Current Issue : April - June Volume : 2012 Issue Number : 2 Articles : 5 Articles
Background: The DNA binding domain of HMG proteins is known to be important in many diseases, with the Sox\r\nsub-family of HMG proteins of particular significance. Numerous natural variants in HMG proteins are associated\r\nwith disease phenotypes. Integrating these natural variants, molecular dynamic simulations of DNA interaction and\r\nsequence and structure alignments give detailed molecular knowledge of potential amino acid function such as\r\nDNA or protein interaction.\r\nResults: A total of 33 amino acids in HMG proteins are known to have natural variants in diseases. Eight of these\r\namino acids are normally conserved in human HMG proteins and 27 are conserved in the human Sox sub-family.\r\nAmong the six non-Sox conserved amino acids, amino acids 16 and 45 are likely targets for interaction with other\r\nproteins. Docking studies between the androgen receptor and Sry/Sox9 reveals a stable amino acid specific\r\ninteraction involving several Sox conserved residues.\r\nConclusion: The HMG box has structural conservation between the first two of the three helixes in the domain as\r\nwell as some DNA contact points. Individual sub-groups of the HMG family have specificity in the location of the\r\nthird helix, DNA specific contact points (such as amino acids 4 and 29), and conserved amino acids interacting\r\nwith other proteins such as androgen receptor. Studies such as this help to distinguish individual members of a\r\nmuch larger family of proteins and can be applied to any protein family of interest....
There is an urgent need for early diagnosis in medicine, whereupon effective treatments could prevent irreversible tissue damage.\r\nThe special structure of the eye provides a unique opportunity for noninvasive light-based imaging of ocular fundus vasculature.\r\nTo detect endothelial injury at the early and reversible stage of adhesion molecule upregulation, some novel imaging agents\r\nthat target retinal endothelial molecules were generated. In vivo molecular imaging has a great potential to impact medicine by\r\ndetecting diseases or screening disease in early stages, identifying extent of disease, selecting disease and patient-specific therapeutic\r\ntreatment, applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current preclinical\r\nfindings and advances in instrumentation such as endoscopes and microcatheters suggest that these molecular imaging modalities\r\nhave numerous clinical applications and will be translated into clinical use in the near future....
Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase\n(LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and\nthe hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa\nand nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S\nby mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent\nCysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished\nexpression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase\n1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype\nof AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization\nprovides therapeutic benefit for AERD patients....
Odanacatib is is novel drug candidate for Cat K receptor inhibition and presently under phase III stage of clinical trial. The present investigation attempted to highlight mechanism of Odanacatib by docking simulation techniques. Docking results divulge that, said drug candidate elicit hydrophobic and hydrogen bonding interaction with Cat K receptor. The hydrophobic nature of Odanacatib enhance affinity towards Cat K wile few functional group like amino group improve selectivity towards Cat K....
Multi-drug therapy is the standard-of-care treatment for tuberculosis. Despite this, virtually all studies of the\npharmacodynamics (PD) of mycobacterial drugs employed for the design of treatment protocols are restricted to single\nagents. In this report, mathematical models and in vitro experiments with Mycobacterium marinum and five\nantimycobacterial drugs are used to quantitatively evaluate the pharmaco-, population and evolutionary dynamics of\ntwo-drug antimicrobial chemotherapy regimes. Time kill experiments with single and pairs of antibiotics are used to\nestimate the parameters and evaluate the fit of Hill-function-based PD models. While Hill functions provide excellent fits for\nthe PD of each single antibiotic studied, rifampin, amikacin, clarithromycin, streptomycin and moxifloxacin, two-drug Hill\nfunctions with a unique interaction parameter cannot account for the PD of any of the 10 pairs of these drugs. If we assume\ntwo antibiotic-concentration dependent functions for the interaction parameter, one for sub-MIC and one for supra-MIC\ndrug concentrations, the modified biphasic Hill function provides a reasonably good fit for the PD of all 10 pairs of\nantibiotics studied. Monte Carlo simulations of antibiotic treatment based on the experimentally-determined PD functions\nare used to evaluate the potential microbiological efficacy (rate of clearance) and evolutionary consequences (likelihood of\ngenerating multi-drug resistance) of these different drug combinations as well as their sensitivity to different forms of nonadherence\nto therapy. These two-drug treatment simulations predict varying outcomes for the different pairs of antibiotics\nwith respect to the aforementioned measures of efficacy. In summary, Hill functions with biphasic drug-drug interaction\nterms provide accurate analogs for the PD of pairs of antibiotics and M. marinum. The models, experimental protocols and\ncomputer simulations used in this study can be applied to evaluate the potential microbiological and evolutionary efficacy\nof two-drug therapy for any bactericidal antibiotics and bacteria that can be cultured in vitro....
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