Association mapping of partitioning loci in barley

BACKGROUND: Association mapping, initially developed in human disease genetics, is now being applied to plant species. The model species Arabidopsis provided some of the first examples of association mapping in plants, identifying previously cloned flowering time genes, despite high population sub-structure. More recently, association genetics has been applied to barley, where breeding activity has resulted in a high degree of population sub-structure. A major genotypic division within barley is that between winter- and spring-sown varieties, which differ in their requirement for vernalization to promote subsequent flowering. To date, all attempts to validate association genetics in barley by identifying major flowering time loci that control vernalization requirement (VRN-H1 and VRN-H2) have failed. Here, we validate the use of association genetics in barley by identifying VRN-H1 and VRN-H2, despite their prominent role in determining population sub-structure. RESULTS: By taking barley as a typical inbreeding crop, and seasonal growth habit as a major partitioning phenotype, we develop an association mapping approach which successfully identifies VRN-H1 and VRN-H2, the underlying loci largely responsible for this agronomic division. We find a combination of Structured Association followed by Genomic Control to correct for population structure and inflation of the test statistic, resolved significant associations only with VRN-H1 and the VRN-H2 candidate genes, as well as two genes closely linked to VRN-H1 (HvCSFs1 and HvPHYC). CONCLUSION: We show that, after employing appropriate statistical methods to correct for population sub-structure, the genome-wide partitioning effect of allelic status at VRN-H1 and VRN-H2 does not result in the high levels of spurious association expected to occur in highly structured samples. Furthermore, we demonstrate that both VRN-H1 and the candidate VRN-H2 genes can be identified using association mapping. Discrimination between intragenic VRN-H1 markers was achieved, indicating that candidate causative polymorphisms may be discerned and prioritised within a larger set of positive associations. This proof of concept study demonstrates the feasibility of association mapping in barley, even within highly structured populations. A major advantage of this method is that it does not require large numbers of genome-wide markers, and is therefore suitable for fine mapping and candidate gene evaluation, especially in species for which large numbers of genetic markers are either unavailable or too costly

Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction.

Abnormal humoral responses toward motor end plate constituents in muscle induce myasthenia gravis (MG). To study the etiology of this disease, and whether it could be induced by host defense molecules, we examined the consequences of interferon (IFN) gamma production within the neuromuscular junction of transgenic mice. The transgenic mice exhibited gradually increasing muscular weakness, flaccid paralysis, and functional disruption of the neuromuscular junction that was reversed after administration of an inhibitor of acetylcholinesterase, features which are strikingly similar to human MG. Furthermore, histological examination revealed infiltration of mononuclear cells and autoantibody deposition at motor end plates. Immunoprecipitation analysis indicated that a previously unidentified 87-kD target antigen was recognized by sera from transgenic mice and also by sera from the majority of human MG patients studied. These results suggest that expression of IFN-gamma at motor end plates provokes an autoimmune humoral response, similar to human MG, thus linking the expression of this factor with development of this disease

Development of strategies for effective communication of food risks and benefits across Europe: Design and conceptual framework of the FoodRisC project

The FoodRisC project is funded under the Seventh Framework Programme (CORDIS FP7) of the European Commission; Grant agreement no.: 245124. Copyright @ 2011 Barnett et al.BACKGROUND: European consumers are faced with a myriad of food related risk and benefit information and it is regularly left up to the consumer to interpret these, often conflicting, pieces of information as a coherent message. This conflict is especially apparent in times of food crises and can have major public health implications. Scientific results and risk assessments cannot always be easily communicated into simple guidelines and advice that non-scientists like the public or the media can easily understand especially when there is conflicting, uncertain or complex information about a particular food or aspects thereof. The need for improved strategies and tools for communication about food risks and benefits is therefore paramount. The FoodRisC project ("Food Risk Communication - Perceptions and communication of food risks/benefits across Europe: development of effective communication strategies") aims to address this issue. The FoodRisC project will examine consumer perceptions and investigate how people acquire and use information in food domains in order to develop targeted strategies for food communication across Europe.METHODS/DESIGN: This project consists of 6 research work packages which, using qualitative and quantitative methodologies, are focused on development of a framework for investigating food risk/benefit issues across Europe, exploration of the role of new and traditional media in food communication and testing of the framework in order to develop evidence based communication strategies and tools. The main outcome of the FoodRisC project will be a toolkit to enable coherent communication of food risk/benefit messages in Europe. The toolkit will integrate theoretical models and new measurement paradigms as well as building on social marketing approaches around consumer segmentation. Use of the toolkit and guides will assist policy makers, food authorities and other end users in developing common approaches to communicating coherent messages to consumers in Europe.DISCUSSION: The FoodRisC project offers a unique approach to the investigation of food risk/benefit communication. The effective spread of food risk/benefit information will assist initiatives aimed at reducing the burden of food-related illness and disease, reducing the economic impact of food crises and ensuring that confidence in safe and nutritious food is fostered and maintained in Europe.This article is available through the Brunel Open Access Publishing Fund

Evidence-based intervention for preschool children with primary speech and language impairments: Child Talk - an exploratory mixed-methods study

BackgroundThe Child Talk study aimed to develop an evidence-based framework to support the decision-making of speech and language therapists (SLTs) as they design and plan interventions appropriate to the needs of individual children with primary speech and language impairments and their families. The need for early identification and effective intervention for these children continues to be a government policy priority because of the link between children’s early speech and language skills and their broader well-being and outcomes in later life. The first phase of Child Talk sought to map and describe current SLT practice for these children; identify and summarise the existing research evidence relating to practice; and investigate the perspectives of parents, early years practitioners, preschool children and ‘underserved’ communities on speech and language therapy. The second phase of Child Talk focused on the development of a toolkit – assessment tools, outcome measures and a data set – to support future service and economic evaluations of the framework.MethodsChild Talk adopted a mixed-methods design. Quantitative methods included surveys and investigated the prevalence and patterns of intervention usage; qualitative data collection methods included focus groups, interviews and reflection to investigate participants’ perspectives and understandings of interventions. Data analysis methods included descriptive and inferential statistics, thematic and content analysis and framework analysis. Participants were recruited nationally through six NHS sites, professional bodies, parent groups and advertising. Participants included SLTs (n = 677), parents (n = 84), preschool children (n = 24), early years practitioners (n = 31) and ‘underserved’ communities (n = 52).Key findingsSpeech and language therapy interventions were characterised in terms of nine themes, viewed as comprehensive and inclusive by practitioners. Relevant assessments, interventions and outcome domains were identified for the nine themes. Areas of tacit knowledge and underspecified processes contributed to variability in the detail of the framework. Systematic reviews identified 58 relevant and robust studies (from 55,271 papers retrieved from the initial literature search). The number of studies relevant to each theme varied from 1 to 33. Observational data on preschool children’s perspectives on speech and language therapy interventions revealed the dynamic nature of their interaction with different activities and people within therapy sessions. Parents’ experiences of speech and language therapy were generally positive although some reported that the rationale for therapy was not always clear. Parental perspectives in underserved communities suggested that, although parents were confident about how to support children’s language development, they were less informed about the nature of language impairments and the function of speech and language therapy. The availability of information regarding resources directed towards speech and language therapy services was poor. In particular, services lacked both a culture of collecting outcome data routinely and measures of professional input and costs associated with their activities.ConclusionA descriptive framework of SLT practice has been developed to support the discussions between therapists and families when making decisions regarding the selection of interventions and outcome measures. Further research is needed to address gaps in the intervention framework and evaluate its effectiveness and cost-effectiveness in improving outcomes for preschool children with primary speech and language impairments.Study registrationThis study is registered as PROSPERO CRD42013006369

Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients

Rationale: Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP. Objectives: To characterize subglottic host defense dysfunction in mechanically ventilated patients in the intensive care unit (ICU). To determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth. Methods: Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 minutes). Isolation and culture of primary subglottic epithelial cells from controls. Laboratory analysis of host innate immune defenses. Measurements and Main Results: Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in ICU was characterized by neutrophilic inflammation, significantly increased pro-inflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic function was reversible upon treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium. Conclusions: Mechanical ventilation in ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil dysfunction and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage

Myopathy in an infant with a fatal peroxisomal disorder

An infant with neonatal adrenoleukodystrophy experienced extreme hypotonia and virtually continuous convulsions at four months of age and died. Light and electron microscopic examination revealed evidence of myopathy and the presence of mitochondrial inclusions. Concentrations of very long-chain fatty acids were elevated in blood and fibroblasts and the oxidation of 14C-labeled fatty acids was defective. Urinary pipecolic acid content was increased. Activity of the peroxisomal dihydroxyacetone phosphate acyltransferase, which catalyzes the first step in plasmalogen synthesis, was decreased.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26173/1/0000252.pd

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer.

Background The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. Methods We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. Results There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). Conclusions At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .)