Global Research Alliance N2 O chamber methodology guidelines: Recommendations for air sample collection, storage, and analysis.

Certain aspects in the collection, handling, storage, and subsequent analysis of discrete air samples from non-steady-state flux chambers are critical to generating accurate and unbiased estimates of nitrous oxide (N2 O) fluxes. The focus of this paper is on air sample collection and storage in small vials (<12 ml) primarily for gas chromatography (GC) analysis. Sample integrity is assured through following simple procedures including storage under pressure and analysis within a few months of collection. Concurrent storage of standards in an identical manner to samples is recommended and allows the storage period to be reliably extended. In the laboratory, an autosampler is typically used in batch analysis of ∼200 sequentially analyzed samples by GC with an electron capture detector (ECD). Some comparisons are given between GC and alternatives including optical N2 O detectors that are increasingly being used for high-precision N2 O measurement. The importance of calibration and traceability of gas standards is discussed, where high-quality standards ensure the most accurate assessment of N2 O concentration and comparability between laboratories. The calibration allows a consistent and best estimate of flux to be derived.

Determining the optimal strategy for the live-attenuated herpes zoster vaccine in adults.

The optimal strategy for the vaccinating against herpes zoster (HZ) vaccine remains unknown. Cost-effectiveness analyses provide insight to the most cost-effective age groups but results vary across studies. The optimal strategy is important given that vaccine efficacy and duration vary depending on vaccination age. Therefore, small changes from the optimal age can affect long-term outcomes and produce sub-optimal results. The objective of this research was to determine the optimal timing policy for HZ vaccination. We simulated cohorts of men and women and use stochastic dynamic programming to evaluate the decision to vaccinate or defer each year from age 50 to 100. If the decision was to defer, the cohort risked developing HZ. If HZ occurred, the cohort was subjected to cost and quality-adjusted life year (QALY) loss for a typical HZ infection (including complications) at that age. If HZ did not occur, the decision was evaluated at the next age. Then, we extend the model to consider the case in which a booster vaccine is available. A set of probabilistic sensitivity analyses were conducted to check model robustness. Results show the optimal policy for women is to vaccinate between ages 66 and 77, and for men between ages 66 and 74, assuming a willingness to pay (WTP) of $100,000 per QALY. It becomes optimal to vaccinate earlier if a booster vaccine is available, and women have a wider range of ages than men. This research is the first to examine exactly when the HZ vaccine should be administered. It is also the first study, to our knowledge, that used stochastic dynamic programming to examine the question of a second dose for any vaccine. This research provides the first simple policy on when to vaccinate and re-vaccinate against HZ.

Respiratory-syncytial-virus- and rhinovirus-related bronchiolitis in children aged <2 years in an English district general hospital.

BACKGROUND: Bronchiolitis is the most common reason for hospitalization in young children. In addition to respiratory syncytial virus (RSV), other viruses have been increasingly implicated. Guidance on testing has also changed. AIMS: To compare clinicopathological outcomes in young children admitted with bronchiolitis due to RSV in comparison with rhinovirus (RV), and identify associated risk/epidemiological factors. METHODS: Children aged less than two years admitted to hospital with a clinical diagnosis of bronchiolitis with positive results for either RSV or RV were included in this study. Polymerase-chain-reaction-negative cases using an extended respiratory virus panel served as a control group. Retrospective data were collected on sex, risk factors, respiratory support, intravenous fluids and antibiotics. Outcomes such as length of stay (LOS) and need for transfer to the high-dependency unit/paediatric intensive care unit were included. FINDINGS: Two hundred and twenty-seven out of 437 nasopharyngeal aspirate samples were positive for either RSV (N = 162) or RV (N = 65). The median age of cases was three months and 75% had at least one risk factor. Risk factors were higher in the RV group (P = 0.004). RV accounted for the majority of cases outside the RSV season (P < 0.01). RV-associated bronchiolitis had a longer LOS (more than seven days) (P < 0.05) and increased need for chest X-rays and/or antibiotics (P < 0.05). Use of intravenous fluids and respiratory support were higher in the RV group, but the difference was not significant. CONCLUSIONS: RV is the second most common pathogen associated with bronchiolitis and is isolated all year round. This may be important in those with risk factors resulting in prolonged LOS. Further research is necessary to establish the exact role of RV in this common condition, particularly outside the traditional RSV season.

HTMD: High-Throughput Molecular Dynamics for Molecular Discovery.

Recent advances in molecular simulations have allowed scientists to investigate slower biological processes than ever before. Together with these advances came an explosion of data that has transformed a traditionally computing-bound into a data-bound problem. Here, we present HTMD, a programmable, extensible platform written in Python that aims to solve the data generation and analysis problem as well as increase reproducibility by providing a complete workspace for simulation-based discovery. So far, HTMD includes system building for CHARMM and AMBER force fields, projection methods, clustering, molecular simulation production, adaptive sampling, an Amazon cloud interface, Markov state models, and visualization. As a result, a single, short HTMD script can lead from a PDB structure to useful quantities such as relaxation time scales, equilibrium populations, metastable conformations, and kinetic rates. In this paper, we focus on the adaptive sampling and Markov state modeling features.

AceCloud: Molecular Dynamics Simulations in the Cloud.

We present AceCloud, an on-demand service for molecular dynamics simulations. AceCloud is designed to facilitate the secure execution of large ensembles of simulations on an external cloud computing service (currently Amazon Web Services). The AceCloud client, integrated into the ACEMD molecular dynamics package, provides an easy-to-use interface that abstracts all aspects of interaction with the cloud services. This gives the user the experience that all simulations are running on their local machine, minimizing the learning curve typically associated with the transition to using high performance computing services.

Reranking docking poses using molecular simulations and approximate free energy methods.

Fast and accurate identification of active compounds is essential for effective use of virtual screening workflows. Here, we have compared the ligand-ranking efficiency of the linear interaction energy (LIE) method against standard docking approaches. Using a trypsin set of 1549 compounds, we performed 12,250 molecular dynamics simulations. The LIE method proved effective but did not yield results significantly better than those obtained with docking codes. The entire database of simulations is released.

Kinetic characterization of fragment binding in AmpC ß-lactamase by high-throughput molecular simulations.

Small molecules used in fragment-based drug discovery form multiple, promiscuous binding complexes difficult to capture experimentally. Here, we identify such binding poses and their associated energetics and kinetics using molecular dynamics simulations on AmpC ß-lactamase. Only one of the crystallographic binding poses was found to be thermodynamically favorable; however, the ligand shows several binding poses within the pocket. This study demonstrates free-binding molecular simulations in the context of fragment-to-lead development and its potential application in drug design.

High-throughput all-atom molecular dynamics simulations using distributed computing.

Although molecular dynamics simulation methods are useful in the modeling of macromolecular systems, they remain computationally expensive, with production work requiring costly high-performance computing (HPC) resources. We review recent innovations in accelerating molecular dynamics on graphics processing units (GPUs), and we describe GPUGRID, a volunteer computing project that uses the GPU resources of nondedicated desktop and workstation computers. In particular, we demonstrate the capability of simulating thousands of all-atom molecular trajectories generated at an average of 20 ns/day each (for systems of approximately 30 000-80 000 atoms). In conjunction with a potential of mean force (PMF) protocol for computing binding free energies, we demonstrate the use of GPUGRID in the computation of accurate binding affinities of the Src SH2 domain/pYEEI ligand complex by reconstructing the PMF over 373 umbrella sampling windows of 55 ns each (20.5 mus of total data). We obtain a standard free energy of binding of -8.7 +/- 0.4 kcal/mol within 0.7 kcal/mol from experimental results. This infrastructure will provide the basis for a robust system for high-throughput accurate binding affinity prediction.

ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale.

The high arithmetic performance and intrinsic parallelism of recent graphical processing units (GPUs) can offer a technological edge for molecular dynamics simulations. ACEMD is a production-class biomolecular dynamics (MD) engine supporting CHARMM and AMBER force fields. Designed specifically for GPUs it is able to achieve supercomputing scale performance of 40 ns/day for all-atom protein systems with over 23 000 atoms. We provide a validation and performance evaluation of the code and run a microsecond-long trajectory for an all-atom molecular system in explicit TIP3P water on a single workstation computer equipped with just 3 GPUs. We believe that microsecond time scale molecular dynamics on cost-effective hardware will have important methodological and scientific implications.

An Implementation of the Smooth Particle Mesh Ewald Method on GPU Hardware.

The smooth particle mesh Ewald summation method is widely used to efficiently compute long-range electrostatic force terms in molecular dynamics simulations, and there has been considerable work in developing optimized implementations for a variety of parallel computer architectures. We describe an implementation for Nvidia graphical processing units (GPUs) which are general purpose computing devices with a high degree of intrinsic parallelism and arithmetic performance. We find that, for typical biomolecular simulations (e.g., DHFR, 26K atoms), a single GPU equipped workstation is able to provide sufficient performance to permit simulation rates of ≈50 ns/day when used in conjunction with the ACEMD molecular dynamics package (1) and exhibits an accuracy comparable to that of a reference double-precision CPU implementation.

Accuracy of the lattice-Boltzmann method using the Cell processor.

Accelerator processors like the new Cell processor are extending the traditional platforms for scientific computation, allowing orders of magnitude more floating-point operations per second (flops) compared to standard central processing units. However, they currently lack double-precision support and support for some IEEE 754 capabilities. In this work, we develop a lattice-Boltzmann (LB) code to run on the Cell processor and test the accuracy of this lattice method on this platform. We run tests for different flow topologies, boundary conditions, and Reynolds numbers in the range Re=6-350 . In one case, simulation results show a reduced mass and momentum conservation compared to an equivalent double-precision LB implementation. All other cases demonstrate the utility of the Cell processor for fluid dynamics simulations. Benchmarks on two Cell-based platforms are performed, the Sony Playstation3 and the QS20/QS21 IBM blade, obtaining a speed-up factor of 7 and 21, respectively, compared to the original PC version of the code, and a conservative sustained performance of 28 gigaflops per single Cell processor. Our results suggest that choice of IEEE 754 rounding mode is possibly as important as double-precision support for this specific scientific application.

The impact of accelerator processors for high-throughput molecular modeling and simulation.

The recent introduction of cost-effective accelerator processors (APs), such as the IBM Cell processor and Nvidia's graphics processing units (GPUs), represents an important technological innovation which promises to unleash the full potential of atomistic molecular modeling and simulation for the biotechnology industry. Present APs can deliver over an order of magnitude more floating-point operations per second (flops) than standard processors, broadly equivalent to a decade of Moore's law growth, and significantly reduce the cost of current atom-based molecular simulations. In conjunction with distributed and grid-computing solutions, accelerated molecular simulations may finally be used to extend current in silico protocols by the use of accurate thermodynamic calculations instead of approximate methods and simulate hundreds of protein-ligand complexes with full molecular specificity, a crucial requirement of in silico drug discovery workflows.

An integrated instrument control and informatics system for combinatorial materials research.

The use of high-throughput synthesis and characterization techniques is increasingly prevalent in materials science research. We describe the London University Search Instrument, a research apparatus designed for the high-throughput synthesis and characterization of thick-film sample libraries of ceramic compounds. The instrument is constructed largely from commodity components, which pose particular engineering challenges for achieving the automated operation required for efficient high-throughput experimentation. This paper describes the architecture and implementation of the software system that provides integrated instrument control and data management functions.

Efficacy of an anti-fertility vaccine based on mammalian gonadotrophin releasing hormone (GnRH-I)--a histological comparison in male animals.

A N-terminal modified gonadotrophin releasing hormone (GnRH-I, tetanus toxoid-CHWSYGLRPG-NH2) conjugate was evaluated histologically in a number of male animal species (mice, dogs and sheep). The immunogen has previously been shown to be highly effective in rats, by suppressing both steroidogenesis and spermatogenesis. However, cross-species efficacy of peptide vaccines is known to be highly variable. Therefore, a comparative evaluation of reproductive tissues from animals immunized against this immunogen adsorbed onto an alum-based adjuvant was made. The sheep and dogs were chosen, as use of anti-fertility vaccines in these species is important in farming and veterinary practice. Changes in testicular size were measured during the immunization period and the greatest alteration (attributed to gonadal atrophy) was observed in the rat. Following euthanasia, the testicular tissue was evaluated for spermatogenesis. The most susceptible species to GnRH-I ablation was the rat, which showed significant (P < 0.0001) arrest in spermatogenesis compared with untreated controls. Testicular sections taken from treated animals were completely devoid of spermatozoa or spermatids, in comparison with 94% of the untreated controls showing evidence of spermatogenesis. The immunized mice and rams also showed significant arrest (P < 0.0001). There was a 30-45% decrease in spermatogenesis and total azoospermia was not apparent. However, the least responsive were the dogs, which showed little significant variation compared to untreated animals and only a 5% decrease in activity. A comparison of the specific IgG response to GnRH-I indicated that in sheep and dogs the response was not maintained, unlike in rodents, suggesting that suppression of fertility may be due to differences in immune responses in different animal species.

Group 13 compounds incorporating Salen ligands.

In a previous review it was predicted that "the reactivity of five-coordinate complexes would certainly be different than that of the four-coordinate derivatives". Structurally and spectroscopically, there is very little difference in the higher-coordinate compounds when compared to the four-coordinate derivatives. However, the prediction was remarkably accurate, if not a bit understated, for the reactivity of these compounds. There appears to be a tremendous potential in catalysis and synthesis for the five-coordinate derivatives, far more possibilities than exist for the lower-coordinate derivatives. Furthermore, the higher-coordinate derivatives are rarely air or moisture sensitive and, thus, may be handled under a wider range of conditions. Although reactions such as oxirane and lactide polymerizations are fairly well-known now with five- and six-coordinate aluminum compounds, the potential of these compounds has only begun to be developed. It is easy to imagine that these types of compounds will see wider use than the related transition-metal compounds.

Monomeric uni-ligated aluminates.

The tetradentate ligand, common name Salban(But)H4 (N,N'-bis(2-hydroxy-3,5-di-tert-butylbenzyl)-1,4-diaminobutane) combines with appropriate amounts of LiAlH4 to produce the unique monomeric, uni-ligated aluminate [Salban(But)Al]Li(thf)2 (1) and the bimetallic derivative Salban(But)(AlH2Li(thf)2)2 (2).

Measurement of plasma oestradiol after an injection of a gonadotrophin as a test for neutered bitches.

Twenty-eight bitches with unknown reproductive histories were injected intravenously with either human chorionic gonadotrophin (hCG) or equine chorionic gonadotrophin (eCG) (pregnant mare's serum gonadotrophin) and their oestradiol responses were measured at the time of the injection and 90 minutes later. They were at various stages of the oestrous cycle as determined by histology and a progesterone assay for luteal function. Twenty-six of them were considered to be entire because they showed either an increase in plasma oestradiol over preinjection values or steady high values. The ovaries were removed from 25 of these animals and the other probably had a remnant of ovary because it came into oestrus some weeks later. In two remaining bitches no oestradiol could be detected either before or after the injection of gonadotrophin and they were predicted to have been neutered, which was confirmed at laparotomy. In the entire bitches, the highest plasma oestradiol concentration was measured during metoestrus and the lowest during anoestrus.

A study of the aetiology of pseudopregnancy in the bitch and the effect of cabergoline therapy.

Thirty-two permanently pseudopregnant bitches were treated with the anti-prolactin drug cabergoline. They had all been ovariohysterectomised up to five months after their last season, in some cases over two years previously, when most were reported as showing no signs of the condition. The clinical signs were mainly behavioural, the majority being aggressive, and a small number were lactating. The efficiency of the cabergoline therapy was classified by the owners as 'excellent' or 'good' in 50 per cent of the cases, and fair in 36 per cent. The rate of success was markedly better than in similar cases treated with reproductive steroids. In all but one of the bitches, the plasma prolactin concentrations were basal.

Effect and mechanisms of the anti-prolactin drug cabergoline on pseudopregnancy in the bitch.

A potent anti-prolactin drug, cabergoline, administered orally for five days, was clinically successful in treating three different clinical manifestations of pseudopregnancy in referred bitches. The clinical conditions treated were categorised as standard pseudopregnant bitches (n = 8), those previously unsuccessfully treated with hormones (n = 10) and those which had behavioural pseudopregnancy following ovariohysterectomy (n = 8). The number of bitches whose owners reported a 'good' response was seven out of eight, six out of 10 and six out of eight, respectively. There were very few side effects in that only one bitch vomited following treatment. The clinical response did not necessarily appear to be related to an alteration in circulating prolactin concentrations, suggesting that the drug may have a direct effect on the tissues as well as in most cases reducing the plasma prolactin concentrations.