Bayesian analysis of genetic change due to selection using Gibbs sampling

International audienc

Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Increased incidence of rare codon clusters at 5' and 3' gene termini:implications for function

<p>Abstract</p> <p>Background</p> <p>The process of translation can be affected by the use of rare versus common codons within the mRNA transcript.</p> <p>Results</p> <p>Here, we show that rare codons are enriched at the 5' and 3' termini of genes from <it>E. coli </it>and other prokaryotes. Genes predicted to be secreted show significant enrichment in 5' rare codon clusters, but not 3' rare codon clusters. Surprisingly, no correlation between 5' mRNA structure and rare codon usage was observed.</p> <p>Conclusions</p> <p>Potential functional roles for the enrichment of rare codons at terminal positions are explored.</p

Quantitative or momentum-based multi-style rotation? UK experience

The objective of this article is to examine whether short-term variation in the ranking of size and style index returns in the UK equity market is better predictable and exploitable by means of quantitative or momentum style-rotation strategies. Using UK index data, we assess the profitability of a number of long-only and long/short multi-stylerotation strategies based on these two alternative methods. The findings suggest that trading rules based on simple short-term momentum strategies are able to generate higher Sharpe ratios and greater end-of-period wealth at a reasonable level of transaction costs than our quantitatively based trading rules. This result is particularly pronounced among the long-only strategies

Carcass conformation and fat cover scores in beef cattle: A comparison of threshold linear models vs grouped data models

Background: Beef carcass conformation and fat cover scores are measured by subjective grading performed by trained technicians. The discrete nature of these scores is taken into account in genetic evaluations using a threshold model, which assumes an underlying continuous distribution called liability that can be modelled by different methods. Methods: Five threshold models were compared in this study: three threshold linear models, one including slaughterhouse and sex effects, along with other systematic effects, with homogeneous thresholds and two extensions with heterogeneous thresholds that vary across slaughterhouses and across slaughterhouse and sex and a generalised linear model with reverse extreme value errors. For this last model, the underlying variable followed a Weibull distribution and was both a log-linear model and a grouped data model. The fifth model was an extension of grouped data models with score-dependent effects in order to allow for heterogeneous thresholds that vary across slaughterhouse and sex. Goodness-of-fit of these models was tested using the bootstrap methodology. Field data included 2,539 carcasses of the Bruna dels Pirineus beef cattle breed. Results: Differences in carcass conformation and fat cover scores among slaughterhouses could not be totally captured by a systematic slaughterhouse effect, as fitted in the threshold linear model with homogeneous thresholds, and different thresholds per slaughterhouse were estimated using a slaughterhouse-specific threshold model. This model fixed most of the deficiencies when stratification by slaughterhouse was done, but it still failed to correctly fit frequencies stratified by sex, especially for fat cover, as 5 of the 8 current percentages were not included within the bootstrap interval. This indicates that scoring varied with sex and a specific sex per slaughterhouse threshold linear model should be used in order to guarantee the goodness-of-fit of the genetic evaluation model. This was also observed in grouped data models that avoided fitting deficiencies when slaughterhouse and sex effects were score-dependent. Conclusions: Both threshold linear models and grouped data models can guarantee the goodness-of-fit of the genetic evaluation for carcass conformation and fat cover, but our results highlight the need for specific thresholds by sex and slaughterhouse in order to avoid fitting deficiencies

Life Expectancy in a Large Cohort of Type 2 Diabetes Patients Treated in Primary Care (ZODIAC-10)

Background: Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess present-day life expectancy of type 2 diabetes patients in an ongoing cohort study. Methodology and Principal Findings: We included 973 primary care type 2 diabetes patients in a prospective cohort study, who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May 2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66 years, mean HbA(1c) 7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17 patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints 'all-cause' and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23-2.37), and HR 2.59 (95% CI 1.56-4.28); and albuminuria: HR 1.72 (95% CI 1.26-2.35), and HR 1.83 (95% CI 1.17-2.89), respectively, were significant predictors, whereas smoking, HbA(1c), systolic blood pressure and diabetes duration were not. Conclusions: This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is achievable in type 2 diabetes patients

Cyclin A2 Mutagenesis Analysis: A New Insight into CDK Activation and Cellular Localization Requirements

Cyclin A2 is essential at two critical points in the somatic cell cycle: during S phase, when it activates CDK2, and during the G2 to M transition when it activates CDK1. Based on the crystal structure of Cyclin A2 in association with CDKs, we generated a panel of mutants to characterize the specific amino acids required for partner binding, CDK activation and subcellular localization. We find that CDK1, CDK2, p21, p27 and p107 have overlapping but distinct requirements for association with this protein. Our data highlight the crucial importance of the N-terminal α helix, in conjunction with the α3 helix within the cyclin box, in activating CDK. Several Cyclin A2 mutants selectively bind to either CDK1 or CDK2. We demonstrate that association of Cyclin A2 to proteins such as CDK2 that was previously suggested as crucial is not a prerequisite for its nuclear localization, and we propose that the whole protein structure is involved

Population Substructure and Control Selection in Genome-Wide Association Studies

Determination of the relevance of both demanding classical epidemiologic criteria for control selection and robust handling of population stratification (PS) represents a major challenge in the design and analysis of genome-wide association studies (GWAS). Empirical data from two GWAS in European Americans of the Cancer Genetic Markers of Susceptibility (CGEMS) project were used to evaluate the impact of PS in studies with different control selection strategies. In each of the two original case-control studies nested in corresponding prospective cohorts, a minor confounding effect due to PS (inflation factor λ of 1.025 and 1.005) was observed. In contrast, when the control groups were exchanged to mimic a cost-effective but theoretically less desirable control selection strategy, the confounding effects were larger (λ of 1.090 and 1.062). A panel of 12,898 autosomal SNPs common to both the Illumina and Affymetrix commercial platforms and with low local background linkage disequilibrium (pair-wise r2<0.004) was selected to infer population substructure with principal component analysis. A novel permutation procedure was developed for the correction of PS that identified a smaller set of principal components and achieved a better control of type I error (to λ of 1.032 and 1.006, respectively) than currently used methods. The overlap between sets of SNPs in the bottom 5% of p-values based on the new test and the test without PS correction was about 80%, with the majority of discordant SNPs having both ranks close to the threshold. Thus, for the CGEMS GWAS of prostate and breast cancer conducted in European Americans, PS does not appear to be a major problem in well-designed studies. A study using suboptimal controls can have acceptable type I error when an effective strategy for the correction of PS is employed