Molecular evolution of pathogenic bacteria based on rrsA gene

Evolution of pathogens in prokaryotic bacteria was studied by 16srRNA genes. In this study rrsA genes of 45 bacteria were considered, which includes pathogens, non-pathogens and out-group bacteria. We considered non-pathogenic bacteria, for each class in bacterial classification, to support the pathogenic evolution. In this investigation, aligned nucleotide sequences of rrsA genes were used for Phylogenetic analysis and they have been clustered precisely. Maximum Likelihood (ML) and Maximum Parsimony (MP) methods were employed for the molecular evolution of pathogenic bacteria. The best-fit substitution model with the lowest Bayesian Information Criterion scores is considered to describe the substitution pattern the best, and non-uniformity of evolutionary rates among sites were modeled by using a discrete Gamma distribution. Nearest Neighbor Interchange (NNI) heuristic method was used to generate the tree for ML and Close Neighbor Interchange (CNI) on random trees search methods for MP. Further both the phylogenetic trees were statistically evaluated for accuracy by bootstrap value. Transition and transversion ratio of the rrsA genes have been estimated for the mutation frequency over the evolution by Maximum Composite Likelihood (MCL) bias and ML bias. Combined pathogenic and non pathogenic bacteria analysis reflected the clear diversity of bacteria over time and agrees with morphological and cytological data. These molecular evolution results should be useful to study the evolution pattern of pathogenic bacteria

Potency and pharmacokinetics of broad spectrum and isoform-specific p110<b>γ</b> and <b>δ</b> inhibitors in cancers

<p>Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110γ and p110δ are evolutionarily divergent; they probably need separate strategies for drug development.</p