focus on its resistance to limited substrates in comparison to SMR protein EmrE. This study examines the conformational characteristics of SugE protein in two detergents, sodium dodecyl sulphate (SDS) and dodecyl maltoside (DDM), commonly used to study SMR proteins. The influence of cetylpyridinium (CTP) and cetrimide (CET) using SugE aromatic residues (4W, 2Y, 1F) as intrinsic spectroscopic probes was also determined. Organically extracted detergent solubilized Escherichia coli SugE protein was examined by SDS-Tricine PAGE and various spectroscopic techniques. SDS-Tricine PAGE analysis of SugE in either detergent demonstrates the protein predominates as a monomer but also dimerizes in SDS. Far-UV region circular dichroism (CD) analysis determined that the overall α-helix content SugE in SDS and DDM was almost identical and unaltered by QCC. Near-UV region CD, fluorescence, and second-derivative ultraviolet absorption (SDUV) indicated that only DDM-SugE promoted hydrophobic environments for its Trp and Tyr residues that were perturbed by QCC addition. This study identified that only the tertiary structure of SugE protein in DDM is altered by QCC.     

Parallel network simulations with NEURON

The NEURON simulation environment has been extended to support parallel network simulations. Each processor integrates the equations for its subnet over an interval equal to the minimum (interprocessor) presynaptic spike generation to postsynaptic spike delivery connection delay. The performance of three published network models with very different spike patterns exhibits superlinear speedup on Beowulf clusters and demonstrates that spike communication overhead is often less than the benefit of an increased fraction of the entire problem fitting into high speed cache. On the EPFL IBM Blue Gene, almost linear speedup was obtained up to 100 processors. Increasing one model from 500 to 40,000 realistic cells exhibited almost linear speedup on 2000 processors, with an integration time of 9.8 seconds and communication time of 1.3 seconds. The potential for speed-ups of several orders of magnitude makes practical the running of large network simulations that could otherwise not be explored. Action Editor: Alain Destexhe     

An efficient approach to collaborative simulation of variable structure systems on multi-core machines

Complex variable-structure systems (CVSSs) are a common type of complex systems that exhibit changes both at structural and behavior levels. Simulations of CVSSs challenge current collaborative execution methods with increasingly big and complex models. The emergence of multi-core paradigm presents an exciting opportunity to address such challenge, so an advanced parallel simulator under multi-core environments is proposed. The simulator: (1) provides thread simulation kernels and five kinds of management services to support dynamic model structure flexibly; (2) can explore both inherent and dynamic parallelism among models based on interaction relations, and employ the multi-thread paradigm to gain good speedup; (3) adopts an efficient dynamic load-balancing method, which can migrate models among cores with very low cost and support dynamic core allocation on demand, to address evident load-imbalance problems brought by variable-structure. The experiments show that structure changes can be supported while up to 23 % performance increase can be gained.     

Genome-wide analysis reveals the effects of artificial selection on production and meat quality traits in Qinchuan cattle

A new strain of Qinchuan cattle (QNS) has been obtained after more than forty years of selective breeding, and it shows good performance and production traits. To characterize the genetic changes that have resulted from breeding, we sequenced 10 QNS and 10 of the original breed Qinchuan cattle (QCC) for the first time, with average of 12.5-fold depth. A total of 31,242,284 and 29,612,517 SNPs were identified in the QCC and QNS genomes, 47.81% and 44.36% of which were found to be novel, respectively. Furthermore, population structure analysis revealed the selection that these cattle had experienced. Then, 332 and 571 potential selected genes were obtained, associated with enhanced immunity and acclimatization in QCC (CD5, SMARCA2, CATHL2, etc.) and production or meat quality traits in QNS (PLCD3, MB, PPARGC1A, etc.). These results revealed the efforts of selective breeding for Chinese Qinchuan cattle, and will be helpful for future cattle breeding.     

Influence of quaternary cation compound on the size of the Escherichia coli small multidrug resistance protein,EmrE

EmrE is a member of the small multidrug resistance (SMR) protein family in Escherichia coli. It confers resistance to a wide variety of quaternary cation compounds (QCCs) as an efflux transporter driven by the transmembrane proton motive force. We have expressed hexahistidinyl (His₆) – myc epitope tagged EmrE, extracted it from membrane preparations using the detergent n-dodecyl-β-D-maltopyranoside (DDM), and purified it using nickel-affinity chromatography. The size of the EmrE protein, in DDM environment, was then examined in the presence and absence of a range of structurally different QCC ligands that varied in their chemical structure, charge and shape. We used dynamic light scattering and showed that the size and oligomeric state distributions are dependent on the type of QCC. We also followed changes in the Trp fluorescence and determined apparent dissociation constants (K_d). Overall, our in vitro analyses of epitope tagged EmrE demonstrated subtle but significant differences in the size distributions with different QCC ligands bound.     

Spectroscopic analysis of small multidrug resistance protein EmrE in the presence of various quaternary cation compounds

Escherichia coli EmrE protein is the archetypical member of the small multidrug resistance protein family in bacteria and confers host resistance to a wide assortment of toxic quaternary cation compounds by secondary active efflux. This protein can form a variety of multimers under various membrane mimetic conditions, and the consensus of most biochemical and biophysical studies indicate that the active form is a dimer. The purpose of this study is to characterize the conformation of organically extracted detergent solubilized EmrE protein known to predominate as monomer yet demonstrates ligand binding ability. Active site EmrE-E14 replacements were also examined as functionally inactive controls for this study. EmrE was solubilized in detergents, sodium dodecyl sulfate (SDS) and dodecyl maltoside (DDM), and protein conformation was examined in the presence of four known quaternary cation compound (QCC) substrates, tetraphenyl phosphonium (TPP), methyl viologen, cetylpyridinium, and ethidium. SDS-Tricine PAGE analysis of both detergent solubilized proteins revealed that DDM-EmrE preparations enhanced the formation of dimer (and in some cases trimer) forms in the presence of all four QCC above 25 QCC:1 EmrE molar ratios. Examination of EmrE and its active site variant tertiary structures in DDM by circular dichroism spectropolarimetry, intrinsic Trp fluorescence quenching and second order derivative ultraviolet absorbance revealed that the variant fails to bind TPP but interacts with all other compounds. The results of this study show that monomeric detergent solubilized EmrE is capable of forming multimeric complexes that are enhanced by chemically diverse QCCs.     

基于Yarn云平台的生物基因多序列比对并行算法

为了解决生物信息学中基因多序列比对的计算速度慢和软件陈旧的问题,提出了基于Yarn(Yet Another Resource Negotiator)云平台的生物基因多序列比对并行计算方法Yarn_clustalW。分析了clustalW算法的数学模型及其面向MapReduce的任务划分方式,Yarn_clustalW中综合考虑了基因的长度和数目,采用一种基于阈值刻度的任务划分方式。利用NCBI的GenBank生物基因数据作为案例程序进行了测试。实验结果表明:Yarn_clustalW比起多序列比对clustalW串行计算方法具有更快的运行时间与加速比,可以使生物科研人员节省很多时间与精力,方便对于药物靶标的发现,缩短生物药物的开发周期。     

Outer Membrane Protein OmpW Participates with Small Multidrug Resistance Protein Member EmrE in Quaternary Cationic Compound Efflux

In Escherichia coli, the small multidrug resistance (SMR) transporter protein EmrE confers host resistance to a broad range of toxic quaternary cation compounds (QCC) via proton motive force in the plasma membrane. Biologically produced QCC also act as EmrE osmoprotectant substrates within the cell and participate in host pH regulation and osmotic tolerance. Although E. coli EmrE is one of the most well-characterized SMR members, it is unclear how the substrates it transports into the periplasm escape across the outer membrane (OM) in Gram-negative bacteria. We tested the hypothesis that E. coli EmrE relies on an unidentified OM protein (OMP) to complete the extracellular release of its QCC. Eleven OMP candidates were screened using an alkaline phenotypic growth assay to identify OMP involvement in EmrE-mediated QCC efflux. E. coli single-gene deletion strains were transformed with plasmid-carried copies of emrE to detect reduced-growth and rescued-growth phenotypes under alkaline conditions. Among the 11 candidates, only the ΔompW strain showed rescued alkaline growth tolerance when transformed with pEmrE, supporting the corresponding protein''s involvement in EmrE osmoprotectant efflux. Coexpression of plasmids carrying the ompW and emrE genes transformed into the E. coli ΔompW and ΔemrE strains demonstrated a functional complementation restoring the original alkaline loss-of-growth phenotype. Methyl viologen drug resistance assays of pEmrE and pOmpW plasmid-complemented E. coli ΔompW and wild-type strains found higher host drug resistance than with other plasmid combinations. This study confirms our hypothesis that the porin OmpW participates in the efflux of EmrE-specific substrates across the OM.     

Speed of Conformational Change: Comparing Explicit and Implicit Solvent Molecular Dynamics Simulations

Adequate sampling of conformation space remains challenging in atomistic simulations, especially if the solvent is treated explicitly. Implicit-solvent simulations can speed up conformational sampling significantly. We compare the speed of conformational sampling between two commonly used methods of each class: the explicit-solvent particle mesh Ewald (PME) with TIP3P water model and a popular generalized Born (GB) implicit-solvent model, as implemented in the AMBER package. We systematically investigate small (dihedral angle flips in a protein), large (nucleosome tail collapse and DNA unwrapping), and mixed (folding of a miniprotein) conformational changes, with nominal simulation times ranging from nanoseconds to microseconds depending on system size. The speedups in conformational sampling for GB relative to PME simulations, are highly system- and problem-dependent. Where the simulation temperatures for PME and GB are the same, the corresponding speedups are approximately onefold (small conformational changes), between ∼1- and ∼100-fold (large changes), and approximately sevenfold (mixed case). The effects of temperature on speedup and free-energy landscapes, which may differ substantially between the solvent models, are discussed in detail for the case of miniprotein folding. In addition to speeding up conformational sampling, due to algorithmic differences, the implicit solvent model can be computationally faster for small systems or slower for large systems, depending on the number of solute and solvent atoms. For the conformational changes considered here, the combined speedups are approximately twofold, ∼1- to 60-fold, and ∼50-fold, respectively, in the low solvent viscosity regime afforded by the implicit solvent. For all the systems studied, 1) conformational sampling speedup increases as Langevin collision frequency (effective viscosity) decreases; and 2) conformational sampling speedup is mainly due to reduction in solvent viscosity rather than possible differences in free-energy landscapes between the solvent models.     

Designing Patterns and Profiles for Faster HMM Search

Profile HMMs are powerful tools for modeling conserved motifs in proteins. They are widely used by search tools to classify new protein sequences into families based on domain architecture. However, the proliferation of known motifs and new proteomic sequence data poses a computational challenge for search, requiring days of CPU time to annotate an organism's proteome. It is highly desirable to speed up HMM search in large databases. We design PROSITE-like patterns and short profiles that are used as filters to rapidly eliminate protein-motif pairs for which a full profile HMM comparison does not yield a significant match. The design of the pattern-based filters is formulated as a multichoice knapsack problem. Profile-based filters with high sensitivity are extracted from a profile HMM based on their theoretical sensitivity and false positive rate. Experiments show that our profile-based filters achieve high sensitivity (near 100 percent) while keeping around 20times speedup with respect to the unfiltered search program. Pattern-based filters typically retain at least 90 percent of the sensitivity of the source HMM with 30-40times speedup. The profile-based filters have sensitivity comparable to the multistage filtering strategy HMMERHEAD and are faster in most of our experiments.     

Environmental pressure rather than ongoing hybridization is responsible for an altitudinal cline in the morphologies of two oaks

在相关类群之间的接触区,表型变异可能源于遗传和/或环境梯度。本研究旨在阐明两种栎属植物[Quercus crispula (QCC)和 Q. mongolicoides (QCM)],在其接触区沿海拔梯度形成叶片形态表型变异的原因。对于源自接触区48个个体和QCC和QCM的每个参照 种群24个个体样本,我们测定其6种叶片形态特征,同时记录13个核微卫星位点的基因型。我们通过构建模型解释表型变异(叶片形态)与环境(海拔)和遗传(参照种群世系)梯度的关系。研究结果表明,形态和遗传标记均能较好地区分参照种群中的两个品种。我们能够确认形态和遗传标记的作用。接触区种群内的个体具有略偏向QCM分支的中间世系,其形态分布与参照种群中两个变种的形态分布重叠。海拔会显著影响叶片形态性状,而遗传对叶片形态性状无显著影响。接触区种群的世系和种间杂合性分布与F₂或后代杂交种中的分布相似。这些结果表明,在两种栎属植物QCC和QCM之间的接触区,并没有发生杂交,但环境压力通过表型可塑性和/或功能基因的变异,导致了其在形态性状上的海拔梯度效应。     

ReaDDyMM: Fast Interacting Particle Reaction-Diffusion Simulations Using Graphical Processing Units

ReaDDy is a modular particle simulation package combining off-lattice reaction kinetics with arbitrary particle interaction forces. Here we present a graphical processing unit implementation of ReaDDy that employs the fast multiplatform molecular dynamics package OpenMM. A speedup of up to two orders of magnitude is demonstrated, giving us access to timescales of multiple seconds on single graphical processing units. This opens up the possibility of simulating cellular signal transduction events while resolving all protein copies.     

Parental age and the risk of childhood acute myeloid leukemia: results from the Childhood Leukemia International Consortium

BackgroundParental age has been associated with several childhood cancers, albeit the evidence is still inconsistent.AimTo examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0–14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies.Material/methodsWe analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants <1 year-old vs. children 1–14 years-old) and by study design, using five-year parental age increments and controlling for sex, ethnicity, birthweight, prematurity, multiple gestation, birth order, maternal smoking and education, age at diagnosis (cases aged 1–14 years), and recruitment time period.ResultsAdjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from RCC, but not from the QCC, studies showed a higher AML risk for infants of mothers ≥40-year-old (OR = 6.87; 95% CI: 2.12–22.25). There were no associations observed between any other maternal or paternal age group and AML risk for children older than one year.ConclusionsAn increased risk of infant AML with advanced maternal age was found using data from RCC, but not from QCC studies; no parental age-AML associations were observed for older children.     

Structural and functional comparison of hexahistidine tagged and untagged forms of small multidrug resistance protein,EmrE

EmrE is a member of the small multidrug resistance (SMR) protein family in Escherichia coli. EmrE confers resistance to a wide variety of quaternary cation compounds (QCCs) as an efflux transporter driven by proton motive force. The purification yield of most membrane proteins are challenging because of difficulties in over expressing, isolating and solubilizing them and the addition of an affinity tag often improves purification. The purpose of this study is to compare the structure and function of hexahistidinyl (His₆) tagged (T-EmrE) and untagged (UT-EmrE) versions of EmrE. In vivo QCC resistance assays determined that T-EmrE demonstrated reduced resistance as compared to UT-EmrE. We isolated EmrE using the two different purification methods, an organic solvent extraction method used to isolate UT-EmrE and nickel affinity chromatography of T-EmrE. All proteins were solubilized in the same buffered n-dodecyl-β-d-maltopyranoside (DDM) detergent and their conformations were examined in the presence/absence of different QCCs. In vitro analysis of protein multimerization using SDS-Tricine PAGE and dynamic light scattering analysis revealed that both proteins predominated as monomers, but the formation of dimers was more constant and uniform in T-EmrE compared to UT-EmrE. The aromatic residue conformations of both proteins indicate that T-EmrE form is more aqueous exposed than UT-EmrE, but UT-EmrE appeared to have a more dynamic environment surrounding its aromatic residues. Using fluorescence to obtain QCC ligand-binding curves indicated that the two forms had differences in dissociation constants (K_d) and maximum specific one-site binding (B_max) values for particular QCCs. In vitro analyses of both proteins demonstrated subtle but significant differences in multimerization and QCC binding. In vivo analysis indicates differences caused by the addition of the tag, we also observed differences in vitro that could be a result of the tag and/or the different purification methods.     

Parallel expression profiling of barley–stem rust interactions

The dominant barley stem rust resistance gene Rpg1 confers resistance to many but not all pathotypes of the stem rust fungus Puccinia graminis f. sp. tritici (Pgt). Transformation of Rpg1 into susceptible cultivar Golden Promise rendered the transgenic plants resistant to Pgt pathotype MCC but not to Pgt pathotype QCC. Our objective was to identify genes that are induced/repressed during the early stages of pathogen infection to elucidate the molecular mechanisms and role of Rpg1 in defense. A messenger ribonucleic acid expression analysis using the 22K Barley1 GeneChip was conducted in all pair-wise combinations of two isolines (cv. Golden Promise and Rpg1 transgenic line G02-448F-3R) and two Pgt pathotypes (MCC and QCC) across six time points. Analysis showed that a total of 34 probe sets exhibited expression pattern differences between Golden Promise (susceptible) and G02-448F-3R (resistant) infected with Pgt-MCC. A total of 14 probe sets exhibited expression pattern differences between Pgt-MCC (avirulent) and Pgt-QCC (virulent) inoculated onto G02-448F-3R. These differentially expressed genes were activated during the early infection process, before the hypersensitive response or fungal growth inhibition occurred. Our analysis provides a list of candidate signaling components, which can be analyzed for function in Rpg1-mediated disease resistance.     

Improved backpropagation learning in neural networks with windowed momentum

Backpropagation, which is frequently used in Neural Network training, often takes a great deal of time to converge on an acceptable solution. Momentum is a standard technique that is used to speed up convergence and maintain generalization performance. In this paper we present the Windowed Momentum algorithm, which increases speedup over Standard Momentum. Windowed Momentum is designed to use a fixed width history of recent weight updates for each connection in a neural network. By using this additional information, Windowed Momentum gives significant speedup over a set of applications with same or improved accuracy. Windowed Momentum achieved an average speedup of 32% in convergence time on 15 data sets, including a large OCR data set with over 500,000 samples. In addition to this speedup, we present the consequences of sample presentation order. We show that Windowed Momentum is able to overcome these effects that can occur with poor presentation order and still maintain its speedup advantages.     

The topology of metabolic isotope labeling networks

Background  

Metabolic Flux Analysis (MFA) based on isotope labeling experiments (ILEs) is a widely established tool for determining fluxes in metabolic pathways. Isotope labeling networks (ILNs) contain all essential information required to describe the flow of labeled material in an ILE. Whereas recent experimental progress paves the way for high-throughput MFA, large network investigations and exact statistical methods, these developments are still limited by the poor performance of computational routines used for the evaluation and design of ILEs. In this context, the global analysis of ILN topology turns out to be a clue for realizing large speedup factors in all required computational procedures.