Gene expression in large pedigrees: analytic approaches.

BackgroundWe currently have the ability to quantify transcript abundance of messenger RNA (mRNA), genome-wide, using microarray technologies. Analyzing genotype, phenotype and expression data from 20 pedigrees, the members of our Genetic Analysis Workshop (GAW) 19 gene expression group published 9 papers, tackling some timely and important problems and questions. To study the complexity and interrelationships of genetics and gene expression, we used established statistical tools, developed newer statistical tools, and developed and applied extensions to these tools.MethodsTo study gene expression correlations in the pedigree members (without incorporating genotype or trait data into the analysis), 2 papers used principal components analysis, weighted gene coexpression network analysis, meta-analyses, gene enrichment analyses, and linear mixed models. To explore the relationship between genetics and gene expression, 2 papers studied expression quantitative trait locus allelic heterogeneity through conditional association analyses, and epistasis through interaction analyses. A third paper assessed the feasibility of applying allele-specific binding to filter potential regulatory single-nucleotide polymorphisms (SNPs). Analytic approaches included linear mixed models based on measured genotypes in pedigrees, permutation tests, and covariance kernels. To incorporate both genotype and phenotype data with gene expression, 4 groups employed linear mixed models, nonparametric weighted U statistics, structural equation modeling, Bayesian unified frameworks, and multiple regression.Results and discussionRegarding the analysis of pedigree data, we found that gene expression is familial, indicating that at least 1 factor for pedigree membership or multiple factors for the degree of relationship should be included in analyses, and we developed a method to adjust for familiality prior to conducting weighted co-expression gene network analysis. For SNP association and conditional analyses, we found FaST-LMM (Factored Spectrally Transformed Linear Mixed Model) and SOLAR-MGA (Sequential Oligogenic Linkage Analysis Routines -Major Gene Analysis) have similar type 1 and type 2 errors and can be used almost interchangeably. To improve the power and precision of association tests, prior knowledge of DNase-I hypersensitivity sites or other relevant biological annotations can be incorporated into the analyses. On a biological level, eQTL (expression quantitative trait loci) are genetically complex, exhibiting both allelic heterogeneity and epistasis. Including both genotype and phenotype data together with measurements of gene expression was found to be generally advantageous in terms of generating improved levels of significance and in providing more interpretable biological models.ConclusionsPedigrees can be used to conduct analyses of and enhance gene expression studies

Public perceptions of recycled water: a survey of visitors to the London 2012 Olympic Park

The Old Ford Water Recycling Plant, operated by Thames Water, was used to supply non-potable recycled blackwater to some of the venues at the London 2012 Games. In an effort to learn from this experience, Thames Water commissioned a survey of visitors to the Olympic Park during the Games to explore public responses to the water recycling project. Results show a very high level of support for using non-potable recycled blackwater, both in public venues and in homes. Such findings may indicate a growing receptivity towards this technology, and show that Thames Water (and other private water companies) are well placed to encourage and even lead public discussion around the role of water reuse in the future of urban water supplies

Inherent work suit buoyancy distribution:effects on lifejacket self-righting performance

Introduction: Accidental immersion in cold water is an occupational risk. Work suits and life jackets (LJ) should work effectively in combination to keep the airway clear of the water (freeboard) and enable self-righting. We hypothesized that inherent buoyancy, in the suit or LJ, would be beneficial for enabling freeboard, but its distribution may influence LJ self-righting. Methods: Six participants consented to complete nine immersions. Suits and LJ tested were: flotation suit (FLOAT; 85 N inherent buoyancy); oilskins 1 (OS-1) and 2 (OS-2), both with no inherent buoyancy; LJs (inherent buoyancy/buoyancy after inflation/total buoyancy), LJ-1 50/150/200 N, LJ-2 0/290/290 N, LJ-3 80/190/270 N. Once dressed, the subject entered an immersion pool where uninflated freeboard, self-righting performance, and inflated freeboard were measured. Data were compared using Friedman’s test to the 0.05 alpha level. Results: All suits and LJs enabled uninflated and inflated freeboard, but differences were seen between the suits and LJs. Self-righting was achieved on 43 of 54 occasions, irrespective of suit or LJ. On all occasions that self-righting was not achieved, this occurred in an LJ that included inherent buoyancy (11/54 occasions). Of these 11 failures, 8 occurred (73% of occasions) when the FLOAT suit was being worn. Discussion: LJs that included inherent buoyancy, that are certified as effective on their own, worked less effectively from the perspective of self-righting in combination with a work suit that also included inherent buoyancy. Equipment that is approved for use in the workplace should be tested in combination to ensure adequate performance in an emergency scenario

Dilaton constraints and LHC prospects

The Standard Model Higgs searches using the first 1-2 fb-1 of LHC data can be used to put interesting constraints on new scalar particles other than the Higgs. We investigate one such scenario in which electroweak symmetry is broken via strongly coupled conformal dynamics. This scenario contains a neutral scalar dilaton---the Goldstone boson associated with spontaneously broken scale invariance---with a mass below the conformal symmetry breaking scale and couplings to Standard Model particles similar (but not identical) to those of the Standard Model Higgs boson. We translate the LEP and LHC Higgs limits to constrain the dilaton mass and conformal breaking scale. The conformal breaking scale f is constrained to be above 1 TeV for dilaton masses between 145 and 600 GeV, though it can be as low as 400 GeV for dilaton masses below 110 GeV. We also show that (i) a dilaton chi with mass below 110 GeV and consistent with the LEP constraints can appear in gg --> chi --> gamma gamma with a rate up to ~10 times the corresponding Standard Model Higgs rate, and (ii) a dilaton with mass of several hundred GeV is much narrower than the corresponding Standard Model Higgs, leading to improved search sensitivity in chi --> ZZ --> 4l.Comment: 15 pages, 12 figures, References added, Figure 10 modified, Figure 11 adde

An Estimation of the Gamma-Ray Burst Afterglow Apparent Optical Brightness Distribution Function

By using recent publicly available observational data obtained in conjunction with the NASA Swift gamma-ray burst mission and a novel data analysis technique, we have been able to make some rough estimates of the GRB afterglow apparent optical brightness distribution function. The results suggest that 71% of all burst afterglows have optical magnitudes with mR < 22.1 at 1000 seconds after the burst onset, the dimmest detected object in the data sample. There is a strong indication that the apparent optical magnitude distribution function peaks at mR ~ 19.5. Such estimates may prove useful in guiding future plans to improve GRB counterpart observation programs. The employed numerical techniques might find application in a variety of other data analysis problems in which the intrinsic distributions must be inferred from a heterogeneous sample.Comment: 15 pages including 2 tables and 7 figures, accepted for publication in Ap

Integrated Serologic Surveillance of Population Immunity and Disease Transmission.

Antibodies are unique among biomarkers in their ability to identify persons with protective immunity to vaccine-preventable diseases and to measure past exposure to diverse pathogens. Most infectious disease surveillance maintains a single-disease focus, but broader testing of existing serologic surveys with multiplex antibody assays would create new opportunities for integrated surveillance. In this perspective, we highlight multiple areas for potential synergy where integrated surveillance could add more value to public health efforts than the current trend of independent disease monitoring through vertical programs. We describe innovations in laboratory and data science that should accelerate integration and identify remaining challenges with respect to specimen collection, testing, and analysis. Throughout, we illustrate how information generated through integrated surveillance platforms can create new opportunities to more quickly and precisely identify global health program gaps that range from undervaccination to emerging pathogens to multilayered health disparities that span diverse communicable diseases

Differential expression of skeletal muscle genes following administration of clenbuterol to exercised horses.

BackgroundClenbuterol, a beta2-adrenergic receptor agonist, is used therapeutically to treat respiratory conditions in the horse. However, by virtue of its mechanism of action it has been suggested that clenbuterol may also have repartitioning affects in horses and as such the potential to affect performance. Clenbuterol decreases the percent fat and increases fat-free mass following high dose administration in combination with intense exercise in horses. In the current study, microarray analysis and real-time PCR were used to study the temporal effects of low and high dose chronic clenbuterol administration on differential gene expression of several skeletal muscle myosin heavy chains, genes involved in lipid metabolism and the β2-adrenergic receptor. The effect of clenbuterol administration on differential gene expression has not been previously reported in the horse, therefore the primary objective of the current study was to describe clenbuterol-induced temporal changes in gene expression following chronic oral administration of clenbuterol at both high and low doses.ResultsSteady state clenbuterol concentrations were achieved at approximately 50&nbsp;h post administration of the first dose for the low dose regimen and at approximately 18-19 days (10&nbsp;days post administration of 3.2&nbsp;μg/kg) for the escalating dosing regimen. Following chronic administration of the low dose (0.8&nbsp;μg/kg BID) of clenbuterol, a total of 114 genes were differentially expressed, however, none of these changes were found to be significant following FDR adjustment of the p-values. A total of 7,093 genes were differentially expressed with 3,623 genes up regulated and 3,470 genes down regulated following chronic high dose administration. Of the genes selected for further study by real-time PCR, down-regulation of genes encoding myosin heavy chains 2 and 7, steroyl CoA desaturase and the β2-adrenergic receptor were noted. For most genes, expression levels returned towards baseline levels following cessation of drug administration.ConclusionThis study showed no evidence of modified gene expression following chronic low dose administration of clenbuterol to horses. However, following chronic administration of high doses of clenbuterol alterations were noted in transcripts encoding various myosin heavy chains, lipid metabolizing enzymes and the β2-adrenergic receptor

Loss of strumpellin in the melanocytic lineage impairs the WASH Complex but does not affect coat colour

The five-subunit WASH complex generates actin networks that participate in endocytic trafficking, migration and invasion in various cell types. Loss of one of the two subunits WASH or strumpellin in mice is lethal, but little is known about their role in mammals in vivo. We explored the role of strumpellin, which has previously been linked to hereditary spastic paraplegia, in the mouse melanocytic lineage. Strumpellin knockout in melanocytes revealed abnormal endocytic vesicle morphology but no impairment of migration in vitro or in vivo and no change in coat colour. Unexpectedly, WASH and filamentous actin could still localize to vesicles in the absence of strumpellin, although the shape and size of vesicles was altered. Blue native PAGE revealed the presence of two distinct WASH complexes, even in strumpellin knockout cells, revealing that the WASH complex can assemble and localize to endocytic compartments in cells in the absence of strumpellin