Cooperative binding and activation of fibronectin by a bacterial surface protein

Integrin-dependent cell invasion of some pathogenic bacteria is mediated by surface proteins targeting the extracellular matrix protein fibronectin (FN). Although the structural basis for bacterial FN recognition is well understood, it has been unclear why proteins such as streptococcal SfbI contain several FN-binding sites. We used microcalorimetry to reveal cooperative binding of FN fragments to arrays of binding sites in SfbI. In combination with thermodynamic analyses, functional cell-based assays show that SfbI induces conformational changes in the N-terminal 100-kDa region of FN (FN100kDa), most likely by competition with intramolecular interactions defining an inactive state of FN100kDa. This study provides insights into how long range conformational changes resulting in FN activation may be triggered by bacterial pathogens.     

DDTRP: Database of Drug Targets for Resistant Pathogens

Emergence of drug resistance is a major threat to public health. Many pathogens have developed resistance to most of the existing antibiotics, and multidrug-resistant and extensively drug resistant strains are extremely difficult to treat. This has resulted in an urgent need for novel drugs. We describe a database called 'Database of Drug Targets for Resistant Pathogens' (DDTRP). The database contains information on drugs with reported resistance, their respective targets, metabolic pathways involving these targets, and a list of potential alternate targets for seven pathogens. The database can be accessed freely at http://bmi.icmr.org.in/DDTRP.     

The Role of Decision Support System (DSS) in Prevention of Cardiovascular Disease: A Systematic Review and Meta-Analysis

Background

The potential role of DSS in CVD prevention remains unclear as only a few studies report on patient outcomes for cardiovascular disease.

Methods and Results

A systematic review and meta-analysis of randomised controlled trials and observational studies was done using Medline, Embase, Cochrane Library, PubMed, Amed, CINAHL, Web of Science, Scopus databases; reference lists of relevant studies to 30 July 2011; and email contact with experts. The primary outcome was prevention of cardiovascular disorders (myocardial infarction, stroke, coronary heart disease, peripheral vascular disorders and heart failure) and management of hypertension owing to decision support systems, clinical decision supports systems, computerized decision support systems, clinical decision making tools and medical decision making (interventions). From 4116 references ten studies met our inclusion criteria (including 16,312 participants). Five papers reported outcomes on blood pressure management, one paper on heart failure, two papers each on stroke, and coronary heart disease. The pooled estimate for CDSS versus control group differences in SBP (mm of Hg) was - 0.99 (95% CI −3.02 to 1.04 mm of Hg; I² = 0; p = 0.851).

Conclusions

DSS show an insignificant benefit in the management and control of hypertension (insignificant reduction of SBP). The paucity of well-designed studies on patient related outcomes is a major hindrance that restricts interpretation for evaluating the role of DSS in secondary prevention. Future studies on DSS should (1) evaluate both physician performance and patient outcome measures (2) integrate into the routine clinical workflow with a provision for decision support at the point of care.     

Large scale motions in a biosensor protein glucose oxidase: a combined approach by QENS, normal mode analysis, and molecular dynamics studies

The characteristics of the glucose oxidase were studied using a combination of experimental and theoretical techniques. Quasi elastic neutron scattering experiments were used to obtain the vibrational frequencies of the protein. These were compared to theoretical results obtained by normal mode analysis. Results indicate a good match between the experimental and theoretical values. Molecular dynamic simulation with covariant analysis was used to study the structure and dynamics of glucose oxidase. Various parameters like the radius of gyration, root mean square fluctuations, solvent accessibility were studied for evaluating the structural stability of the protein. The frequency of vibration calculated from the three methods is used to derive the large scale motions. Theses studies were used to predict the suitable lysine residues for linkage with carbon nanotubes.     

Radiosynthesis and evaluation of IGF1R PET ligand [11C]GSK1838705A

Radiosynthesis and evaluation of [¹¹C]GSK1838705A in mice using microPET and determination of specificity in human GBM UG87MR cells are described herein. The radioligand was synthesized by reacting desmethyl-GSK1838705A with [¹¹C]CH₃I using GE FX2MeI module in ～5% yield (EOS), >95% radiochemical purity and a specific activity of 2.5 ± 0.5 Ci/μmol. MicroPET imaging in mice indicated that [¹¹C]GSK1838705A penetrated blood brain barrier (BBB) and showed retention of radiotracer in brain. The radioligand exhibited high uptake in U87MG cells with >70% specific binding to IGF1R. Our experiments suggest that [¹¹C]GSK-1838705A can be a potential PET radiotracer for the in vivo quantification of IGF1R expression in GBM and other brain tumors.     

Structural properties of scaffolds: Crucial parameters towards stem cells differentiation

Tissue engineering is a multidisciplinary field that applies the principles of engineering and life-sciences for regeneration of damaged tissues. Stem cells have attracted much interest in tissue engineering as a cell source due to their ability to proliferate in an undifferentiated state for prolonged time and capability of differentiating to different cell types after induction. Scaffolds play an important role in tissue engineering as a substrate that can mimic the native extracellular matrix and the properties of scaffolds have been shown to affect the cell behavior such as the cell attachment, proliferation and differentiation. Here, we focus on the recent reports that investigated the various aspects of scaffolds including the materials used for scaffold fabrication, surface modification of scaffolds, topography and mechanical properties of scaffolds towards stem cells differentiation effect. We will present a more detailed overview on the effect of mechanical properties of scaffolds on stem cells fate.     

Modeling of Neuropeptide Receptors Y1, Y4, Y5, and Docking Studies with Neuropeptide Antagonist Analogues: Implications for Selectivity

Abstract Neuropeptide Y (NPY), receptors belong to the G-protein coupled receptor superfamily. NPY mediates several physiological responses, such as blood pressure, food intake, sedation. These actions of NPY are mediated by six receptor subtypes denoted as Y(1)-Y(5) and y(6). Modeling of receptor subtypes and binding site identification is an important step in developing new therapeutic agents. We have attempted to model the three NPY receptor types, Y1, Y4, and Y5 using homology modeling and threading methods. The models are consistent with previously reported experimental evidence. To understand the interaction and selectivity of NPY analogues with different neuropeptide receptors, docking studies of two neuropeptide analogues (BVD10 and BVD15) with receptors Y1 and Y4 were carried out. Results of the docking studies indicated that the interaction of ligands BVD10 and BVD15 with Y1 and Y4 receptors are different. These results were evaluated for selectivity of peptide analogues BVD10 and BVD15 towards the receptors.     

Spatial assignment of amino acid residues in globular proteins: An approach from information theory

In the native folded state of globular proteins, amino acid residues place themselves at various positions from the centroid of the molecule. Applying information theory on 19 protein crystals the spatial preferences have been found out from the frequencies of occurrence of residues within various concentric ellipsoidal zones of proteins. The intrinsic spatial preferences of individual residues are related to their physical and chemical properties. The directing power of the individual residues on the chain path and the spatial information contained by doublets of residues have been found out. The derived information is used to predict the spatial/zonal preference of residues in carp myogen using the knowledge of amino acid sequence. The implication of packing densities in different spatial zones are discussed.     

Molecular-dynamics simulation of phenylalanine transfer RNA. II. Amplitudes, anisotropies, and anharmonicities of atomic motions

The atomic motions from a molecular-dynamics simulation of yeast tRNA^Phe are analyzed and compared with those observed in protein simulations. In general, the tRNA motions are of larger amplitude, they are more anisotropic, and they arise from potentials of mean force that are more anharmonic than in the protein case. In both cases, the amplitudes are largest for atoms on the surface of the molecules. On the other hand, the most anisotropic and anharmonic atomic motions are generally found in the interior of the tRNA, while they are found on the surface of the protein. These differences are discussed in terms of the differences in structure between nucleic acids and proteins.