Damaging effect of antibiotics on the structure of synaptonemal complexes of meiotic chromosome of mice

The structure of synaptonemal complexes (SCs) of chromosomes of mouse primary spermatocytes were studied using electron microscopy on days 1, 10, and 36 after the completion of per os administration of drugs belonging to three groups of antibiotics: tetracyclins, macrolides, and fluoroquinolones. The antibiotics were administered to mice during ten days. At the substages of early and middle pachytene, heteromorphic SC bivalents and fragments of chromosome-core elements were detected in spermatocytes at all times studied after the administration of the antibiotics of three groups. As cells passed through the period from early to middle pachytene, the number of cells containing heteromorphic SC bivalents and the fragments of chromosome cores gradually decreased, which could be an indication of selection of cells with chromosomal aberrations. A high level of associations between the X chromosome and autosome bivalents (including heteromorphic ones) also favors this suggestion. A gradual decrease in the number of chromosomal aberrations was detected, as time elapsed from the completion of antibiotics administration. The study of sperm obtained from epididymises of males did not reveal significant differences in both morphology and motility of sperm between males of the control and experimental groups.     

Polymorphism of the theta1 and mu1 glutathione s-transferase genes (GSTT1, GSTM1) in patients with atopic bronchial asthma from the West Siberian region

Polymorphism for the GSTT1 and GSTM1 null alleles was analyzed in 69 patients with atopic bronchial asthma (BA) and in 57 healthy individuals from Tomsk. The two samples did not differ in frequencies of genotypes 0/0 and + of either gene or in frequencies of genotype combinations. No association was observed for GST and BA severity. Thus, the GST null alleles proved to be unimportant for BA.     

Fas-stimulated generation of reactive oxygen species or exogenous oxidative stress sensitize cells to Fas-mediated apoptosis

Inhibition of Fas-mediated apoptosis in B cell lymphomas by thiol antioxidants (glutathione and N-acetylcysteine) supported previous studies, suggesting that Fas-stimulated ROS generation may play a role in Fas-mediated apoptosis. Thus, the goal of the current study was to determine if Fas stimulation could induce ROS generation and what role, if any, it played in apoptosis. Fas crosslinking induced rapid generation of ROS (within 15 min) well before the appearance of characteristic apoptotic changes. Overexpression of catalase or superoxide dismutase suggested that Fas induced production of both superoxide anion and hydrogen peroxide. ROS generation was only observed, however, in cells that were sensitive to apoptosis and not in B cells inherently resistant to anti-Fas or in those in which resistance was induced by B cell receptor crosslinking. The exogenous addition of 250 microM hydrogen peroxide could reverse the resistant phenotype and sensitize cells to Fas-induced apoptosis. In Fas-sensitive cells, depletion of endogenous antioxidant defenses with buthionine sulfoximine increased the sensitivity to Fas-induced apoptosis, while overexpression of antioxidant enzymes and antiapoptotic proteins suggested a role for Fas-induced production of hydrogen peroxide in apoptosis. Further analysis suggested a redox-sensitive step early in Fas signaling at the level of initiator caspase (caspase-8) activation. Thus, the data suggest that the level of oxidative stress, either from exogenous sources or generated endogenously upon receptor stimulation, regulates the sensitivity to Fas-mediated apoptosis.     

Characteristic of the genetic variability of four polymorphic variants (rs2069705, rs17880053, rs11126176, and rs804271) in representative samples of indigenous and arrived populations of Siberia

Russian Journal of Genetics - The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176...     

Birth Cohort,Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies

Insights into genetic origin of diseases and related traits could substantially impact strategies for improving human health. The results of genome-wide association studies (GWAS) are often positioned as discoveries of unconditional risk alleles of complex health traits. We re-analyzed the associations of single nucleotide polymorphisms (SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis. We focused on three generations of genotyped participants of the Framingham Heart Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific manner. The sample size and procedure-therapeutic issues play, at most, a minor role in this clustering. An important result was clustering of significant associations with the strongest effects in the youngest, or 3^rd Generation, cohort. These results imply that an assumption of unconditional connections of these SNPs with TC is generally implausible and that a demographic perspective can substantially improve GWAS efficiency. The analyses of genetic effects in age-matched samples suggest a role of environmental and age-related mechanisms in the associations of different SNPs with TC. Analysis of the literature supports systemic roles for genes for these SNPs beyond those related to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409 (the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next generation of lipid drugs. Our results suggest that standard GWAS strategies need to be advanced in order to appropriately address the problem of genetic susceptibility to complex traits that is imperative for translation to health care.     

Synthesis of lipophilic tetraphenylporphyrins to design lipid-porphyrin ensembles

Synthesis of symmetrical meso-arylsubstituted porphyrins with long chain hydrophobic substituents in the phenyl rings was achieved. The lipoporphyrins can be used to design supramolecular lipid ensembles of nanometer size.