Chipper: discovering transcription-factor targets from chromatin immunoprecipitation microarrays using variance stabilization

Chromatin immunoprecipitation combined with microarray technology (Chip(2)) allows genome-wide determination of protein-DNA binding sites. The current standard method for analyzing Chip(2 )data requires additional control experiments that are subject to systematic error. We developed methods to assess significance using variance stabilization, learning error-model parameters without external control experiments. The method was validated experimentally, shows greater sensitivity than the current standard method, and incorporates false-discovery rate analysis. The corresponding software ('Chipper') is freely available. The method described here should help reveal an organism's transcription-regulatory 'wiring diagram'

An en masse phenotype and function prediction system for Mus musculus

Background: Individual researchers are struggling to keep up with the accelerating emergence of high-throughput biological data, and to extract information that relates to their specific questions. Integration of accumulated evidence should permit researchers to form fewer - and more accurate - hypotheses for further study through experimentation. Results: Here a method previously used to predict Gene Ontology (GO) terms for Saccharomyces cerevisiae (Tian et al.: Combining guilt-by-association and guilt-by-profiling to predict Saccharomyces cerevisiae gene function. Genome Biol 2008, 9(Suppl 1):S7) is applied to predict GO terms and phenotypes for 21,603 Mus musculus genes, using a diverse collection of integrated data sources (including expression, interaction, and sequence-based data). This combined 'guilt-by-profiling' and 'guilt-by-association' approach optimizes the combination of two inference methodologies. Predictions at all levels of confidence are evaluated by examining genes not used in training, and top predictions are examined manually using available literature and knowledge base resources. Conclusion: We assigned a confidence score to each gene/term combination. The results provided high prediction performance, with nearly every GO term achieving greater than 40% precision at 1% recall. Among the 36 novel predictions for GO terms and 40 for phenotypes that were studied manually, >80% and >40%, respectively, were identified as accurate. We also illustrate that a combination of 'guilt-by-profiling' and 'guilt-by-association' outperforms either approach alone in their application to M. musculus.Molecular and Cellular Biolog

Combining guilt-by-association and guilt-by-profiling to predict Saccharomyces cerevisiae gene function

BackgroundLearning the function of genes is a major goal of computational genomics. Methods for inferring gene function have typically fallen into two categories: 'guilt-by-profiling', which exploits correlation between function and other gene characteristics; and 'guilt-by-association', which transfers function from one gene to another via biological relationships.ResultsWe have developed a strategy ('Funckenstein') that performs guilt-by-profiling and guilt-by-association and combines the results. Using a benchmark set of functional categories and input data for protein-coding genes in Saccharomyces cerevisiae, Funckenstein was compared with a previous combined strategy. Subsequently, we applied Funckenstein to 2,455 Gene Ontology terms. In the process, we developed 2,455 guilt-by-profiling classifiers based on 8,848 gene characteristics and 12 functional linkage graphs based on 23 biological relationships.ConclusionFunckenstein outperforms a previous combined strategy using a common benchmark dataset. The combination of 'guilt-by-profiling' and 'guilt-by-association' gave significant improvement over the component classifiers, showing the greatest synergy for the most specific functions. Performance was evaluated by cross-validation and by literature examination of the top-scoring novel predictions. These quantitative predictions should help prioritize experimental study of yeast gene functions

Mycetoma in Timor-Leste and first report of nocardiosis

Mycetoma is a neglected tropical disease with an unknown global burden. Although considered endemic to South-east Asia, it has not previously been reported from Timor-Lest. We describe two cases in Timor-Leste, highlighting the challenges surrounding microbiological diagnosis and management shared by many low to middle-income countries. As characteristically described, both patients lived rurally and presented late with marked soft tissue involvement and multiple draining sinuses following a prolonged period of high morbidity. Nocardia brasiliensis, a beadedbranched, modified acid-fast, gram-positive bacilli, was isolated and confirmed by molecular testing in the first case. The causative organism in the second case could not be confirmed due to limited microbiological capabilities. Due to limited local laboratory capabilities, Nocardia spp. infection cannot be routinely confirmed in Timor- Leste. However, the microbiology laboratory is essential for the successful diagnosis and management of Mycetoma. In both cases, medical therapy alone resulted in cure and favorable outcomes, although supply of antibiotic remains an ongoing resource issue

Patient experience feedback in UK hospitals : What types are available and what are their potential roles in quality improvement (QI)?

BACKGROUND & OBJECTIVES: The comparative uses of different types of patient experience (PE) feedback as data within quality improvement (QI) are poorly understood. This paper reviews what types are currently available and categorizes them by their characteristics in order to better understand their roles in QI. METHODS: A scoping review of types of feedback currently available to hospital staff in the UK was undertaken. This comprised academic database searches for "measures of PE outcomes" (2000-2016), and grey literature and websites for all types of "PE feedback" potentially available (2005-2016). Through an iterative consensus process, we developed a list of characteristics and used this to present categories of similar types. MAIN RESULTS: The scoping review returned 37 feedback types. A list of 12 characteristics was developed and applied, enabling identification of 4 categories that help understand potential use within QI-(1) Hospital-initiated (validated) quantitative surveys: for example the NHS Adult Inpatient Survey; (2) Patient-initiated qualitative feedback: for example complaints or twitter comments; (3) Hospital-initiated qualitative feedback: for example Experience Based Co-Design; (4) Other: for example Friends & Family Test. Of those routinely collected, few elicit "ready-to-use" data and those that do elicit data most suitable for measuring accountability, not for informing ward-based improvement. Guidance does exist for linking collection of feedback to QI for some feedback types in Category 3 but these types are not routinely used. CONCLUSION: If feedback is to be used more frequently within QI, more attention must be paid to obtaining and making available the most appropriate types

Stochastic atmospheric assistance and the use of emergency staging sites by migrants

Numerous animals move vast distances through media with stochastic dynamic properties. Avian migrants must cope with variable wind speeds and directions en route, which potentially jeopardize fine-tuned migration routes and itineraries. We show how unpredictable winds affect flight times and the use of an intermediate staging site by red knots (Calidris canutus canutus) migrating from west Africa to the central north Siberian breeding areas via the German Wadden Sea. A dynamic migration model incorporating wind conditions during flight shows that flight durations between Mauritania and the Wadden Sea vary between 2 and 8 days. The number of birds counted at the only known intermediate staging site on the French Atlantic coast was strongly positively correlated with simulated flight times. In addition, particularly light-weight birds occurred at this location. These independent results support the idea that stochastic wind conditions are the main driver of the use of this intermediate stopover site as an emergency staging area. Because of the ubiquity of stochastically varying media, we expect such emergency habitats to exist in many other migratory systems, both airborne and oceanic. Our model provides a tool to quantify the effect of winds and currents en route

Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson's disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson's disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations

Search for New Physics with Jets and Missing Transverse Momentum in pp collisions at sqrt(s) = 7 TeV

A search for new physics is presented based on an event signature of at least three jets accompanied by large missing transverse momentum, using a data sample corresponding to an integrated luminosity of 36 inverse picobarns collected in proton--proton collisions at sqrt(s)=7 TeV with the CMS detector at the LHC. No excess of events is observed above the expected standard model backgrounds, which are all estimated from the data. Exclusion limits are presented for the constrained minimal supersymmetric extension of the standard model. Cross section limits are also presented using simplified models with new particles decaying to an undetected particle and one or two jets