Bayesian profiling of molecular signatures to predict event times

BACKGROUND: It is of particular interest to identify cancer-specific molecular signatures for early diagnosis, monitoring effects of treatment and predicting patient survival time. Molecular information about patients is usually generated from high throughput technologies such as microarray and mass spectrometry. Statistically, we are challenged by the large number of candidates but only a small number of patients in the study, and the right-censored clinical data further complicate the analysis. RESULTS: We present a two-stage procedure to profile molecular signatures for survival outcomes. Firstly, we group closely-related molecular features into linkage clusters, each portraying either similar or opposite functions and playing similar roles in prognosis; secondly, a Bayesian approach is developed to rank the centroids of these linkage clusters and provide a list of the main molecular features closely related to the outcome of interest. A simulation study showed the superior performance of our approach. When it was applied to data on diffuse large B-cell lymphoma (DLBCL), we were able to identify some new candidate signatures for disease prognosis. CONCLUSION: This multivariate approach provides researchers with a more reliable list of molecular features profiled in terms of their prognostic relationship to the event times, and generates dependable information for subsequent identification of prognostic molecular signatures through either biological procedures or further data analysis

Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia

<p>Abstract</p> <p>Background</p> <p>Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1).</p> <p>Methods</p> <p>In this study, an inexpensive allele-specific PCR (AS-PCR) assay was designed that allowed the relative quantification of the two RyR1 transcripts in heterozygous samples found to be susceptible to MH (MHS). Allele-specific differences in RyR1 expression levels can provide insight into the observed variable penetrance and variations in MH phenotypes between individuals. The presence/absence of the H4833Y mutation in <it>RYR</it>1 transcripts was employed as a marker that allowed discrimination between the two alleles.</p> <p>Results</p> <p>In four skeletal muscle samples and two lymphoblastoid cell lines (LCLs) from different MHS patients, the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. For both LCLs, the ratios between the wild type and mutant <it>RYR</it>1 alleles did not change after different incubation times with actinomycin D. This suggests that there are no allele-specific differences in RyR1 mRNA stability, at least in these cells.</p> <p>Conclusion</p> <p>The data presented here revealed for the first time allele-specific differences in <it>RYR</it>1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes.</p

Hydrocarbon Contamination Decreases Mating Success in a Marine Planktonic Copepod

The mating behavior and the mating success of copepods rely on chemoreception to locate and track a sexual partner. However, the potential impact of the water-soluble fraction of hydrocarbons on these aspects of copepod reproduction has never been tested despite the widely acknowledged acute chemosensory abilities of copepods. I examined whether three concentrations of the water-soluble fraction of diesel oil (0.01%, 0.1% and 1%) impacts (i) the swimming behavior of both adult males and females of the widespread calanoid copepod Temora longcornis, and (ii) the ability of males to locate, track and mate with females. The three concentrations of the water-soluble fraction of diesel oil (WSF) significantly and non-significantly affect female and male swimming velocities, respectively. In contrast, both the complexity of male and female swimming paths significantly decreased with increasing WSF concentrations, hence suggesting a sex-specific sensitivity to WSF contaminated seawater. In addition, the three WSF concentrations impacted both T. longicornis mating behavior and mating success. Specifically, the ability of males to detect female pheromone trails, to accurately follow trails and to successfully track a female significantly decreased with increasing WSF concentrations. This led to a significant decrease in contact and capture rates from control to WSF contaminated seawater. These results indicate that hydrocarbon contamination of seawater decreases the ability of male copepods to detect and track a female, hence suggest an overall impact on population fitness and dynamics

Dissection of a QTL Hotspot on Mouse Distal Chromosome 1 that Modulates Neurobehavioral Phenotypes and Gene Expression

A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21–q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of ∼20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes

A model of 'contested' Europeanization: the European Union and the Turkish-Cypriot administration

This article investigates the European Union’s (EU) relevance to the Turkish-Cypriot (TC) administration, pegged to the Europeanization debate. The study contributes to the discussion on Europeanization and the EU’s international role, especially in cases of contested states, which constitute an important element of the EU’s current global agenda but remain an under-researched topic. The argument advanced is that the Europeanization of the TC administration, although similar to previous cases of EU Enlargement, is importantly mediated by the conditions of contested statehood that exist in northern Cyprus. In this respect, the TC example holds strong comparative value for the study of Europeanization of contested states and the wider debate on international role of the EU, in variety of contexts and in relation to a diverse range of actors, beyond conventional states that dominate discourse

Europeanized, Marketized but Still Governed by the State? Private Health Insurance in France

Historically, private health insurance (PHI) in France (which covers the complementary share of health expenditures) has been dominated by non-profit entities, namely mutual benefit societies. The sector has experienced a manifold marketization process over the recent years, partly due to the application of EU law and regulation. Yet this chapter argues that it has been decisively reinforced and sometimes shaped by a series of policies adopted at the national level. Indeed, over the last 20 years, successive French governments have tried to increase health coverage without increasing the share already covered by the public purse. This strategy ostensibly involved private health insurers in achieving several governmental objectives, yet the prior effects of Europeanization on these entities were poorly acknowledged by policymakers. As such, the many consequences associated with the rise of a “European-driven” market now increasingly conflict with a “State-driven” market. This, in turn, has strong implications for the scope and the nature of health coverage

Re-discovering international executive institutions

Public Administration is in an era of change. This article aims at re-discovering one underresearched part of public administration, the executive arms of International Governmental Organizations (IGOs). These are referred to as International Executives (IEs). The article provides a conceptual mapping and an empirical illustration of three important dynamics of IEs – intergovernmental, supranational and transgovernmental dynamics. The study also offers a middle-range organization theory perspective that suggests five independent variables that foster the advent of supranational and transgovernmental behavior and roles among IE civil servants. The variables suggested are (H1) the organizational properties of IEs, (H2) the degrees of institutionalization of IEs, (H3) the recruitment procedures of the IEs, (H4) characteristics of the relationships between IEs and external institutions, and finally (H5) demographic characteristics of the IE civil servants. The empirical illustrations are drawn from the European Commission, the OECD Secretariat and the WTO Secretariat. The concern here is to theoretically account for and empirically illustrate the assumed relationships between the five hypotheses and the behavioral dynamics evolving among IE incumbents. The article argues that the IEs of the EU, the OECD and the WTO seem to share important behavioral dynamics due to several organizational similarities