Reverse engineering a gene network using an asynchronous parallel evolution strategy.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: The use of reverse engineering methods to infer gene regulatory networks by fitting mathematical models to gene expression data is becoming increasingly popular and successful. However, increasing model complexity means that more powerful global optimisation techniques are required for model fitting. The parallel Lam Simulated Annealing (pLSA) algorithm has been used in such approaches, but recent research has shown that island Evolutionary Strategies can produce faster, more reliable results. However, no parallel island Evolutionary Strategy (piES) has yet been demonstrated to be effective for this task. RESULTS: Here, we present synchronous and asynchronous versions of the piES algorithm, and apply them to a real reverse engineering problem: inferring parameters in the gap gene network. We find that the asynchronous piES exhibits very little communication overhead, and shows significant speed-up for up to 50 nodes: the piES running on 50 nodes is nearly 10 times faster than the best serial algorithm. We compare the asynchronous piES to pLSA on the same test problem, measuring the time required to reach particular levels of residual error, and show that it shows much faster convergence than pLSA across all optimisation conditions tested. CONCLUSIONS: Our results demonstrate that the piES is consistently faster and more reliable than the pLSA algorithm on this problem, and scales better with increasing numbers of nodes. In addition, the piES is especially well suited to further improvements and adaptations: Firstly, the algorithm's fast initial descent speed and high reliability make it a good candidate for being used as part of a global/local search hybrid algorithm. Secondly, it has the potential to be used as part of a hierarchical evolutionary algorithm, which takes advantage of modern multi-core computing architectures

Bayesian meta-analysis across genome-wide association studies of diverse phenotypes

Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic basis of diseases and traits, but most studies have been conducted in isolation, with a focus on either a single or a set of closely related phenotypes. We describe MetABF, a simple Bayesian framework for performing integrative meta-analysis across multiple GWAS using summary statistics. The approach is applicable across a wide range of study designs and can increase the power by 50% compared with standard frequentist tests when only a subset of studies have a true effect. We demonstrate its utility in a meta-analysis of 20 diverse GWAS which were part of the Wellcome Trust Case Control Consortium 2. The novelty of the approach is its ability to explore, and assess the evidence for a range of possible true patterns of association across studies in a computationally efficient framework.Peer reviewe

Genomic profiling of T-cell activation suggests increased sensitivity of memory T cells to CD28 costimulation

T-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 costimulation than naive T cells. To deconvolute how the T-cell receptor (TCR) and CD28 orchestrate activation of human T cells, we stimulate cells using varying intensities of TCR and CD28 and profiled gene expression. We show that genes involved in cell cycle progression and division are CD28-driven in memory cells, but under TCR control in naive cells. We further demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Using chromatin accessibility profiling, we observe that AP1 transcriptional regulation is enriched when both TCR and CD28 are engaged, whereas open chromatin near CD28- sensitive genes is enriched for NF-kB motifs. Lastly, we show that CD28-sensitive genes are enriched in GWAS regions associated with immune diseases, implicating a role for CD28 in disease development. Our study provides important insights into the differential role of costimulation in naive and memory T-cell responses and disease susceptibility

Association between high dietary intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid and reduced risk of Crohn's disease

Background: There are plausible mechanisms for how dietary docosahexaenoic acid (DHA), an n−3 polyunsaturated fatty acid, could prevent Crohn's disease (CD). Aim: To conduct a prospective study to investigate the association between increased intake of DHA and risk of CD. Methods: Overall, 229 702 participants were recruited from nine European centres between 1991 and 1998. At recruitment, dietary intakes of DHA and fatty acids were measured using validated food frequency questionnaires. The cohort was monitored through to June 2004 to identify participants who developed incident CD. In a nested case–control analysis, each case was matched with four controls; odds ratios (ORs) were calculated for quintiles of DHA intake, adjusted for total energy intake, smoking, other dietary fatty acids, dietary vitamin D and body mass index. Results: Seventy-three participants developed incident CD. All higher quintiles of DHA intake were inversely associated with development of CD; the highest quintile had the greatest effect size (OR = 0.07; 95% CI = 0.02–0.81). The OR trend across quintiles of DHA was 0.54 (95% CI = 0.30–0.99, Ptrend = 0.04). Including BMI in the multivariate analysis, due to its correlation with dietary fat showed similar associations. There were no associations with the other dietary fatty acids studied. Conclusion: There were inverse associations, with a biological gradient between increasing dietary docosahexaenoic acid intakes and incident Crohn's disease. Further studies in other populations should measure docosahexaenoic acid to determine if the association is consistent and the hypothesis tested in randomised controlled trials of purely docosahexaenoic acid supplementation

Electronic integration of fuel cell and battery system in novel hybrid vehicle

AbstractThe objective of this work was to integrate a lithium ion battery pack, together with its management system, into a hydrogen fuel cell drive train contained in a lightweight city car. Electronic units were designed to link the drive train components using conventional circuitry. These were built, tested and shown to perform according to the design. These circuits allowed start-up of battery management system, motor controller, fuel cell warm-up and torque monitoring. After assembling the fuel cell and battery in the vehicle, full system tests were performed. Analysis of results from vehicle demonstrations showed operation was satisfactory. The conclusion was that the electronic integration was successful, but the design needed optimisation and fine tuning. Eight vehicles were then fitted with the electronically integrated fuel cell-battery power pack. Trials were then started to test the integration more fully, with a duration of 12 months from 2011 to 2012 in the CABLED project