Glucocorticoid receptor gene polymorphisms associated with progression of lung disease in young patients with cystic fibrosis

Background

The variability in the inflammatory burden of the lung in cystic fibrosis (CF) patients together with the variable effect of glucocorticoid treatment led us to hypothesize that glucocorticoid receptor (GR) gene polymorphisms may affect glucocorticoid sensitivity in CF and, consequently, may contribute to variations in the inflammatory response.

Methods

We evaluated the association between four GR gene polymorphisms, TthIII, ER22/23EK, N363S and BclI, and disease progression in a cohort of 255 young patients with CF. Genotypes were tested for association with changes in lung function tests, infection with Pseudomonas aeruginosa and nutritional status by multivariable analysis.

Results

A significant non-corrected for multiple tests association was found between BclI genotypes and decline in lung function measured as the forced expiratory volume in one second (FEV₁) and the forced vital capacity (FVC). Deterioration in FEV₁ and FVC was more pronounced in patients with the BclI GG genotype compared to the group of patients with BclI CG and CC genotypes (p = 0.02 and p = 0.04 respectively for the entire cohort and p = 0.01 and p = 0.02 respectively for F508del homozygous patients).

Conclusion

The BclI polymorphism may modulate the inflammatory burden in the CF lung and in this way influence progression of lung function.     

ISHAPE: new rapid and accurate software for haplotyping

Background  

We have developed a new haplotyping program based on the combination of an iterative multiallelic EM algorithm (IEM), bootstrap resampling and a pseudo Gibbs sampler. The use of the IEM-bootstrap procedure considerably reduces the space of possible haplotype configurations to be explored, greatly reducing computation time, while the adaptation of the Gibbs sampler with a recombination model on this restricted space maintains high accuracy. On large SNP datasets (>30 SNPs), we used a segmented approach based on a specific partition-ligation strategy. We compared this software, Ishape (Iterative Segmented HAPlotyping by Em), with reference programs such as Phase, Fastphase, and PL-EM. Analogously with Phase, there are 2 versions of Ishape: Ishape1 which uses a simple coalescence model for the pseudo Gibbs sampler step, and Ishape2 which uses a recombination model instead.     

Detailed Contact Data and the Dissemination of Staphylococcus aureus in Hospitals

Close proximity interactions (CPIs) measured by wireless electronic devices are increasingly used in epidemiological models. However, no evidence supports that electronically collected CPIs inform on the contacts leading to transmission. Here, we analyzed Staphylococcus aureus carriage and CPIs recorded simultaneously in a long-term care facility for 4 months in 329 patients and 261 healthcare workers to test this hypothesis. In the broad diversity of isolated S. aureus strains, 173 transmission events were observed between participants. The joint analysis of carriage and CPIs showed that CPI paths linking incident cases to other individuals carrying the same strain (i.e. possible infectors) had fewer intermediaries than predicted by chance (P < 0.001), a feature that simulations showed to be the signature of transmission along CPIs. Additional analyses revealed a higher dissemination risk between patients via healthcare workers than via other patients. In conclusion, S. aureus transmission was consistent with contacts defined by electronically collected CPIs, illustrating their potential as a tool to control hospital-acquired infections and help direct surveillance.     

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.     

Comparative analysis of reproductive traits in 65 freshwater fish species: application to the domestication of new fish species

Based on an extensive literature search (1,000 references), the objectives of the present study were to establish a numerical clustering of temperate freshwater fish based on their reproductive traits and to evaluate whether it was possible to extrapolate zootechnical knowledge among species belonging to the same cluster. About 65 species were classified into ten homogeneous clusters from the analysis of 29 reproductive traits, among which the most important were temperature during spawning, egg incubation and larval rearing, degree-days for incubation, larval size upon hatching, spawning season, and parental care. From this typology, a rather regular continuum of reproductive clusters emerges with two obvious endpoints. Between these two extremes, species could be ordered chiefly according to temperature requirement, spawning season and parental care. In conclusion, this new typology, differing significantly from all others proposed earlier, may now serve as a possible framework to help enhancing the domestication of new species by comparison to species belonging to the same cluster.