Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation

Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,10-(3)H]oleate, [U-(14)C]glucose, and [1-(13)C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity for malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomenon.     

Kin recognition and adjustment of reproductive effort in zebra finches

The differential allocation theory predicts that females should invest more in offspring produced with attractive partners, and a number of studies support this prediction in birds. Females have been shown to increase reproductive investment when mated to males showing elaborated sexual traits. However, mate attractiveness might also depend on the interaction between male and female genotypes. Accordingly, females should invest more in offspring sired by individuals that are genetically dissimilar or carry superior alleles. Here, we show in zebra finches (Taeniopygia guttata) that pairs of unfamiliar genetic brothers and sisters are less likely to reproduce in comparison with randomly mated pairs. Among the brother–sister pairs, those that attempted to breed laid smaller clutches and of lower total clutch mass. Our results provide the first experimental evidence that females adjust their reproductive effort in response to the genetic similarity of their partners. Importantly, these results imply a female ability to assess relatedness of a social mate without prior association.     

Environmental factors influencing the occurrence of freshwater snails in woodland water bodies

Studies were carried out in eight woodland water bodies that are situated in an urbanised area of Southern Poland (Upper Silesia). The aim of this study was to determine the influence of auto- and allochthonous plant detritus and exposure to sunlight on the structure of snail communities in woodland ponds. Among some physico-chemical water parameters, pH influenced the occurrence of snails, whereas sunlight caused an increase in diversity of the snail communities. In the total snail collection, 72.1% of specimens were gathered in sun-exposed sites. By the same degree of insolation more preferred by snails were the sites with allochthonic detritus. The snail fauna of subsidence ponds located inside a forest area differs from those occurring in urban agglomerations. The most conspicuous difference is the high numbers in three woodland ponds of Hippeutis complanatus (L.), which is rare in this area.     

Acid-base equilibria at interface separating electrolyte solution and lipid bilayer formed from phosphatidylcholine

The dependence of the interfacial tension of a lipid membrane formed from phosphatidylcholine on the pH of the aqueous solution has been studied. The model describing the H(+) and OH(-) ions adsorption in the bilayer lipid surface has been presented in this work. We take suitable equations to describe the dependence of interfacial tension of a lipid bilayer membrane on H(+) and OH(-) ion concentrations. A theoretical equation is derived to describe this dependence in the whole pH range.     

Pooled sample-based GWAS: a cost-effective alternative for identifying colorectal and prostate cancer risk variants in the Polish population

Background

Prostate cancer (PCa) and colorectal cancer (CRC) are the most commonly diagnosed cancers and cancer-related causes of death in Poland. To date, numerous single nucleotide polymorphisms (SNPs) associated with susceptibility to both cancer types have been identified, but their effect on disease risk may differ among populations.

Methods

To identify new SNPs associated with PCa and CRC in the Polish population, a genome-wide association study (GWAS) was performed using DNA sample pools on Affymetrix Genome-Wide Human SNP 6.0 arrays. A total of 135 PCa patients and 270 healthy men (PCa sub-study) and 525 patients with adenoma (AD), 630 patients with CRC and 690 controls (AD/CRC sub-study) were included in the analysis. Allele frequency distributions were compared with t-tests and χ²-tests. Only those significantly associated SNPs with a proxy SNP (p<0.001; distance of 100 kb; r²>0.7) were selected. GWAS marker selection was conducted using PLINK. The study was replicated using extended cohorts of patients and controls. The association with previously reported PCa and CRC susceptibility variants was also examined. Individual patients were genotyped using TaqMan SNP Genotyping Assays.

Results

The GWAS selected six and 24 new candidate SNPs associated with PCa and CRC susceptibility, respectively. In the replication study, 17 of these associations were confirmed as significant in additive model of inheritance. Seven of them remained significant after correction for multiple hypothesis testing. Additionally, 17 previously reported risk variants have been identified, five of which remained significant after correction.

Conclusion

Pooled-DNA GWAS enabled the identification of new susceptibility loci for CRC in the Polish population. Previously reported CRC and PCa predisposition variants were also identified, validating the global nature of their associations. Further independent replication studies are required to confirm significance of the newly uncovered candidate susceptibility loci.     

Selected airborne allergenic fungal spores and meteorological factors in Szczecin,Poland, 2004–2006

Airborne fungal spore concentrations in Szczecin, Poland, were studied between 2004 and 2006 with the objective of determining a seasonal variation in the concentrations of selected fungal spore types in relation to meteorological parameters. The presence of spores of five taxa, namely, Cladosporium, Ganoderma, Alternaria, Leptosphaeria and Didymella, was recorded using a volumetric method (Hirst type). Fungal spores were present in the air in large numbers during the summer, with the highest concentrations recorded mainly in June, July and August. The peak concentrations of two of the studied spore types, Ganoderma and Alternaria, occurred in August, while the concentrations of Cladosporium, Leptosphaeria and Didymella spores were the highest in July. Multiple regression analysis was performed for three fungal seasons—2004, 2005 and 2006. Spore concentration was found to be positively correlated with the minimum temperature. For some spore types, there was also a significant correlation between concentrations, relative humidity and rain.     

Ubc9-induced inhibition of diadenosine triphosphate hydrolase activity of the putative tumor suppressor protein Fhit

Fhit protein is the product of the putative tumor suppressor fragile histidine triad (FHIT) gene. The way by which Fhit exerts its antitumor activity remains largely unknown, although the Fhit-Ap3A complex is believed to be the native signaling form of Fhit. Here, we have shown that Fhit protein interacts with hUbc9, a recombinant human SUMO-1 conjugating enzyme, in an adenosine(5')triphospho(5')nucleoside (Ap3N)-dependent manner. Our experiments showed that the dinucleoside polyphosphate hydrolase activity of Fhit is suppressed by interacting with hUbc9 protein. In the presence of equimolar hUbc9 the Vmax and Km activity of Fhit was decreased by 35%. Analysis of Fhit kinetics in the presence of different fixed concentrations of Ubc9 showed that Ubc9 is an uncompetitive inhibitor. Including SUMO-1 protein in the assay neither affected the Fhit activity nor modified the effect of Ubc9 on Fhit kinetics. Our data suggest that hUbc9-induced inhibition of Fhit may result in an elongation of the Fhit-Ap3A signaling complex lifetime leading to alteration of its antitumor activity.     

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.     

Costs of immune response in cold-stressed laboratory mice selected for high and low basal metabolism rates

To study whether mounting an immune response is energetically costly, mice from two lines divergently selected for high (H-BMR) and low (L-BMR) basal metabolic rate (BMR) were immunized with sheep red blood cells. Their energy budgets were then additionally burdened by sudden transfer from an ambient temperature of 23 degrees C to 5 degrees C. We found that the immune response of H-BMR mice was lower than that of L-BMR mice. However, the interaction between line affiliation and ambient temperature was not significant and cold exposure did not result in immunosuppression in either line. At 23 degrees C the animals of both lines seemed to cover the costs of immune response by increasing food consumption and digestive efficiency. This was not observed at 5 degrees C, so these costs must have been covered at the expense of other components of the energy budget. Cold exposure itself elicited a considerable increase in food intake and the mass of internal organs, which were also heavier in H-BMR than in L-BMR mice. However, irrespective of the temperature or line affiliation, immunized mice had smaller intestines, while cold-exposed immunized mice had smaller hearts. Furthermore, the observed larger mass of the liver and kidneys in immunized mice of both lines kept at 23 degrees C was not observed at 5 degrees C. Hence, immunization compromised upregulation of the function of metabolically active internal organs, essential for meeting the energetic demands of cold. We conclude that the difficulties with a straightforward demonstration of the energetic costs of immune responses in these animals stem from the extreme flexibility of their energy budgets.