Similarity-Based Analysis of Allele Frequency Distribution among Multiple Populations Identifies Adaptive Genomic Structural Variants

Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a similarity-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 576 structural variants that show unusual population differentiation. Of these putatively adaptive structural variants, we further showed that 24 variants are multiallelic and overlap with coding sequences, and 20 variants are significantly associated with GWAS traits. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to: 1) population differentiation of rapidly evolving multiallelic variants, 2) incomplete sweeps, and 3) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants.     

Antioxidant effect of zinc in humans

Oxidative stress is known to be an important contributing factor in many chronic diseases. We tested the hypothesis that in healthy normal volunteers zinc acts as an effective anti-inflammatory and antioxidant agent. Ten normal volunteers were administered daily oral zinc supplementation (45 mg zinc as gluconate) and 10 volunteers received placebo for 8 weeks. Plasma zinc, MDA, HAE, and 8-OHdG levels; LPS-induced TNF-alpha and IL-1beta mRNA; and ex vivo TNF-alpha-induced NF-kappaB activity in mononuclear cells (MNC) were determined before and after supplementation. In subjects receiving zinc, plasma levels of lipid peroxidation products and DNA adducts were decreased, whereas no change was observed in the placebo group. LPS-stimulated MNC isolated from zinc-supplemented subjects showed reduced mRNA for TNF-alpha and IL-1beta compared to placebo. Ex vivo, zinc protected MNC from TNF-alpha-induced NF-kappaB activation. In parallel studies using HL-60, a promyelocytic cell line, we observed that zinc enhances the upregulation of mRNA and DNA-specific binding for A20, a transactivating factor which inhibits the activation of NF-kappaB. Our results suggest that zinc supplementation may lead to downregulation of the inflammatory cytokines through upregulation of the negative feedback loop A20 to inhibit induced NF-kappaB activation. Zinc administration to human subjects with conditions associated with increased oxidative stress should be explored.     

Effect of fish oil supplementation on plasma oxidant/antioxidant status in rats

The aim of this study was to investigate effect of dietary omega-3 fatty acid supplementation on the indices of in vivo lipid peroxidation and oxidant/antioxidant status of plasma in rats. The plasma thiobarbituric acid reactive substances (TBARS) and nitric oxide (NO) levels, and activities of xanthine oxidase (XO), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were studied in male Wistar Albino rats after ingestion of 0.4 g/kg fish oil (rich in omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid) for 30 days and compared to untreated control rats. The rats in the treated group had significantly higher SOD activity (P < 0.001), NO levels (P < 0.01) and decreased TBARS levels (P < 0.05) with respect to controls whereas GSH-Px and XO activities were not significantly different between the groups. None of the measured parameters had significant correlation with each other in both groups. We conclude that dietary supplementation of omega-3 fatty acids may enhance resistance to free radical attack and reduce lipid peroxidation. These results support the notion that omega-3 fatty acids may be effective dietary supplements in the management of various diseases in which oxidant/antioxidant defence mechanisms are decelerated.     

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.     

Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF(3)-promoted reaction of hydrazine with 2-alkoxy pyridines

Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different alpha,beta-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system. Lewis acid-catalyzed reaction of 4 with hydrazine afforded the corresponding 1H-pyrazolo[3,4-b]pyridines 5. The potency of the results as antimicrobial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR and NMR spectra. Molecular mechanics (MM2) and semiemperical (AM1) molecular orbital calculations have been performed for the most biologically active compounds 5b and c to get insight into their molecular structures and to learn more about their stable molecular conformations.     

Single-cell protein production from ram horn hydrolysate by bacteria

The alcoholysis (transesterification) of the refined cotton seed oil of Turkish origin with primary and secondary alcohols was investigated in the presence of an immobilized enzyme from Candida antarctica, commercially called Novozym 435 in a solvent-free medium. The optimum conditions of the methanolysis were as follows: 30% enzyme based on oil weight; oil/alcohol molar ratio 1:4; temperature: 50 degrees C and reaction time: 7 h. Maximum methyl esters (ME) yield was 91.5%. At the same conditions cotton seed oil was converted with short-chain primary and secondary alcohols to its corresponding esters with conversions between 72% and 94%. Our results indicated that alcoholysis products of cotton seed oil could be used as valuable intermediates in oleochemistry.     

Healing-promoting effect of bombesin treatment on chronic gastric ulcer in rats

To evaluate whether bombesin treatment has a facilitatory effect on the healing of chronic gastric ulcer, following the induction of ulcer by serosal application of acetic acid, rats were given bombesin (30 microg/kg/day; subcutaneously) or vehicle three times a day for 7, 14 or 21 days until they were decapitated. Neither food intake nor gastric emptying rate in either vehicle-treated or bombesin-treated groups was not statistically different from control rats. Similarly, ulcer indices and gastric myeloperoxidase (MPO) activities at the first and second weeks of injury were not different among the groups. However, in the 3-week ulcer group, bombesin treatment reduced tissue MPO level significantly back to control levels. Moreover, the analysis of the surface epithelium by scanning electron and light microscopy demonstrated a significant reduction in the severity of ulcers by bombesin treatment. Pretreatment with CCK antagonists (L-364,718 or L365,260; 25 micromol/kg/day) before bombesin treatment showed that neither of the CCK antagonists had a significant effect on the bombesin-mediated healing process, suggesting that CCK receptors are not involved in the action of bombesin. In accordance with the previous studies that show its acute gastroprotective effects, bombesin is also effective in promoting the healing process of chronic gastric ulcer in rats.