Inhibitory studies of DNA, RNA and protein synthesis in Escherichia coli by platinum containing complexes

Previous studies have shown various platinum containing compounds to be effective anti-tumor agents in man and animals. Many of these compounds have also been shown to be effective inhibitors of bacterial DNA, RNA and protein synthesis. Data is presented here which compares the inhibitory effectiveness of a number of recently synthesized platinum compounds toward the inhibition of the synthesis of DNA, RNA and protein in Escherichia coli. We also compared the effectiveness of these compounds toward the inhibition of bacterial growth. Some of these new derivatives appear to be nearly 3-fold more potent than the more thoroughly studied cis-diamminedichloroplatinum(II) (cis-PDD) and trans-diamminedichloroplatinum(II) (trans-PDD).     

Structural fingerprints,interactions, and signaling networks of RAS family proteins beyond RAS isoforms

Among the signaling molecules indirectly linked to many different cell surface receptors, RAS proteins essentially respond to a diverse range of extracellular cues. They control activities of multiple signaling pathways and consequently a wide array of cellular processes, including survival, growth, adhesion, migration, and differentiation. Any dysregulation of these pathway leads, thus, to cancer, developmental disorders, metabolic, and cardiovascular diseases. The biochemistry of RAS family proteins has become multifaceted since the discovery of the first members, more than 40 years ago. Substantial knowledge has been attained about molecular mechanisms underlying post-translational modification, membrane localization, regulation, and signal transduction through diverse effector molecules. However, the increasing complexity of the underlying signaling mechanisms is considerable, in part due to multiple effector pathways, crosstalks between them and eventually feedback mechanisms. Here, we take a broad view of regulatory and signaling networks of all RAS family proteins that extends beyond RAS paralogs. As described in this review, a lot is known but a lot has to be discovered yet.     

Association Between Trace Element Status and Depression in HTLV-1-Infected Patients: a Retrospective Cohort Study

Depression and Anxiety are two important public health problems that are known to be associated with viral infections. The association between the intake of nutrients such as zinc and copper with symptoms of depression has been studied previously. The aim of the current study was to investigate the association between depression with human T cell lymphotropic virus type 1 (HTLV-1) infection and serum content of zinc and copper in a large Iranian population cohort. The study population consisted of 279 HTLV-1-positive patients who were identified after recruitment as part of a large cohort study: the Mashhad Stroke and Heart Association Disorder (MASHAD) study. They were divided into two groups of diagnosed with or without depression based on their symptoms. Serum zinc and copper levels of all subjects were measured using the flame atomic absorption spectrometry. The population sample comprised of 279 individuals infected with HTLV-1 of whom 192 (68.8%) were women. The mean serum zinc in the group with and without depression was 78.69 ± 13.79 μg/dl and 86.87 ± 19.44 μg/dl, respectively (p < 0.001). Also, the serum copper level was higher in the depressive group (116.75 ± 39.56) than in the non-depressive group (104.76 ± 30.77) (p 0.004). The association between serum zinc and copper with depression in HTLV-1-infected patients which was shown in this study could be considered in the treatment strategies in these patients.

     

Role of CpG context and content in evolutionary signatures of brain DNA methylation

DNA methylation is essential in brain function and behavior; therefore, understanding the role of DNA methylation in brain-based disorders begins with the study of DNA methylation profiles in normal brain. Determining the patterns and scale of methylation conservation and alteration in an evolutionary context enables the design of focused but effective methylation studies of disease states. We applied an enzymatic-based approach, Methylation Mapping Analysis by Paired-end Sequencing (Methyl-MAPS), which utilizes second-generation sequencing technology to provide an unbiased representation of genome-wide DNA methylation profiles of human and mouse brains. In this large-scale study, we assayed CpG methylation in cerebral cortex of neurologically and psychiatrically normal human postmortem specimens, as well as mouse forebrain specimens. Cross-species human-mouse DNA methylation conservation analysis shows that DNA methylation is not correlated with sequence conservation. Instead, greater DNA methylation conservation is correlated with increasing CpG density. In addition to CpG density, these data show that genomic context is a critical factor in DNA methylation conservation and alteration signatures throughout mammalian brain evolution. We identify key genomic features that can be targeted for identification of epigenetic loci that may be developmentally and evolutionarily conserved and wherein aberrations in DNA methylation patterns can confer risk for disease.     

A fast method for large-scale multichromosomal breakpoint median problems

We provide a computationally realistic mathematical framework for the NP-hard problem of the multichromosomal breakpoint median for linear genomes that can be used in constructing phylogenies. A novel approach is provided that can handle signed, unsigned, and partially signed cases of the multichromosomal breakpoint median problem. Our method provides an avenue for incorporating biological assumptions (whenever available) such as the number of chromosomes in the ancestor, and thus it can be tailored to obtain a more biologically relevant picture of the median. We demonstrate the usefulness of our method by performing an empirical study on both simulated and real data with a comparison to other methods.     

Identification of a Dual-Specific T Cell Epitope of the Hemagglutinin Antigen of an H5 Avian Influenza Virus in Chickens

Avian influenza viruses (AIV) of the H5N1 subtype have caused morbidity and mortality in humans. Although some migratory birds constitute the natural reservoir for this virus, chickens may play a role in transmission of the virus to humans. Despite the importance of avian species in transmission of AIV H5N1 to humans, very little is known about host immune system interactions with this virus in these species. The objective of the present study was to identify putative T cell epitopes of the hemagglutinin (HA) antigen of an H5 AIV in chickens. Using an overlapping peptide library covering the HA protein, we identified a 15-mer peptide, H5_246–260, within the HA1 domain which induced activation of T cells in chickens immunized against the HA antigen of an H5 virus. Furthermore, H5_246–260 epitope was found to be presented by both major histocompatibility complex (MHC) class I and II molecules, leading to activation of CD4+ and CD8+ T cell subsets, marked by proliferation and expression of interferon (IFN)-γ by both of these cell subsets as well as the expression of granzyme A by CD8+ T cells. This is the first report of a T cell epitope of AIV recognized by chicken T cells. Furthermore, this study extends the previous finding of the existence of dual-specific epitopes in other species to chickens. Taken together, these results elucidate some of the mechanisms of immune response to AIV in chickens and provide a platform for creation of rational vaccines against AIV in this species.     

A bias-ed assessment of the use of SNPs in human complex traits

Although many biotechnological advancements have been made in the past decade, there has been very limited success in unraveling the genetic component of complex traits. Heavily invested research has been initiated based on etiological models of unrealistic simplicity and conducted under poor experimental designs, on data sets of insufficient size, leading to an overestimation of the effect sizes of genetic variants and the quantity and quality of linkage disequilibrium (LD). Arguments about whether families or unrelated individuals provide more power for gene mapping have been erroneously debated as issues of whether linkage or LD are more detectable sorts of correlation. Although the latter issue may be subject to debate, there is no doubt that family-based analysis is more powerful for detecting linkage and/or LD. If the recent advances in biotechnology are to be exploited effectively, vastly improved study designs will be imperative, as the reasons for the lack of success to date have much more to do with biology than technology, an issue that has become increasingly clear with the findings of the past years.     

A genetic variant of human erythrocyte glucose 6-phosphate dehydrogenase

Human erythrocyte G6PD activity was measured in more than 500 subjects in Isfahan, Iran, and the percent of enzyme deficiency for males and females are reported. Some properties of the abnormal enzyme is compared with its normal counterpart. Apparent Km values of glucose 6-phosphate for the variant and normal enzymes were 37 and 101 microM, respectively. The variant enzyme was less resistant to inhibition by 40 microM NADPH (72% inhibition) than the normal enzyme (48% inhibition). The mode of inhibition for both enzymes was competitive with NADP+. ATP at 1.5 mM concentration also inhibited normal and variant enzymes at 17% and 10%, respectively. The inhibition was competitive with glucose 6-phosphate. Polyacrylamide gel electrophores showed that normal enzyme has one major and another weak active bands, while the variant enzyme under identical conditions shows only one active band corresponding to the major band of the normal enzyme. Thermostability of variant G6PD was slightly lower that normal but no significant differences observed in their energy of activation. The activity pH profile of the variant enzyme was truncate.