Common variants of xeroderma pigmentosum genes and prostate cancer risk

The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA–XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR = 2.60; p < 0.001) and with the AA genotype (OR = 531; p < 0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer.     

Acclimation of denitrifying activated sludge to a single vs. complex external carbon source during a start-up of sequencing batch reactors treating ammonium-rich anaerobic sludge digester liquors

In this study, denitrification of ammonium-reach anaerobic sludge digester liquor was investigated during start-up periods of two laboratory-scale “fill-and-draw” reactors. One reactor was fed with a single carbon source (ethanol), whereas the other reactor was fed with a complex carbon source (fusel oil). During two acclimation experiments, the structure of microbial community involved in denitrification was analyzed using 16S rDNA polymerase chain reaction-denaturing gradient gel electrophoresis fingerprints and fluorescent in situ hybridization. The characteristics of the mixed liquor were additionally supported by regular measurements of nitrate uptake rates. The addition of fusel oil and ethanol resulted in a significant enhancement of the denitrification rate and efficiency combined with the increasing volumetric addition of sludge digester liquor up to 15 % of the reactor volume. The microbiological analyses revealed that the addition of sludge digester liquor as well as both external carbon sources (fusel oil and ethanol) did not affect the structure of microbial communities in a severe way. In both reactors, Curvibacter sp. and Azoarcus sp. were found as the most abundant representatives of denitrifiers.     

Anterograde and Retrograde Regulation of Nuclear Genes Encoding Mitochondrial Proteins during Growth,Development, and Stress

Mitochondrial biogenesis and function in plants require the expression of over 1000 nuclear genes encoding mitochondrial proteins （NGEMPs）. The expression of these genes is regulated by tissue-specific, developmental, internal, and external stimuli that result in a dynamic organelle involved in both metabolic and a variety of signaling processes. Although the metabolic and biosynthetic machinery of mitochondria is relatively well understood, the factors that regu- late these processes and the various signaling pathways involved are only beginning to be identified at a molecular level. The molecular components of anterograde （nuclear to mitochondrial） and retrograde （mitochondrial to nuclear） signaling pathways that regulate the expression of NGEMPs interact with chloroplast-, growth-, and stress-signaling pathways in the cell at a variety of levels, with common components involved in transmission and execution of these signals. This positions mitochondria as important hubs for signaling in the cell, not only in direct signaling of mitochondrial function per se, but also in sensing and/or integrating a variety of other internal and external signals. This integrates and optimizes growth with energy metabolism and stress responses, which is required in both photosynthetic and non-photosynthetic cells.     

Immunocompetence and high metabolic rates enhance overwinter survival in the root vole,Microtus oeconomus

Despite its presumed significance, the association between immune defence, energy expenditures and overwinter survival is rarely studied. We analysed individual variation in immunocompetence quantified as neutrophil-to-lymphocyte ratio (N/L), total white blood cells (WBC) and natural antibody levels, along with resting (RMR) and peak metabolic rates (PMR) and mortality during three consecutive winter seasons in a natural population of the root vole, Microtus oeconomus. In early winter, WBC count was negatively correlated with RMR, whereas N/L ratio was negatively correlated with swim-elicited PMR. We suggest that while the first correlation reflected the trade-off between energy allocation in immunocompetence and other metabolically demanding processes, the latter correlation stemmed from stress-induced immunosuppression elicited by the necessity to cope with swimming in frequently flooded habitat. In addition, the analysis carried out during the first year of study characterized by a high population density and prevalence of infestation with a blood parasite—Babesia spp., showed that its intensity was inversely correlated with the N/L ratio. In summary, our results suggest that elevated N/L ratio increases the winter survival of free-ranging rodents by increasing their ability to cope with parasitic infections.     

Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells

Antifungal drug ketoconazole causes severe drug-drug interactions by influencing gene expression and catalytic activity of major drug-metabolizing enzyme cytochrome P450 CYP3A4. Ketoconazole is administered in the form of racemic mixture of two cis-enantiomers, i.e. (+)-ketoconazole and (−)-ketoconazole. Many enantiopure drugs were introduced to human pharmacotherapy in last two decades. In the current paper, we have examined the effects of ketoconazole cis-enantiomers on the expression of CYP3A4 in human hepatocytes and HepG2 cells and on catalytic activity of CYP3A4 in human liver microsomes. We show that both ketoconazole enantiomers induce CYP3A4 mRNA and protein in human hepatocytes and HepG2 cells. Gene reporter assays revealed partial agonist activity of ketoconazole enantiomers towards pregnane X receptor PXR. Catalytic activity of CYP3A4/5 towards two prototypic substrates of CYP3A enzymes, testosterone and midazolam, was determined in presence of both (+)-ketoconazole and (−)-ketoconazole in human liver microsomes. Overall, both ketoconazole cis-enantiomers induced CYP3A4 in human cells and inhibited CYP3A4 in human liver microsomes. While interaction of ketoconazole with PXR and induction of CYP3A4 did not display enantiospecific pattern, inhibition of CYP3A4 catalytic activity by ketoconazole differed for ketoconazole cis-enantiomers ((+)-ketoconazole IC₅₀ 1.69 µM, K_i 0.92 µM for testosterone, IC₅₀ 1.46 µM, K_i 2.52 µM for midazolam; (−)-ketoconazole IC₅₀ 0.90 µM, K_i 0.17 µM for testosterone, IC₅₀ 1.04 µM, K_i 1.51 µM for midazolam).