Bioinformatic Extraction of Functional Genetic Diversity from Heterogeneous Germplasm Collections for Crop Improvement

Efficient utilization of genetic variation in plant germplasm collections is impeded by large collection size, uneven characterization of traits, and unpredictable apportionment of allelic diversity among heterogeneous accessions. Distributing compact subsets of the complete collection that contain maximum allelic diversity at functional loci of interest could streamline conventional and precision breeding. Using heterogeneous population samples from Arabidopsis, Populus and sorghum, we show that genomewide single nucleotide polymorphism (SNP) data permits the capture of 3–78 fold more haplotypic diversity in subsets than geographic or environmental data, which are commonly used surrogate predictors of genetic diversity. Using a large genomewide SNP data set from landrace sorghum, we demonstrate three bioinformatic approaches to extract functional genetic diversity. First, in a “candidate gene” approach, we assembled subsets that maximized haplotypic diversity at 135 putative lignin biosynthetic loci, relevant to biomass breeding programs. Secondly, we applied a keyword search against the Gene Ontology to identify 1040 regulatory loci and assembled subsets capturing genomewide regulatory gene diversity, a general source of phenotypic variation. Third, we developed a machine-learning approach to rank semantic similarity between Gene Ontology term definitions and the textual content of scientific publications on crop adaptation to climate, a complex breeding objective. We identified 505 sorghum loci whose defined function is semantically-related to climate adaptation concepts. The assembled subsets could be used to address climatic pressures on sorghum production. To face impending agricultural challenges and foster rapid extraction and use of novel genetic diversity resident in heterogeneous germplasm collections, whole genome resequencing efforts should be prioritized

Challenges in evaluating surgical innovation

Research on surgical interventions is associated with several methodological and practical challenges of which few, if any, apply only to surgery. However, surgical evaluation is especially demanding because many of these challenges coincide. In this report, the second of three on surgical innovation and evaluation, we discuss obstacles related to the study design of randomised controlled trials and non-randomised studies assessing surgical interventions. We also describe the issues related to the nature of surgical procedures—for example, their complexity, surgeon-related factors, and the range of outcomes. Although difficult, surgical evaluation is achievable and necessary. Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential.The Balliol Colloquium has been supported by Ethicon UK with unrestricted educational grants and by the National Institute of Health Research Health Technology Assessment Programme. The Balliol Colloquium was administratively and financially supported by the Nuffield Department of Surgery at the University of Oxford and the Department of Surgery at McGill University. JAC holds a Medical Research Council UK special training fellowship. The University of Aberdeen’s Health Services Research Unit is core funded by the Chief Scientist Offi ce of the Scottish Government Health Directorates. IB is supported by a grant from the Société Française de Rhumatologie and Lavoisier Program (Ministère des Aff aires Etrangères et Européennes). PLE is a DPhil Candidate in Evidence-Based Health Care at Oxford University

Protocol for the economic evaluation of metacognitive therapy for cardiac rehabilitation participants with symptoms of anxiety and/or depression

INTRODUCTION: Cardiac rehabilitation (CR) is offered to reduce the risk of further cardiac events and to improve patients' health and quality of life following a cardiac event. Psychological care is a common component of CR as symptoms of depression and/or anxiety are more prevalent in this population, however evidence for the cost-effectiveness of current interventions is limited. Metacognitive therapy (MCT), is a recent treatment development that is effective in treating anxiety and depression in mental health settings and is being evaluated in CR patients. This protocol describes the planned approach to the economic evaluation of MCT for CR patients. METHODS AND ANALYSIS: The economic evaluation work will consist of a within-trial analysis and an economic model. The PATHWAY Group MCT study has been prospectively designed to collect comprehensive self-reported resource use and health outcome data, including the EQ-5D, within a randomised controlled trial study design (UK Clinical Trials Gateway). A within-trial economic evaluation and economic model will compare the cost-effectiveness of MCT plus usual care (UC) to UC, from a health and social care perspective in the UK. The within-trial analysis will use intention-to-treat and estimate total costs and quality-adjusted life-years (QALYs) for the trial follow-up. Single imputation will be used to impute missing baseline variables. Multiple imputation will be used to impute values missing at follow-up. Items of resource use will be multiplied by published national healthcare costs. Regression analysis will be used to estimate net costs and net QALYs and these estimates will be bootstrapped to generate 10 000 net pairs of costs and QALYs to inform the probability of cost-effectiveness. A decision analytical economic model will be developed to synthesise trial data with the published literature over a longer time frame. Sensitivity analysis will explore uncertainty. Guidance of the methods for economic models will be followed and dissemination will adhere to reporting guidelines. ETHICS AND DISSEMINATION: The economic evaluation includes a within-trial analysis. The trial which included the collection of this data was reviewed and approved by Ethics. Ethics approval was obtained by the Preston Research Ethics Committee (project ID 156862). The modelling analysis is not applicable for Ethics as it will use data from the trial (secondary analysis) and the published literature. Results of the main trial and economic evaluation will be published in the peer-reviewed National Institute for Health Research (NIHR) journals library (Programme Grants for Applied Research), submitted to a peer-reviewed journal and presented at appropriate conferences. TRIAL REGISTRATION NUMBER: ISRCTN74643496; Pre-results

Analysis of Water Surplus at the Lunar Outpost

This paper evaluates the benefits to the lunar architecture and outpost of having a surplus of water, or a surplus of energy in the form of hydrogen and oxygen, as it has been predicted by Constellation Program's Lunar Surface System analyses. Assumptions and a scenario are presented leading to the water surplus and the revolutionary surface element options for improving the lunar exploration architecture and mission objectives. For example, some of the elements that can benefit from a water surplus are: the power system energy storage can minimize the use of battery systems by replacing batteries with higher energy density fuel cell systems; battery packs on logistics pallets can also be minimized; mobility asset power system mass can be reduced enabling more consumables and extended roving duration and distance; small robotic vehicles (hoppers) can be used to increase the science exploration range by sending round-trip robotic missions to anywhere on the Moon using in-situ produced propellants

An XMM-Newton view of the `bare' nucleus of Fairall 9

We present the spectral results from a 130 ks observation, obtained from the X-ray Multi-Mirror Mission-Newton (XMM-Newton) observatory, of the type I Seyfert galaxy Fairall 9. An X-ray hardness-ratio analysis of the light-curves, reveals a `softer-when-brighter' behaviour which is typical for radio-quiet type I Seyfert galaxies. Moreover, we analyse the high spectral-resolution data of the reflection grating spectrometer and we did not find any significant evidence supporting the presence of warm-absorber in the low X-ray energy part of the source's spectrum. This means that the central nucleus of Fairall 9 is `clean' and thus its X-ray spectral properties probe directly the physical conditions of the central engine. The overall X-ray spectrum in the 0.5-10 keV energy-range, derived from the EPIC data, can be modelled by a relativistically blurred disc-reflection model. This spectral model yields for Fairall 9 an intermediate black-hole best-fit spin parameter of $\alpha=0.39^{+0.48}_{-0.30}$.Comment: Accepted for publication in MNRAS. The paper contains 11 figures and 1 tabl

A Compensatory Mutation Provides Resistance to Disparate HIV Fusion Inhibitor Peptides and Enhances Membrane Fusion

Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations. © 2013 Wood et al