Beyond HPV: Oncomirs as new players in cervical cancer

MicroRNAs (miRNAs) are a recently discovered family of 18-24 nucleotide non-coding RNAs that can negatively regulate target mRNAs. All studied multicellular eukaryotes utilize miRNAs to regulate basic cellular functions including proliferation, differentiation, and death. It is now apparent that abnormal miRNA expression is a common feature of human malignancies. This review discusses the various cancer-relevant miRNAs (oncomirs) especially in cervical tumorigenesis and the potential role of oncomirs as therapeutic agents and targets for the treatment of cervical cancer.     

Analysis of oligomeric proteins during unfolding by pH and temperature

During thermal transition and variation of pH, structural properties of 35 proteins and their complexes (bound with substrate and co-factor) were analyzed in detail. During pH alteration, these proteins were shown to have substantial differences in conformations. pH conformers were analyzed in detail. Free energy and other energy parameters were also estimated for these proteins at various pH and temperatures. Detailed structural analysis and binding interfaces of various substrates, inhibitors and cofactor of these proteins were also investigated using docking and molecular dynamic simulation. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A novel approach to the identification and quantitative elemental analysis of amyloid deposits—Insights into the pathology of Alzheimer’s disease

There is considerable interest in the role of metals such as iron, copper, and zinc in amyloid plaque formation in Alzheimer’s disease. However to convincingly establish their presence in plaques in vivo, a sensitive technique is required that is both quantitatively accurate and avoids isolation of plaques or staining/fixing brain tissue, since these processes introduce contaminants and redistribute elements within the tissue. Combining the three ion beam techniques of scanning transmission ion microscopy, Rutherford back scattering spectrometry and particle induced X-ray emission in conjunction with a high energy (MeV) proton microprobe we have imaged plaques in freeze-dried unstained brain sections from CRND-8 mice, and simultaneously quantified iron, copper, and zinc. Our results show increased metal concentrations within the amyloid plaques compared with the surrounding tissue: iron (85 ppm compared with 42 ppm), copper (16 ppm compared to 6 ppm), and zinc (87 ppm compared to 34 ppm).     

Genetic Analysis of Variation in Human Meiotic Recombination

The number of recombination events per meiosis varies extensively among individuals. This recombination phenotype differs between female and male, and also among individuals of each gender. In this study, we used high-density SNP genotypes of over 2,300 individuals and their offspring in two datasets to characterize recombination landscape and to map the genetic variants that contribute to variation in recombination phenotypes. We found six genetic loci that are associated with recombination phenotypes. Two of these (RNF212 and an inversion on chromosome 17q21.31) were previously reported in the Icelandic population, and this is the first replication in any other population. Of the four newly identified loci (KIAA1462, PDZK1, UGCG, NUB1), results from expression studies provide support for their roles in meiosis. Each of the variants that we identified explains only a small fraction of the individual variation in recombination. Notably, we found different sequence variants associated with female and male recombination phenotypes, suggesting that they are regulated by different genes. Characterization of genetic variants that influence natural variation in meiotic recombination will lead to a better understanding of normal meiotic events as well as of non-disjunction, the primary cause of pregnancy loss.     

Altered patterns of multiple recombinant events are associated with nondisjunction of chromosome 21

We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.     

Discovery of novel, highly potent and selective beta-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles

Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring β-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound β-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized in iterative cycles, resulting in the CXCR4 inhibitors POL2438 and POL3026. The inhibitory potencies of these compounds were confirmed in a series of HIV-1 invasion assays in vitro. POL3026 showed excellent plasma stability, high selectivity for CXCR4, favorable pharmacokinetic properties in the dog, and thus has the potential to become a therapeutic compound for application in the treatment of HIV infections (as an entry inhibitor), cancer (for angiogenesis suppression and inhibition of metastasis), inflammation, and in stem cell transplant therapy.     

Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet

Developing atherosclerotic lesions in hypercholesterolemic rabbits are depleted in zinc, while iron accumulates. This study examined the influence of zinc supplementation on the development of atherosclerosis and used isotope dilution gas chromatography-mass spectrometry techniques to measure biomarkers of oxidative lipid damage in atherosclerotic rabbit aorta. Our previous method for F(2)-isoprostane measurement was adapted to include the quantitation of cholesterol oxidation products in the same sample. Two groups of New Zealand white rabbits were fed a high cholesterol (1% w/w) diet and one group was also supplemented with zinc (1 g/kg) for 8 weeks. Controls were fed a normal diet. Zinc supplementation did not significantly alter the increase in total plasma cholesterol levels observed in animals fed high cholesterol. However, in cholesterol-fed animals zinc supplementation significantly reduced the accumulation of total cholesterol levels in aorta which was accompanied by a significant reduction in average aortic lesion cross-sectional areas of the animals. Elevated levels of cholesterol oxidation products (5,6-alpha and beta cholesterol epoxides, 7beta-hydroxycholesterol, 7-ketocholesterol) in aorta and total F(2)-isoprostanes in plasma and aorta of rabbits fed a cholesterol diet were significantly decreased by zinc supplementation. Our data indicate that zinc has an antiatherogenic effect, possibly due to a reduction in iron-catalyzed free radical reactions.