An important challenge in translational bioinformatics is to understand how genetic variation gives rise to molecular changes at the protein level that can precipitate both monogenic and complex disease. To this end, we compiled datasets of human disease-associated amino acid substitutions (AAS) in the contexts of inherited monogenic disease, complex disease, functional polymorphisms with no known disease association, and somatic mutations in cancer, and compared them with respect to predicted functional sites in proteins. Using the sequence homology-based tool SIFT to estimate the proportion of deleterious AAS in each dataset, only complex disease AAS were found to be indistinguishable from neutral polymorphic AAS. Investigation of monogenic disease AAS predicted to be non-deleterious by SIFT were characterized by a significant enrichment for inherited AAS within solvent accessible residues, regions of intrinsic protein disorder, and an association with the loss or gain of various post-translational modifications. Sites of structural and/or functional interest were therefore surmised to constitute useful additional features with which to identify the molecular disruptions caused by deleterious AAS. A range of bioinformatic tools, designed to predict structural and functional sites in protein sequences, were then employed to demonstrate that intrinsic biases exist in terms of the distribution of different types of human AAS with respect to specific structural, functional and pathological features. Our web tool, designed to potentiate the functional profiling of novel AAS, has been made available at http://profile.mutdb.org/.
BackgroundResveratrol, a constituent of red wine, is important for cardioprotection. MicroRNAs are known regulators for genes involved in resveratrol-mediated cardiac remodeling and the regulatory pathway involving microRNA has not been studied so far.MethodsWe explored the cardioprotection by resveratrol in ischemia/reperfusion model of rat and determined cardiac functions. miRNA profile was determined from isolated RNA using quantitative Real-time PCR based array. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches.ResultsCardioprotection by resveratrol and its derivative in ischemia/reperfusion [I/R] rat model was examined with miRNA expression profile. Unique expression pattern were found for each sample, particularly with resveratrol [pure compound] and longevinex [commercial resveratrol formulation] pretreated hearts. Longevinex and resveratrol pretreatment modulates the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 25 miRNAs, some of them, such as miR-21 were previously implicated in cardiac remodeling. The target genes for the differentially expressed miRNA include genes of various molecular function such as metal ion binding, sodium-potassium ion, transcription factors, which may play key role in reducing I/R injury.ConclusionRats pretreated with resveratrol for 3 weeks leads to significant cardioprotection against ischemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or longevinex. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R mice.
Twelve chemolithotrophic strains were isolated from temperate orchard soil on reduced sulfur compounds as energy and electron sources and characterized on the basis of their physiological properties and ability to oxidize various reduced sulfur compounds. The new isolates could oxidize tetrathionate as well as thiosulfate, and oxidation of the latter involved conversion of thiosulfate to tetrathionate followed by its accumulation and eventual oxidation to sulfate, manifested in the production of acid. The mesophilic, neutrophilic, Gram-negative and coccoid bacteria had a respiratory metabolism. Physiologically and biochemically, all the strains were more or less similar, differing only in their growth rates and ability to utilize a few carbon compounds as single heterotrophic substrates. 16S rRNA gene sequence analysis was performed with five representative strains, which revealed a high degree of similarity (⩾99 %) among them and placed the cluster in the ‘Betaproteobacteria’. The strains showed low levels (93·5–95·3 %) of 16S rRNA gene sequence similarity to Pigmentiphaga kullae, Achromobacter xylosoxidans, Pelistega europaea and species belonging to the genera Alcaligenes, Taylorella and Bordetella. The taxonomic coherence of the new isolates was confirmed by DNA–DNA hybridization. On the basis of their uniformly low 16S rRNA gene sequence similarities to species of all the closest genera, unique fatty acid profile, distinct G+C content (54–55·2 mol%) and phenotypic characteristics that include efficient chemolithotrophic utilization of tetrathionate, the organisms were classified in a new genus, Tetrathiobacter gen. nov. In the absence of any significant discriminatory phenotypic or genotypic characteristics, all the new isolates are considered to constitute a single species, for which the name Tetrathiobacter kashmirensis sp. nov. (type strain WT001T=LMG 22695T=MTCC 7002T) is proposed.
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