WorldWideScience

Sample records for binding pocket similarity

  1. The PickPocket method for predicting binding specificities for receptors based on receptor pocket similarities: application to MHC-peptide binding

    DEFF Research Database (Denmark)

    Zhang, H.; Lund, Ole; Nielsen, M.

    2009-01-01

    the polymorphic pocket residues in MHC molecules that are in close proximity to the peptide residue. For MHC molecules with known specificities, we established a library of pocket-residues and corresponding binding specificities. The binding specificity for a novel MHC molecule is calculated as the average...

  2. Definition of the G protein-coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design

    DEFF Research Database (Denmark)

    Gloriam, David Erik Immanuel; Foord, Steven M; Blaney, Frank E;

    2009-01-01

    Recent advances in structural biology for G-protein-coupled receptors (GPCRs) have provided new opportunities to improve the definition of the transmembrane binding pocket. Here a reference set of 44 residue positions accessible for ligand binding was defined through detailed analysis of all curr...

  3. POVME: An Algorithm for Measuring Binding-Pocket Volumes

    OpenAIRE

    Durrant, Jacob D; de Oliveira, César Augusto F; McCammon, J. Andrew

    2010-01-01

    Researchers engaged in computer-aided drug design often wish to measure the volume of a ligand-binding pocket in order to predict pharmacology. We have recently developed a simple algorithm, called POVME (POcket Volume MEasurer), for this purpose. POVME is Python implemented, fast, and freely available. To demonstrate its utility, we use the new algorithm to study three members of the matrix-metalloproteinase family of proteins. Despite the structural similarity of these proteins, differences...

  4. Architectural repertoire of ligand-binding pockets on protein surfaces.

    Science.gov (United States)

    Weisel, Martin; Kriegl, Jan M; Schneider, Gisbert

    2010-03-01

    Knowledge of the three-dimensional structure of ligand binding sites in proteins provides valuable information for computer-assisted drug design. We present a method for the automated extraction and classification of ligand binding site topologies, in which protein surface cavities are represented as branched frameworks. The procedure employs a growing neural gas approach for pocket topology assignment and pocket framework generation. We assessed the structural diversity of 623 known ligand binding site topologies based on framework cluster analysis. At a resolution of 5 A only 23 structurally distinct topology groups were formed; this suggests an overall limited structural diversity of ligand-accommodating protein cavities. Higher resolution allowed for identification of protein-family specific pocket features. Pocket frameworks highlight potentially preferred modes of ligand-receptor interactions and will help facilitate the identification of druggable subpockets suitable for ligand affinity and selectivity optimization. PMID:20069621

  5. The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation

    OpenAIRE

    Gao, Mu; Skolnick, Jeffrey

    2012-01-01

    Protein-protein and protein-ligand interactions are ubiquitous in a biological cell. Here, we report a comprehensive study of the distribution of protein-ligand interaction sites, namely ligand-binding pockets, around protein-protein interfaces where protein-protein interactions occur. We inspected a representative set of 1,611 representative protein-protein complexes and identified pockets with a potential for binding small molecule ligands. The majority of these pockets are within a 6 Å dis...

  6. Perturbation Approaches for Exploring Protein Binding Site Flexibility to Predict Transient Binding Pockets.

    Science.gov (United States)

    Kokh, Daria B; Czodrowski, Paul; Rippmann, Friedrich; Wade, Rebecca C

    2016-08-01

    Simulations of the long-time scale motions of a ligand binding pocket in a protein may open up new perspectives for the design of compounds with steric or chemical properties differing from those of known binders. However, slow motions of proteins are difficult to access using standard molecular dynamics (MD) simulations and are thus usually neglected in computational drug design. Here, we introduce two nonequilibrium MD approaches to identify conformational changes of a binding site and detect transient pockets associated with these motions. The methods proposed are based on the rotamerically induced perturbation (RIP) MD approach, which employs perturbation of side-chain torsional motion for initiating large-scale protein movement. The first approach, Langevin-RIP (L-RIP), entails a series of short Langevin MD simulations, each starting with perturbation of one of the side-chains lining the binding site of interest. L-RIP provides extensive sampling of conformational changes of the binding site. In less than 1 ns of MD simulation with L-RIP, we observed distortions of the α-helix in the ATP binding site of HSP90 and flipping of the DFG loop in Src kinase. In the second approach, RIPlig, a perturbation is applied to a pseudoligand placed in different parts of a binding pocket, which enables flexible regions of the binding site to be identified in a small number of 10 ps MD simulations. The methods were evaluated for four test proteins displaying different types and degrees of binding site flexibility. Both methods reveal all transient pocket regions in less than a total of 10 ns of simulations, even though many of these regions remained closed in 100 ns conventional MD. The proposed methods provide computationally efficient tools to explore binding site flexibility and can aid in the functional characterization of protein pockets, and the identification of transient pockets for ligand design. PMID:27399277

  7. Importance of a Hydrophobic Pocket for Peptide Binding in Lactococcal OppA▿

    OpenAIRE

    Berntsson, Ronnie P-A; Thunnissen, Andy-Mark W H; Poolman, Bert; Slotboom, Dirk-Jan

    2011-01-01

    Lactococcal oligopeptide-binding protein A (OppA) binds peptides with widely varied lengths and sequences. We previously hypothesized that a hydrophobic pocket in OppA preferentially binds a hydrophobic peptide side chain and thus determines its binding register. Two crystal structures of OppA with different nonapeptides now indeed show binding in different registers.

  8. The minor binding pocket: a major player in 7TM receptor activation

    DEFF Research Database (Denmark)

    Rosenkilde, Mette Marie; Benned-Jensen, Tau; Frimurer, Thomas M.;

    2010-01-01

    From the deep part of the main ligand-binding crevice, a minor, often shallower pocket extends between the extracellular ends of transmembrane domains (TM)-I, II, III and VII of 7TM receptors. This minor binding pocket is defined by a highly conserved kink in TM-II that is induced by a proline...... residue located in one of two adjacent positions. Here we argue that this minor binding pocket is important for receptor activation. Functional coupling of the receptors seems to be mediated through the hydrogen bond network located between the intracellular segments of these TMs, with the allosteric...... interface between TM-II and TM-VII being of particular significance. Importantly, the minor binding pocket, especially the proline-kink in TM-II, is involved in G protein versus arrestin pathway-biased signaling, for example in the angiotensin AT1 system. Consequently, this pocket could be specifically...

  9. Do drugs have access to the P-glycoprotein drug-binding pocket through gates?

    Science.gov (United States)

    Ferreira, Ricardo J; Ferreira, Maria-José U; Dos Santos, Daniel J V A

    2015-10-13

    The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction coordinate obtained with the WHAM approach were similar, with no activation energy required for crossing the gate. Moreover, drug transit from bulk water into the DBP was characterized as an overall free-energy downhill process. PMID:26574244

  10. Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol

    Energy Technology Data Exchange (ETDEWEB)

    Suino-Powell, Kelly; Xu, Yong; Zhang, Chenghai; Tao, Yong-guang; Tolbert, W. David; Simons, Jr., S. Stoney; Xu, H. Eric (NIH)

    2010-03-08

    A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 {angstrom}{sup 3}, effectively doubling the size of the GR dexamethasone-binding pocket of 540 {angstrom}{sup 3} and yet leaving the structure of the coactivator binding site intact. DAC occupies only {approx}50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.

  11. Solvent fluctuations induce non-Markovian kinetics in hydrophobic pocket-ligand binding

    CERN Document Server

    Weiß, R Gregor; Dzubiella, Joachim

    2016-01-01

    We investigate the impact of water fluctuations on the key-lock association kinetics of a hydrophobic ligand (key) binding to a hydrophobic pocket (lock) by means of a minimalistic stochastic model system. It describes the collective hydration behavior of the pocket by bimodal fluctuations of a water-pocket interface that dynamically couples to the diffusive motion of the approaching ligand via the hydrophobic interaction. This leads to a set of overdamped Langevin equations in 2D-coordinate-space, that is Markovian in each dimension. Numerical simulations demonstrate locally increased friction of the ligand, decelerated binding kinetics, and local non-Markovian (memory) effects in the ligand's reaction coordinate as found previously in explicit-water molecular dynamics studies of model hydrophobic pocket-ligand binding [1,2]. Our minimalistic model elucidates the origin of effectively enhanced friction in the process that can be traced back to long-time decays in the force-autocorrelation function induced by...

  12. A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation

    DEFF Research Database (Denmark)

    Frödin, Morten; Antal, Torben L; Dümmler, Bettina A;

    2002-01-01

    The growth factor-activated AGC protein kinases RSK, S6K, PKB, MSK and SGK are activated by serine/threonine phosphorylation in the activation loop and in the hydrophobic motif, C-terminal to the kinase domain. In some of these kinases, phosphorylation of the hydrophobic motif creates a specific...... docking site that recruits and activates PDK1, which then phosphorylates the activation loop. Here, we discover a pocket in the kinase domain of PDK1 that recognizes the phosphoserine/phosphothreonine in the hydrophobic motif by identifying two oppositely positioned arginine and lysine residues that bind...... the phosphate. Moreover, we demonstrate that RSK2, S6K1, PKBalpha, MSK1 and SGK1 contain a similar phosphate-binding pocket, which they use for intramolecular interaction with their own phosphorylated hydrophobic motif. Molecular modelling and experimental data provide evidence for a common activation mechanism...

  13. Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study.

    Science.gov (United States)

    Sharaf, Naima G; Ishima, Rieko; Gronenborn, Angela M

    2016-07-19

    HIV-1 reverse transcriptase (RT) is a major drug target in the treatment of HIV-1 infection. RT inhibitors currently in use include non-nucleoside, allosteric RT inhibitors (NNRTIs), which bind to a hydrophobic pocket, distinct from the enzyme's active site. We investigated RT-NNRTI interactions by solution (19)F nuclear magnetic resonance (NMR), using singly (19)F-labeled RT proteins. Comparison of (19)F chemical shifts of fluorinated RT and drug-resistant variants revealed that the fluorine resonance is a sensitive probe for identifying mutation-induced changes in the enzyme. Our data show that in the unliganded enzyme, the NNRTI-binding pocket is highly plastic and not locked into a single conformation. Upon inhibitor binding, the binding pocket becomes rigidified. In the inhibitor-bound state, the (19)F signal of RT is similar to that of drug-resistant mutant enzymes, distinct from what is observed for the free state. Our results demonstrate the power of (19)F NMR spectroscopy to characterize conformational properties using selectively (19)F-labeled protein.

  14. Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study.

    Science.gov (United States)

    Sharaf, Naima G; Ishima, Rieko; Gronenborn, Angela M

    2016-07-19

    HIV-1 reverse transcriptase (RT) is a major drug target in the treatment of HIV-1 infection. RT inhibitors currently in use include non-nucleoside, allosteric RT inhibitors (NNRTIs), which bind to a hydrophobic pocket, distinct from the enzyme's active site. We investigated RT-NNRTI interactions by solution (19)F nuclear magnetic resonance (NMR), using singly (19)F-labeled RT proteins. Comparison of (19)F chemical shifts of fluorinated RT and drug-resistant variants revealed that the fluorine resonance is a sensitive probe for identifying mutation-induced changes in the enzyme. Our data show that in the unliganded enzyme, the NNRTI-binding pocket is highly plastic and not locked into a single conformation. Upon inhibitor binding, the binding pocket becomes rigidified. In the inhibitor-bound state, the (19)F signal of RT is similar to that of drug-resistant mutant enzymes, distinct from what is observed for the free state. Our results demonstrate the power of (19)F NMR spectroscopy to characterize conformational properties using selectively (19)F-labeled protein. PMID:27163463

  15. G protein-coupled receptor transmembrane binding pockets and their applications in GPCR research and drug discovery: a survey.

    Science.gov (United States)

    Kratochwil, Nicole A; Gatti-McArthur, Silvia; Hoener, Marius C; Lindemann, Lothar; Christ, Andreas D; Green, Luke G; Guba, Wolfgang; Martin, Rainer E; Malherbe, Pari; Porter, Richard H P; Slack, Jay P; Winnig, Marcel; Dehmlow, Henrietta; Grether, Uwe; Hertel, Cornelia; Narquizian, Robert; Panousis, Constantinos G; Kolczewski, Sabine; Steward, Lucinda

    2011-01-01

    G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor.

  16. Microbial diversity similarities in periodontal pockets and atheromatous plaques of cardiovascular disease patients.

    Directory of Open Access Journals (Sweden)

    Wagner Serra e Silva Filho

    Full Text Available BACKGROUND AND OBJECTIVE: The immune and infectious alterations occurring in periodontitis have been shown to alter the development and severity of cardiovascular disease. One of these relationships is the translocation of oral bacteria to atheroma plaques, thereby promoting plaque development. Thus, the aim of this study was to assess, by 16s cloning and sequencing, the microbial diversity of the subgingival environment and atheroma plaques of patients concomitantly suffering from periodontitis and obstructive coronary artery atherosclerosis (OCAA. METHODS: Subgingival biofilm and coronary balloons used in percutaneous transluminal coronary angioplasty were collected from 18 subjects presenting with generalized moderate to severe periodontitis and OCAA. DNA was extracted and the gene 16S was amplified, cloned and sequenced. RESULTS: Significant differences in microbial diversity were observed between both environments. While subgingival samples mostly contained the phylum Firmicutes, in coronary balloons, Proteobacteria (p<0.05 was predominant. In addition, the most commonly detected genera in coronary balloons were Acinetobacter, Alloprevotella, Pseudomonas, Enterobacter, Sphingomonas and Moraxella, while in subgingival samples Porphyromonas, Filifactor, Veillonella, Aggregatibacter and Treponema (p<0.05 were found. Interestingly, 17 identical phylotypes were found in atheroma and subgingival samples, indicating possible bacterial translocation between periodontal pockets and coronary arteries. CONCLUSION: Periodontal pockets and atheromatous plaques of cardiovascular disease patients can present similarities in the microbial diversity.

  17. The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function.

    Science.gov (United States)

    Breslin, Claire; Hornyak, Peter; Ridley, Andrew; Rulten, Stuart L; Hanzlikova, Hana; Oliver, Antony W; Caldecott, Keith W

    2015-08-18

    Poly (ADP-ribose) is synthesized at DNA single-strand breaks and can promote the recruitment of the scaffold protein, XRCC1. However, the mechanism and importance of this process has been challenged. To address this issue, we have characterized the mechanism of poly (ADP-ribose) binding by XRCC1 and examined its importance for XRCC1 function. We show that the phosphate-binding pocket in the central BRCT1 domain of XRCC1 is required for selective binding to poly (ADP-ribose) at low levels of ADP-ribosylation, and promotes interaction with cellular PARP1. We also show that the phosphate-binding pocket is required for EGFP-XRCC1 accumulation at DNA damage induced by UVA laser, H2O2, and at sites of sub-nuclear PCNA foci, suggesting that poly (ADP-ribose) promotes XRCC1 recruitment both at single-strand breaks globally across the genome and at sites of DNA replication stress. Finally, we show that the phosphate-binding pocket is required following DNA damage for XRCC1-dependent acceleration of DNA single-strand break repair, DNA base excision repair, and cell survival. These data support the hypothesis that poly (ADP-ribose) synthesis promotes XRCC1 recruitment at DNA damage sites and is important for XRCC1 function. PMID:26130715

  18. The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function

    Science.gov (United States)

    Breslin, Claire; Hornyak, Peter; Ridley, Andrew; Rulten, Stuart L.; Hanzlikova, Hana; Oliver, Antony W.; Caldecott, Keith W.

    2015-01-01

    Poly (ADP-ribose) is synthesized at DNA single-strand breaks and can promote the recruitment of the scaffold protein, XRCC1. However, the mechanism and importance of this process has been challenged. To address this issue, we have characterized the mechanism of poly (ADP-ribose) binding by XRCC1 and examined its importance for XRCC1 function. We show that the phosphate-binding pocket in the central BRCT1 domain of XRCC1 is required for selective binding to poly (ADP-ribose) at low levels of ADP-ribosylation, and promotes interaction with cellular PARP1. We also show that the phosphate-binding pocket is required for EGFP-XRCC1 accumulation at DNA damage induced by UVA laser, H2O2, and at sites of sub-nuclear PCNA foci, suggesting that poly (ADP-ribose) promotes XRCC1 recruitment both at single-strand breaks globally across the genome and at sites of DNA replication stress. Finally, we show that the phosphate-binding pocket is required following DNA damage for XRCC1-dependent acceleration of DNA single-strand break repair, DNA base excision repair, and cell survival. These data support the hypothesis that poly (ADP-ribose) synthesis promotes XRCC1 recruitment at DNA damage sites and is important for XRCC1 function. PMID:26130715

  19. Retinoid-binding proteins: similar protein architectures bind similar ligands via completely different ways.

    Directory of Open Access Journals (Sweden)

    Yu-Ru Zhang

    Full Text Available BACKGROUND: Retinoids are a class of compounds that are chemically related to vitamin A, which is an essential nutrient that plays a key role in vision, cell growth and differentiation. In vivo, retinoids must bind with specific proteins to perform their necessary functions. Plasma retinol-binding protein (RBP and epididymal retinoic acid binding protein (ERABP carry retinoids in bodily fluids, while cellular retinol-binding proteins (CRBPs and cellular retinoic acid-binding proteins (CRABPs carry retinoids within cells. Interestingly, although all of these transport proteins possess similar structures, the modes of binding for the different retinoid ligands with their carrier proteins are different. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we analyzed the various retinoid transport mechanisms using structure and sequence comparisons, binding site analyses and molecular dynamics simulations. Our results show that in the same family of proteins and subcellular location, the orientation of a retinoid molecule within a binding protein is same, whereas when different families of proteins are considered, the orientation of the bound retinoid is completely different. In addition, none of the amino acid residues involved in ligand binding is conserved between the transport proteins. However, for each specific binding protein, the amino acids involved in the ligand binding are conserved. The results of this study allow us to propose a possible transport model for retinoids. CONCLUSIONS/SIGNIFICANCE: Our results reveal the differences in the binding modes between the different retinoid-binding proteins.

  20. Computational approaches for identification of conserved/unique binding pockets in the A chain of ricin

    Energy Technology Data Exchange (ETDEWEB)

    Ecale Zhou, C L; Zemla, A T; Roe, D; Young, M; Lam, M; Schoeniger, J; Balhorn, R

    2005-01-29

    Specific and sensitive ligand-based protein detection assays that employ antibodies or small molecules such as peptides, aptamers, or other small molecules require that the corresponding surface region of the protein be accessible and that there be minimal cross-reactivity with non-target proteins. To reduce the time and cost of laboratory screening efforts for diagnostic reagents, we developed new methods for evaluating and selecting protein surface regions for ligand targeting. We devised combined structure- and sequence-based methods for identifying 3D epitopes and binding pockets on the surface of the A chain of ricin that are conserved with respect to a set of ricin A chains and unique with respect to other proteins. We (1) used structure alignment software to detect structural deviations and extracted from this analysis the residue-residue correspondence, (2) devised a method to compare corresponding residues across sets of ricin structures and structures of closely related proteins, (3) devised a sequence-based approach to determine residue infrequency in local sequence context, and (4) modified a pocket-finding algorithm to identify surface crevices in close proximity to residues determined to be conserved/unique based on our structure- and sequence-based methods. In applying this combined informatics approach to ricin A we identified a conserved/unique pocket in close proximity (but not overlapping) the active site that is suitable for bi-dentate ligand development. These methods are generally applicable to identification of surface epitopes and binding pockets for development of diagnostic reagents, therapeutics, and vaccines.

  1. eMatchSite: sequence order-independent structure alignments of ligand binding pockets in protein models.

    Directory of Open Access Journals (Sweden)

    Michal Brylinski

    2014-09-01

    Full Text Available Detecting similarities between ligand binding sites in the absence of global homology between target proteins has been recognized as one of the critical components of modern drug discovery. Local binding site alignments can be constructed using sequence order-independent techniques, however, to achieve a high accuracy, many current algorithms for binding site comparison require high-quality experimental protein structures, preferably in the bound conformational state. This, in turn, complicates proteome scale applications, where only various quality structure models are available for the majority of gene products. To improve the state-of-the-art, we developed eMatchSite, a new method for constructing sequence order-independent alignments of ligand binding sites in protein models. Large-scale benchmarking calculations using adenine-binding pockets in crystal structures demonstrate that eMatchSite generates accurate alignments for almost three times more protein pairs than SOIPPA. More importantly, eMatchSite offers a high tolerance to structural distortions in ligand binding regions in protein models. For example, the percentage of correctly aligned pairs of adenine-binding sites in weakly homologous protein models is only 4-9% lower than those aligned using crystal structures. This represents a significant improvement over other algorithms, e.g. the performance of eMatchSite in recognizing similar binding sites is 6% and 13% higher than that of SiteEngine using high- and moderate-quality protein models, respectively. Constructing biologically correct alignments using predicted ligand binding sites in protein models opens up the possibility to investigate drug-protein interaction networks for complete proteomes with prospective systems-level applications in polypharmacology and rational drug repositioning. eMatchSite is freely available to the academic community as a web-server and a stand-alone software distribution at http://www.brylinski.org/ematchsite.

  2. Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.

    Science.gov (United States)

    Khrapunovich-Baine, Marina; Menon, Vilas; Verdier-Pinard, Pascal; Smith, Amos B; Angeletti, Ruth Hogue; Fiser, Andras; Horwitz, Susan Band; Xiao, Hui

    2009-12-15

    The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in beta-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that, like Taxol, discodermolide binds to the taxane binding pocket in beta-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and toward the N-terminal H1-S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the alpha-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent beta-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.

  3. Influences of the Hydrophobicity of the Heme-binding Pocket on the Propreties and Functions of Cytochrome b5 Mutants

    Institute of Scientific and Technical Information of China (English)

    GAN, Jian-Hua; WANG, Yun-Hua; WU, Jian; HUANG, Zhong-Xian; XIA, Zong-Xiang

    2003-01-01

    The mutation sites of the four mutants F35Y, P40V, V45E and V45Y of cytochrome b5 are located at the edge of the hemebinding pocket. The solvent accessible areas of the "pocket interior" of the four mutants and the wild-type cytochrome b5 have been calculated based on their crystal structures at high resolution. The change in the hydrophobicity of the heme-binding pocket resulting from the mutation can be quantitatively described using the difference of the solvent accessible area of the "pocket interior" of each mutant from that of the wild-type cytochrome b5. The influences of the hydrophobicity of the hemebinding pocket on the protein stability and redox potential are discussed.

  4. Gates and binding pockets for nitric oxide with cytochrome c', according to molecular dynamics.

    Science.gov (United States)

    Pietra, Francesco

    2013-09-01

    Random-acceleration molecular-dynamics (RAMD) simulations with models of homodimeric 6-ligated distal-NO and 5-ligated proximal-NO cytochrome c' complexes, in TIP3 H2 O, showed two distinct, non-intercommunicating worlds. In the framework of a long cavity formed by four protein helices with heme at one extremity, NO was observed to follow different pathways with the two complexes to reach the solvent. With the 6-ligated complex, NO was observed to progress by exploiting protein internal channels created by thermal fluctuations, and be temporarily trapped into binding pockets before reaching the preferred gate at the heme end of the cavity. In contrast, with the 5-ligated complex, NO was observed to surface the solvent-exposed helix 7, up to a gate at the other extremity of the protein, only occasionally finding an earlier, direct way out toward the solvent. That only bulk NO gets involved in forming the 5-ligated proximal-NO complex is in agreement with previous experimental observations, while the occurrence of binding pockets suggests that also reservoir NO might play a role with the distal-NO complex.

  5. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    Science.gov (United States)

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  6. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Jing; Gurung, Buddha; Wan, Bingbing; Matkar, Smita; Veniaminova, Natalia A.; Wan, Ke; Merchant, Juanita L.; Hua, Xianxin; Lei, Ming (Michigan); (Michigan-Med); (UPENN-MED)

    2013-04-08

    Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.

  7. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin

    Energy Technology Data Exchange (ETDEWEB)

    Whittle, James R.R.; Zhang, Ruijun; Khurana, Surender; King, Lisa R.; Manischewitz, Jody; Golding, Hana; Dormitzer, Philip R.; Haynes, Barton F.; Walter, Emmanuel B.; Moody, M. Anthony; Kepler, Thomas B.; Liao, Hua-Xin; Harrison, Stephen C. (Harvard-Med); (Novartis); (US-FDA); (Duke)

    2011-09-20

    Seasonal antigenic drift of circulating influenza virus leads to a requirement for frequent changes in vaccine composition, because exposure or vaccination elicits human antibodies with limited cross-neutralization of drifted strains. We describe a human monoclonal antibody, CH65, obtained by isolating rearranged heavy- and light-chain genes from sorted single plasma cells, coming from a subject immunized with the 2007 trivalent influenza vaccine. The crystal structure of a complex of the hemagglutinin (HA) from H1N1 strain A/Solomon Islands/3/2006 with the Fab of CH65 shows that the tip of the CH65 heavy-chain complementarity determining region 3 (CDR3) inserts into the receptor binding pocket on HA1, mimicking in many respects the interaction of the physiological receptor, sialic acid. CH65 neutralizes infectivity of 30 out of 36 H1N1 strains tested. The resistant strains have a single-residue insertion near the rim of the sialic-acid pocket. We conclude that broad neutralization of influenza virus can be achieved by antibodies with contacts that mimic those of the receptor.

  8. Evidence for an intrinsic binding force between dodecaborate dianions and receptors with hydrophobic binding pockets.

    Science.gov (United States)

    Warneke, Jonas; Jenne, Carsten; Bernarding, Johannes; Azov, Vladimir A; Plaumann, Markus

    2016-05-01

    A gas phase binding study revealed strong intrinsic intermolecular interactions between dianionic halogenated closo-dodecaborates [B12X12](2-) and several neutral organic receptors. Oxidation of a tetrathiafulvalene host allowed switching between two host-guest binding modes in a supramolecular complex. Complexes of β-cyclodextrin with [B12F12](2-) show remarkable stability in the gas phase and were successfully tested as carriers for the delivery of boron clusters into cancer cells. PMID:27087168

  9. Kinetic evidence for an anion binding pocket in the active site of nitronate monooxygenase.

    Science.gov (United States)

    Francis, Kevin; Gadda, Giovanni

    2009-10-01

    A series of monovalent, inorganic anions and aliphatic aldehydes were tested as inhibitors for Hansenula mrakii and Neurospora crassa nitronate monooxygenase, formerly known as 2-nitropropane dioxygenase, to investigate the structural features that contribute to the binding of the anionic nitronate substrates to the enzymes. A linear correlation between the volumes of the inorganic anions and their effectiveness as competitive inhibitors of the enzymes was observed in a plot of pK(is)versus the ionic volume of the anion with slopes of 0.041+/-0.001 mM/A(3) and 0.027+/-0.001 mM/A(3) for the H. mrakii and N. crassa enzymes, respectively. Aliphatic aldehydes were weak competitive inhibitors of the enzymes, with inhibition constants that are independent of their alkyl chain lengths. The reductive half reactions of H. mrakii nitronate monooxygenase with primary nitronates containing two to four carbon atoms all showed apparent K(d) values of approximately 5 mM. These results are consistent with the presence of an anion binding pocket in the active site of nitronate monooxygenase that interacts with the nitro group of the substrate, and suggest a minimal contribution of the hydrocarbon chain of the nitronates to the binding of the ligands to the enzyme. PMID:19683782

  10. Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering.

    Science.gov (United States)

    Gutierrez-Mazariegos, Juliana; Nadendla, Eswar Kumar; Studer, Romain A; Alvarez, Susana; de Lera, Angel R; Kuraku, Shigehiro; Bourguet, William; Schubert, Michael; Laudet, Vincent

    2016-03-01

    Whole genome duplications (WGDs) have been classically associated with the origin of evolutionary novelties and the so-called duplication-degeneration-complementation model describes the possible fates of genes after duplication. However, how sequence divergence effectively allows functional changes between gene duplicates is still unclear. In the vertebrate lineage, two rounds of WGDs took place, giving rise to paralogous gene copies observed for many gene families. For the retinoic acid receptors (RARs), for example, which are members of the nuclear hormone receptor (NR) superfamily, a unique ancestral gene has been duplicated resulting in three vertebrate paralogues: RARα, RARβ and RARγ. It has previously been shown that this single ancestral RAR was neofunctionalized to give rise to a larger substrate specificity range in the RARs of extant jawed vertebrates (also called gnathostomes). To understand RAR diversification, the members of the cyclostomes (lamprey and hagfish), jawless vertebrates representing the extant sister group of gnathostomes, provide an intermediate situation and thus allow the characterization of the evolutionary steps that shaped RAR ligand-binding properties following the WGDs. In this study, we assessed the ligand-binding specificity of cyclostome RARs and found that their ligand-binding pockets resemble those of gnathostome RARα and RARβ. In contrast, none of the cyclostome receptors studied showed any RARγ-like specificity. Together, our results suggest that cyclostome RARs cover only a portion of the specificity repertoire of the ancestral gnathostome RARs and indicate that the establishment of ligand-binding specificity was a stepwise event. This iterative process thus provides a rare example for the diversification of receptor-ligand interactions of NRs following WGDs. PMID:27069642

  11. Comparative study of the binding pockets of mammalian proprotein convertases and its implications for the design of specific small molecule inhibitors

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    Sun Tian, Wu Jianhua

    2010-01-01

    Full Text Available Proprotein convertases are enzymes that proteolytically cleave protein precursors in the secretory pathway to yield functional proteins. Seven mammalian subtilisin/Kex2p-like proprotein convertases have been identified: furin, PC1, PC2, PC4, PACE4, PC5 and PC7. The binding pockets of all seven proprotein convertases are evolutionarily conserved and highly similar. Among the seven proprotein convertases, the furin cleavage site motif has recently been characterized as a 20-residue motif that includes one core region P6-P2´ inside the furin binding pocket. This study extended this information by examining the 3D structural environment of the furin binding pocket surrounding the core region P6-P2´ of furin substrates. The physical properties of mutations in the binding pockets of the other six mammalian proprotein convertases were compared. The results suggest that: 1 mutations at two positions, Glu230 and Glu257, change the overall density of the negative charge of the binding pockets, and govern the substrate specificities of mammalian proprotein convertases; 2 two proprotein convertases (PC1 and PC2 may have reduced sensitivity for positively charged residues at substrate position P5 or P6, whereas the substrate specificities of three proprotein convertases (furin, PACE4, and PC5 are similar to each other. This finding led to a novel design of a short peptide pattern for small molecule inhibitors: [K/R]-X-V-X-K-R. Compared with the widely used small molecule dec-RVKR-cmk that inhibits all seven proprotein convertases, a finely-tuned derivative of the short peptide pattern [K/R]-X-V-X-K-R may have the potential to more effectively inhibit five of the proprotein convertases (furin, PC4, PACE4, PC5 and PC7 compared to the remaining two (PC1 and PC2. The results not only provide insights into the molecular evolution of enzyme function in the proprotein convertase family, but will also aid the study of the functional redundancy of proprotein

  12. Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein-protein interface.

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    Metz, Alexander; Pfleger, Christopher; Kopitz, Hannes; Pfeiffer-Marek, Stefania; Baringhaus, Karl-Heinz; Gohlke, Holger

    2012-01-23

    Protein-protein interfaces are considered difficult targets for small-molecule protein-protein interaction modulators (PPIMs ). Here, we present for the first time a computational strategy that simultaneously considers aspects of energetics and plasticity in the context of PPIM binding to a protein interface. The strategy aims at identifying the determinants of small-molecule binding, hot spots, and transient pockets, in a protein-protein interface in order to make use of this knowledge for predicting binding modes of and ranking PPIMs with respect to their affinity. When applied to interleukin-2 (IL-2), the computationally inexpensive constrained geometric simulation method FRODA outperforms molecular dynamics simulations in sampling hydrophobic transient pockets. We introduce the PPIAnalyzer approach for identifying transient pockets on the basis of geometrical criteria only. A sequence of docking to identified transient pockets, starting structure selection based on hot spot information, RMSD clustering and intermolecular docking energies, and MM-PBSA calculations allows one to enrich IL-2 PPIMs from a set of decoys and to discriminate between subgroups of IL-2 PPIMs with low and high affinity. Our strategy will be applicable in a prospective manner where nothing else than a protein-protein complex structure is known; hence, it can well be the first step in a structure-based endeavor to identify PPIMs. PMID:22087639

  13. Structures of BmrR-Drug Complexes Reveal a Rigid Multidrug Binding Pocket And Transcription Activation Through Tyrosine Expulsion

    Energy Technology Data Exchange (ETDEWEB)

    Newberry, K.J.; Huffman, J.L.; Miller, M.C.; Vazquez-Laslop, N.; Neyfakh, A.A.; Brennan, R.G.

    2009-05-22

    BmrR is a member of the MerR family and a multidrug binding transcription factor that up-regulates the expression of the bmr multidrug efflux transporter gene in response to myriad lipophilic cationic compounds. The structural mechanism by which BmrR binds these chemically and structurally different drugs and subsequently activates transcription is poorly understood. Here, we describe the crystal structures of BmrR bound to rhodamine 6G (R6G) or berberine (Ber) and cognate DNA. These structures reveal each drug stacks against multiple aromatic residues with their positive charges most proximal to the carboxylate group of Glu-253 and that, unlike other multidrug binding pockets, that of BmrR is rigid. Substitution of Glu-253 with either alanine (E253A) or glutamine (E253Q) results in unpredictable binding affinities for R6G, Ber, and tetraphenylphosphonium. Moreover, these drug binding studies reveal that the negative charge of Glu-253 is not important for high affinity binding to Ber and tetraphenylphosphonium but plays a more significant, but unpredictable, role in R6G binding. In vitro transcription data show that E253A and E253Q are constitutively active, and structures of the drug-free E253A-DNA and E253Q-DNA complexes support a transcription activation mechanism requiring the expulsion of Tyr-152 from the multidrug binding pocket. In sum, these data delineate the mechanism by which BmrR binds lipophilic, monovalent cationic compounds and suggest the importance of the redundant negative electrostatic nature of this rigid drug binding pocket that can be used to discriminate against molecules that are not substrates of the Bmr multidrug efflux pump.

  14. An induced pocket for the binding of potent fusion inhibitor CL-385319 with H5N1 influenza virus hemagglutinin.

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    Runming Li

    Full Text Available The influenza glycoprotein hemagglutinin (HA plays crucial roles in the early stage of virus infection, including receptor binding and membrane fusion. Therefore, HA is a potential target for developing anti-influenza drugs. Recently, we characterized a novel inhibitor of highly pathogenic H5N1 influenza virus, CL-385319, which specifically inhibits HA-mediated viral entry. Studies presented here identified the critical binding residues for CL-385319, which clustered in the stem region of the HA trimer by site-directed mutagenesis. Extensive computational simulations, including molecular docking, molecular dynamics simulations, molecular mechanics generalized Born surface area (MM_GBSA calculations, charge density and Laplacian calculations, have been carried out to uncover the detailed molecular mechanism that underlies the binding of CL-385319 to H5N1 influenza virus HA. It was found that the recognition and binding of CL-385319 to HA proceeds by a process of "induced fit" whereby the binding pocket is formed during their interaction. Occupation of this pocket by CL-385319 stabilizes the neutral pH structure of hemagglutinin, thus inhibiting the conformational rearrangements required for membrane fusion. This "induced fit" pocket may be a target for structure-based design of more potent influenza fusion inhibitors.

  15. Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket.

    Science.gov (United States)

    Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun; Wu, Cheng-Yang; Chuang, Jacinta L; Wernstedt-Asterholm, Ingrid; Morlock, Lorraine K; Owens, Kyle R; Scherer, Philipp E; Williams, Noelle S; Tambar, Uttam K; Wynn, R Max; Chuang, David T

    2014-02-14

    Pyruvate dehydrogenase kinase isoforms (PDKs 1-4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure, and cancer and are potential therapeutic targets for these important human diseases. Here, we employed a structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl]isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 μM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments pyruvate dehydrogenase complex activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes. PMID:24356970

  16. Flanking p10 contribution and sequence bias in matrix based epitope prediction: revisiting the assumption of independent binding pockets

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    Parry Christian S

    2008-10-01

    Full Text Available Abstract Background Eluted natural peptides from major histocompatibility molecules show patterns of conserved residues. Crystallographic structures show that the bound peptide in class II major histocompatibility complex adopts a near uniform polyproline II-like conformation. This way allele-specific favoured residues are able to anchor into pockets in the binding groove leaving other peptide side chains exposed for recognition by T cells. The anchor residues form a motif. This sequence pattern can be used to screen large sequences for potential epitopes. Quantitative matrices extend the motif idea to include the contribution of non-anchor peptide residues. This report examines two new matrices that extend the binding register to incorporate the polymorphic p10 pocket of human leukocyte antigen DR1. Their performance is quantified against experimental binding measurements and against the canonical nine-residue register matrix. Results One new matrix shows significant improvement over the base matrix; the other does not. The new matrices differ in the sequence of the peptide library. Conclusion One of the extended quantitative matrices showed significant improvement in prediction over the original nine residue matrix and over the other extended matrix. Proline in the sequence of the peptide library of the better performing matrix presumably stabilizes the peptide conformation through neighbour interactions. Such interactions may influence epitope prediction in this test of quantitative matrices. This calls into question the assumption of the independent contribution of individual binding pockets.

  17. Reshaping an enzyme binding pocket for enhanced and inverted stereoselectivity: use of smallest amino acid alphabets in directed evolution.

    Science.gov (United States)

    Sun, Zhoutong; Lonsdale, Richard; Kong, Xu-Dong; Xu, Jian-He; Zhou, Jiahai; Reetz, Manfred T

    2015-10-12

    Directed evolution based on saturation mutagenesis at sites lining the binding pocket is a commonly practiced strategy for enhancing or inverting the stereoselectivity of enzymes for use in organic chemistry or biotechnology. However, as the number of residues in a randomization site increases to five or more, the screening effort for 95 % library coverage increases astronomically until it is no longer feasible. We propose the use of a single amino acid for saturation mutagenesis at superlarge randomization sites comprising 10 or more residues. When used to reshape the binding pocket of limonene epoxide hydrolase, this strategy, which drastically reduces the search space and thus the screening effort, resulted in R,R- and S,S-selective mutants for the hydrolytic desymmetrization of cyclohexene oxide and other epoxides. X-ray crystal structures and docking studies of the mutants unveiled the source of stereoselectivity and shed light on the mechanistic intricacies of this enzyme. PMID:25891639

  18. Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key.

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    V Joachim Haupt

    Full Text Available Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology - a drug's ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand

  19. Mutations in FMN Binding Pocket Diminish Chromate Reduction Rates for Gh-ChrR Isolated from Gluconacetobacter hansenii

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    Khaleel, Janin A.; Gong, Chunhong; Zhang, Yanfeng; Tan, Ruimin; Squier, Thomas C.; Jin, Hongjun

    2013-06-01

    A putative chromate ion binding site was identified proximal to a rigidly bound FMN from electron densities in the crystal structure of the quinone reductase from Gluconacetobacter hansenii (Gh-ChrR) (3s2y.pdb). To clarify the location of the chromate binding site, and to understand the role of FMN in the NADPH-dependent reduction of chromate, we have expressed and purified four mutant enzymes involving the site-specific substitution of individual side chains within the FMN binding pocket that form non-covalent bonds with the ribityl phosphate (i.e., S15A and R17A in loop 1 between β1 sheet and α1 helix) or the isoalloxanzine ring (E83A or Y84A in loop 4 between the β3 sheet and α4 helix). Mutations that selectively disrupt hydrogen bonds between either the N3 nitrogen on the isoalloxanzine ring (i.e., E83) or the ribitylphos- phoate (i.e., S15) respectively result in 50% or 70% reductions in catalytic rates of chromate reduction. In comparison, mutations that disrupt π-π ring stacking interactions with the isoal-loxanzine ring (i.e., Y84) or a salt bridge with the ribityl phosphate result in 87% and 97% inhibittion. In all cases there are minimal alterations in chromate binding affinities. Collectively, these results support the hypothesis that chromate binds proximal to FMN, and implicate a structural role for FMN positioning for optimal chromate reduction rates. As side chains proximal to the β3/α4 FMN binding loop 4 contribute to both NADH and metal ion binding, we propose a model in which structural changes around the FMN binding pocket couples to both chromate and NADH binding sites.

  20. Structural and mechanistic investigations on Salmonella typhimurium acetate kinase (AckA: identification of a putative ligand binding pocket at the dimeric interface

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    Chittori Sagar

    2012-10-01

    Full Text Available Abstract Background Bacteria such as Escherichia coli and Salmonella typhimurium can utilize acetate as the sole source of carbon and energy. Acetate kinase (AckA and phosphotransacetylase (Pta, key enzymes of acetate utilization pathway, regulate flux of metabolites in glycolysis, gluconeogenesis, TCA cycle, glyoxylate bypass and fatty acid metabolism. Results Here we report kinetic characterization of S. typhimurium AckA (StAckA and structures of its unliganded (Form-I, 2.70 Å resolution and citrate-bound (Form-II, 1.90 Å resolution forms. The enzyme showed broad substrate specificity with kcat/Km in the order of acetate > propionate > formate. Further, the Km for acetyl-phosphate was significantly lower than for acetate and the enzyme could catalyze the reverse reaction (i.e. ATP synthesis more efficiently. ATP and Mg2+ could be substituted by other nucleoside 5′-triphosphates (GTP, UTP and CTP and divalent cations (Mn2+ and Co2+, respectively. Form-I StAckA represents the first structural report of an unliganded AckA. StAckA protomer consists of two domains with characteristic βββαβαβα topology of ASKHA superfamily of proteins. These domains adopt an intermediate conformation compared to that of open and closed forms of ligand-bound Methanosarcina thermophila AckA (MtAckA. Spectroscopic and structural analyses of StAckA further suggested occurrence of inter-domain motion upon ligand-binding. Unexpectedly, Form-II StAckA structure showed a drastic change in the conformation of residues 230–300 compared to that of Form-I. Further investigation revealed electron density corresponding to a citrate molecule in a pocket located at the dimeric interface of Form-II StAckA. Interestingly, a similar dimeric interface pocket lined with largely conserved residues could be identified in Form-I StAckA as well as in other enzymes homologous to AckA suggesting that ligand binding at this pocket may influence the function of these

  1. Protein function annotation by local binding site surface similarity.

    Science.gov (United States)

    Spitzer, Russell; Cleves, Ann E; Varela, Rocco; Jain, Ajay N

    2014-04-01

    Hundreds of protein crystal structures exist for proteins whose function cannot be confidently determined from sequence similarity. Surflex-PSIM, a previously reported surface-based protein similarity algorithm, provides an alternative method for hypothesizing function for such proteins. The method now supports fully automatic binding site detection and is fast enough to screen comprehensive databases of protein binding sites. The binding site detection methodology was validated on apo/holo cognate protein pairs, correctly identifying 91% of ligand binding sites in holo structures and 88% in apo structures where corresponding sites existed. For correctly detected apo binding sites, the cognate holo site was the most similar binding site 87% of the time. PSIM was used to screen a set of proteins that had poorly characterized functions at the time of crystallization, but were later biochemically annotated. Using a fully automated protocol, this set of 8 proteins was screened against ∼60,000 ligand binding sites from the PDB. PSIM correctly identified functional matches that predated query protein biochemical annotation for five out of the eight query proteins. A panel of 12 currently unannotated proteins was also screened, resulting in a large number of statistically significant binding site matches, some of which suggest likely functions for the poorly characterized proteins.

  2. Computational predictions suggest that structural similarity in viral polymerases may lead to comparable allosteric binding sites.

    Science.gov (United States)

    Brown, Jodian A; Espiritu, Marie V; Abraham, Joel; Thorpe, Ian F

    2016-08-15

    The identification of ligand-binding sites is often the first step in drug targeting and design. To date there are numerous computational tools available to predict ligand binding sites. These tools can guide or mitigate the need for experimental methods to identify binding sites, which often require significant resources and time. Here, we evaluate four ligand-binding site predictor (LBSP) tools for their ability to predict allosteric sites within the Hepatitis C Virus (HCV) polymerase. Our results show that the LISE LBSP is able to identify all three target allosteric sites within the HCV polymerase as well as a known allosteric site in the Coxsackievirus polymerase. LISE was then employed to identify novel binding sites within the polymerases of the Dengue, West Nile, and Foot-and-mouth Disease viruses. Our results suggest that all three viral polymerases have putative sites that share structural or chemical similarities with allosteric pockets of the HCV polymerase. Thus, these binding locations may represent an evolutionarily conserved structural feature of several viral polymerases that could be exploited for the development of small molecule therapeutics. PMID:27262620

  3. Allosteric Regulation of Serine Protease HtrA2 through Novel Non-Canonical Substrate Binding Pocket

    Science.gov (United States)

    Singh, Nitu; Gadewal, Nikhil; Chaganti, Lalith K.; Sastry, G. Madhavi; Bose, Kakoli

    2013-01-01

    HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucidated. Although allostery has been found in some of its homologs, it has not been characterized in HtrA2 so far. Here, with an in silico and biochemical approach we have shown that allostery does regulate HtrA2 activity. Our studies identified a novel non-canonical selective binding pocket in HtrA2 which initiates signal propagation to the distal active site through a complex allosteric mechanism. This non-classical binding pocket is unique among HtrA family proteins and thus unfolds a novel mechanism of regulation of HtrA2 activity and hence apoptosis. PMID:23457469

  4. Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.

    Directory of Open Access Journals (Sweden)

    Pruthvi Raj Bejugam

    Full Text Available HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucidated. Although allostery has been found in some of its homologs, it has not been characterized in HtrA2 so far. Here, with an in silico and biochemical approach we have shown that allostery does regulate HtrA2 activity. Our studies identified a novel non-canonical selective binding pocket in HtrA2 which initiates signal propagation to the distal active site through a complex allosteric mechanism. This non-classical binding pocket is unique among HtrA family proteins and thus unfolds a novel mechanism of regulation of HtrA2 activity and hence apoptosis.

  5. Exploring the binding nature of pyrrolidine pocket-dependent interactions in the polo-box domain of polo-like kinase 1.

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    Ravichandran N Murugan

    Full Text Available BACKGROUND: Over the years, a great deal of effort has been focused on the design and synthesis of potent, linear peptide inhibitors targeting the polo-like kinase 1 (Plk1, which is critically involved in multiple mitotic processes and has been established as an adverse prognostic marker for tumor patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain, and inhibiting the Plk1 polo-box domain has been considered as an approach to circumvent the specificity problems associated with inhibiting the conserved adenosine triphosphate-binding pocket. The polo-box domain consists of two different binding regions, such as the unique, broader pyrrolidine-binding pocket and the conserved, narrow, Tyr-rich hydrophobic channel, among the three Plk polo-box domains (Plks 1-3, respectively. Therefore, the studies that provide insights into the binding nature of the unique, broader pyrrolidine-binding pocket might lead to the development of selective Plk1-inhibitory compounds. METHODOLOGY/PRINCIPAL FINDINGS: In an attempt to retain the monospecificity by targeting the unique, broader pyrrolidine-binding pocket, here, for the first time, a systematic approach was undertaken to examine the structure-activity relationship of N-terminal-truncated PLHSpTM derivatives, to apply a site-directed ligand approach using bulky aromatic and non-aromatic systems, and to characterize the binding nature of these analogues using X-ray crystallographic studies. We have identified a new mode of binding interactions, having improved binding affinity and retaining the Plk1 polo-box domain specificity, at the pyrrolidine-binding pocket. Furthermore, our data revealed that the pyrrolidine-binding pocket was very specific to recognize a short and bulky hydrophobic ligand like adamantane, whereas the Tyr-rich hydrophobic channel was specific with lengthy and small hydrophobic groups. CONCLUSION/SIGNIFICANCE: The progress made using our site

  6. Sequence similarity between the erythrocyte binding domain 1 of the Plasmodium vivax Duffy binding protein and the V3 loop of HIV-1 strain MN reveals binding residues for the Duffy Antigen Receptor for Chemokines

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    Garry Robert F

    2011-01-01

    Full Text Available Abstract Background The surface glycoprotein (SU, gp120 of the human immunodeficiency virus (HIV must bind to a chemokine receptor, CCR5 or CXCR4, to invade CD4+ cells. Plasmodium vivax uses the Duffy Binding Protein (DBP to bind the Duffy Antigen Receptor for Chemokines (DARC and invade reticulocytes. Results Variable loop 3 (V3 of HIV-1 SU and domain 1 of the Plasmodium vivax DBP share a sequence similarity. The site of amino acid sequence similarity was necessary, but not sufficient, for DARC binding and contained a consensus heparin binding site essential for DARC binding. Both HIV-1 and P. vivax can be blocked from binding to their chemokine receptors by the chemokine, RANTES and its analog AOP-RANTES. Site directed mutagenesis of the heparin binding motif in members of the DBP family, the P. knowlesi alpha, beta and gamma proteins abrogated their binding to erythrocytes. Positively charged residues within domain 1 are required for binding of P. vivax and P. knowlesi erythrocyte binding proteins. Conclusion A heparin binding site motif in members of the DBP family may form part of a conserved erythrocyte receptor binding pocket.

  7. N,C-Capped dipeptides with selectivity for mycobacterial proteasome over human proteasomes: role of S3 and S1 binding pockets.

    Science.gov (United States)

    Lin, Gang; Chidawanyika, Tamutenda; Tsu, Christopher; Warrier, Thulasi; Vaubourgeix, Julien; Blackburn, Christopher; Gigstad, Kenneth; Sintchak, Michael; Dick, Lawrence; Nathan, Carl

    2013-07-10

    We identified N,C-capped dipeptides that are selective for the Mycobacterium tuberculosis proteasome over human constitutive and immunoproteasomes. Differences in the S3 and S1 binding pockets appeared to account for the species selectivity. The inhibitors can penetrate mycobacteria and kill nonreplicating M. tuberculosis under nitrosative stress.

  8. An automated system for the analysis of G protein-coupled receptor transmembrane binding pockets: alignment, receptor-based pharmacophores, and their application.

    Science.gov (United States)

    Kratochwil, Nicole A; Malherbe, Pari; Lindemann, Lothar; Ebeling, Martin; Hoener, Marius C; Mühlemann, Andreas; Porter, Richard H P; Stahl, Martin; Gerber, Paul R

    2005-01-01

    G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Here, a comprehensive and automated method allowing fast analysis and comparison of these putative binding pockets across the entire GPCR family is presented. The method relies on a robust alignment algorithm based on conservation indices, focusing on pharmacophore-like relationships between amino acids. Analysis of conservation patterns across the GPCR family and alignment to the rhodopsin X-ray structure allows the extraction of the amino acids lining the TM binding pocket in a so-called ligand binding pocket vector (LPV). In a second step, LPVs are translated to simple 3D receptor pharmacophore models, where each amino acid is represented by a single spherical pharmacophore feature and all atomic detail is omitted. Applications of the method include the assessment of selectivity issues, support of mutagenesis studies, and the derivation of rules for focused screening to identify chemical starting points in early drug discovery projects. Because of the coarseness of this 3D receptor pharmacophore model, however, meaningful scoring and ranking procedures of large sets of molecules are not justified. The LPV analysis of the trace amine-associated receptor family and its experimental validation is discussed as an example. The value of the 3D receptor model is demonstrated for a class C GPCR family, the metabotropic glutamate receptors.

  9. Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis

    Science.gov (United States)

    Hov, Johannes R; Kosmoliaptsis, Vasilis; Traherne, James A; Olsson, Marita; Boberg, Kirsten M; Bergquist, Annika; Schrumpf, Erik; Bradley, J Andrew; Taylor, Craig J; Lie, Benedicte A; Trowsdale, John; Karlsen, Tom H

    2011-01-01

    The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10−32 and P = 1.8 × 10−22 in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented. (Hepatology 2011;53:1967-1976) PMID:21413052

  10. Fine-tuning of the binding and dissociation of CO by the amino acids of the heme pocket of Coprinus cinereus peroxidase.

    Science.gov (United States)

    Feis, Alessandro; Santoni, Elisa; Neri, Francesca; Ciaccio, Chiara; De Sanctis, Giampiero; Coletta, Massimo; Welinder, Karen G; Smulevich, Giulietta

    2002-11-01

    Resonance Raman and infrared spectra and the CO dissociation rates (k(off)) were measured in Coprinus cinereus peroxidase (CIP) and several mutants in the heme binding pocket. These mutants included the Asp245Asn, Arg51Leu, Arg51Gln, Arg51Asn, Arg51Lys, Phe54Trp, and Phe54Val mutants. Binding of CO to CIP produced different CO adducts at pH 6 and 10. At pH 6, the bound CO is H-bonded to the protonated distal His55 residue, whereas at alkaline pH, the vibrational signatures and the rate of CO dissociation indicate a distal side which is more open or flexible than in other plant peroxidases. The distal Arg51 residue is important in determining the rate of dissociation in the acid form, increasing by 8-17-fold in the Arg51 mutants compared to that for the wild-type protein. Replacement of the distal Phe with Trp created a new acid form characterized by vibrational frequencies and k(off) values very similar to those of cytochrome c peroxidase.

  11. Aromatic Amino Acid Mutagenesis at the Substrate Binding Pocket of Yarrowia lipolytica Lipase Lip2 Affects Its Activity and Thermostability

    Directory of Open Access Journals (Sweden)

    Guilong Wang

    2014-01-01

    Full Text Available The lipase2 from Yarrowia lipolytica (YLLip2 is a yeast lipase exhibiting high homologous to filamentous fungal lipase family. Though its crystal structure has been resolved, its structure-function relationship has rarely been reported. By contrast, there are two amino acid residues (V94 and I100 with significant difference in the substrate binding pocket of YLLip2; they were subjected to site-directed mutagenesis (SDM to introduce aromatic amino acid mutations. Two mutants (V94W and I100F were created. The enzymatic properties of the mutant lipases were detected and compared with the wild-type. The activities of mutant enzymes dropped to some extent towards p-nitrophenyl palmitate (pNPC16 and their optimum temperature was 35°C, which was 5°C lower than that of the wild-type. However, the thermostability of I100F increased 22.44% after incubation for 1 h at 40°C and its optimum substrate shifted from p-nitrophenyl laurate (pNPC12 to p-nitrophenyl caprate (pNPC10. The above results demonstrated that the two substituted amino acid residuals have close relationship with such enzymatic properties as thermostability and substrate selectivity.

  12. Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets.

    Science.gov (United States)

    Van Aller, Glenn S; Graves, Alan P; Elkins, Patricia A; Bonnette, William G; McDevitt, Patrick J; Zappacosta, Francesca; Annan, Roland S; Dean, Tony W; Su, Dai-Shi; Carpenter, Christopher L; Mohammad, Helai P; Kruger, Ryan G

    2016-05-01

    SMYD3 is a lysine methyltransferase overexpressed in colorectal, breast, prostate, and hepatocellular tumors, and has been implicated as an oncogene in human malignancies. Methylation of MEKK2 by SMYD3 is important for regulation of the MEK/ERK pathway, suggesting the possibility of selectively targeting SMYD3 in RAS-driven cancers. Structural and kinetic characterization of SMYD3 was undertaken leading to a co-crystal structure of SMYD3 with a MEKK2-peptide substrate bound, and the observation that SMYD3 follows a partially processive mechanism. These insights allowed for the design of GSK2807, a potent and selective, SAM-competitive inhibitor of SMYD3 (Ki = 14 nM). A high-resolution crystal structure reveals that GSK2807 bridges the gap between the SAM-binding pocket and the substrate lysine tunnel of SMYD3. Taken together, our data demonstrate that small-molecule inhibitors of SMYD3 can be designed to prevent methylation of MEKK2 and these could have potential use as anticancer therapeutics.

  13. Study on the Gas Phase Stability of Heme-binding Pocket in Cytochrome Tb5 and Its Mutants by Electrospray Mass Spectrometry

    Institute of Scientific and Technical Information of China (English)

    YU,Chong-Tian(余翀天); GUO,Yin-Long(郭寅龙); L(U),Long(吕龙); WANG,Yun-Hua(王韵华); YAO,Ping(姚萍); HUANG,Zhong-Xian(黄仲贤)

    2002-01-01

    To ehucidate the effect of various amino acid residues on the heme-binding pocket in cytochrome Tbs, several residues were chosen for replacement by means of site-directed mutagenesis.Comparison of the mass spectrmn between the F35Y mutant and the wild type shows that the relative abundance of holoprotein ion of F35Y is lower than that of the wild type in gas phase. It is concluded that mutation from Phe35 residue to tyrosine decreases the hydrophobic character of cytochrome Tbs heme pocket, which decreases the stability of heme-binding pocket. ESI-MS spectra of the mutants V61E, V61K, V61H and V61Y show various contribution of amino acid to the stability of heme-binding pocket. The small and non-polar residue Vat61 was replaced with large or polar residues, resulting in enhancing the trend of heme leaving from the pocket. In addition, comparison of the mass relative abundance of bolo-proteins among all the Va161-mutants, shows that their stability in gas phase appropriately submit the following order: wild type > V61H > V61E > V61K ≈ V61Y. The extra great stability of quadruple sites mutant E44/48/56A/D60A shows that reduction of electrostatic or hydrogen bond interactions among the residues locating in the outside region of the heme edge remarkably affect the stability of heme. The results of analyzing the oxidation states of heme iron in Tbs and its mutants by insource-CAD experiment suggest that the charge states of heme iron maintain inflexible in mutation process.

  14. Pocket Money

    Institute of Scientific and Technical Information of China (English)

    刘杰莹; 赵惠; 李世芹; 袁琳

    2007-01-01

    Do you get any poch’et money from your parents? What do you do with it?刘杰莹Pocket Money (1st Floor) I get some pocket money from Mom every day.But I never spend it casually.Except the money for breakfast,

  15. CNDOL: A fast and reliable method for the calculation of electronic properties of very large systems. Applications to retinal binding pocket in rhodopsin and gas phase porphine.

    Science.gov (United States)

    Montero-Cabrera, Luis Alberto; Röhrig, Ute; Padrón-Garcia, Juan A; Crespo-Otero, Rachel; Montero-Alejo, Ana L; Garcia de la Vega, José M; Chergui, Majed; Rothlisberger, Ursula

    2007-10-14

    Very large molecular systems can be calculated with the so called CNDOL approximate Hamiltonians that have been developed by avoiding oversimplifications and only using a priori parameters and formulas from the simpler NDO methods. A new diagonal monoelectronic term named CNDOL/21 shows great consistency and easier SCF convergence when used together with an appropriate function for charge repulsion energies that is derived from traditional formulas. It is possible to obtain a priori molecular orbitals and electron excitation properties after the configuration interaction of single excited determinants with reliability, maintaining interpretative possibilities even being a simplified Hamiltonian. Tests with some unequivocal gas phase maxima of simple molecules (benzene, furfural, acetaldehyde, hexyl alcohol, methyl amine, 2,5 dimethyl 2,4 hexadiene, and ethyl sulfide) ratify the general quality of this approach in comparison with other methods. The calculation of large systems as porphine in gas phase and a model of the complete retinal binding pocket in rhodopsin with 622 basis functions on 280 atoms at the quantum mechanical level show reliability leading to a resulting first allowed transition in 483 nm, very similar to the known experimental value of 500 nm of "dark state." In this very important case, our model gives a central role in this excitation to a charge transfer from the neighboring Glu(-) counterion to the retinaldehyde polyene chain. Tests with gas phase maxima of some important molecules corroborate the reliability of CNDOL/2 Hamiltonians.

  16. Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Yu Mi; Clare, Michael; Ensinger, Carol L.; Hood, Molly M.; Lord, John W.; Lu, Wei-Ping; Miller, David F.; Patt, William C.; Smith, Bryan D.; Vogeti, Lakshminarayana; Kaufman, Michael D.; Petillo, Peter A.; Wise, Scott C.; Abendroth, Jan; Chun, Lawrence; Clark, Robin; Feese, Michael; Kim, Hidong; Stewart, Lance; Flynn, Daniel L. (Deciphera); (Emerald); (Cocrystal)

    2012-01-20

    Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.

  17. Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region.

    Science.gov (United States)

    Ahn, Yu Mi; Clare, Michael; Ensinger, Carol L; Hood, Molly M; Lord, John W; Lu, Wei-Ping; Miller, David F; Patt, William C; Smith, Bryan D; Vogeti, Lakshminarayana; Kaufman, Michael D; Petillo, Peter A; Wise, Scott C; Abendroth, Jan; Chun, Lawrence; Clark, Robin; Feese, Michael; Kim, Hidong; Stewart, Lance; Flynn, Daniel L

    2010-10-01

    Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.

  18. Modulation of ligand-heme reactivity by binding pocket residues demonstrated in cytochrome c' over the femtosecond-second temporal range.

    Science.gov (United States)

    Russell, Henry J; Hardman, Samantha J O; Heyes, Derren J; Hough, Michael A; Greetham, Gregory M; Towrie, Michael; Hay, Sam; Scrutton, Nigel S

    2013-12-01

    The ability of hemoproteins to discriminate between diatomic molecules, and the subsequent affinity for their chosen ligand, is fundamental to the existence of life. These processes are often controlled by precise structural arrangements in proteins, with heme pocket residues driving reactivity and specificity. One such protein is cytochrome c', which has the ability to bind nitric oxide (NO) and carbon monoxide (CO) on opposite faces of the heme, a property that is shared with soluble guanylate cycle. Like soluble guanylate cyclase, cytochrome c' also excludes O2 completely from the binding pocket. Previous studies have shown that the NO binding mechanism is regulated by a proximal arginine residue (R124) and a distal leucine residue (L16). Here, we have investigated the roles of these residues in maintaining the affinity for NO in the heme binding environment by using various time-resolved spectroscopy techniques that span the entire femtosecond-second temporal range in the UV-vis spectrum, and the femtosecond-nanosecond range by IR spectroscopy. Our findings indicate that the tightly regulated NO rebinding events following excitation in wild-type cytochrome c' are affected in the R124A variant. In the R124A variant, vibrational and electronic changes extend continuously across all time scales (from fs-s), in contrast to wild-type cytochrome c' and the L16A variant. Based on these findings, we propose a NO (re)binding mechanism for the R124A variant of cytochrome c' that is distinct from that in wild-type cytochrome c'. In the wider context, these findings emphasize the importance of heme pocket architecture in maintaining the reactivity of hemoproteins towards their chosen ligand, and demonstrate the power of spectroscopic probes spanning a wide temporal range.

  19. Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists.

    Science.gov (United States)

    Karaman, Rafik; Nowak, Stefanie; Di Pizio, Antonella; Kitaneh, Hothaifa; Abu-Jaish, Alaa; Meyerhof, Wolfgang; Niv, Masha Y; Behrens, Maik

    2016-07-01

    Sensing potentially harmful bitter substances in the oral cavity is achieved by a group of (˜) 25 receptors, named TAS2Rs, which are expressed in specialized sensory cells and recognize individual but overlapping sets of bitter compounds. The receptors differ in their tuning breadths ranging from narrowly to broadly tuned receptors. One of the most broadly tuned human bitter taste receptors is the TAS2R14 recognizing an enormous variety of chemically diverse synthetic and natural bitter compounds, including numerous medicinal drugs. This suggests that this receptor possesses a large readily accessible ligand binding pocket. To allow probing the accessibility and size of the ligand binding pocket, we chemically modified cognate agonists and tested receptor responses in functional assays. The addition of large functional groups to agonists was usually possible without abolishing agonistic activity. The newly synthesized agonist derivatives were modeled in the binding site of the receptor, providing comparison to the mother substances and rationalization of the in vitro activities of this series of compounds. PMID:26825540

  20. Targeting the Small- and Intermediate-Conductance Ca2+-Activated Potassium Channels: The Drug-Binding Pocket at the Channel/Calmodulin Interface

    Directory of Open Access Journals (Sweden)

    Meng Cui

    2014-10-01

    Full Text Available The small- and intermediate-conductance Ca2+-activated potassium (SK/IK channels play important roles in the regulation of excitable cells in both the central nervous and cardiovascular systems. Evidence from animal models has implicated SK/IK channels in neurological conditions such as ataxia and alcohol use disorders. Further, genome-wide association studies have suggested that cardiovascular abnormalities such as arrhythmias and hypertension are associated with single nucleotide polymorphisms that occur within the genes encoding the SK/IK channels. The Ca2+ sensitivity of the SK/IK channels stems from a constitutively bound Ca2+-binding protein: calmodulin. Small-molecule positive modulators of SK/IK channels have been developed over the past decade, and recent structural studies have revealed that the binding pocket of these positive modulators is located at the interface between the channel and calmodulin. SK/IK channel positive modulators can potentiate channel activity by enhancing the coupling between Ca2+ sensing via calmodulin and mechanical opening of the channel. Here, we review binding pocket studies that have provided structural insight into the mechanism of action for SK/IK channel positive modulators. These studies lay the foundation for structure-based drug discovery efforts that can identify novel SK/IK channel positive modulators. © 2014 S. Karger AG, Basel

  1. Pocket Bikes

    Institute of Scientific and Technical Information of China (English)

    Terry Mccarthy; 陈青

    2004-01-01

    @@ The next big thing out of California is 18 in. High, weighs about 50 lbs. And is capable of traveling up to 70 m. P. H. Meet the pocket bike, a scaled-down①motorcycle that is selling faster than low-carb hot cakes across the Golden State②-and causing nightmares③ for traffic police.

  2. Response similarity as a basis for perceptual binding.

    Science.gov (United States)

    Sterkin, Anna; Sterkin, Alexander; Polat, Uri

    2008-07-07

    Detection of low-contrast Gabor patches (GPs) is improved when flanked by collinear GPs, whereas suppression is observed for high-contrast GPs. The facilitation resembles the principles of Gestalt theory of perceptual organization. We propose a model for contour integration in the context of noise that incorporates a temporal element into this spatial architecture. The basic principles are (1) the response increases with increasing contrast, whereas the latency decreases; (2) activity-dependent interactions: facilitation for low and suppression for high activity; (3) the variance increases with contrast for responses, rates, and latency; and (4) inhibition has a shorter time constant than excitation. When a texture of randomly oriented GPs is presented, the response to every element decreases due to fast inhibition between the neighboring elements, shifting the activity toward the range of collinear facilitation. Next, the slower excitation induces selective facilitation along the contour elements. Consequently, the response to the contour increases, whereas the variance of the rate and latency decreases, providing better temporal correlation between the contour elements. Thus, collinear facilitation increases the saliency of contours. Our model may suggest a solution to the binding problem by bridging between the temporal and spatial aspects of lateral interactions that determine the encoding of perceptual grouping.

  3. A covalent adduct of MbtN, an acyl-ACP dehydrogenase from Mycobacterium tuberculosis, reveals an unusual acyl-binding pocket.

    Science.gov (United States)

    Chai, Ai-Fen; Bulloch, Esther M M; Evans, Genevieve L; Lott, J Shaun; Baker, Edward N; Johnston, Jodie M

    2015-04-01

    Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Access to iron in host macrophages depends on iron-chelating siderophores called mycobactins and is strongly correlated with Mtb virulence. Here, the crystal structure of an Mtb enzyme involved in mycobactin biosynthesis, MbtN, in complex with its FAD cofactor is presented at 2.30 Å resolution. The polypeptide fold of MbtN conforms to that of the acyl-CoA dehydrogenase (ACAD) family, consistent with its predicted role of introducing a double bond into the acyl chain of mycobactin. Structural comparisons and the presence of an acyl carrier protein, MbtL, in the same gene locus suggest that MbtN acts on an acyl-(acyl carrier protein) rather than an acyl-CoA. A notable feature of the crystal structure is the tubular density projecting from N(5) of FAD. This was interpreted as a covalently bound polyethylene glycol (PEG) fragment and resides in a hydrophobic pocket where the substrate acyl group is likely to bind. The pocket could accommodate an acyl chain of 14-21 C atoms, consistent with the expected length of the mycobactin acyl chain. Supporting this, steady-state kinetics show that MbtN has ACAD activity, preferring acyl chains of at least 16 C atoms. The acyl-binding pocket adopts a different orientation (relative to the FAD) to other structurally characterized ACADs. This difference may be correlated with the apparent ability of MbtN to catalyse the formation of an unusual cis double bond in the mycobactin acyl chain.

  4. Pathogenicity of the BRCA1 Missense Variant M1775K is Determined by the Disruption of the BRCT Phosphopeptide-Binding Pocket: a Multi-Modal Approach

    Energy Technology Data Exchange (ETDEWEB)

    Tischkowitz,M.; Hamel, N.; Carvalho, M.; Birrane, G.; Soni, A.; van Beers, E.; Joosse, S.; Wong, N.; Novak, D.; et al

    2008-01-01

    A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.

  5. Exploring Chromophore-Binding Pocket: High-Resolution Solid-State H-C Interfacial Correlation NMR Spectra with Windowed PMLG Scheme.

    Science.gov (United States)

    Song, Chen; Lang, Christina; Mailliet, Jo; Hughes, Jon; Gärtner, Wolfgang; Matysik, Jörg

    2012-02-01

    High-resolution two-dimensional (2D) (1)H-(13)C heteronuclear correlation spectra are recorded for selective observation of interfacial 3-5.5 Å contacts of the uniformly (13)C-labeled phycocyanobilin (PCB) chromophore with its unlabeled binding pocket. The experiment is based on a medium- and long-distance heteronuclear correlation (MELODI-HETCOR) method. For improving (1)H spectral resolution, a windowed phase-modulated Lee-Goldburg (wPMLG) decoupling scheme is applied during the t(1) evolution period. Our approach allows for identification of chromophore-protein interactions, in particular for elucidation of the hydrogen-bonding networks and charge distributions within the chromophore-binding pocket. The resulting pulse sequence is tested on the cyanobacterial (Cph1) phytochrome sensory module (residues 1-514, Cph1Δ2) containing uniformly (13)C- and (15)N-labeled PCB chromophore (u-[(13)C,(15)N]-PCB-Cph1Δ2) at 17.6 T. PMID:22303079

  6. Isolation of a Thiamine-binding Protein from Rice Germ and Distribution of Similar Proteins.

    Science.gov (United States)

    Shimizu, M; Yoshida, T; Toda, T; Iwashima, A; Mitsunaga, T

    1996-01-01

    A thiamine-binding protein was purified from rice germ (Oryza sativa L.) by extraction, salting-out with ammonium sulfate, and column chromatography. From the results of molecular mass, Kd and Bmax values for thiamine-binding, binding specificity for thiamine phosphates and analog, the protein was suggested to be identical to the thiamine-binding protein in rice bran. The thiamine-binding protein w as more efficiently purified from rice germ than from rice bran. The protein was rich in glutamic acid (and/or glutamine) and glycine. The protein did not show immunological similarity to thiamine-binding proteins in buckwheat and sesame seeds. However proteins similar to the thiamine-binding protein from rice germ existed in gramineous seeds. They were suggested to have thiamine-binding activity and to be of the same molecular mass as the thiamine-binding protein. PMID:27299548

  7. Verification of a novel NADH-binding motif: combinatorial mutagenesis of three amino acids in the cofactor-binding pocket of Corynebacterium 2,5-diketo-D-gluconic acid reductase.

    Science.gov (United States)

    Banta, Scott; Anderson, Stephen

    2002-12-01

    A screening method has been developed to support randomized mutagenesis of amino acids in the cofactor-binding pocket of the NADPH-dependent 2,5-diketo-D-gluconic acid (2,5-DKG) reductase. Such an approach could enable the isolation of an enzyme that can better catalyze the reduction of 2,5-DKG to 2-keto-L-gulonic acid (2-KLG) using NADH as a cofactor. 2-KLG is a valuable precursor to ascorbic acid, or vitamin C, and an enzyme with increased activity with NADH may be able to improve two potential vitamin C production processes. Previously we have identified three amino acid residues that can be mutated to improve activity with NADH as a cofactor. As a pilot study to show feasibility, a library was made with these three amino acids randomized, and 300 random colonies were screened for increased NADH activity. The activities of seven mutants with apparent improvements were verified using activity-stained native gels, and sequencing showed that the amino acids obtained were similar to some of those already discovered using rational design. The four most active mutants were purified and kinetically characterized. All of the new mutations resulted in apparent kcat values that were equal to or higher than that of the best mutant obtained through rational design. At saturating levels of cofactor, the best mutant obtained was almost twice as active with NADH as a cofactor as the wild-type enzyme is with NADPH. This screen is a valuable tool for improving 2,5-DKG reductase, and it could easily be modified for improving other aspects of this protein or similar enzymes.

  8. Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies

    Science.gov (United States)

    Bornholdt, Zachary A.; Ndungo, Esther; Fusco, Marnie L.; Bale, Shridhar; Flyak, Andrew I.; Crowe, James E.

    2016-01-01

    ABSTRACT The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics. PMID:26908579

  9. Tetranectin-binding site on plasminogen kringle 4 involves the lysine-binding pocket and at least one additional amino acid residue

    DEFF Research Database (Denmark)

    Graversen, Jonas Heilskov; Sigurskjold, B W; Thøgersen, H C;

    2000-01-01

    of plasminogen kringle 4, which both were found to interact with the low molecular weight ligand with an almost identical geometry in the crystal of the complex, are not of equal functional importance in t-AMCHA binding. Mutating Asp 57 to an Asn totally eliminates binding, whereas the Asp 55 to Asn...

  10. Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies.

    Science.gov (United States)

    Sabbah, Dima A; Zhong, Haizhen A

    2016-07-01

    β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is -1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors. PMID:27474865

  11. Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent

    Directory of Open Access Journals (Sweden)

    Liu W

    2015-07-01

    Full Text Available Wei Liu,1,* Jin-Feng Ning,2,* Qing-Wei Meng,1 Jing Hu,1 Yan-Bin Zhao,1 Chao Liu,3 Li Cai11The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 2The Thoracic Surgery Department, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 3General Surgery Department, Mudanjiang Guanliju Central Hospital, Mishan, Heilongjiang Province, People’s Republic of China*These authors contributed equally to this workAbstract: The epidermal growth factor receptor (EGFR family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC, particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB. Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10 against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase–ligand interaction space in the PDB.Keywords: EGFR, kinase

  12. Strength of hydrogen bond network takes crucial roles in the dissociation process of inhibitors from the HIV-1 protease binding pocket.

    Directory of Open Access Journals (Sweden)

    Dechang Li

    Full Text Available To understand the underlying mechanisms of significant differences in dissociation rate constant among different inhibitors for HIV-1 protease, we performed steered molecular dynamics (SMD simulations to analyze the entire dissociation processes of inhibitors from the binding pocket of protease at atomistic details. We found that the strength of hydrogen bond network between inhibitor and the protease takes crucial roles in the dissociation process. We showed that the hydrogen bond network in the cyclic urea inhibitors AHA001/XK263 is less stable than that of the approved inhibitor ABT538 because of their large differences in the structures of the networks. In the cyclic urea inhibitor bound complex, the hydrogen bonds often distribute at the flap tips and the active site. In contrast, there are additional accessorial hydrogen bonds formed at the lateral sides of the flaps and the active site in the ABT538 bound complex, which take crucial roles in stabilizing the hydrogen bond network. In addition, the water molecule W301 also plays important roles in stabilizing the hydrogen bond network through its flexible movement by acting as a collision buffer and helping the rebinding of hydrogen bonds at the flap tips. Because of its high stability, the hydrogen bond network of ABT538 complex can work together with the hydrophobic clusters to resist the dissociation, resulting in much lower dissociation rate constant than those of cyclic urea inhibitor complexes. This study may provide useful guidelines for design of novel potent inhibitors with optimized interactions.

  13. Strength of hydrogen bond network takes crucial roles in the dissociation process of inhibitors from the HIV-1 protease binding pocket.

    Science.gov (United States)

    Li, Dechang; Ji, Baohua; Hwang, Keh-Chih; Huang, Yonggang

    2011-01-01

    To understand the underlying mechanisms of significant differences in dissociation rate constant among different inhibitors for HIV-1 protease, we performed steered molecular dynamics (SMD) simulations to analyze the entire dissociation processes of inhibitors from the binding pocket of protease at atomistic details. We found that the strength of hydrogen bond network between inhibitor and the protease takes crucial roles in the dissociation process. We showed that the hydrogen bond network in the cyclic urea inhibitors AHA001/XK263 is less stable than that of the approved inhibitor ABT538 because of their large differences in the structures of the networks. In the cyclic urea inhibitor bound complex, the hydrogen bonds often distribute at the flap tips and the active site. In contrast, there are additional accessorial hydrogen bonds formed at the lateral sides of the flaps and the active site in the ABT538 bound complex, which take crucial roles in stabilizing the hydrogen bond network. In addition, the water molecule W301 also plays important roles in stabilizing the hydrogen bond network through its flexible movement by acting as a collision buffer and helping the rebinding of hydrogen bonds at the flap tips. Because of its high stability, the hydrogen bond network of ABT538 complex can work together with the hydrophobic clusters to resist the dissociation, resulting in much lower dissociation rate constant than those of cyclic urea inhibitor complexes. This study may provide useful guidelines for design of novel potent inhibitors with optimized interactions.

  14. Quantum Hall conductance and de Haas-van Alphen oscillation in a tight-binding model with electron and hole pockets for (TMTSF) 2NO3

    Science.gov (United States)

    Kishigi, Keita; Hasegawa, Yasumasa

    2016-08-01

    Quantized Hall conductance and de Haas-van Alphen (dHvA) oscillation are studied theoretically in the tight-binding model for (TMTSF) 2NO3 , in which there are small pockets of electrons and holes due to the periodic potentials of anion ordering in the a direction. The magnetic field is treated by hoppings as complex numbers due to the phase caused by the vector potential, i.e., Peierls substitution. In realistic values of parameters and the magnetic field, the energy as a function of the magnetic field (Hofstadter butterfly diagram) is obtained. It is shown that the energy levels are broadened and the gaps are closed or almost closed periodically as a function of the inverse magnetic field, which is not seen in the semiclassical theory of the magnetic breakdown. The Hall conductance is quantized with an integer obtained by the Diophantine equation when the chemical potential lies in an energy gap. When electrons or holes are doped in this system, the Hall conductance is quantized in some regions of a magnetic field but it is not quantized in other regions of a magnetic field due to the broadening of the Landau levels. The amplitude of the dHvA oscillation at zero temperature decreases as the magnetic field increases, while it is constant in the semiclassical Lifshitz Kosevich formula.

  15. Fungal lytic polysaccharide monooxygenases bind starch and β-cyclodextrin similarly to amylolytic hydrolases

    DEFF Research Database (Denmark)

    Nekiunaite, Laura; Isaksen, Trine; Vaaje-Kolstad, Gustav;

    2016-01-01

    Starch-binding modules of family 20 (CBM20) are present in 60% of lytic polysaccharide monooxygenases (LPMOs) catalyzing the oxidative breakdown of starch, which highlights functional importance in LPMO activity. The substrate-binding properties of starch-active LMPOs, however, are currently...... unexplored. Affinities and binding-thermodynamics of two recombinant fungal LPMOs toward starch and β-cyclodextrin were shown to be similar to fungal CBM20s. Amplex Red assays showed ascorbate and Cu-dependent activity, which was inhibited in the presence of β-cylodextrin and amylose. Phylogenetically......, the clustering of CBM20s from starch-targeting LPMOs and hydrolases was in accord with taxonomy and did not correlate to appended catalytic activity. Altogether, these results demonstrate that the CBM20-binding scaffold is retained in the evolution of hydrolytic and oxidative starch-degrading activities....

  16. SPIC: A novel similarity metric for comparing transcription factor binding site motifs based on information contents

    OpenAIRE

    Zhang, Shaoqiang; Zhou, Xiguo; Du, Chuanbin; Su, Zhengchang

    2013-01-01

    Background Discovering transcription factor binding sites (TFBS) is one of primary challenges to decipher complex gene regulatory networks encrypted in a genome. A set of short DNA sequences identified by a transcription factor (TF) is known as a motif, which can be expressed accurately in matrix form such as a position-specific scoring matrix (PSSM) and a position frequency matrix. Very frequently, we need to query a motif in a database of motifs by seeking its similar motifs, merge similar ...

  17. SPOT-Ligand: Fast and effective structure-based virtual screening by binding homology search according to ligand and receptor similarity.

    Science.gov (United States)

    Yang, Yuedong; Zhan, Jian; Zhou, Yaoqi

    2016-07-01

    Structure-based virtual screening usually involves docking of a library of chemical compounds onto the functional pocket of the target receptor so as to discover novel classes of ligands. However, the overall success rate remains low and screening a large library is computationally intensive. An alternative to this "ab initio" approach is virtual screening by binding homology search. In this approach, potential ligands are predicted based on similar interaction pairs (similarity in receptors and ligands). SPOT-Ligand is an approach that integrates ligand similarity by Tanimoto coefficient and receptor similarity by protein structure alignment program SPalign. The method was found to yield a consistent performance in DUD and DUD-E docking benchmarks even if model structures were employed. It improves over docking methods (DOCK6 and AUTODOCK Vina) and has a performance comparable to or better than other binding-homology methods (FINDsite and PoLi) with higher computational efficiency. The server is available at http://sparks-lab.org. © 2016 Wiley Periodicals, Inc. PMID:27074979

  18. Crystal structure of silkworm Bombyx mori JHBP in complex with 2-methyl-2,4-pentanediol: plasticity of JH-binding pocket and ligand-induced conformational change of the second cavity in JHBP.

    Directory of Open Access Journals (Sweden)

    Zui Fujimoto

    Full Text Available Juvenile hormones (JHs control a diversity of crucial life events in insects. In Lepidoptera which major agricultural pests belong to, JH signaling is critically controlled by a species-specific high-affinity, low molecular weight JH-binding protein (JHBP in hemolymph, which transports JH from the site of its synthesis to target tissues. Hence, JHBP is expected to be an excellent target for the development of novel specific insect growth regulators (IGRs and insecticides. A better understanding of the structural biology of JHBP should pave the way for the structure-based drug design of such compounds. Here, we report the crystal structure of the silkworm Bombyx mori JHBP in complex with two molecules of 2-methyl-2,4-pentanediol (MPD, one molecule (MPD1 bound in the JH-binding pocket while the other (MPD2 in a second cavity. Detailed comparison with the apo-JHBP and JHBP-JH II complex structures previously reported by us led to a number of intriguing findings. First, the JH-binding pocket changes its size in a ligand-dependent manner due to flexibility of the gate α1 helix. Second, MPD1 mimics interactions of the epoxide moiety of JH previously observed in the JHBP-JH complex, and MPD can compete with JH in binding to the JH-binding pocket. We also confirmed that methoprene, which has an MPD-like structure, inhibits the complex formation between JHBP and JH while the unepoxydated JH III (methyl farnesoate does not. These findings may open the door to the development of novel IGRs targeted against JHBP. Third, binding of MPD to the second cavity of JHBP induces significant conformational changes accompanied with a cavity expansion. This finding, together with MPD2-JHBP interaction mechanism identified in the JHBP-MPD complex, should provide important guidance in the search for the natural ligand of the second cavity.

  19. Binding in working memory and frontal lobe in normal aging: is there any similarity with autism?

    OpenAIRE

    Lecouvey, Grégory; Quinette, Peggy; Kalpouzos, Grégoria; Guillery-Girard, Bérengère; Bejanin, Alexandre; Gonneaud, Julie; Abbas,Ahmed; Viader, Fausto; Eustache, Francis; Desgranges, Béatrice

    2015-01-01

    Some studies highlight similarities between Autism Spectrum Disorder (ASD) and healthy aging. Indeed, the decline in older individuals’ ability to create a unified representation of the individual features of an event is thought to arise from a disruption of binding within the episodic buffer of working memory (WM) as the same way as observed in ASD. In both cases, this deficit may result from an abnormal engagement of a frontohippocampal network. The objective of the present study is to iden...

  20. Searching the protein structure database for ligand-binding site similarities using CPASS v.2

    Directory of Open Access Journals (Sweden)

    Caprez Adam

    2011-01-01

    Full Text Available Abstract Background A recent analysis of protein sequences deposited in the NCBI RefSeq database indicates that ~8.5 million protein sequences are encoded in prokaryotic and eukaryotic genomes, where ~30% are explicitly annotated as "hypothetical" or "uncharacterized" protein. Our Comparison of Protein Active-Site Structures (CPASS v.2 database and software compares the sequence and structural characteristics of experimentally determined ligand binding sites to infer a functional relationship in the absence of global sequence or structure similarity. CPASS is an important component of our Functional Annotation Screening Technology by NMR (FAST-NMR protocol and has been successfully applied to aid the annotation of a number of proteins of unknown function. Findings We report a major upgrade to our CPASS software and database that significantly improves its broad utility. CPASS v.2 is designed with a layered architecture to increase flexibility and portability that also enables job distribution over the Open Science Grid (OSG to increase speed. Similarly, the CPASS interface was enhanced to provide more user flexibility in submitting a CPASS query. CPASS v.2 now allows for both automatic and manual definition of ligand-binding sites and permits pair-wise, one versus all, one versus list, or list versus list comparisons. Solvent accessible surface area, ligand root-mean square difference, and Cβ distances have been incorporated into the CPASS similarity function to improve the quality of the results. The CPASS database has also been updated. Conclusions CPASS v.2 is more than an order of magnitude faster than the original implementation, and allows for multiple simultaneous job submissions. Similarly, the CPASS database of ligand-defined binding sites has increased in size by ~ 38%, dramatically increasing the likelihood of a positive search result. The modification to the CPASS similarity function is effective in reducing CPASS similarity scores

  1. Sequence similarity between the erythrocyte binding domain of the Plasmodium vivax Duffy binding protein and the V3 loop of HIV-1 strain MN reveals a functional heparin binding motif involved in binding to the Duffy antigen receptor for chemokines

    Directory of Open Access Journals (Sweden)

    Bolton Michael J

    2011-11-01

    Full Text Available Abstract Background The HIV surface glycoprotein gp120 (SU, gp120 and the Plasmodium vivax Duffy binding protein (PvDBP bind to chemokine receptors during infection and have a site of amino acid sequence similarity in their binding domains that often includes a heparin binding motif (HBM. Infection by either pathogen has been found to be inhibited by polyanions. Results Specific polyanions that inhibit HIV infection and bind to the V3 loop of X4 strains also inhibited DBP-mediated infection of erythrocytes and DBP binding to the Duffy Antigen Receptor for Chemokines (DARC. A peptide including the HBM of PvDBP had similar affinity for heparin as RANTES and V3 loop peptides, and could be specifically inhibited from heparin binding by the same polyanions that inhibit DBP binding to DARC. However, some V3 peptides can competitively inhibit RANTES binding to heparin, but not the PvDBP HBM peptide. Three other members of the DBP family have an HBM sequence that is necessary for erythrocyte binding, however only the protein which binds to DARC, the P. knowlesi alpha protein, is inhibited by heparin from binding to erythrocytes. Heparitinase digestion does not affect the binding of DBP to erythrocytes. Conclusion The HBMs of DBPs that bind to DARC have similar heparin binding affinities as some V3 loop peptides and chemokines, are responsible for specific sulfated polysaccharide inhibition of parasite binding and invasion of red blood cells, and are more likely to bind to negative charges on the receptor than cell surface glycosaminoglycans.

  2. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET.

    Science.gov (United States)

    Fang, Bing; Zhang, Ming; Tian, Mai; Jiang, Lu; Guo, Hui Yuan; Ren, Fa Zheng

    2014-04-01

    α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes. PMID:24368211

  3. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET.

    Science.gov (United States)

    Fang, Bing; Zhang, Ming; Tian, Mai; Jiang, Lu; Guo, Hui Yuan; Ren, Fa Zheng

    2014-04-01

    α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes.

  4. FISim: A new similarity measure between transcription factor binding sites based on the fuzzy integral

    Directory of Open Access Journals (Sweden)

    Cano Carlos

    2009-07-01

    Full Text Available Abstract Background Regulatory motifs describe sets of related transcription factor binding sites (TFBSs and can be represented as position frequency matrices (PFMs. De novo identification of TFBSs is a crucial problem in computational biology which includes the issue of comparing putative motifs with one another and with motifs that are already known. The relative importance of each nucleotide within a given position in the PFMs should be considered in order to compute PFM similarities. Furthermore, biological data are inherently noisy and imprecise. Fuzzy set theory is particularly suitable for modeling imprecise data, whereas fuzzy integrals are highly appropriate for representing the interaction among different information sources. Results We propose FISim, a new similarity measure between PFMs, based on the fuzzy integral of the distance of the nucleotides with respect to the information content of the positions. Unlike existing methods, FISim is designed to consider the higher contribution of better conserved positions to the binding affinity. FISim provides excellent results when dealing with sets of randomly generated motifs, and outperforms the remaining methods when handling real datasets of related motifs. Furthermore, we propose a new cluster methodology based on kernel theory together with FISim to obtain groups of related motifs potentially bound by the same TFs, providing more robust results than existing approaches. Conclusion FISim corrects a design flaw of the most popular methods, whose measures favour similarity of low information content positions. We use our measure to successfully identify motifs that describe binding sites for the same TF and to solve real-life problems. In this study the reliability of fuzzy technology for motif comparison tasks is proven.

  5. Investigation on the differences of four flavonoids with similar structure binding to human serum albumin

    Directory of Open Access Journals (Sweden)

    Chao-Zhan Lin

    2014-12-01

    Full Text Available Flavonoids are structurally diverse and the most ubiquitous groups of polyphenols distributed in the various plants, which possess intensive biological activities. In this study, the interaction mechanisms between four flavonoids containing one glucose unit with similar molecular weight isolated from the Tibetan medicinal herb Pyrethrum tatsienense, namely, apigenin-7-O-β-D-glucoside(1, luteolin-7-O-β-D-glucoside(2, quercetin-7-O-β-D-glucoside(3, quercetin-3-O-β-D-glycoside(4, and human serum albumin(HSA, were investigated by fluorescence, UV–vis absorbance, circular dichroism, and molecular modeling. The effects of biological metal ions Mg2+, Zn2+, and Cu2+ on the binding affinity between flavonoids and HSA were further examined. Structure–activity relationships of four flavonoids binding to HSA were discussed in depth and some meaningful conclusions have been drawn by the experiment data and theoretical simulation. In addition, an interesting phenomenon was observed that the microenvironment of the binding site I in HSA has hardly changed in the presence of 4 differentiating from the other three flavonoids on the basis of conformation investigations.

  6. Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction.

    Science.gov (United States)

    Brylinski, Michal

    2013-11-25

    A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 Å (<3 Å). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 Å for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 Å Cα-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ∼0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely

  7. Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction.

    Science.gov (United States)

    Brylinski, Michal

    2013-11-25

    A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 Å (<3 Å). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 Å for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 Å Cα-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ∼0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely

  8. Reinventing Pocket Microscopy

    CERN Document Server

    Kamal, T; Lee, W M

    2015-01-01

    The key to the success of pocket microscopes stems from the convenience for anyone to magnify the fine details (tens of micrometres) of any object on-thespot. The capability with a portable microscope lets us surpass our limited vision and is commonly used in many areas of science, industry, education. The growth of imaging and computing power in smartphones is creating the possibility of converting your smartphone into a high power pocket microscope. In this article, we briefly describe the history of pocket microscopy and elucidate how mobile technologies are set to become the next platform for pocket microscopes

  9. The Pocket Companion's architecture

    NARCIS (Netherlands)

    Havinga, Paul J.M.; Smit, Gerard J.M.

    1998-01-01

    The Pocket Companion is a small personal portable computer with wireless communication facilities. The typical use of the Pocket Companion induces a number of requirements concerning security, performance, energy consumption, communication and size. The energy consumption due to the increasing deman

  10. Pocket pumped image analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kotov, I.V., E-mail: kotov@bnl.gov [Brookhaven National Laboratory, Upton, NY 11973 (United States); O' Connor, P. [Brookhaven National Laboratory, Upton, NY 11973 (United States); Murray, N. [Centre for Electronic Imaging, Open University, Milton Keynes, MK7 6AA (United Kingdom)

    2015-07-01

    The pocket pumping technique is used to detect small electron trap sites. These traps, if present, degrade CCD charge transfer efficiency. To reveal traps in the active area, a CCD is illuminated with a flat field and, before image is read out, accumulated charges are moved back and forth number of times in parallel direction. As charges are moved over a trap, an electron is removed from the original pocket and re-emitted in the following pocket. As process repeats one pocket gets depleted and the neighboring pocket gets excess of charges. As a result a “dipole” signal appears on the otherwise flat background level. The amplitude of the dipole signal depends on the trap pumping efficiency. This paper is focused on trap identification technique and particularly on new methods developed for this purpose. The sensor with bad segments was deliberately chosen for algorithms development and to demonstrate sensitivity and power of new methods in uncovering sensor defects.

  11. Structure of the HIV-1 reverse transcriptase Q151M mutant: insights into the inhibitor resistance of HIV-1 reverse transcriptase and the structure of the nucleotide-binding pocket of Hepatitis B virus polymerase

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Akiyoshi; Tamura, Noriko; Yasutake, Yoshiaki, E-mail: y-yasutake@aist.go.jp [National Institute of Advanced Industrial Science and Technology (AIST), 2-17-2-1 Tsukisamu-Higashi, Toyohira, Sapporo, Hokkaido 062-8517 (Japan)

    2015-10-23

    The structure of the HIV-1 reverse transcriptase Q151M mutant was determined at a resolution of 2.6 Å in space group P321. Hepatitis B virus polymerase (HBV Pol) is an important target for anti-HBV drug development; however, its low solubility and stability in vitro has hindered detailed structural studies. Certain nucleotide reverse transcriptase (RT) inhibitors (NRTIs) such as tenofovir and lamivudine can inhibit both HBV Pol and Human immunodeficiency virus 1 (HIV-1) RT, leading to speculation on structural and mechanistic analogies between the deoxynucleotide triphosphate (dNTP)-binding sites of these enzymes. The Q151M mutation in HIV-1 RT, located at the dNTP-binding site, confers resistance to various NRTIs, while maintaining sensitivity to tenofovir and lamivudine. The residue corresponding to Gln151 is strictly conserved as a methionine in HBV Pol. Therefore, the structure of the dNTP-binding pocket of the HIV-1 RT Q151M mutant may reflect that of HBV Pol. Here, the crystal structure of HIV-1 RT Q151M, determined at 2.6 Å resolution, in a new crystal form with space group P321 is presented. Although the structure of HIV-1 RT Q151M superimposes well onto that of HIV-1 RT in a closed conformation, a slight movement of the β-strands (β2–β3) that partially create the dNTP-binding pocket was observed. This movement might be caused by the introduction of the bulky thioether group of Met151. The structure also highlighted the possibility that the hydrogen-bonding network among amino acids and NRTIs is rearranged by the Q151M mutation, leading to a difference in the affinity of NRTIs for HIV-1 RT and HBV Pol.

  12. How Similar Are Protein Folding and Protein Binding Nuclei? Examination of Vibrational Motions of Energy Hot Spots and Conserved Residues

    OpenAIRE

    Haliloglu, Turkan; Keskin, Ozlem; Ma, Buyong; Nussinov, Ruth

    2004-01-01

    The underlying physico-chemical principles of the interactions between domains in protein folding are similar to those between protein molecules in binding. Here we show that conserved residues and experimental hot spots at intermolecular binding interfaces overlap residues that vibrate with high frequencies. Similarly, conserved residues and hot spots are found in protein cores and are also observed to vibrate with high frequencies. In both cases, these residues contribute significantly to t...

  13. Binding in working memory and frontal lobe in normal aging: is there any similarity with autism?

    Directory of Open Access Journals (Sweden)

    Gregory eLecouvey

    2015-03-01

    Full Text Available Some studies highlight similarities between Autism Spectrum Disorder (ASD and healthy aging. Indeed, the decline in older individuals’ ability to create a unified representation of the individual features of an event is thought to arise from a disruption of integration within the episodic buffer of working memory as the same way as observed in ASD. In both cases, this deficit may result from an abnormal engagement of a frontohippocampal network. The objective of the present study is to identify both cognitive processes and neural substrates associated to the deficit of integration in healthy aging. We studied the capacity of integration and the cognitive processes that might mediate its decline in 72 healthy participants aged 18-84 years. We confronted the behavioral data to the changes in brain metabolism associated with the age-related decline in a subgroup of 34 healthy participants aged 20-77 years using the resting-state [18F] fluorodeoxyglucose positron emission tomography (18F-FDG PET. Forward stepwise regression analyses showed that the age-related decline in binding was partially explained by a decline in inhibition and processing speed. PET correlation analyses indicated that metabolism of the medial frontal regions, anterior and middle cingulate cortices is implicated in this phenomenon. These data suggest that executive functions and processing speed may play a crucial rule in the capacity to integrate unified representations in memory in aging. Possible implications are discussed in ASD.

  14. Acetylcholine-Binding Protein Engineered to Mimic the α4-α4 Binding Pocket in α4β2 Nicotinic Acetylcholine Receptors Reveals Interface Specific Interactions Important for Binding and Activity

    DEFF Research Database (Denmark)

    Shahsavar, Azadeh; Ahring, Philip K; Olsen, Jeppe A;

    2015-01-01

    Neuronal α4β2 nicotinic acetylcholine receptors are attractive drug targets for psychiatric and neurodegenerative disorders and smoking cessation aids. Recently, a third agonist binding site between two α4 subunits in the (α4)(3)(β2)(2) receptor subpopulation was discovered. In particular, three...

  15. The CK2 alpha/CK2 beta interface of human protein kinase CK2 harbors a binding pocket for small molecules

    DEFF Research Database (Denmark)

    Raaf, Jennifer; Brunstein, Elena; Issinger, Olaf-Georg;

    2008-01-01

    , selective CK2 inhibitors are required. An often-used CK2 inhibitor is 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). In a complex structure with human CK2 alpha, DRB binds to the canonical ATP cleft, but additionally it occupies an allosteric site that can be alternatively filled by glycerol....... Inhibition kinetic studies corroborate the dual binding mode of the inhibitor. Structural comparisons reveal a surprising conformational plasticity of human CK2 alpha around both DRB binding sites. After local rearrangement, the allosteric site serves as a CK2 beta interface. This opens the potential...

  16. Trends for isolated amino acids and dipeptides: Conformation, divalent ion binding, and remarkable similarity of binding to calcium and lead

    CERN Document Server

    Ropo, Matti; Baldauf, Carsten

    2016-01-01

    We derive structural and binding energy trends for twenty amino acids, their dipeptides, and their interactions with the divalent cations Ca$^{2+}$, Ba$^{2+}$, Sr$^{2+}$, Cd$^{2+}$, Pb$^{2+}$, and Hg$^{2+}$. The underlying data set consists of 45,892 first-principles predicted conformers with relative energies up to about 4 eV (about 400kJ/mol). We show that only very few distinct backbone structures of isolated amino acids and their dipeptides emerge as lowest-energy conformers. The isolated amino acids predominantly adopt structures that involve an acidic proton shared between the carboxy and amino function. Dipeptides adopt one of two intramolecular-hydrogen bonded conformations C$_5$ or equatorial C$_7$. Upon complexation with a divalent cation, the accessible conformational space shrinks and intramolecular hydrogen bonding is prevented due to strong electrostatic interaction of backbone and side chain functional groups with cations. Clear correlations emerge from the binding energies of the six divalent ...

  17. Derivation of an amino acid similarity matrix for peptide:MHC binding and its application as a Bayesian prior

    Directory of Open Access Journals (Sweden)

    Sette Alessandro

    2009-11-01

    Full Text Available Abstract Background Experts in peptide:MHC binding studies are often able to estimate the impact of a single residue substitution based on a heuristic understanding of amino acid similarity in an experimental context. Our aim is to quantify this measure of similarity to improve peptide:MHC binding prediction methods. This should help compensate for holes and bias in the sequence space coverage of existing peptide binding datasets. Results Here, a novel amino acid similarity matrix (PMBEC is directly derived from the binding affinity data of combinatorial peptide mixtures. Like BLOSUM62, this matrix captures well-known physicochemical properties of amino acid residues. However, PMBEC differs markedly from existing matrices in cases where residue substitution involves a reversal of electrostatic charge. To demonstrate its usefulness, we have developed a new peptide:MHC class I binding prediction method, using the matrix as a Bayesian prior. We show that the new method can compensate for missing information on specific residues in the training data. We also carried out a large-scale benchmark, and its results indicate that prediction performance of the new method is comparable to that of the best neural network based approaches for peptide:MHC class I binding. Conclusion A novel amino acid similarity matrix has been derived for peptide:MHC binding interactions. One prominent feature of the matrix is that it disfavors substitution of residues with opposite charges. Given that the matrix was derived from experimentally determined peptide:MHC binding affinity measurements, this feature is likely shared by all peptide:protein interactions. In addition, we have demonstrated the usefulness of the matrix as a Bayesian prior in an improved scoring-matrix based peptide:MHC class I prediction method. A software implementation of the method is available at: http://www.mhc-pathway.net/smmpmbec.

  18. Google Pocket Guide

    CERN Document Server

    Calishain, Tara; Adams, DJ

    2003-01-01

    Beneath its deceptively simple search form, Google is a remarkably powerful and flexible search engine that indexes billions of web pages, handling more than 150 million searches a day. You know that what you're looking for must be in there somewhere, but how do you make Google work for you? Crafted from our best-selling Google Hacks title, the Google Pocket Guide provides exactly the information you need to make your searches faster and more effective, right from the start. The Google Pocket Guide unleashes the power behind that blinking cursor by delivering: A thorough but concise tour o

  19. VBScript pocket reference

    CERN Document Server

    Lomax, Paul; Petrusha, Ron

    2008-01-01

    Microsoft's Visual Basic Scripting Edition (VBScript), a subset of Visual Basic for Applications, is a powerful language for Internet application development, where it can serve as a scripting language for server-side, client-side, and system scripting. Whether you're developing code for Active Server Pages, client-side scripts for Internet Explorer, code for Outlook forms, or scripts for Windows Script Host, VBScript Pocket Reference will be your constant companion. Don't let the pocket-friendly format fool you. Based on the bestsellingVBScript in a Nutshell, this small book details every V

  20. HTML & XHTML Pocket Reference

    CERN Document Server

    Robbins, Jennifer

    2010-01-01

    After years of using spacer GIFs, layers of nested tables, and other improvised solutions for building your web sites, getting used to the more stringent standards-compliant design can be intimidating. HTML and XHTML Pocket Reference is the perfect little book when you need answers immediately. Jennifer Niederst-Robbins, author Web Design in a Nutshell, has revised and updated the fourth edition of this pocket guide by taking the top 20% of vital reference information from her Nutshell book, augmenting it judiciously, cross-referencing everything, and organizing it according to the most com

  1. Newnes electrical pocket book

    CERN Document Server

    Reeves, E A

    2013-01-01

    Newnes Electrical Pocket Book, Twenty-first Edition, provides engineers with convenient access to various facts, tables, and formulae relating to the particular branch of engineering being dealt with. In the case of electrical engineering, it is essential that the engineer have a clear understanding of the methods by which the various formulae are derived to ensure that any particular formulae is applicable to the conditions being considered. The first section of the Pocket Book is devoted to the theoretical groundwork upon which all the practical applications are based. This covers symbols,

  2. Molecular recognition of CYP26A1 binding pockets and structure-activity relationship studies for design of potent and selective retinoic acid metabolism blocking agents.

    Science.gov (United States)

    Sun, Bin; Song, Shuai; Hao, Chen-Zhou; Huang, Wan-Xu; Liu, Chun-Chi; Xie, Hong-Lei; Lin, Bin; Cheng, Mao-Sheng; Zhao, Dong-Mei

    2015-03-01

    All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A, plays a major role in the regulation of cellular differentiation and proliferation, and it is also an important pharmacological agent particularly used in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. However, ATRA is very easy to be metabolized into 4-hydroxyl-RA in vivo by CYP26A1, an inducible cytochrome P450 enzyme, eventually into more polar metabolites. Therefore, it is vital to develop specific retinoic acid metabolism blocking agents (RAMBAs) to inhibit the metabolic enzyme CYP26A1 in the treatment of relevant diseases aforementioned. In this study, CYP26A1 and its interactions with retinoic acid-competitive metabolism blocking agents were investigated by a combined ligand- and structure-based approach. First, since the crystal structure of CYP26A1 protein has not been determined, we constructed the 3D structure of CYP26A1 using homology modeling. In order to achieve a deeper insight into the mode of action of RAMBAs in the active site, the molecular superimposition model and the common feature pharmacophore model were constructed, and molecular docking was performed. The molecular superimposition model is composed of three features: the main chain groups, side chain groups, and azole groups. The common feature pharmacophore model consists of five chemical features: four hydrophobic groups and one hydrogen acceptor (HHHHA). The results of molecular docking show that the characteristic groups of RAMBAs were mapped into three different active pockets, respectively. A structure-activity relationship (SAR) was obtained by a combination of the molecular superimposition and docking results with the pharmacophore model. This study gives more insight into the interaction model inside the CYP26A1 active site and provides guidance for the design of more potent and possibly more selective RAMBAs.

  3. Similar serotonin-2A receptor binding in rats with different coping styles or levels of aggression

    DEFF Research Database (Denmark)

    Visser, Anniek Kd; Ettrup, Anders; Klein, Anders Bue;

    2015-01-01

    Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin-2A receptor (5-HT2A R) binding in the brain of rats with d...

  4. Data communications pocket book

    CERN Document Server

    Tooley, Michael

    2014-01-01

    Data Communications Pocket Book, Second Edition presents information relevant to data communication. The book provides tabulated reference materials with a brief description and diagrams. The coverage of the text includes abbreviations, terminal control codes, and conversion tables. The text will be of great use to individuals involved in the interconnection of computer systems.

  5. Structural comparison of highly similar nucleoside-diphosphate kinases: Molecular explanation of distinct membrane-binding behavior.

    Science.gov (United States)

    Francois-Moutal, L; Marcillat, O; Granjon, T

    2014-10-01

    NDPK-A, NDPK-B and NDPK-D are three enzymes which belong to the NDPK group I isoforms and are not only involved in metabolism process but also in transcriptional regulation, DNA cleavage, histidine protein kinase activity and metastasis development. Those enzymes were reported to bind to membranes either in mitochondria where NDPK-D influences cardiolipin lateral organization and is thought to be involved in apoptotic pathway or in cytosol where NDPK-A and NDPK-B membrane association was shown to influence several cellular processes like endocytosis, cellular adhesion, ion transport, etc. However, despite numerous studies, the role of NDPK-membrane association and the molecular details of the binding process are still elusive. In the present work, a comparative study of the three NDPK isoforms allowed us to show that although membrane binding is a common feature of these enzymes, mechanisms differ at the molecular scale. NDPK-A was not able to bind to model membranes mimicking the inner leaflet of plasma membrane, suggesting that its in vivo membrane association is mediated by a non-lipidic partner or other partners than the studied phospholipids. On the contrary, NDPK-B and NDPK-D were shown to bind efficiently to liposomes mimicking plasma membrane and mitochondrial inner membrane respectively but details of the binding mechanism differ between the two enzymes as NDPK-B binding necessarily involved an anionic phospholipid partner while NDPK-D can bind either zwitterionic or anionic phospholipids. Although sharing similar secondary structure and homohexameric quaternary arrangement, tryptophan fluorescence revealed fine disparities in NDPK tertiary structures. Interfacial behavior as well as ANS fluorescence showed further dissimilarities between NDPK isoforms, notably the presence of distinct accessible hydrophobic areas as well as different capacity to form Gibbs monolayers related to their surface activity properties. Those distinct features may contribute to

  6. Structure of an Odorant-Vinding Protein form the Mosquito Aedes aegypti Suggests a Binding Pocket Covered by a pH-Sensitive

    Energy Technology Data Exchange (ETDEWEB)

    N Leite; R Krogh; W Xu; Y Ishida; J Iulek; W Leal; G Oliva

    2011-12-31

    The yellow fever mosquito, Aedes aegypti, is the primary vector for the viruses that cause yellow fever, mostly in tropical regions of Africa and in parts of South America, and human dengue, which infects 100 million people yearly in the tropics and subtropics. A better understanding of the structural biology of olfactory proteins may pave the way for the development of environmentally-friendly mosquito attractants and repellents, which may ultimately contribute to reduction of mosquito biting and disease transmission. Previously, we isolated and cloned a major, female-enriched odorant-binding protein (OBP) from the yellow fever mosquito, AaegOBP1, which was later inadvertently renamed AaegOBP39. We prepared recombinant samples of AaegOBP1 by using an expression system that allows proper formation of disulfide bridges and generates functional OBPs, which are indistinguishable from native OBPs. We crystallized AaegOBP1 and determined its three-dimensional structure at 1.85 {angstrom} resolution by molecular replacement based on the structure of the malaria mosquito OBP, AgamOBP1, the only mosquito OBP structure known to date. The structure of AaegOBP1 (= AaegOBP39) shares the common fold of insect OBPs with six {alpha}-helices knitted by three disulfide bonds. A long molecule of polyethylene glycol (PEG) was built into the electron-density maps identified in a long tunnel formed by a crystallographic dimer of AaegOBP1. Circular dichroism analysis indicated that delipidated AaegOBP1 undergoes a pH-dependent conformational change, which may lead to release of odorant at low pH (as in the environment in the vicinity of odorant receptors). A C-terminal loop covers the binding cavity and this 'lid' may be opened by disruption of an array of acid-labile hydrogen bonds thus explaining reduced or no binding affinity at low pH.

  7. Functions of key residues in the ligand-binding pocket of vitamin D receptor: Fragment molecular orbital interfragment interaction energy analysis

    Science.gov (United States)

    Yamagishi, Kenji; Yamamoto, Keiko; Yamada, Sachiko; Tokiwa, Hiroaki

    2006-03-01

    Fragment molecular orbital-interfragment interaction energy calculations of the vitamin D receptor (VDR)/1α,25-dihydroxyvitamin D 3 complex were utilized to assign functions of key residues of the VDR. Only one residue forms a significant interaction with the corresponding hydroxy group of the ligand, although two residues are located around each hydroxy group. The degradation of binding affinity for derivatives upon removal of a hydroxy group is closely related to the trend in the strength of the hydrogen bonds. Type II hereditary rickets due to an Arg274 point mutation is caused by the lack of the strongest hydrogen bond.

  8. Interaction pattern of Arg 62 in the A-pocket of differentially disease-associated HLA-B27 subtypes suggests distinct TCR binding modes.

    Directory of Open Access Journals (Sweden)

    Elisa Nurzia

    Full Text Available The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL and TIS (RRLPIFSRL, and the viral peptides pLMP2 (RRRWRRLTV and NPflu (SRYWAIRTR. Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K and non-conservative (R62A B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype.

  9. SQL Pocket Guide

    CERN Document Server

    Gennick, Jonathan

    2010-01-01

    If you're a programmer or database administrator who uses SQL in your day-to-day work, this popular pocket guide is the ideal on-the-job reference. You'll find many examples that address the language's complexity, along with key aspects of SQL used in IBM DB2 Release 9.7, MySQL 5.1, Oracle Database 11g Release 2, PostgreSQL 9.0, and Microsoft SQL Server 2008 Release 2. SQL Pocket Guide describes how these database systems implement SQL syntax for querying, managing transactions, and making changes to data. It also shows how the systems use SQL functions, regular expression syntax, and type c

  10. GDB Pocket Reference

    CERN Document Server

    Robbins, Arnold

    2009-01-01

    The GNU debugger is valuable for testing, fixing, and retesting software because it allows you to see exactly what's going on inside of a program as it's executing. This new pocket reference shows you how to specify a target for debugging, perform a careful examination to find the cause of program failure, and make quick changes for further testing. The guide covers several popular programming languages.

  11. Software engineer's pocket book

    CERN Document Server

    Tooley, Michael

    2013-01-01

    Software Engineer's Pocket Book provides a concise discussion on various aspects of software engineering. The book is comprised of six chapters that tackle various areas of concerns in software engineering. Chapter 1 discusses software development, and Chapter 2 covers programming languages. Chapter 3 deals with operating systems. The book also tackles discrete mathematics and numerical computation. Data structures and algorithms are also explained. The text will be of great use to individuals involved in the specification, design, development, implementation, testing, maintenance, and qualit

  12. A KAS2 cDNA complements the phenotypes of the Arabidopsis fab1 mutant that differs in a single residue bordering the substrate binding pocket

    DEFF Research Database (Denmark)

    Carlsson, A.S.; LaBrie, S.T.; Kinney, A.J.;

    2002-01-01

    The fab1 mutant of Arabidopsis is partially deficient in activity of ß-ketoacyl-[acyl carrier protein] synthase II (KAS II). This defect results in increased levels of 16 : 0 fatty acid and is associated with damage and death of the mutants at low temperature. Transformation of fab1 plants with a c......DNA from Brassica napus encoding a KAS II enzyme resulted in complementation of both mutant phenotypes. The dual complementation by expression of the single gene proves that low-temperature damage is a consequence of altered membrane unsaturation. The fab1 mutation is a single nucleotide change...... chain to bend. For functional analysis the equivalent Leu207Phe mutation was introduced into the fabB gene encoding the E. coli KAS I enzyme. Compared to wild-type, the Leu207Phe protein showed a 10-fold decrease in binding affinity for the fatty acid substrate, exhibited a modified behavior during size...

  13. A tight-binding model of CO chemisorption on Pd/Ta(110) and similar systems

    International Nuclear Information System (INIS)

    Chemisorption of an isolated CO molecule at various adsorption sites above the epitaxial Pd overlayer on Ta(110), and on related systems, is studied by using a self-consistent tight-binding scheme. Basic assumptions of the model are discussed in detail. The σ donation and especially the π backdonation are generally a good deal reduced at the bimetallic surface as compared with the pure Pd(111) surface. Simultaneously, the bond between CO and the surface becomes weaker. However, for CO in the atop position the effect is considerably smaller than for sites with twofold or threefold coordination and the atop site can therefore become preferred. A simple bonding picture explaining the gross trends is suggested. Core-level shifts induced in surface atoms by the adsorption are briefly discussed. (authors)

  14. Comparative Analysis of QSAR-based vs. Chemical Similarity Based Predictors of GPCRs Binding Affinity.

    Science.gov (United States)

    Luo, Man; Wang, Xiang S; Tropsha, Alexander

    2016-01-01

    Ligand based virtual screening (LBVS) approaches could be broadly divided into those relying on chemical similarity searches and those employing Quantitative Structure-Activity Relationship (QSAR) models. We have compared the predictive power of these approaches using some datasets of compounds tested against several G-Protein Coupled Receptors (GPCRs). The k-Nearest Neighbors (kNN) QSAR models were built for known ligands of each GPCR target independently, with a fraction of tested ligands for each target set aside as a validation set. The prediction accuracies of QSAR models for making active/inactive calls for compounds in both training and validation sets were compared to those achieved by the Prediction of Activity Spectra for Substances' (PASS) and the Similarity Ensemble Approach (SEA) tools both available online. Models developed with the kNN QSAR method showed the highest predictive power for almost all tested GPCR datasets. The PASS software, which incorporates multiple end-point specific QSAR models demonstrated a moderate predictive power, while SEA, a chemical similarity based approach, had the lowest prediction power. Our studies suggest that when sufficient amount of data is available to develop and rigorously validate QSAR models such models should be chosen as the preferred virtual screening tool in ligand-based computational drug discovery as compared to chemical similarity based approaches. PMID:27491652

  15. CSS Pocket Reference

    CERN Document Server

    Meyer, Eric

    2011-01-01

    When you're working with CSS and need a quick answer, CSS Pocket Reference delivers. This handy, concise book provides all of the essential information you need to implement CSS on the fly. Ideal for intermediate to advanced web designers and developers, the 4th edition is revised and updated for CSS3, the latest version of the Cascading Style Sheet specification. Along with a complete alphabetical reference to CSS3 selectors and properties, you'll also find a short introduction to the key concepts of CSS. Based on Cascading Style Sheets: The Definitive Guide, this reference is an easy-to-us

  16. Regular Expression Pocket Reference

    CERN Document Server

    Stubblebine, Tony

    2007-01-01

    This handy little book offers programmers a complete overview of the syntax and semantics of regular expressions that are at the heart of every text-processing application. Ideal as a quick reference, Regular Expression Pocket Reference covers the regular expression APIs for Perl 5.8, Ruby (including some upcoming 1.9 features), Java, PHP, .NET and C#, Python, vi, JavaScript, and the PCRE regular expression libraries. This concise and easy-to-use reference puts a very powerful tool for manipulating text and data right at your fingertips. Composed of a mixture of symbols and text, regular exp

  17. Pocket ECG electrode

    Science.gov (United States)

    Lund, Gordon F. (Inventor)

    1982-01-01

    A low-noise electrode suited for sensing electrocardiograms when chronically and subcutaneously implanted in a free-ranging subject. The electrode comprises a pocket-shaped electrically conductive member with a single entrance adapted to receive body fluids. The exterior of the member and the entrance region is coated with electrical insulation so that the only electrolyte/electrode interface is within the member remote from artifact-generating tissue. Cloth straps are bonded to the member to permit the electrode to be sutured to tissue and to provide electrical lead flexure relief.

  18. STL pocket reference

    CERN Document Server

    Lischner, Ray

    2003-01-01

    The STL Pocket Reference describes the functions, classes, and templates in that part of the C++ standard library often referred to as the Standard Template Library (STL). The STL encompasses containers, iterators, algorithms, and function objects, which collectively represent one of the most important and widely used subsets of standard library functionality. The C++ standard library, even the subset known as the STL, is vast. It's next to impossible to work with the STL without some sort of reference at your side to remind you of template parameters, function invocations, return types--ind

  19. Python pocket reference

    CERN Document Server

    Lutz, Mark

    2010-01-01

    This is the book to reach for when you're coding on the fly and need an answer now. It's an easy-to-use reference to the core language, with descriptions of commonly used modules and toolkits, and a guide to recent changes, new features, and upgraded built-ins -- all updated to cover Python 3.X as well as version 2.6. You'll also quickly find exactly what you need with the handy index. Written by Mark Lutz -- widely recognized as the world's leading Python trainer -- Python Pocket Reference, Fourth Edition, is the perfect companion to O'Reilly's classic Python tutorials, also written by Mark

  20. Linux Desktop Pocket Guide

    CERN Document Server

    Brickner, David

    2005-01-01

    While Mac OS X garners all the praise from pundits, and Windows XP attracts all the viruses, Linux is quietly being installed on millions of desktops every year. For programmers and system administrators, business users, and educators, desktop Linux is a breath of fresh air and a needed alternative to other operating systems. The Linux Desktop Pocket Guide is your introduction to using Linux on five of the most popular distributions: Fedora, Gentoo, Mandriva, SUSE, and Ubuntu. Despite what you may have heard, using Linux is not all that hard. Firefox and Konqueror can handle all your web bro

  1. RTF Pocket Guide

    CERN Document Server

    Burke, Sean

    2008-01-01

    Rich Text Format, or RTF, is the internal markup language used by Microsoft Word and understood by dozens of other word processors. RTF is a universal file format that pervades practically every desktop. Because RTF is text, it's much easier to generate and process than binary .doc files. Any programmer working with word processing documents needs to learn enough RTF to get around, whether it's to format text for Word (or almost any other word processor), to make global changes to an existing document, or to convert Word files to (or from) another format. RTF Pocket Guide is a concise and e

  2. XSLT 10 Pocket Reference

    CERN Document Server

    Lenz, Evan

    2008-01-01

    XSLT is an essential tool for converting XML into other kinds of documents: HTML, PDF file, and many others. It's a critical technology for XML-based platforms such as Microsoft .NET, Sun Microsystems' Sun One, as well as for most web browsers and authoring tools. As useful as XSLT is, however, most people have a difficult time getting used to its peculiar characteristics. The ability to use advanced techniques depends on a clear and exact understanding of how XSLT templates work and interact. The XSLT 1.0 Pocket Reference from O'Reilly wants to make sure you achieve that level of understan

  3. LINQ Pocket Reference

    CERN Document Server

    Albahari, Joseph

    2008-01-01

    Ready to take advantage of LINQ with C# 3.0? This guide has the detail you need to grasp Microsoft's new querying technology, and concise explanations to help you learn it quickly. And once you begin to apply LINQ, the book serves as an on-the-job reference when you need immediate reminders. All the examples in the LINQ Pocket Reference are preloaded into LINQPad, the highly praised utility that lets you work with LINQ interactively. Created by the authors and free to download, LINQPad will not only help you learn LINQ, it will have you thinking in LINQ. This reference explains: LINQ's ke

  4. JDBC Pocket Reference

    CERN Document Server

    Bales, Donald

    2003-01-01

    JDBC--the Java Database Connectivity specification--is a complex set of application programming interfaces (APIs) that developers need to understand if they want their Java applications to work with databases. JDBC is so complex that even the most experienced developers need to refresh their memories from time to time on specific methods and details. But, practically speaking, who wants to stop and thumb through a weighty tutorial volume each time a question arises? The answer is the JDBC Pocket Reference, a data-packed quick reference that is both a time-saver and a lifesaver. The JDBC P

  5. Electronics pocket book

    CERN Document Server

    Parr, E A

    1981-01-01

    Electronics Pocket Book, Fourth Edition is a nonmathematical presentation of the many varied topics covered by electronics. The book tackles electron physics, electronic components (i.e. resistors, capacitors, and conductors), integrated circuits, and the principles of a.c. and d.c. amplifiers. The text also discusses oscillators, digital circuits, digital computers, and optoelectronics (i.e., sensors, emitters, and devices that utilize light). Communications (such as line and radio communications, transmitters, receivers, and digital techniques); the principles and examples of servosystems; a

  6. Newnes microprocessor pocket book

    CERN Document Server

    Money, Steve

    2014-01-01

    Newnes Microprocessor Pocket Book explains the basic hardware operation of a microprocessor and describes the actions of the various types of instruction that can be executed. A summary of the characteristics of many of the popular microprocessors is presented. Apart from the popular 8- and 16-bit microprocessors, some details are also given of the popular single chip microcomputers and of the reduced instruction set computer (RISC) type processors such as the Transputer, Novix FORTH processor, and Acorn ARM processor.Comprised of 15 chapters, this book discusses the principles involved in bot

  7. CSS Pocket Reference

    CERN Document Server

    Meyer, Eric A

    2007-01-01

    They say that good things come in small packages, and it's certainly true for this edition of CSS Pocket Reference. Completely revised and updated to reflect the latest Cascading Style Sheet specifications in CSS 2.1, this indispensable little book covers the most essential information that web designers and developers need to implement CSS effectively across all browsers. Inside, you'll find: A short introduction to the key concepts of CSS A complete alphabetical reference to all CSS 2.1 selectors and properties A chart displaying detailed information about CSS support for every style ele

  8. Rails Pocket Reference

    CERN Document Server

    Berry, Eric

    2008-01-01

    Rails 2.1 brings a new level of stability and power to this acclaimed web development framework, but keeping track of its numerous moving parts is still a chore. Rails Pocket Reference offers you a painless alternative to hunting for resources online, with brief yet thorough explanations of the most frequently used methods and structures supported by Rails 2.1, along with key concepts you need to work through the framework's most tangled corners. Organized to help you quickly find what you need, this book will not only get you up to speed on how Rails works, it also provides a handy referenc

  9. Word Pocket Guide

    CERN Document Server

    Glenn, Walter

    2004-01-01

    Millions of people use Microsoft Word every day and, chances are, you're one of them. Like most Word users, you've attained a certain level of proficiency--enough to get by, with a few extra tricks and tips--but don't get the opportunity to probe much further into the real power of Word. And Word is so rich in features that regardless of your level of expertise, there's always more to master. If you've ever wanted a quick answer to a nagging question or had the thought that there must be a better way, then this second edition of Word Pocket Guide is just what you need. Updated for Word 2003

  10. A serpin-induced extensive proteolytic susceptibility of urokinase-type plasminogen activator implicates distortion of the proteinase substrate-binding pocket and oxyanion hole in the serpin inhibitory mechanism.

    Science.gov (United States)

    Egelund, R; Petersen, T E; Andreasen, P A

    2001-02-01

    The formation of stable complexes between serpins and their target serine proteinases indicates formation of an ester bond between the proteinase active-site serine and the serpin P1 residue [Egelund, R., Rodenburg, K.W., Andreasen, P.A., Rasmussen, M.S., Guldberg, R.E. & Petersen, T.E. (1998) Biochemistry 37, 6375-6379]. An important question concerning serpin inhibition is the contrast between the stability of the ester bond in the complex and the rapid hydrolysis of the acyl-enzyme intermediate in general serine proteinase-catalysed peptide bond hydrolysis. To answer this question, we used limited proteolysis to detect conformational differences between free urokinase-type plasminogen activator (uPA) and uPA in complex with plasminogen activator inhibitor-1 (PAI-1). Whereas the catalytic domain of free uPA, pro-uPA, uPA in complex with non-serpin inhibitors and anhydro-uPA in a non-covalent complex with PAI-1 was resistant to proteolysis, the catalytic domain of PAI-1-complexed uPA was susceptible to proteolysis. The cleavage sites for four different proteinases were localized in specific areas of the C-terminal beta-barrel of the catalytic domain of uPA, providing evidence that the serpin inhibitory mechanism involves a serpin-induced massive rearrangement of the proteinase active site, including the specificity pocket, the oxyanion hole, and main-chain binding area, rendering the proteinase unable to complete the normal hydrolysis of the acyl-enzyme intermediate. The distorted region includes the so-called activation domain, also known to change conformation on zymogen activation.

  11. BS25999 a pocket guide

    CERN Document Server

    Drewitt, Tony

    2008-01-01

    This new pocket guide provides an easy to read and straightforward introduction to the subjects of business continuity and BS 25999. If your organisation is implementing, or considering implementing, a BS 25999 business continuity management system (BCMS) then you need to read a copy of this pocket guide.

  12. MgaSpn and H-NS: Two Unrelated Global Regulators with Similar DNA-Binding Properties

    Science.gov (United States)

    Solano-Collado, Virtu; Hüttener, Mário; Espinosa, Manuel; Juárez, Antonio; Bravo, Alicia

    2016-01-01

    Global regulators play an essential role in the adaptation of bacterial cells to specific niches. Bacterial pathogens thriving in the tissues and organs of their eukaryotic hosts are a well-studied example. Some of the proteins that recognize local DNA structures rather than specific nucleotide sequences act as global modulators in many bacteria, both Gram-negative and -positive. To this class of regulators belong the H-NS-like proteins, mainly identified in γ-Proteobacteria, and the MgaSpn-like proteins identified in Firmicutes. H-NS and MgaSpn from Escherichia coli and Streptococcus pneumoniae, respectively, neither have sequence similarity nor share structural domains. Nevertheless, they display common features in their interaction with DNA, namely: (i) they bind to DNA in a non-sequence-specific manner, (ii) they have a preference for intrinsically curved DNA regions, and (iii) they are able to form multimeric complexes on linear DNA. Using DNA fragments from the hemolysin operon regulatory region of the E. coli plasmid pHly152, we show in this work that MgaSpn is able to recognize particular regions on extended H-NS binding sites. Such regions are either located at or flanked by regions of potential bendability. Moreover, we show that the regulatory region of the pneumococcal P1623B promoter, which is recognized by MgaSpn, contains DNA motifs that are recognized by H-NS. These motifs are adjacent to regions of potential bendability. Our results suggest that both regulatory proteins recognize similar structural characteristics of DNA. PMID:27747214

  13. Testicular androgen-binding protein (ABP): comparison of ABP in rabbit testis and epididymis with a similar androgen-binding protein (TeBG) in rabbit serum.

    Science.gov (United States)

    Hansson, V; Ritzen, M E; French, F S; Weddington, S C; Nayfeh, S N

    1975-07-01

    Testicular androgen-binding proteins (ABP) in rabbit testis, caput epididymis and efferent duct fluid (EDF) were compared to a similar androgen-binding protein TeBg) in rabbit serum. The affinity of these proteins for 5alpha-dihydrotesterone (DHT) at 0 degrees C (KaABP = 1.6 X 10(9) M-1 and KaTeBG = 1.9 X 10(9) M-1) and their steroid specificities were similar (DHT greater than androstanediol greater than progesterone and androstenedione). ABP and TeBG had also almost identical Stokes radii (42.8 +/- 1.2 and 43.9 +- 0.8 A, respectively), sedimentation coefficients (4.7 +/- 0.2 S and 4.4 +/- 0.2 S, respectively) and electrophoretic mobility (Rf = 0.4 in 6 1/2% polyacrylamide gels). Calculation of molecular weights from Stokes radii and sedimentation rates indicated a molecular weight of 74,000 (69,000-78,000) for TeBG and 76,000 (71,000-82,000) for ABP. The corresponding frictional ratios were 1.61 for TeBG and 1.55 for ABP assuming a partial specific volume (v) of 0.70 cm3/g. Polyacrylamide gel electrophoresis (PAGE) at different gel concentrations gave a mean molecular radius of 2.74 nm, also indicating a molecular weight of about 75,000 (v = 0.70 cm3/g. ABP and TeBG could not be separated by PAGE; however, partial separation of ABP and TeBG was achieved by isoelectric focusing and ion-exchange chromatography on DEAE-cellulose. TeBG focused at pH 5.4, whereas ABP formed a distinct peak of bound radioactivity at pH 4.7. Also by ionexchange chromatography, ABP in both testis and epididymal supernatants was shown to have an apparently higher surface charge than TeBG in rabbit serum. The concentration of ABP in efferent duct fluid (2 X 10(-7) M = 60 pmol/mg protien) was much higher than TeBG in male rabbit serum (5.2 X 10(-8) M = 0.7 pmol/mg protein). These findings ruled against the possibility that ABP in the testis and epididymis could have been derived directly from serum. It is concluded that ABP and TeBG are very similar if not identical proteins both serving as

  14. Two arginine residues in the substrate pocket predominantly control the substrate selectivity of thiocyanate hydrolase.

    Science.gov (United States)

    Yamanaka, Yasuaki; Arakawa, Takatoshi; Watanabe, Toshinori; Namima, Satoshi; Sato, Masa; Hori, Shota; Ohtaki, Akashi; Noguchi, Keiichi; Katayama, Yoko; Yohda, Masafumi; Odaka, Masafumi

    2013-07-01

    Thiocyanate hydrolase (SCNase) of Thiobacillus thioparus THI115 is a cobalt (Co)-containing enzyme that catalyzes the hydrolysis of thiocyanate (SCN⁻), a major component of wastewater from coke oven factories, to carbonyl sulfide and ammonia. Although SCNase exhibits high structural similarities to Co-type nitrile hydratase (NHase), including a unique Co³⁺ catalytic center with two oxidized Cys ligands, both SCNase and NHase exclusively catalyze only their own substrates. Based on the differences in the substrate-binding pockets of these enzymes, βArg90 and γArg136 of SCNase, with side chains extending toward the pocket, were separately substituted with Phe and Trp, the corresponding residues, respectively, in Co-type NHase. Both SCNase βArg90 and SCNase γArg136 mutants showed no SCN⁻ hydrolysis activity but did catalyze the hydration of nitriles. The estimated kcat values (∼2 s⁻¹) corresponded to approximately 0.2% of that of Co-type NHase for nitrile hydration and approximately 3% of that of wild-type SCNase for SCN⁻ hydrolysis. The crystal structure of SCNase γR136W is essentially identical to that of the wild-type, including the Co³⁺ center having Cys oxidations; the size of the substrate pocket was enlarged because of conformational changes on the side chains of the mutated residue. Discussion of the difference in the environments around the substrate-binding pockets among the wild-type and mutant SCNases and Co-type NHase strongly suggests that βArg90 and γArg136, positioned at the top of the Co³⁺ center, predominantly control the substrate selectivity of SCNase. PMID:23453853

  15. Hydrophobic pocket targeting probes for enteroviruses

    Science.gov (United States)

    Martikainen, Mari; Salorinne, Kirsi; Lahtinen, Tanja; Malola, Sami; Permi, Perttu; Häkkinen, Hannu; Marjomäki, Varpu

    2015-10-01

    Visualization and tracking of viruses without compromising their functionality is crucial in order to understand virus targeting to cells and tissues, and to understand the subsequent subcellular steps leading to virus uncoating and replication. Enteroviruses are important human pathogens causing a vast number of acute infections, and are also suggested to contribute to the development of chronic diseases like type I diabetes. Here, we demonstrate a novel method to target site-specifically the hydrophobic pocket of enteroviruses. A probe, a derivative of Pleconaril, was developed and conjugated to various labels that enabled the visualization of enteroviruses under light and electron microscopes. The probe mildly stabilized the virus particle by increasing the melting temperature by 1-3 degrees, and caused a delay in the uncoating of the virus in the cellular endosomes, but could not however inhibit the receptor binding, cellular entry or infectivity of the virus. The hydrophobic pocket binding moiety of the probe was shown to bind to echovirus 1 particle by STD and tr-NOESY NMR methods. Furthermore, binding to echovirus 1 and Coxsackievirus A9, and to a lesser extent to Coxsackie virus B3 was verified by using a gold nanocluster labeled probe by TEM analysis. Molecular modelling suggested that the probe fits the hydrophobic pockets of EV1 and CVA9, but not of CVB3 as expected, correlating well with the variations in the infectivity and stability of the virus particles. EV1 conjugated to the fluorescent dye labeled probe was efficiently internalized into the cells. The virus-fluorescent probe conjugate accumulated in the cytoplasmic endosomes and caused infection starting from 6 hours onwards. Remarkably, before and during the time of replication, the fluorescent probe was seen to leak from the virus-positive endosomes and thus separate from the capsid proteins that were left in the endosomes. These results suggest that, like the physiological hydrophobic content

  16. Reasons not to ''pocket shoot''

    International Nuclear Information System (INIS)

    The authors' large population of intravenous drug abusers (IVDA) has increasingly resorted to supraclavicular central venous injection for vascular access. Few reports of complications associated with the practice of supraclavicular ''pocket'' injection have appeared in the radiologic literature. This exhibit demonstrates the complications associated with this practice, including pneumothorax, mycotic aneurysm, arteriovenous fistual, jugular vein thrombosis, cellulitis, foreign body and neck abscess. In addition, they show examples of sternoclavicular osteomyelities. The anatomy of the ''pocket'' and the pathophysiology and radiographic manifestations of these complications are reviewed

  17. Unbound position II in MXCXXC metallochaperone model peptides impacts metal binding mode and reactivity: Distinct similarities to whole proteins.

    Science.gov (United States)

    Shoshan, Michal S; Dekel, Noa; Goch, Wojciech; Shalev, Deborah E; Danieli, Tsafi; Lebendiker, Mario; Bal, Wojciech; Tshuva, Edit Y

    2016-06-01

    The effect of position II in the binding sequence of copper metallochaperones, which varies between Thr and His, was investigated through structural analysis and affinity and oxidation kinetic studies of model peptides. A first Cys-Cu(I)-Cys model obtained for the His peptide at acidic and neutral pH, correlated with higher affinity and more rapid oxidation of its complex; in contrast, the Thr peptide with the Cys-Cu(I)-Met coordination under neutral conditions demonstrated weaker and pH dependent binding. Studies with human antioxidant protein 1 (Atox1) and three of its mutants where S residues were replaced with Ala suggested that (a) the binding affinity is influenced more by the binding sequence than by the protein fold (b) pH may play a role in binding reactivity, and (c) mutating the Met impacted the affinity and oxidation rate more drastically than did mutating one of the Cys, supporting its important role in protein function. Position II thus plays a dominant role in metal binding and transport. PMID:26901629

  18. Species B adenovirus serotypes 3, 7, 11 and 35 share similar binding sites on the membrane cofactor protein CD46 receptor.

    Science.gov (United States)

    Fleischli, Christoph; Sirena, Dominique; Lesage, Guillaume; Havenga, Menzo J E; Cattaneo, Roberto; Greber, Urs F; Hemmi, Silvio

    2007-11-01

    We recently characterized the domains of the human cofactor protein CD46 involved in binding species B2 adenovirus (Ad) serotype 35. Here, the CD46 binding determinants are mapped for the species B1 Ad serotypes 3 and 7 and for the species B2 Ad11. Ad3, 7 and 11 bound and transduced CD46-positive rodent BHK cells at levels similar to Ad35. By using antibody-blocking experiments, hybrid CD46-CD4 receptor constructs and CD46 single point mutants, it is shown that Ad3, 7 and 11 share many of the Ad35-binding features on CD46. Both CD46 short consensus repeat domains SCR I and SCR II were necessary and sufficient for optimal binding and transgene expression, provided that they were positioned at an appropriate distance from the cell membrane. Similar to Ad35, most of the putative binding residues of Ad3, 7 and 11 were located on the same glycan-free, solvent-exposed face of the SCR I or SCR II domains, largely overlapping with the binding surface of the recently solved fiber knob Ad11-SCR I-II three-dimensional structure. Differences between species B1 and B2 Ads were documented with competition experiments based on anti-CD46 antibodies directed against epitopes flanking the putative Ad-binding sites, and with competition experiments based on soluble CD46 protein. It is concluded that the B1 and B2 species of Ad engage CD46 through similar binding surfaces.

  19. Mr Black'sPocket

    Institute of Scientific and Technical Information of China (English)

    耿志华

    2002-01-01

    ground and put that in his pocket too. He was very happy now. He stopped digging for a minute and shouted to his wife. "Elizabeth, come quickly. Someone's hidden(隐蔽) a lot of money in our garden and I' m finding it.”

  20. Newnes electronics assembly pocket book

    CERN Document Server

    Brindley, Keith

    2013-01-01

    Produced in association with the Engineering Training Authority with contributions from dozens of people in the electronics industry. The material covers common skills in electrical and electronic engineering and concentrates mainly on wiring and assembly. 'Newnes Electronics Assembly Pocket Book' is for electronics technicians, students and apprentices.

  1. IT governance a pocket guide

    CERN Document Server

    Calder, Alan

    2007-01-01

    This new downloadable pocket guide in the Practical IT Governance series, is designed to provide the reader with a basic understanding of how an organization's Information Technology supports and enables the achievement of its strategies and objectives.

  2. Viral Coat Protein Peptides with Limited Sequence Homology Bind Similar Domains of Alfalfa Mosaic Virus and Tobacco Streak Virus RNAs

    Science.gov (United States)

    Swanson, Maud M.; Ansel-McKinney, Patricia; Houser-Scott, Felicia; Yusibov, Vidadi; Loesch-Fries, L. Sue; Gehrke, Lee

    1998-01-01

    An unusual and distinguishing feature of alfalfa mosaic virus (AMV) and ilarviruses such as tobacco streak virus (TSV) is that the viral coat protein is required to activate the early stages of viral RNA replication, a phenomenon known as genome activation. AMV-TSV coat protein homology is limited; however, they are functionally interchangeable in activating virus replication. For example, TSV coat protein will activate AMV RNA replication and vice versa. Although AMV and TSV coat proteins have little obvious amino acid homology, we recently reported that they share an N-terminal RNA binding consensus sequence (Ansel-McKinney et al., EMBO J. 15:5077–5084, 1996). Here, we biochemically compare the binding of chemically synthesized peptides that include the consensus RNA binding sequence and lysine-rich (AMV) or arginine-rich (TSV) environment to 3′-terminal TSV and AMV RNA fragments. The arginine-rich TSV coat protein peptide binds viral RNA with lower affinity than the lysine-rich AMV coat protein peptides; however, the ribose moieties protected from hydroxyl radical attack by the two different peptides are localized in the same area of the predicted RNA structures. When included in an infectious inoculum, both AMV and TSV 3′-terminal RNA fragments inhibited AMV RNA replication, while variant RNAs unable to bind coat protein did not affect replication significantly. The data suggest that RNA binding and genome activation functions may reside in the consensus RNA binding sequence that is apparently unique to AMV and ilarvirus coat proteins. PMID:9525649

  3. Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo.

    Directory of Open Access Journals (Sweden)

    Annie Yang

    Full Text Available BACKGROUND: The p53 homologs, p63 and p73, share approximately 85% amino acid identity in their DNA-binding domains, but they have distinct biological functions. PRINCIPAL FINDINGS: Using chromatin immunoprecipitation and high-resolution tiling arrays covering the human genome, we identify p73 DNA binding sites on a genome-wide level in ME180 human cervical carcinoma cells. Strikingly, the p73 binding profile is indistinguishable from the previously described binding profile for p63 in the same cells. Moreover, the p73:p63 binding ratio is similar at all genomic loci tested, suggesting that there are few, if any, targets that are specific for one of these factors. As assayed by sequential chromatin immunoprecipitation, p63 and p73 co-occupy DNA target sites in vivo, suggesting that p63 and p73 bind primarily as heterotetrameric complexes in ME180 cells. CONCLUSIONS: The observation that p63 and p73 associate with the same genomic targets suggest that their distinct biological functions are due to cell-type specific expression and/or protein domains that involve functions other than DNA binding.

  4. Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX-specific quinine-dependent antibodies

    NARCIS (Netherlands)

    Burgess, J K; Lopez, J A; Gaudry, L E; Chong, B H

    2000-01-01

    The drug-dependent antibody of a patient with rifampicin-induced thrombocytopenia was characterized using the antigen-capture enzyme-linked immunosorbent assay (MAIPA assay), flow cytometry, and immunoprecipitation. The antibody was found to bind glycoprotein (GP) Ib-IX but not GPIIb-IIIa because (1

  5. TclTk Pocket Reference

    CERN Document Server

    Raines, Paul

    1998-01-01

    The Tcl/Tk combination is increasingly popular because it lets you produce sophisticated graphical interfaces with a few easy commands, develop and change scripts quickly, and conveniently tie together existing utilities or programming libraries. The Tcl/Tk Pocket Reference,a handy reference guide to the basic Tcl language elements, Tcl and Tk commands, and Tk widgets, is a companion volume to Tcl/Tk in a Nutshell.

  6. Heparan sulfate chains from glypican and syndecans bind the Hep II domain of fibronectin similarly despite minor structural differences

    DEFF Research Database (Denmark)

    Tumova, S; Woods, A; Couchman, J R

    2000-01-01

    structure, where highly sulfated, iduronate-rich domains alternate with N-acetylated domains. Syndecan-4, a cell surface heparan sulfate proteoglycan, has a distinct role in cell adhesion, suggesting its chains may differ from those of other cell surface proteoglycans. To determine whether the specific role...... of syndecan-4 correlates with a distinct heparan sulfate structure, we have analyzed heparan sulfate chains from the different surface proteoglycans of a single fibroblast strain and compared their ability to bind the Hep II domain of fibronectin, a ligand known to promote focal adhesion formation through...

  7. Prince2 2009 edition a pocket guide

    CERN Document Server

    Hedeman, Bert

    2010-01-01

    This Pocket Guide supplies a summary of the PRINCE2 method, to provide a quick introduction as well as a structured overview of the method;Main target Group for this pocket guide is anyone who wants to get to know the method PRINCE2 or a methodical approach for project management. The book is also very useful for members of a project management team on a project using the PRINCE2 method. Furthermore this pocket guide can be used as literature for the preparation of the PRINCE2 2009 Edition Foundation exam;This pocket guide is based on PRINCE2 2009 Edition;This pocket book deals with processes,

  8. In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function

    DEFF Research Database (Denmark)

    Follin, Elna; Karlsson, Maria; Lundegaard, Claus;

    2013-01-01

    compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (α1–α3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide-binding predictions to investigate...... is of functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably......, there were also overlapping peptide-binding specificities in the allomorphs from house sparrow and great reed warbler, although these species diverged 30 MYA. This overlap was not found in a tree based on amino acid sequences. Our interpretation is that convergent evolution on the level of the protein...

  9. (-)-Rhazinilam and the diphenylpyridazinone NSC 613241: Two compounds inducing the formation of morphologically similar tubulin spirals but binding apparently to two distinct sites on tubulin.

    Science.gov (United States)

    Bai, Ruoli; Hamel, Ernest

    2016-08-15

    The most potent microtubule assembly inhibitor of newer diphenylpyridazinone derivatives examined was NSC 613241. Because NSC 613241 and (-)-rhazinilam also induce the formation of similar 2-filament spirals, these aberrant reactions were compared. Spiral formation with both compounds was enhanced by GTP and inhibited by GDP and by 15 other inhibitors of microtubule assembly. Similarly, microtubule assembly induced by paclitaxel or laulimalide is enhanced by GTP and inhibited by GDP and assembly inhibitors, but neither [(3)H]NSC 613241 nor [(3)H](-)-rhazinilam bound to microtubules or inhibited the binding of [(3)H]paclitaxel or [(3)H]peloruside A to microtubules. Differences in the pitch of aberrant polymers were found: NSC 613241-induced and (-)-rhazinilam-induced spirals had average repeats of 85 and 79-80 nm, respectively. We found no binding of [(3)H]NSC 613241 or [(3)H](-)-rhazinilam to αβ-tubulin dimer, but both compounds were incorporated into the polymers they induced in substoichiometric reactions, with as little as 0.1-0.2 mol compound/mol of tubulin, and no cross-inhibition by NSC 613241 or (-)-rhazinilam into spirals occurred. Under reaction conditions where neither compound induced spiral formation, both compounds together synergistically induced substantial spiral formation. We conclude that (-)-rhazinilam and NSC 613241 bind to different sites on tubulin that differ from binding sites for other antitubulin agents. PMID:27311615

  10. Vaccinia protein F12 has structural similarity to kinesin light chain and contains a motor binding motif required for virion export.

    Directory of Open Access Journals (Sweden)

    Gareth W Morgan

    2010-02-01

    Full Text Available Vaccinia virus (VACV uses microtubules for export of virions to the cell surface and this process requires the viral protein F12. Here we show that F12 has structural similarity to kinesin light chain (KLC, a subunit of the kinesin-1 motor that binds cargo. F12 and KLC share similar size, pI, hydropathy and cargo-binding tetratricopeptide repeats (TPRs. Moreover, molecular modeling of F12 TPRs upon the crystal structure of KLC2 TPRs showed a striking conservation of structure. We also identified multiple TPRs in VACV proteins E2 and A36. Data presented demonstrate that F12 is critical for recruitment of kinesin-1 to virions and that a conserved tryptophan and aspartic acid (WD motif, which is conserved in the kinesin-1-binding sequence (KBS of the neuronal protein calsyntenin/alcadein and several other cellular kinesin-1 binding proteins, is essential for kinesin-1 recruitment and virion transport. In contrast, mutation of WD motifs in protein A36 revealed they were not required for kinesin-1 recruitment or IEV transport. This report of a viral KLC-like protein containing a KBS that is conserved in several cellular proteins advances our understanding of how VACV recruits the kinesin motor to virions, and exemplifies how viruses use molecular mimicry of cellular components to their advantage.

  11. Duplicate abalone egg coat proteins bind sperm lysin similarly, but evolve oppositely, consistent with molecular mimicry at fertilization.

    Directory of Open Access Journals (Sweden)

    Jan E Aagaard

    Full Text Available Sperm and egg proteins constitute a remarkable paradigm in evolutionary biology: despite their fundamental role in mediating fertilization (suggesting stasis, some of these molecules are among the most rapidly evolving ones known, and their divergence can lead to reproductive isolation. Because of strong selection to maintain function among interbreeding individuals, interacting fertilization proteins should also exhibit a strong signal of correlated divergence among closely related species. We use evidence of such molecular co-evolution to target biochemical studies of fertilization in North Pacific abalone (Haliotis spp., a model system of reproductive protein evolution. We test the evolutionary rates (d(N/d(S of abalone sperm lysin and two duplicated egg coat proteins (VERL and VEZP14, and find a signal of co-evolution specific to ZP-N, a putative sperm binding motif previously identified by homology modeling. Positively selected residues in VERL and VEZP14 occur on the same face of the structural model, suggesting a common mode of interaction with sperm lysin. We test this computational prediction biochemically, confirming that the ZP-N motif is sufficient to bind lysin and that the affinities of VERL and VEZP14 are comparable. However, we also find that on phylogenetic lineages where lysin and VERL evolve rapidly, VEZP14 evolves slowly, and vice versa. We describe a model of sexual conflict that can recreate this pattern of anti-correlated evolution by assuming that VEZP14 acts as a VERL mimic, reducing the intensity of sexual conflict and slowing the co-evolution of lysin and VERL.

  12. Oracle Data Dictionary Pocket Reference

    CERN Document Server

    Kreines, David

    2003-01-01

    If you work with Oracle, then you don't need to be told that the data dictionary is large and complex, and grows larger with each new Oracle release. It's one of the basic elements of the Oracle database you interact with regularly, but the sheer number of tables and views makes it difficult to remember which view you need, much less the name of the specific column. Want to make it simpler? The Oracle Data Dictionary Pocket Reference puts all the information you need right at your fingertips. Its handy and compact format lets you locate the table and view you need effortlessly without stoppin

  13. Pocket atlas of dental radiology

    Energy Technology Data Exchange (ETDEWEB)

    Pasler, F.A. [Geneva Univ. (Switzerland). Dept. of Radiology, Dental Institute; Visser, H. [Goettingen Univ. (Germany). Dental School

    2007-07-01

    In this age of highly specialized medical imaging, an examination of the teeth and alveolar bone is almost unthinkable without the use of radiographs. This highly informative and easy-to-read book with a collection of 798 radiographs, tables, and photos provides a myriad of problem-solving tips concerning the fundamentals of radiographic techniques, quality assurance, image processing, radiographic anatomy, and radiographic diagnosis. Information is easy to find, enabling the reader to literally get a grasp of essential new knowledge in next to no time. The dental practice team now has a pocket 'consultant' at its fingertips, providing practical ways to incorporate new technique into daily practice. (orig.)

  14. Electrical engineering a pocket reference

    CERN Document Server

    Schmidt-Walter, Heinz

    2007-01-01

    This essential reference offers you a well-organized resource for accessing the basic electrical engineering knowledge you need for your work. Whether you're an experienced engineer who appreciates an occasional refresher in key areas, or a student preparing to enter the field, Electrical Engineering: A Pocket Reference provides quick and easy access to fundamental principles and their applications. You also find an extensive collection of time-saving equations that help simplify your daily projects.Supported with more than 500 diagrams and figures, 60 tables, and an extensive index, this uniq

  15. Windows Vista Administrator's Pocket Guide

    CERN Document Server

    Stanek, William R

    2007-01-01

    Portable and precise, this pocket-sized guide delivers immediate answers for the day-to-day administration of Windows Vista. Zero in on core support and maintenance tasks using quick-reference tables, instructions, and lists. You'll get the precise information you need to solve problems and get the job done-whether you're at your desk or in the field! Get fast facts to: Install and configure Windows Vista-and optimize the user workspaceMaintain operating system components, hardware devices, and driversCreate user and group accounts-and control rights and permissionsAdminister group policy se

  16. JavaScript Pocket Reference

    CERN Document Server

    Flanagan, David

    1998-01-01

    JavaScript is a powerful, object-based scripting language that can be embedded directly in HTML pages. It allows you to create dynamic, interactive Web-based applications that run completely within a Web browser -- JavaScript is the language of choice for developing Dynamic HTML (DHTML) content. JavaScript can be integrated effectively with CGI and Java to produce sophisticated Web applications, although, in many cases, JavaScript eliminates the need for complex CGI scripts and Java applets altogether. The JavaScript Pocket Reference is a companion volume to JavaScript: The Definitive Guide

  17. Newnes electronics engineers pocket book

    CERN Document Server

    Brindley, Keith

    2013-01-01

    This book is packed with information and material which everyone involved in electronics will find indispensable. Now when you need to know a transistor's characteristics, or an integrated circuit's pinout details, simply look it up! The book is full of tables, symbols, formulae, conversions and illustrations.Promotion via the new Newnes Pocket Book catalogue to the electronics trade will drive sales into the book trade Covers component data; encapsulations; pin-outs; symbols & codings Extensive material on conversion factors, formulae; units and relationships

  18. IsoCleft Finder - a web-based tool for the detection and analysis of protein binding-site geometric and chemical similarities.

    Science.gov (United States)

    Kurbatova, Natalja; Chartier, Matthieu; Zylber, María Inés; Najmanovich, Rafael

    2013-01-01

    IsoCleft Finder is a web-based tool for the detection of local geometric and chemical similarities between potential small-molecule binding cavities and a non-redundant dataset of ligand-bound known small-molecule binding-sites. The non-redundant dataset developed as part of this study is composed of 7339 entries representing unique Pfam/PDB-ligand (hetero group code) combinations with known levels of cognate ligand similarity. The query cavity can be uploaded by the user or detected automatically by the system using existing PDB entries as well as user-provided structures in PDB format. In all cases, the user can refine the definition of the cavity interactively via a browser-based Jmol 3D molecular visualization interface. Furthermore, users can restrict the search to a subset of the dataset using a cognate-similarity threshold. Local structural similarities are detected using the IsoCleft software and ranked according to two criteria (number of atoms in common and Tanimoto score of local structural similarity) and the associated Z-score and p-value measures of statistical significance. The results, including predicted ligands, target proteins, similarity scores, number of atoms in common, etc., are shown in a powerful interactive graphical interface. This interface permits the visualization of target ligands superimposed on the query cavity and additionally provides a table of pairwise ligand topological similarities. Similarities between top scoring ligands serve as an additional tool to judge the quality of the results obtained. We present several examples where IsoCleft Finder provides useful functional information. IsoCleft Finder results are complementary to existing approaches for the prediction of protein function from structure, rational drug design and x-ray crystallography. IsoCleft Finder can be found at: http://bcb.med.usherbrooke.ca/isocleftfinder.

  19. Exploration of electrostatic interaction in the hydrophobic pocket of lysozyme: Importance of ligand-induced perturbation of the secondary structure on the mode of binding of exogenous ligand and possible consequences.

    Science.gov (United States)

    Panja, Sudipta; Halder, Mintu

    2016-08-01

    Exogenous ligand binding can be adequate to alter the secondary structure of biomolecules besides other external stimuli. In such cases, structural alterations can complicate on the nature of interaction with the exogenous molecules. In order to accommodate the exogenous ligand, the biomolecule has to unfold resulting in a considerable change to its properties. If the bound ligand can be unbound, the biomolecule gets the opportunity to refold back and return to its native state. Keeping this in mind, we have purposely investigated the interaction of tartrazine (TZ), a well abundant azo food colorant, with two homologous lysozymes, namely, human lysozyme (HLZ) and chicken egg white lysozyme (CEWLZ) in physiological pH condition. The binding of TZ with lysozymes has been identified to accompany a ligand-induced secondary structure alteration as indicated by the circular dichroism spectra, and the reduction of α-helical content is more with HLZ than CEWLZ. Interestingly, the binding is identified to occur in the electronic ground state of TZ with lysozyme in its hydrophobic cavity, containing excess of positive charge, predominantly via electrostatic interaction. With increase of salinity of the medium the protein tends to refold back due to wakening of electrostatic forces and consequent reduction of strength of ligand interaction and unbinding. The entropy enthalpy compensation (EEC) has been probed to understand the binding features and it is found that CEWLZ-TZ shows better compensation than HLZ-TZ complex. This is presumably due to the fact that with CEWLZ the binding does not accompany substantial change in the protein secondary structure and hence ineffective to scramble the EEC. The present study initiates the importance of ligand-perturbed structural alteration of biomolecule in controlling the thermodynamics of binding. If there is a considerable alteration of the protein secondary structure due to binding, it is indicative that such changes should bring in

  20. Exploration of electrostatic interaction in the hydrophobic pocket of lysozyme: Importance of ligand-induced perturbation of the secondary structure on the mode of binding of exogenous ligand and possible consequences.

    Science.gov (United States)

    Panja, Sudipta; Halder, Mintu

    2016-08-01

    Exogenous ligand binding can be adequate to alter the secondary structure of biomolecules besides other external stimuli. In such cases, structural alterations can complicate on the nature of interaction with the exogenous molecules. In order to accommodate the exogenous ligand, the biomolecule has to unfold resulting in a considerable change to its properties. If the bound ligand can be unbound, the biomolecule gets the opportunity to refold back and return to its native state. Keeping this in mind, we have purposely investigated the interaction of tartrazine (TZ), a well abundant azo food colorant, with two homologous lysozymes, namely, human lysozyme (HLZ) and chicken egg white lysozyme (CEWLZ) in physiological pH condition. The binding of TZ with lysozymes has been identified to accompany a ligand-induced secondary structure alteration as indicated by the circular dichroism spectra, and the reduction of α-helical content is more with HLZ than CEWLZ. Interestingly, the binding is identified to occur in the electronic ground state of TZ with lysozyme in its hydrophobic cavity, containing excess of positive charge, predominantly via electrostatic interaction. With increase of salinity of the medium the protein tends to refold back due to wakening of electrostatic forces and consequent reduction of strength of ligand interaction and unbinding. The entropy enthalpy compensation (EEC) has been probed to understand the binding features and it is found that CEWLZ-TZ shows better compensation than HLZ-TZ complex. This is presumably due to the fact that with CEWLZ the binding does not accompany substantial change in the protein secondary structure and hence ineffective to scramble the EEC. The present study initiates the importance of ligand-perturbed structural alteration of biomolecule in controlling the thermodynamics of binding. If there is a considerable alteration of the protein secondary structure due to binding, it is indicative that such changes should bring in

  1. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus

    Institute of Scientific and Technical Information of China (English)

    Beuy; Joob; Viroj; Wiwanitkit

    2014-01-01

    The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present.Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus.The in-depth analysis of the viral protein to find the binding site,active pocket is needed.Here,the authors analyzed the envelope glycoprotein GP2 from Ebola virus.Identification of active pocket and protein draggability within envelope glycoprotein GP2 from Ebola virus was done.According to this assessment,7 active pockets with varied draggability could be identified.

  2. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus

    Institute of Scientific and Technical Information of China (English)

    Beuy Joob; Viroj Wiwanitkit

    2014-01-01

    The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present. Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus. The in-depth analysis of the viral protein to find the binding site, active pocket is needed. Here, the authors analyzed the envelope glycoprotein GP2 from Ebola virus. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus was done. According to this assessment, 7 active pockets with varied druggability could be identified.

  3. The pocket dictionary of energy

    International Nuclear Information System (INIS)

    The pocket dictionary of energy does not only address the interested amateur but also students, pupils, teachers, scientists, technicians, and polititcians in like manner. The dictionary contains ca. 900 key-words from the fields of energy, consumption, energy types, energy deposits, energy programmes, energy industry, thermal insulation, governmental aids for energy conservation measures, heating cost calculation, energy utilization and energy conservation. The problems of the costs and efficiency of energy conversion, energy pricing, the promotion of research projects, the rentability of heating devices or insulation, the sanitation of old buildings, governmental aids by subsidies or tax abatement according to the modernization and energy conservation law etc., as well as the problem of pollution and the endangering of the environment by exhaust air, waste heat, ash and litter are emphasized particularly. Considering the space available the criterion for the selection of the key-words was not a scientific completeness but the provision of a fundamental understanding of the matter. (orig.)

  4. Single-chain antibody-fragment M6P-1 possesses a mannose 6-phosphate monosaccharide-specific binding pocket that distinguishes N-glycan phosphorylation in a branch-specific manner†.

    Science.gov (United States)

    Blackler, Ryan J; Evans, Dylan W; Smith, David F; Cummings, Richard D; Brooks, Cory L; Braulke, Thomas; Liu, Xinyu; Evans, Stephen V; Müller-Loennies, Sven

    2016-02-01

    The acquisition of mannose 6-phosphate (Man6P) on N-linked glycans of lysosomal enzymes is a structural requirement for their transport from the Golgi apparatus to lysosomes mediated by the mannose 6-phosphate receptors, 300 kDa cation-independent mannose 6-phosphate receptor (MPR300) and 46 kDa cation-dependent mannose 6-phosphate receptor (MPR46). Here we report that the single-chain variable domain (scFv) M6P-1 is a unique antibody fragment with specificity for Man6P monosaccharide that, through an array-screening approach against a number of phosphorylated N-glycans, is shown to bind mono- and diphosphorylated Man6 and Man7 glycans that contain terminal αMan6P(1 → 2)αMan(1 → 3)αMan. In contrast to MPR300, scFv M6P-1 does not bind phosphodiesters, monophosphorylated Man8 or mono- or diphosphorylated Man9 structures. Single crystal X-ray diffraction analysis to 2.7 Å resolution of Fv M6P-1 in complex with Man6P reveals that specificity and affinity is achieved via multiple hydrogen bonds to the mannose ring and two salt bridges to the phosphate moiety. In common with both MPRs, loss of binding was observed for scFv M6P-1 at pH values below the second pKa of Man6P (pKa = 6.1). The structures of Fv M6P-1 and the MPRs suggest that the change of the ionization state of Man6P is the main driving force for the loss of binding at acidic lysosomal pH (e.g. lysosome pH ∼ 4.6), which provides justification for the evolution of a lysosomal enzyme transport pathway based on Man6P recognition. PMID:26503547

  5. The system architecture of the Pocket Companion

    NARCIS (Netherlands)

    Havinga, Paul J.M.; Smit, Gerard J.M.

    1997-01-01

    In the Moby Dick project we design the architecture of a so-called Pocket Companion. It is a small personal portable computer with wireless communication facilities for every day use. The typical use of the Pocket Companion induces a number of requirements concerning security, performance, energy co

  6. Air pocket removal from downward sloping pipes

    NARCIS (Netherlands)

    Pothof, I.W.M.; Clemens, F.H.L.R.

    2012-01-01

    Air-water flow is an undesired condition in water pipelines and hydropower tunnels. Water pipelines and wastewater pressure mains in particular are subject to air pocket accumulation in downward sloping reaches, such as inverted siphons or terrain slopes. Air pockets cause energy losses and an assoc

  7. Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6.

    Science.gov (United States)

    Kempkens, Ozlem; Médina, Emmanuelle; Fernandez-Ballester, Gregorio; Ozüyaman, Susann; Le Bivic, André; Serrano, Luis; Knust, Elisabeth

    2006-08-01

    Formation of multiprotein complexes is a common theme to pattern a cell, thereby generating spatially and functionally distinct entities at specialised regions. Central components of these complexes are scaffold proteins, which contain several protein-protein interaction domains and provide a platform to recruit a variety of additional components. There is increasing evidence that protein complexes are dynamic structures and that their components can undergo various interactions depending on the cellular context. However, little is known so far about the factors regulating this behaviour. One evolutionarily conserved protein complex, which can be found both in Drosophila and mammalian epithelial cells, is composed of the transmembrane protein Crumbs/Crb3 and the scaffolding proteins Stardust/Pals1 and DPATJ/PATJ, respectively, and localises apically to the zonula adherens. Here we show by in vitro analysis that, similar as in vertebrates, the single PDZ domain of Drosophila DmPar-6 can bind to the four C-terminal amino acids (ERLI) of the transmembrane protein Crumbs. To further evaluate the binding capability of Crumbs to DmPar-6 and the MAGUK protein Stardust, analysis of the PDZ structural database and modelling of the interactions between the C-terminus of Crumbs and the PDZ domains of these two proteins were performed. The results suggest that both PDZ domains bind Crumbs with similar affinities. These data are supported by quantitative yeast two-hybrid interactions. In vivo analysis performed in cell cultures and in the Drosophila embryo show that the cytoplasmic domain of Crumbs can recruit DmPar-6 and DaPKC to the plasma membrane. The data presented here are discussed with respect to possible dynamic interactions between these proteins.

  8. Pocket companion to PMI's PMBOK guide

    CERN Document Server

    Snijders, Paul; Zandhuis, Anton

    2010-01-01

    This pocket guide is based on the PMBOK Guide® Fourth Edition.This pocket guide supplies a summary of the PMBOK Guide® , to provide a quick introduction as well as a structured overview of this method for project management.This pocket guide deals with the key issues and themes within project management and PMBOK:A short overview of the activities of PMI Inc., The organization and its standards: PMBOK Guide®, Standard for Project Portfolio Management, Standard for Program Management, OPM3.The essentials of the Project Lifecycle and Organization.What are the key project management knowledge ar

  9. Thimet oligopeptidase: similarity to 'soluble angiotensin II-binding protein' and some corrections to the published amino acid sequence of the rat testis enzyme.

    Science.gov (United States)

    McKie, N; Dando, P M; Rawlings, N D; Barrett, A J

    1993-01-01

    The deduced amino acid sequence of pig liver soluble angiotensin II-binding protein [Sugiura, Hagiwara and Hirose (1992) J. Biol. Chem. 267, 18067-18072] is similar over most of its length to that reported for rat testis thimet oligopeptidase (EC 3.4.24.15) by Pierotti, Dong, Glucksman, Orlowski and Roberts [(1990) (Biochemistry 29, 10323-10329]. We have found that homogeneous rat testis thimet oligopeptidase binds angiotensin II with the same distinctive characteristics as the pig liver protein. Analysis of the nucleotide sequences reported for the two proteins pointed to the likelihood that sequencing errors had caused two segments of the amino acid sequence of the rat protein to be translated out of frame, and re-sequencing of selected parts of the clone (kindly provided by the previous authors) confirmed this. The revised deduced amino acid sequence of rat thimet oligopeptidase contains 687 residues, representing a protein of 78,308 Da, and is more closely related to those of the pig liver protein and other known homologues of thimet oligopeptidase than that described previously. Images Figure 1 PMID:8216239

  10. Crystal Structure of the Bovine lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity of the C2 Domains of Factor V and Factor VIII

    Energy Technology Data Exchange (ETDEWEB)

    Lin,L.; Huai, Q.; Huang, M.; Furie, B.; Furie, B.

    2007-01-01

    Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 Angstroms. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C? atoms of 0.9 Angstroms and 1.2 Angstroms, and sequence identities of 43% and 38%, respectively). The lactadherin C2 domain has a discoidin-like fold containing two ?-sheets of five and three antiparallel ?-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One ?-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain ?-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.

  11. Crystal Structure of the Bovine lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity to the C2 Domains of Factor V and Factor VIII

    Energy Technology Data Exchange (ETDEWEB)

    Lin,L.

    2007-01-01

    Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 {angstrom}. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C{sub {alpha}} atoms of 0.9 {angstrom} and 1.2 {angstrom}, and sequence identities of 43% and 38%, respectively). The lactadherin C2 domain has a discoidin-like fold containing two {beta}-sheets of five and three antiparallel {beta}-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One {beta}-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain {beta}-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.

  12. Parameter selection of pocket extraction algorithm using interaction interface

    Institute of Scientific and Technical Information of China (English)

    KIM Chong-Min; WON Chung-In; RYU Joonghyun; CHO Cheol-Hyung; BHAK Jonghwa; KIM Deok-Soo

    2006-01-01

    Pockets in proteins have been known to be very important for the life process. There have been several studies in the past to automatically extract the pockets from the structure information of known proteins. However, it is difficult to find a study comparing the precision of the extracted pockets from known pockets on the protein. In this paper, we propose an algorithm for extracting pockets from structure data of proteins and analyze the quality of the algorithm by comparing the extracted pockets with some known pockets. These results in this paper can be used to set the parameter values of the pocket extraction algorithm for getting better results.

  13. Macintosh Troubleshooting Pocket Guide for Mac OS

    CERN Document Server

    Lerner, David; Corporation, Tekserve

    2009-01-01

    The Macintosh Troubleshooting Pocket Guide covers the most common user hardware and software trouble. It's not just a book for Mac OS X (although it includes tips for OS X and Jaguar), it's for anyone who owns a Mac of any type-- there are software tips going back as far as OS 6. This slim guide distills the answers to the urgent questions that Tekserve's employee's answer every week into a handy guide that fits in your back pocket or alongside your keyboard.

  14. Response of SCP-2L domain of human MFE-2 to ligand removal: binding site closure and burial of peroxisomal targeting signal.

    Science.gov (United States)

    Lensink, M F; Haapalainen, A M; Hiltunen, J K; Glumoff, T; Juffer, A H

    2002-10-11

    In the study of the structure and function relationship of human MFE-2, we have investigated the dynamics of human MFE-2SCP-2L (hSCP-2L) and its response to ligand removal. A comparison was made with homologous rabbit SCP-2. Breathing and a closing motion are found, identifiable with an adjustment in size and a closing off of the binding pocket. Crucial residues for structural integrity have been identified. Particularly mobile areas of the protein are loop 1 that is connecting helices A and C in space, and helix D, next to the entrance of the pocket. In hSCP-2L, the binding pocket gets occupied by Phe93, which is making a tight hydrophobic contact with Trp36. In addition, it is found that the C-terminal peroxisomal targeting signal (PTS1) that is solvent exposed in the complexed structure becomes buried when no ligand is present. Moreover, an anti-correlation exists between burial of PTS1 and the size of the binding pocket. The results are in accordance with plant nsLTPs, where a similar accommodation of binding pocket size was found after ligand binding/removal. Furthermore, the calculations support the suggestion of a ligand-assisted targeting mechanism.

  15. Bacterial periplasmic sialic acid-binding proteins exhibit a conserved binding site

    Energy Technology Data Exchange (ETDEWEB)

    Gangi Setty, Thanuja [Institute for Stem Cell Biology and Regenerative Medicine, NCBS Campus, GKVK Post, Bangalore, Karnataka 560 065 (India); Cho, Christine [Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109 (United States); Govindappa, Sowmya [Institute for Stem Cell Biology and Regenerative Medicine, NCBS Campus, GKVK Post, Bangalore, Karnataka 560 065 (India); Apicella, Michael A. [Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109 (United States); Ramaswamy, S., E-mail: ramas@instem.res.in [Institute for Stem Cell Biology and Regenerative Medicine, NCBS Campus, GKVK Post, Bangalore, Karnataka 560 065 (India)

    2014-07-01

    Structure–function studies of sialic acid-binding proteins from F. nucleatum, P. multocida, V. cholerae and H. influenzae reveal a conserved network of hydrogen bonds involved in conformational change on ligand binding. Sialic acids are a family of related nine-carbon sugar acids that play important roles in both eukaryotes and prokaryotes. These sialic acids are incorporated/decorated onto lipooligosaccharides as terminal sugars in multiple bacteria to evade the host immune system. Many pathogenic bacteria scavenge sialic acids from their host and use them for molecular mimicry. The first step of this process is the transport of sialic acid to the cytoplasm, which often takes place using a tripartite ATP-independent transport system consisting of a periplasmic binding protein and a membrane transporter. In this paper, the structural characterization of periplasmic binding proteins from the pathogenic bacteria Fusobacterium nucleatum, Pasteurella multocida and Vibrio cholerae and their thermodynamic characterization are reported. The binding affinities of several mutations in the Neu5Ac binding site of the Haemophilus influenzae protein are also reported. The structure and the thermodynamics of the binding of sugars suggest that all of these proteins have a very well conserved binding pocket and similar binding affinities. A significant conformational change occurs when these proteins bind the sugar. While the C1 carboxylate has been identified as the primary binding site, a second conserved hydrogen-bonding network is involved in the initiation and stabilization of the conformational states.

  16. Bacterial periplasmic sialic acid-binding proteins exhibit a conserved binding site

    International Nuclear Information System (INIS)

    Structure–function studies of sialic acid-binding proteins from F. nucleatum, P. multocida, V. cholerae and H. influenzae reveal a conserved network of hydrogen bonds involved in conformational change on ligand binding. Sialic acids are a family of related nine-carbon sugar acids that play important roles in both eukaryotes and prokaryotes. These sialic acids are incorporated/decorated onto lipooligosaccharides as terminal sugars in multiple bacteria to evade the host immune system. Many pathogenic bacteria scavenge sialic acids from their host and use them for molecular mimicry. The first step of this process is the transport of sialic acid to the cytoplasm, which often takes place using a tripartite ATP-independent transport system consisting of a periplasmic binding protein and a membrane transporter. In this paper, the structural characterization of periplasmic binding proteins from the pathogenic bacteria Fusobacterium nucleatum, Pasteurella multocida and Vibrio cholerae and their thermodynamic characterization are reported. The binding affinities of several mutations in the Neu5Ac binding site of the Haemophilus influenzae protein are also reported. The structure and the thermodynamics of the binding of sugars suggest that all of these proteins have a very well conserved binding pocket and similar binding affinities. A significant conformational change occurs when these proteins bind the sugar. While the C1 carboxylate has been identified as the primary binding site, a second conserved hydrogen-bonding network is involved in the initiation and stabilization of the conformational states

  17. Pocket Checklists of Indonesian timber trees

    NARCIS (Netherlands)

    Prawira, Soewanda A.; Tantra, I.G.M.; Whitmore, T.C.

    1984-01-01

    Indonesia as yet does not have a comprehensive account of the forest trees which reach timber size (35 cm dbh = 14 inch or 105 cm gbh = 42 inch). A project has been started in August 1983 by the Botany Section of the Forest Research Institute in Bogor, Indonesia, to prepare pocket checklists of the

  18. Frameworks for IT management a pocket guide

    CERN Document Server

    Rozemeijer, Eric

    2008-01-01

    This Pocket Guide is a concise summary of the Frameworks for IT Management. A quick, portable reference tool to the standards used within the Service Management community.English version available: September 2007, Dutch, French, Japanese, Spanish, German available February 2008.

  19. A strategy using NMR peptide structures of thromboxane A2 receptor as templates to construct ligand-recognition pocket of prostacyclin receptor

    Directory of Open Access Journals (Sweden)

    Ruan Ke-He

    2005-11-01

    Full Text Available Abstract Background: Prostacyclin receptor (IP and thromboxane A2 receptor (TP belong to rhodopsin-type G protein-coupling receptors and respectively bind to prostacyclin and thromboxane A2 derived from arachidonic acid. Recently, we have determined the extracellular loop (eLP structures of the human TP receptor by 2-D 1H NMR spectroscopy using constrained peptides mimicking the individual eLP segments. The studies have identified the segment along with several residues in the eLP domains important to ligand recognition, as well as proposed a ligand recognition pocket for the TP receptor. Results: The IP receptor shares a similar primary structure in the eLPs with those of the TP receptor. Forty percent residues in the second eLPs of the receptors are identical, which is the major region involved in forming the ligand recognition pocket in the TP receptor. Based on the high homology score, the eLP domains of the IP receptor were constructed by the homology modeling approach using the NMR structures of the TP eLPs as templates, and then configured to the seven transmembrane (TM domains model constructed using the crystal structure of the bovine rhodopsin as a template. A NMR structure of iloprost was docked into the modeled IP ligand recognition pocket. After dynamic studies, the segments and residues involved in the IP ligand recognition were proposed. A key residue, Arg173 involved in the ligand recognition for the IP receptor, as predicted from the modeling, was confirmed by site-directed mutagenesis. Conclusion: A 3-D model of the human IP receptor was constructed by homology modeling using the crystal structure of bovine rhodopsin TM domains and the NMR structures of the synthetic constrained peptides of the eLP domains of the TP receptor as templates. This strategy can be applied to molecular modeling and the prediction of ligand recognition pockets for other prostanoid receptors.

  20. Structural and Functional Studies Indicate That the EPEC Effector, EspG, Directly Binds p21-Activated Kinase

    Energy Technology Data Exchange (ETDEWEB)

    Germane, Katherine L.; Spiller, Benjamin W. (Vanderbilt)

    2011-09-20

    Bacterial pathogens secrete effectors into their hosts that subvert host defenses and redirect host processes. EspG is a type three secretion effector with a disputed function that is found in enteropathogenic Escherichia coli. Here we show that EspG is structurally similar to VirA, a Shigella virulence factor; EspG has a large, conserved pocket on its surface; EspG binds directly to the amino-terminal inhibitory domain of human p21-activated kinase (PAK); and mutations to conserved residues in the surface pocket disrupt the interaction with PAK.

  1. Evidence for designing health promoting pocket parks

    DEFF Research Database (Denmark)

    Peschardt, Karin Kragsig; Stigsdotter, Ulrika K.

    2014-01-01

    pocket park, Dantes Plads, before and after a redesign. Six people were interviewed about their perception of the change. First of all, the results show that Dantes Plads is primarily used for ‘rest and restitution’. Furthermore, the interviewees prefer to have the presence of sun, shade and planting......The use of urban green environments has repeatedly been associated with improved health and well-being for people living in cities. This study focuses on the health promoting potential of pocket parks in the dense city area of Copenhagen. A natural experiment was conducted, which evaluated one...... in relation to rest and restitution, while varied ‘terrain’ may create fascination thereby providing the opportunity for restoration. ‘Noise level’ is perceived differently from subject to subject, while ‘benches’ as well as ‘visual angels’ should not be oriented directly towards disturbing surroundings...

  2. Distributed classification for pocket data mining

    OpenAIRE

    Stahl, F.; Gaber, M; Liu, Han; Bramer, Max; Yu, P.

    2011-01-01

    Distributed and collaborative data stream mining in a mobile computing environment is referred to as Pocket Data Mining PDM. Large amounts of available data streams to which smart phones can subscribe to or sense, coupled with the increasing computational power of handheld devices motivates the development of PDM as a decision making system. This emerging area of study has shown to be feasible in an earlier study using technological enablers of mobile software agents and stream mining techniq...

  3. Pocket Checklists of Indonesian timber trees

    OpenAIRE

    Prawira, Soewanda A.; Tantra, I.G.M.; Whitmore, T.C.

    1984-01-01

    Indonesia as yet does not have a comprehensive account of the forest trees which reach timber size (35 cm dbh = 14 inch or 105 cm gbh = 42 inch). A project has been started in August 1983 by the Botany Section of the Forest Research Institute in Bogor, Indonesia, to prepare pocket checklists of the timber trees of all regions of the country. These lists will include forest-based descriptions, keys and line drawings.

  4. Windows® 7 Administrator's Pocket Consultant

    CERN Document Server

    Stanek, William

    2009-01-01

    Portable and precise, this pocket-sized guide delivers immediate answers for the day-to-day administration of Windows 7-from desktop configuration and management to networking and security issues. Zero in on core support and maintenance tasks by using quick-reference tables, instructions, and lists. You'll get the precise information you need to solve problems and get the job done-whether at your desk or in the field!

  5. ISO27001 / ISO27002 a pocket guide

    CERN Document Server

    Calder, Alan

    2013-01-01

    Information is one of your organisation's most important resources. Keeping it secure is therefore vital to your business. This handy pocket guide is an essential overview of two key information security standards that cover the formal requirements (ISO27001:2013) for creating an Information Security Management System (ISMS), and the best-practice recommendations (ISO27002:2013) for those responsible for initiating, implementing or maintaining it.

  6. Newnes radio and electronics engineer's pocket book

    CERN Document Server

    Moorshead, H W; Perry, J

    1978-01-01

    Newnes Radio and Electronics Engineer's Pocket Book, Fifteenth Edition provides reference of the information relevant in radio and electronics engineering. The book presents tables, illustrations, and diagrams of various data used in radio and electronics engineering. The coverage of the text includes abbreviations and symbols, electrical equations, and code conversions. The text will be useful to engineers, technicians, and other professionals who require a reference about the different aspects of radio and electronics.

  7. Detailed scrutiny of the anion receptor pocket in subdomain IIA of serum proteins toward individual response to specific ligands: HSA-pocket resembles flexible biological slide-wrench unlike BSA.

    Science.gov (United States)

    Datta, Shubhashis; Halder, Mintu

    2014-06-12

    Present study reveals that the subdomain IIA cavity of two homologous serum albumins (HSA, BSA) has inherent mutual structural and functional deviations which render noticeable difference in behavior toward specific ligands. The major drug binding site (subdomain IIA) of HSA is found to be largely hydrophobic while that of BSA is partially exposed to water. Larger shift in REE spectra and greater change in solvent reorganization energy of coumarin 343 (C343)-anion in HSA clearly reveals that binding pocket is relatively large and water molecules penetrate deeper into it unlike BSA. The individual response of proteins to perturbation by ligands is found to be way different. Although the subdomain IIA is primarily anion receptive (prefers anionic ligands), the present study suggests that HSA may also like to bind neutral guests due to its remarkable conformational features. Actually, HSA is capable of adopting favorable conformation like mechanical slide-wrench, when required, to accommodate neutral ligands [e.g., coumarin 314 (C314)], as well. But due to less flexible solution structure, BSA behaves like fixed mechanical spanners and hence is not very responsive to C314. Therefore, the generally speaking functional-structural similarities of homologous proteins can be apparent and needs to be analyzed exhaustively.

  8. Efficacy of a physicians' pocket guide about prenatal substance use: a randomized trial.

    Science.gov (United States)

    Midmer, Deana; Kahan, Meldon; Kim, Theresa; Ordean, Alice; Graves, Lisa

    2011-10-01

    A pocket guide on management of substance use during pregnancy was developed by a group of Canadian care providers. One hundred and fifteen family medicine residents in 6 Canadian teaching sites were randomized to receive either the pocket guide or a paper summary on similar clinical topics, based on UpToDate, a comprehensive Web-based resource. At baseline, both groups completed a survey containing questions on beliefs, attitudes, experience, and training on pregnancy and substance use. Participants then answered 28 multiple choice questions about substance use in pregnancy, using either the pocket guide or UpToDate. Finally participants were asked to rate ease of use for the 2 resources. The results showed that the pocket guide group had higher knowledge scores than the UpToDate group overall and at each study site (61.27% vs. 42.86%, P UpToDate (mean = 2.73 vs. 4.36, P UpToDate, P = .005). It is concluded that the pocket guide is a practical source of clinical information at point of care, particularly for "orphan" subjects such as substance use in pregnancy.

  9. Characterization of polymer release from the flagellar pocket of Leishmania mexicana promastigotes.

    Science.gov (United States)

    Stierhof, Y D; Ilg, T; Russell, D G; Hohenberg, H; Overath, P

    1994-04-01

    Trypanosomatids contain a unique compartment, the flagellar pocket, formed by an invagination of the plasma membrane at the base of the flagellum, which is considered to be the sole cellular site for endocytosis and exocytosis of macromolecules. The culture supernatant of Leishmania mexicana promastigotes, the insect stage of this protozoan parasite, contains two types of polymers: a filamentous acid phosphatase (sAP) composed of a 100-kD phosphoglycoprotein with non-covalently associated proteo high molecular weight phosphoglycan (proteo-HMWPG) and fibrous material termed network consisting of complex phosphoglycans. Secretion of both polymers is investigated using mAbs and a combination of light and electron microscopic techniques. Long filaments of sAP are detectable in the lumen of the flagellar pocket. Both sAP filaments and network material emerge from the ostium of the flagellar pocket. While sAP filaments detach from the cells, the fibrous network frequently remains associated with the anterior end of the parasites and can be found in the center of cell aggregates. The related species L. major forms similar networks. Since polymeric structures cannot be detected in intracellular compartments, it is proposed that monomeric or, possibly, oligomeric subunits synthesized in the cells are secreted into the flagellar pocket. Polymer formation from subunits is suggested to occur in the lumen of the pocket before release into the culture medium or, naturally, into the gut of infected sandflies. PMID:8163549

  10. Flagellar pocket restructuring through the Leishmania life cycle involves a discrete flagellum attachment zone.

    Science.gov (United States)

    Wheeler, Richard J; Sunter, Jack D; Gull, Keith

    2016-02-15

    Leishmania promastigote parasites have a flagellum, which protrudes from the flagellar pocket at the cell anterior, yet, surprisingly, have homologs of many flagellum attachment zone (FAZ) proteins--proteins used in the related Trypanosoma species to laterally attach the flagellum to the cell body from the flagellar pocket to the cell posterior. Here, we use seven Leishmania mexicana cell lines that expressed eYFP fusions of FAZ protein homologs to show that the Leishmania flagellar pocket includes a FAZ structure. Electron tomography revealed a precisely defined 3D organisation for both the flagellar pocket and FAZ, with striking similarities to those of Trypanosoma brucei. Expression of two T. brucei FAZ proteins in L. mexicana showed that T. brucei FAZ proteins can assemble into the Leishmania FAZ structure. Leishmania therefore have a previously unrecognised FAZ structure, which we show undergoes major structural reorganisation in the transition from the promastigote (sandfly vector) to amastigote (in mammalian macrophages). Morphogenesis of the Leishmania flagellar pocket, a structure important for pathogenicity, is therefore intimately associated with a FAZ; a finding with implications for understanding shape changes involving component modules during evolution. PMID:26746239

  11. Holo- And Apo- Structures of Bacterial Periplasmic Heme Binding Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Ho, W.W.; Li, H.; Eakanunkul, S.; Tong, Y.; Wilks, A.; Guo, M.; Poulos, T.L.

    2009-06-01

    An essential component of heme transport in Gram-negative bacterial pathogens is the periplasmic protein that shuttles heme between outer and inner membranes. We have solved the first crystal structures of two such proteins, ShuT from Shigella dysenteriae and PhuT from Pseudomonas aeruginosa. Both share a common architecture typical of Class III periplasmic binding proteins. The heme binds in a narrow cleft between the N- and C-terminal binding domains and is coordinated by a Tyr residue. A comparison of the heme-free (apo) and -bound (holo) structures indicates little change in structure other than minor alterations in the heme pocket and movement of the Tyr heme ligand from an 'in' position where it can coordinate the heme iron to an 'out' orientation where it points away from the heme pocket. The detailed architecture of the heme pocket is quite different in ShuT and PhuT. Although Arg{sup 228} in PhuT H-bonds with a heme propionate, in ShuT a peptide loop partially takes up the space occupied by Arg{sup 228}, and there is no Lys or Arg H-bonding with the heme propionates. A comparison of PhuT/ShuT with the vitamin B{sub 12}-binding protein BtuF and the hydroxamic-type siderophore-binding protein FhuD, the only two other structurally characterized Class III periplasmic binding proteins, demonstrates that PhuT/ShuT more closely resembles BtuF, which reflects the closer similarity in ligands, heme and B{sub 12}, compared with ligands for FhuD, a peptide siderophore.

  12. AIR for Javascript Developers Pocket Guide

    CERN Document Server

    Chambers, Mike; Hoyt, Kevin; Georgita, Dragos

    2009-01-01

    This book is the official guide to Adobe ® AIR[TM], written by members of the AIR team. With Adobe AIR, web developers can use technologies like HTML and JavaScript to build and deploy web applications to the desktop. Packed with examples, this book explains how AIR works and features recipes for performing common runtime tasks. Part of the Adobe Developer Library, this concise pocket guide explains: What Adobe AIR is, and the problems this runtime aims to solveHow to set up your development environmentThe HTML and JavaScript environments within AIRHow to create your first AIR application

  13. Pardon my French pocket French slang dictionary

    CERN Document Server

    Nicholson, Kate

    2009-01-01

    A runaway bestseller since its launch, Pardon My French! is a pocket-sized dictionary of French and English slang as it is spoken today. This edition includes even more non-standard language from the colloquial to the vulgar, with over 2,500 terms added. Ideal for both Francophobes and Francophiles alike. Over 14,000 referencesDozens of helpful usage notes to explain interesting meanings and originsThematic panels on the slang of sex, alcohol, violence etcFully updated and revised panels on varieties of slang (eg verlan, javanais, Black American slang)

  14. Mac OS X Snow Leopard pocket guide

    CERN Document Server

    Seiblod, Chris

    2009-01-01

    Whether you're new to the Mac or a longtime user, this handy book is the quickest way to get up to speed on Snow Leopard. Packed with concise information in an easy-to-read format, Mac OS X Snow Leopard Pocket Guide covers what you need to know and is an ideal resource for problem-solving on the fly. This book goes right to the heart of Snow Leopard, with details on system preferences, built-in applications, and utilities. You'll also find configuration tips, keyboard shortcuts, guides for troubleshooting, lots of step-by-step instructions, and more. Learn about new features and changes s

  15. Newnes passive and discrete circuits pocket book

    CERN Document Server

    MARSTON, R M

    2000-01-01

    Newnes Passive and Discrete Circuits Pocket Book is aimed at all engineers, technicians, students and experimenters who can build a design directly from a circuit diagram. In a highly concise form Ray Marston presents a huge compendium of circuits that can be built as they appear, adapted or used as building blocks. The devices used have been carefully chosen for their ease of availability and reasonable price. The selection of devices has been thoroughly updated for the second edition, which has also been expanded to cover the latest ICs.The three sections of the book cover: Moder

  16. Pocket guide for improving board performance.

    Science.gov (United States)

    1994-01-01

    This pocket guide, a supplement to "The Family Planning Manager," provides suggestions for building an effective, supportive board of directors. Among the topics covered are defining the board's terms of office, board committees, criteria for selecting board members and the board leader, dealing with key family planning issues, and ethical concerns. Also included is a sample chart for keeping track of board diversity in terms of age, gender, ethnicity, and professional and organizational experience. Yet another section sets forth a sample board member job description, including requirements, functional responsibilities, and expectations. PMID:12291665

  17. Python pocket reference, version 2.4

    CERN Document Server

    Lutz, Mark

    2005-01-01

    Python is optimized for quality, productivity, portability, and integration. Hundreds of thousands of Python developers around the world rely on Python for general-purpose tasks, Internet scripting, systems programming, user interfaces, and product customization. Available on all major computing platforms, including commercial versions of Unix, Linux, Windows, and Mac OS X, Python is portable, powerful and remarkable easy to use. With its convenient, quick-reference format, Python Pocket Reference, 3rd Edition is the perfect on-the-job reference. More importantly, it's now been refreshed

  18. The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation.

    Science.gov (United States)

    Selvaraman, Nagamani; Selvam, Saravana Kumar; Muthusamy, Karthikeyan

    2016-08-01

    Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity.

  19. The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation.

    Science.gov (United States)

    Selvaraman, Nagamani; Selvam, Saravana Kumar; Muthusamy, Karthikeyan

    2016-08-01

    Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity. PMID:26945790

  20. Pairwise structure alignment specifically tuned for surface pockets and interaction interfaces

    KAUST Repository

    Cui, Xuefeng

    2015-09-09

    To detect and evaluate the similarities between the three-dimensional (3D) structures of two molecules, various kinds of methods have been proposed for the pairwise structure alignment problem [6, 9, 7, 11]. The problem plays important roles when studying the function and the evolution of biological molecules. Recently, pairwise structure alignment methods have been extended and applied on surface pocket structures [10, 3, 5] and interaction interface structures [8, 4]. The results show that, even when there are no global similarities discovered between the global sequences and the global structures, biological molecules or complexes could share similar functions because of well conserved pockets and interfaces. Thus, pairwise pocket and interface structure alignments are promising to unveil such shared functions that cannot be discovered by the well-studied global sequence and global structure alignments. State-of-the-art methods for pairwise pocket and interface structure alignments [4, 5] are direct extensions of the classic pairwise protein structure alignment methods, and thus such methods share a few limitations. First, the goal of the classic protein structure alignment methods is to align single-chain protein structures (i.e., a single fragment of residues connected by peptide bonds). However, we observed that pockets and interfaces tend to consist of tens of extremely short backbone fragments (i.e., three or fewer residues connected by peptide bonds). Thus, existing pocket and interface alignment methods based on the protein structure alignment methods still rely on the existence of long-enough backbone fragments, and the fragmentation issue of pockets and interfaces rises the risk of missing the optimal alignments. Moreover, existing interface structure alignment methods focus on protein-protein interfaces, and require a "blackbox preprocessing" before aligning protein-DNA and protein-RNA interfaces. Therefore, we introduce the PROtein STucture Alignment

  1. The sweet quartet: Binding of fucose to the norovirus capsid.

    Science.gov (United States)

    Koromyslova, Anna D; Leuthold, Mila M; Bowler, Matthew W; Hansman, Grant S

    2015-09-01

    Human noroviruses bind histo-blood group antigens (HBGAs) and this interaction is thought to be important for an infection. We identified two additional fucose-binding pockets (termed fucose-3/4 sites) on a genogroup II human (GII.10) norovirus-protruding (P) dimer using X-ray crystallography. Fucose-3/4 sites were located between two previously determined HBGA binding pockets (termed fucose-1/2 sites). We found that four fucose molecules were capable of binding altogether at fucose-1/2/3/4 sites on the P dimer, though the fucose molecules bound in a dose-dependent and step-wise manner. We also showed that HBGA B-trisaccharide molecules bound in a similar way at the fucose-1/2 sites. Interestingly, we discovered that the monomers of the P dimer were asymmetrical in an unliganded state and when a single B-trisaccharide molecule bound, but were symmetrical when two B-trisaccharide molecules bound. We postulate that the symmetrical dimers might favor HBGA binding interactions at fucose-1/2 sites.

  2. Approaches for Identification of HIV-1 Entry Inhibitors Targeting gp41 Pocket

    Directory of Open Access Journals (Sweden)

    Asim K. Debnath

    2013-01-01

    Full Text Available The hydrophobic pocket in the HIV-1 gp41 N-terminal heptad repeat (NHR domain plays an important role in viral fusion and entry into the host cell, and serves as an attractive target for development of HIV-1 fusion/entry inhibitors. The peptide anti-HIV drug targeting gp41 NHR, T-20 (generic name: enfuvirtide; brand name: Fuzeon, was approved by the U.S. FDA in 2003 as the first HIV fusion/entry inhibitor for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, because T20 lacks the pocket-binding domain (PBD, it exhibits low anti-HIV-1 activity and short half-life. Therefore, several next-generation HIV fusion inhibitory peptides with PBD have been developed. They possess longer half-life and more potent antiviral activity against a broad spectrum of HIV-1 strains, including the T-20-resistant variants. Nonetheless, the clinical application of these peptides is still limited by the lack of oral availability and the high cost of production. Thus, development of small molecule compounds targeting the gp41 pocket with oral availability has been promoted. This review describes the main approaches for identification of HIV fusion/entry inhibitors targeting the gp41 pocket and summarizes the latest progress in developing these inhibitors as a new class of anti-HIV drugs.

  3. The Influence of Injection Pockets on the Performance of Tilting-Pad Thrust Bearings - Part I: Theory

    DEFF Research Database (Denmark)

    Heinrichson, Niels; Santos, Ilmar; Fuerst, Axel

    2007-01-01

    This is Part I of a two-part series of papers describing the effects of high-pressure injection pockets on the operating conditions of tilting-pad thrust bearings. In Part I a numerical model based on the Reynolds equation is developed extending the threedimensional thermoelastohydrodynamic (TEHD......) analysis of tilting-pad thrust bearings to include the effects of high-pressure injection and recesses in the bearing pads. The model is applied to the analysis of an existing bearing of large dimensions and the influence of the pocket is analyzed. In the analysis, the high-pressure oil injection used...... for hydrostatic jacking is turned off (i.e., only the effect of the pocket is studied). It is shown that a shallow pocket positively influences the performance of the bearing because it has characteristics similar to those of a Rayleigh-step bearing. In Part II of the paper (Heinrichson, N., Fuerst, A...

  4. Modal Similarity

    OpenAIRE

    Vigo , Dr. Ronaldo

    2009-01-01

    Just as Boolean rules define Boolean categories, the Boolean operators define higher-order Boolean categories referred to as modal categories. We examine the similarity order between these categories and the standard category of logical identity (i.e. the modal category defined by the biconditional or equivalence operator). Our goal is 4-fold: first, to introduce a similarity measure for determining this similarity order; second, to show that such a measure is a good predictor of the similari...

  5. Web Similarity

    OpenAIRE

    Cohen, Andrew; Vitányi, Paul

    2015-01-01

    Normalized web distance (NWD) is a similarity or normalized semantic distance based on the World Wide Web or any other large electronic database, for instance Wikipedia, and a search engine that returns reliable aggregate page counts. For sets of search terms the NWD gives a similarity on a scale from 0 (identical) to 1 (completely different). The NWD approximates the similarity according to all (upper semi)computable properties. We develop the theory and give applications. The derivation of ...

  6. IsoCleft Finder – a web-based tool for the detection and analysis of protein binding-site geometric and chemical similarities [v2; ref status: indexed, http://f1000r.es/13y

    Directory of Open Access Journals (Sweden)

    Natalja Kurbatova

    2013-05-01

    Full Text Available IsoCleft Finder is a web-based tool for the detection of local geometric and chemical similarities between potential small-molecule binding cavities and a non-redundant dataset of ligand-bound known small-molecule binding-sites. The non-redundant dataset developed as part of this study is composed of 7339 entries representing unique Pfam/PDB-ligand (hetero group code combinations with known levels of cognate ligand similarity. The query cavity can be uploaded by the user or detected automatically by the system using existing PDB entries as well as user-provided structures in PDB format. In all cases, the user can refine the definition of the cavity interactively via a browser-based Jmol 3D molecular visualization interface. Furthermore, users can restrict the search to a subset of the dataset using a cognate-similarity threshold. Local structural similarities are detected using the IsoCleft software and ranked according to two criteria (number of atoms in common and Tanimoto score of local structural similarity and the associated Z-score and p-value measures of statistical significance. The results, including predicted ligands, target proteins, similarity scores, number of atoms in common, etc., are shown in a powerful interactive graphical interface. This interface permits the visualization of target ligands superimposed on the query cavity and additionally provides a table of pairwise ligand topological similarities. Similarities between top scoring ligands serve as an additional tool to judge the quality of the results obtained. We present several examples where IsoCleft Finder provides useful functional information. IsoCleft Finder results are complementary to existing approaches for the prediction of protein function from structure, rational drug design and x-ray crystallography. IsoCleft Finder can be found at: http://bcb.med.usherbrooke.ca/isocleftfinder.

  7. An in silico analysis of the binding modes and binding affinities of small molecule modulators of PDZ-peptide interactions.

    Directory of Open Access Journals (Sweden)

    Garima Tiwari

    Full Text Available Inhibitors of PDZ-peptide interactions have important implications in a variety of biological processes including treatment of cancer and Parkinson's disease. Even though experimental studies have reported characterization of peptidomimetic inhibitors of PDZ-peptide interactions, the binding modes for most of them have not been characterized by structural studies. In this study we have attempted to understand the structural basis of the small molecule-PDZ interactions by in silico analysis of the binding modes and binding affinities of a set of 38 small molecules with known K(i or K(d values for PDZ2 and PDZ3 domains of PSD-95 protein. These two PDZ domains show differential selectivity for these compounds despite having a high degree of sequence similarity and almost identical peptide binding pockets. Optimum binding modes for these ligands for PDZ2 and PDZ3 domains were identified by using a novel combination of semi-flexible docking and explicit solvent molecular dynamics (MD simulations. Analysis of the binding modes revealed most of the peptidomimectic ligands which had high K(i or K(d moved away from the peptide binding pocket, while ligands with high binding affinities remained in the peptide binding pocket. The differential specificities of the PDZ2 and PDZ3 domains primarily arise from differences in the conformation of the loop connecting βB and βC strands, because this loop interacts with the N-terminal chemical moieties of the ligands. We have also computed the MM/PBSA binding free energy values for these 38 compounds with both the PDZ domains from multiple 5 ns MD trajectories on each complex i.e. a total of 228 MD trajectories of 5 ns length each. Interestingly, computational binding free energies show good agreement with experimental binding free energies with a correlation coefficient of approximately 0.6. Thus our study demonstrates that combined use of docking and MD simulations can help in identification of potent inhibitors

  8. CityInMyPocket: Digital Walking Guides

    OpenAIRE

    S. Depuydt; J. Vanattenhoven; Engelen, J.

    2006-01-01

    By the end of this year visitors to the Flemish town of Mechelen can discover the city with the help of the new CityInMyPocket walking guide. Instead of following a person or a book, people can pick up a CityInMyPocket digital walking guide and go sightseeing at their own speed. So, leave your heavy guide books and many flyers at home. CityInMyPocket will tell you just as much, and even more. CityInMyPocket is like having a friend who lives in the neighbourhood showing you around. The goals a...

  9. TEPITOPEpan: extending TEPITOPE for peptide binding prediction covering over 700 HLA-DR molecules.

    Directory of Open Access Journals (Sweden)

    Lianming Zhang

    Full Text Available MOTIVATION: Accurate identification of peptides binding to specific Major Histocompatibility Complex Class II (MHC-II molecules is of great importance for elucidating the underlying mechanism of immune recognition, as well as for developing effective epitope-based vaccines and promising immunotherapies for many severe diseases. Due to extreme polymorphism of MHC-II alleles and the high cost of biochemical experiments, the development of computational methods for accurate prediction of binding peptides of MHC-II molecules, particularly for the ones with few or no experimental data, has become a topic of increasing interest. TEPITOPE is a well-used computational approach because of its good interpretability and relatively high performance. However, TEPITOPE can be applied to only 51 out of over 700 known HLA DR molecules. METHOD: We have developed a new method, called TEPITOPEpan, by extrapolating from the binding specificities of HLA DR molecules characterized by TEPITOPE to those uncharacterized. First, each HLA-DR binding pocket is represented by amino acid residues that have close contact with the corresponding peptide binding core residues. Then the pocket similarity between two HLA-DR molecules is calculated as the sequence similarity of the residues. Finally, for an uncharacterized HLA-DR molecule, the binding specificity of each pocket is computed as a weighted average in pocket binding specificities over HLA-DR molecules characterized by TEPITOPE. RESULT: The performance of TEPITOPEpan has been extensively evaluated using various data sets from different viewpoints: predicting MHC binding peptides, identifying HLA ligands and T-cell epitopes and recognizing binding cores. Among the four state-of-the-art competing pan-specific methods, for predicting binding specificities of unknown HLA-DR molecules, TEPITOPEpan was roughly the second best method next to NETMHCIIpan-2.0. Additionally, TEPITOPEpan achieved the best performance in

  10. Oracle PL/SQL Language Pocket Reference

    CERN Document Server

    Feuerstein, Steven; Dawes, Chip

    2004-01-01

    While it's good to have a book with all the answers--like your trusty copy of Oracle PL/SQL Programming-- how often do you need all the answers? More likely, you just need a reminder, a quick answer to a problem you're up against. For these times, nothing's handier than the new edition of the Oracle PL/SQL Language Pocket Reference by PL/SQL experts Stephen Feuerstein, Bill Pribyl, and Chip Dawes. Newly updated for Oracle10g, this little book is always at the ready for the quick problem solving you need. The 3rd edition of this popular mini-reference boils down the most vital information fr

  11. The use of isomeric testosterone dimers to explore allosteric effects in substrate binding to cytochrome P450 CYP3A4.

    Science.gov (United States)

    Denisov, Ilia G; Mak, Piotr J; Grinkova, Yelena V; Bastien, Dominic; Bérubé, Gervais; Sligar, Stephen G; Kincaid, James R

    2016-05-01

    Cytochrome P450 CYP3A4 is the main drug-metabolizing enzyme in the human liver, being responsible for oxidation of 50% of all pharmaceuticals metabolized by human P450 enzymes. Possessing a large substrate binding pocket, it can simultaneously bind several substrate molecules and often exhibits a complex pattern of drug-drug interactions. In order to better understand structural and functional aspects of binding of multiple substrate molecules to CYP3A4 we used resonance Raman and UV-VIS spectroscopy to document the effects of binding of synthetic testosterone dimers of different configurations, cis-TST2 and trans-TST2. We directly demonstrate that the binding of two steroid molecules, which can assume multiple possible configurations inside the substrate binding pocket of monomeric CYP3A4, can lead to active site structural changes that affect functional properties. Using resonance Raman spectroscopy, we have documented perturbations in the ferric and Fe-CO states by these substrates, and compared these results with effects caused by binding of monomeric TST. While the binding of trans-TST2 yields results similar to those obtained with monomeric TST, the binding of cis-TST2 is much tighter and results in significantly more pronounced conformational changes of the porphyrin side chains and Fe-CO unit. In addition, binding of an additional monomeric TST molecule in the remote allosteric site significantly improves binding affinity and the overall spin shift for CYP3A4 with trans-TST2 dimer bound inside the substrate binding pocket. This result provides the first direct evidence for an allosteric effect of the peripheral binding site at the protein-membrane interface on the functional properties of CYP3A4. PMID:26774838

  12. Fpocket: An open source platform for ligand pocket detection

    Directory of Open Access Journals (Sweden)

    Le Guilloux Vincent

    2009-06-01

    Full Text Available Abstract Background Virtual screening methods start to be well established as effective approaches to identify hits, candidates and leads for drug discovery research. Among those, structure based virtual screening (SBVS approaches aim at docking collections of small compounds in the target structure to identify potent compounds. For SBVS, the identification of candidate pockets in protein structures is a key feature, and the recent years have seen increasing interest in developing methods for pocket and cavity detection on protein surfaces. Results Fpocket is an open source pocket detection package based on Voronoi tessellation and alpha spheres built on top of the publicly available package Qhull. The modular source code is organised around a central library of functions, a basis for three main programs: (i Fpocket, to perform pocket identification, (ii Tpocket, to organise pocket detection benchmarking on a set of known protein-ligand complexes, and (iii Dpocket, to collect pocket descriptor values on a set of proteins. Fpocket is written in the C programming language, which makes it a platform well suited for the scientific community willing to develop new scoring functions and extract various pocket descriptors on a large scale level. Fpocket 1.0, relying on a simple scoring function, is able to detect 94% and 92% of the pockets within the best three ranked pockets from the holo and apo proteins respectively, outperforming the standards of the field, while being faster. Conclusion Fpocket provides a rapid, open source and stable basis for further developments related to protein pocket detection, efficient pocket descriptor extraction, or drugablity prediction purposes. Fpocket is freely available under the GNU GPL license at http://fpocket.sourceforge.net.

  13. 30 CFR 56.19103 - Dumping facilities and loading pockets.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Dumping facilities and loading pockets. 56.19103 Section 56.19103 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... Personnel Hoisting Shafts § 56.19103 Dumping facilities and loading pockets. Dumping facilities and...

  14. 30 CFR 57.19103 - Dumping facilities and loading pockets.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Dumping facilities and loading pockets. 57.19103 Section 57.19103 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... MINES Personnel Hoisting Shafts § 57.19103 Dumping facilities and loading pockets. Dumping...

  15. ADAMTS13, lucky to have a hydrophobic pocket

    OpenAIRE

    Zheng, X. Long

    2015-01-01

    In this issue of Blood, de Groot et al identify a hydrophobic pocket in the Cys-rich domain of ADAMTS13 that appears to interact with the hydrophobic pocket in the central A2 domain of von Willebrand factor (VWF) for its proteolysis.1

  16. Neopatrimonialism and Development: Pockets of Effectiveness as Drivers of Change

    NARCIS (Netherlands)

    W. Hout (Wil)

    2014-01-01

    markdownabstract__Abstract__ This paper focuses on the notion of ‘pockets of effectiveness’ in the light of the theorisation of regulated neopatrimonialism. The attention to pockets of effectiveness – understood as public organisations which deliver public goods and services relatively effectively

  17. The migration of fragments of glass from the pockets to the surfaces of clothing.

    Science.gov (United States)

    O'Sullivan, S; Geddes, T; Lovelock, T J

    2011-05-20

    During the last decade or so there has been some discussion in the forensic community in the United Kingdom concerning whether it is necessary to search the pockets for glass particles in garments attributed to suspects arrested for glass breaking crimes. The removal of this practice would help expedite the searching and recovery process since examining only the surfaces of clothing would reduce the cost of recovering glass evidence. However, it is believed by many scientists that some glass fragments originally acquired in pockets can migrate to the surfaces of clothing prior to examination by the forensic scientist. As glass fragments have been encountered in the pockets of garments during examinations of casework items in the LGC Laboratories, the implications of this change in practice needs to be assessed. Hence, the aim of this study was to investigate this possibility that fragments of glass migrate from a pocket of a garment to its surfaces during police and laboratory handling after a person is suspected of breaking glass during an offence. If this occurs to a significant extent then it could affect the evaluation of the glass evidence when using a Bayesian approach. Sixty fragments of glass were seeded into a pocket of a fleece jacket and a pair of denim jeans. Three experiments were performed; one examined a searching, recovery and blanking procedure, another examined the pre-laboratory 'handling' process of an item in an evidence bag, and the third experiment looked at the removal of an object from a pocket laden with glass and subsequent removal and packaging of the garment. Up to two (3.3%) fragments were recovered from the surfaces of the fleece jacket and the denim jeans via the searching, recovery and blanking procedure. Similar numbers were also recovered from the insides of the evidence bags. Up to four (6.7%) fragments were recovered from the surface of the fleece jacket and up to five (8.3%) fragments were recovered from the surface of the

  18. A Swiss Pocket Knife for Computability

    Directory of Open Access Journals (Sweden)

    Neil D. Jones

    2013-09-01

    Full Text Available This research is about operational- and complexity-oriented aspects of classical foundations of computability theory. The approach is to re-examine some classical theorems and constructions, but with new criteria for success that are natural from a programming language perspective. Three cornerstones of computability theory are the S-m-ntheorem; Turing's "universal machine''; and Kleene's second recursion theorem. In today's programming language parlance these are respectively partial evaluation, self-interpretation, and reflection. In retrospect it is fascinating that Kleene's 1938 proof is constructive; and in essence builds a self-reproducing program. Computability theory originated in the 1930s, long before the invention of computers and programs. Its emphasis was on delimiting the boundaries of computability. Some milestones include 1936 (Turing, 1938 (Kleene, 1967 (isomorphism of programming languages, 1985 (partial evaluation, 1989 (theory implementation, 1993 (efficient self-interpretation and 2006 (term register machines. The "Swiss pocket knife'' of the title is a programming language that allows efficient computer implementation of all three computability cornerstones, emphasising the third: Kleene's second recursion theorem. We describe experiments with a tree-based computational model aiming for both fast program generation and fast execution of the generated programs.

  19. Pocket book of integrals and mathematical formulas

    CERN Document Server

    Tallarida, Ronald J

    2008-01-01

    Convenient Organization of Essential Material so You Can Look up Formulas Fast Containing a careful selection of standard and timely topics, the Pocket Book of Integrals and Mathematical Formulas, Fourth Edition presents many numerical and statistical tables, scores of worked examples, and the most useful mathematical formulas for engineering and scientific applications. This fourth edition of a bestseller provides even more comprehensive coverage with the inclusion of several additional topics, all while maintaining its accessible, clear style and handy size. New to the Fourth Edition           An expanded chapter on series that covers many fascinating properties of the natural numbers that follow from number theory           New applications such as geostationary satellite orbits and drug kinetics           An expanded statistics section that discusses nonlinear regression as well as the normal approximation of the binomial distribution           Revised f...

  20. Analysis of ASTER data for mapping bauxite rich pockets within high altitude lateritic bauxite, Jharkhand, India

    Science.gov (United States)

    Guha, Arindam; Singh, Vivek Kr.; Parveen, Reshma; Kumar, K. Vinod; Jeyaseelan, A. T.; Dhanamjaya Rao, E. N.

    2013-04-01

    Bauxite deposits of Jharkhand in India are resulted from the lateritization process and therefore are often associated with the laterites. In the present study, ASTER (Advanced Space borne Thermal Emission and Reflection Radiometer) image is processed to delineate bauxite rich pockets within the laterites. In this regard, spectral signatures of lateritic bauxite samples are analyzed in the laboratory with reference to the spectral features of gibbsite (main mineral constituent of bauxite) and goethite (main mineral constituent of laterite) in VNIR-SWIR (visible-near infrared and short wave infrared) electromagnetic domain. The analysis of spectral signatures of lateritic bauxite samples helps in understanding the differences in the spectral features of bauxites and laterites. Based on these differences; ASTER data based relative band depth and simple ratio images are derived for spatial mapping of the bauxites developed within the lateritic province. In order to integrate the complementary information of different index image, an index based principal component (IPC) image is derived to incorporate the correlative information of these indices to delineate bauxite rich pockets. The occurrences of bauxite rich pockets derived from density sliced IPC image are further delimited by the topographic controls as it has been observed that the major bauxite occurrences of the area are controlled by slope and altitude. In addition to above, IPC image is draped over the digital elevation model (DEM) to illustrate how bauxite rich pockets are distributed with reference to the topographic variability of the terrain. Bauxite rich pockets delineated in the IPC image are also validated based on the known mine occurrences and existing geological map of the bauxite. It is also conceptually validated based on the spectral similarity of the bauxite pixels delineated in the IPC image with the ASTER convolved laboratory spectra of bauxite samples.

  1. Calibrations of pocket dosemeters using a comparison method

    International Nuclear Information System (INIS)

    This monograph is dedicated mainly to the calibration of pocket dosemeters. Various types of radiation sources used in hospitals and different radiation detectors with emphasis on ionization chambers are briefly presented. Calibration methods based on the use of a reference dosemeter were developed to calibrate all pocket dosemeters existing at the Radiation Physics and Metrology Laboratory. Some of these dosemeters were used in personnel dosimetry at hospitals. Moreover, a study was realized about factors that affect the measurements with pocket dosemeters in the long term, such as discharges due to cosmic radiation. A DBASE IV program was developed to store the information included in the hospital's registry

  2. New pseudodimeric aurones as palm pocket inhibitors of Hepatitis C virus RNA-dependent RNA polymerase.

    Science.gov (United States)

    Meguellati, Amel; Ahmed-Belkacem, Abdelhakim; Nurisso, Alessandra; Yi, Wei; Brillet, Rozenn; Berqouch, Nawel; Chavoutier, Laura; Fortuné, Antoine; Pawlotsky, Jean-Michel; Boumendjel, Ahcène; Peuchmaur, Marine

    2016-06-10

    The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 μM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives. PMID:27017550

  3. Computational Analysis of the Ligand Binding Site of the Extracellular ATP Receptor, DORN1.

    Science.gov (United States)

    Nguyen, Cuong The; Tanaka, Kiwamu; Cao, Yangrong; Cho, Sung-Hwan; Xu, Dong; Stacey, Gary

    2016-01-01

    DORN1 (also known as P2K1) is a plant receptor for extracellular ATP, which belongs to a large gene family of legume-type (L-type) lectin receptor kinases. Extracellular ATP binds to DORN1 with strong affinity through its lectin domain, and the binding triggers a variety of intracellular activities in response to biotic and abiotic stresses. However, information on the tertiary structure of the ligand binding site of DORN1is lacking, which hampers efforts to fully elucidate the mechanism of receptor action. Available data of the crystal structures from more than 50 L-type lectins enable us to perform an in silico study of molecular interaction between DORN1 and ATP. In this study, we employed a computational approach to develop a tertiary structure model of the DORN1 lectin domain. A blind docking analysis demonstrated that ATP binds to a cavity made by four loops (defined as loops A B, C and D) of the DORN1 lectin domain with high affinity. In silico target docking of ATP to the DORN1 binding site predicted interaction with 12 residues, located on the four loops, via hydrogen bonds and hydrophobic interactions. The ATP binding pocket is structurally similar in location to the carbohydrate binding pocket of the canonical L-type lectins. However, four of the residues predicted to interact with ATP are not conserved between DORN1 and the other carbohydrate-binding lectins, suggesting that diversifying selection acting on these key residues may have led to the ATP binding activity of DORN1. The in silico model was validated by in vitro ATP binding assays using the purified extracellular lectin domain of wild-type DORN1, as well as mutated DORN1 lacking key ATP binding residues. PMID:27583834

  4. Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery

    Directory of Open Access Journals (Sweden)

    Daura Xavier

    2010-03-01

    Full Text Available Abstract Background With the classical, active-site oriented drug-development approach reaching its limits, protein ligand-binding sites in general and allosteric sites in particular are increasingly attracting the interest of medicinal chemists in the search for new types of targets and strategies to drug development. Given that allostery represents one of the most common and powerful means to regulate protein function, the traditional drug discovery approach of targeting active sites can be extended by targeting allosteric or regulatory protein pockets that may allow the discovery of not only novel drug-like inhibitors, but activators as well. The wealth of available protein structural data can be exploited to further increase our understanding of allosterism, which in turn may have therapeutic applications. A first step in this direction is to identify and characterize putative effector sites that may be present in already available structural data. Results We performed a large-scale study of protein cavities as potential allosteric and functional sites, by integrating publicly available information on protein sequences, structures and active sites for more than a thousand protein families. By identifying common pockets across different structures of the same protein family we developed a method to measure the pocket's structural conservation. The method was first parameterized using known active sites. We characterized the predicted pockets in terms of sequence and structural conservation, backbone flexibility and electrostatic potential. Although these different measures do not tend to correlate, their combination is useful in selecting functional and regulatory sites, as a detailed analysis of a handful of protein families shows. We finally estimated the numbers of potential allosteric or regulatory pockets that may be present in the data set, finding that pockets with putative functional and effector characteristics are widespread across

  5. Out-of-Pocket Costs Rose Moderately Under Obamacare: Report

    Science.gov (United States)

    ... for higher out-of-pocket expenses. Copayments for brand-name prescription drugs were also higher, on average, in marketplace plans than in employer-based plans, the study revealed. Under marketplace plans, ...

  6. Investigation on the gas pockets in a rotodynamic multiphase pump

    Science.gov (United States)

    Zhang, J. Y.; Li, Y. J.; Cai, S. J.; Zhu, H. W.; Zhang, Y. X.

    2016-05-01

    The appearance of gas pockets has an obvious impact on the performance of the rotodynamic multiphase pump. In order to study the formation of gas pockets in the pump and its effects on pump's performance, the unsteady numerical simulation and the visualization experiments were done to investigate gas pockets in a three-stage rotodynamic multiphase pump developed by authors. Meanwhile, the mixture of water and air was selected as the medium. According to the distributions of pressure, gas volume fraction and velocity vector in three compression cells in unsteady flow process, the process of the formation of gas pockets in the pump were analysed generally. The visualization experiments were used to verify the validity of the numerical simulation. The results will be benefit for the hydraulic design of the compression cell of rotodynamic multiphase pump.

  7. Pocket epithelium in the pathological setting for HMGB1 release.

    Science.gov (United States)

    Ebe, N; Hara-Yokoyama, M; Iwasaki, K; Iseki, S; Okuhara, S; Podyma-Inoue, K A; Terasawa, K; Watanabe, A; Akizuki, T; Watanabe, H; Yanagishita, M; Izumi, Y

    2011-02-01

    High-mobility group box-1 (HMGB1) protein acts as a transcription factor in the nucleus and also as a pro-inflammatory cytokine when released into extracellular fluids. The presence of higher levels of HMGB1 is reported in the gingival crevicular fluid from periodontal patients. Since the proliferation of bacteria within the periodontal pocket is closely involved in the exacerbation of periodontal disease, it is hypothesized that the periodontal pocket causes the release of HMGB1. Immunohistochemical staining of inflamed gingiva revealed that HMGB1 is exclusively dislocated from the nucleus to the cytoplasm in the pocket epithelium, whereas it is mainly present in the nucleus in the gingival epithelium. Butyric acid, an extracellular metabolite from periodontopathic bacteria populating the periodontal pocket, induced the passive release of HMGB1 as a result of eliciting necrosis in the human gingival epithelial cell line. Thus, the periodontal epithelium may provide a unique pathological setting for HMGB1 release by bacterial insult.

  8. Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres

    DEFF Research Database (Denmark)

    Petersen, Jette G; Bergmann, Rikke; Krogsgaard-Larsen, Povl;

    2013-01-01

    the orthosteric binding site. The physicochemical properties of the heterocyclic moieties making them suitable for bioisosteric replacement of the carboxylic acid in the molecule of GABA are discussed. A variety of synthetic strategies for synthesis of the heterocyclic scaffolds are available. Likewise, methods...... for introduction of substituents into specific positions of the heterocyclic scaffolds facilitate the investigation of different regions in the orthosteric binding pocket in close vicinity of the core scaffolds of muscimol/GABA. The development of structural models, from pharmacophore models to receptor homology...... models, has provided more insight into the molecular basis for binding. Similar binding modes are proposed for the heterocyclic GABA analogues covered in this review by use of ligand-receptor docking into the receptor homology model and the presented structure-activity relationships. A network...

  9. Water flow and retention in coarse soil pockets in the shallow subsurface

    Science.gov (United States)

    Sakaki, T.; Limsuwat, A.; Illangasekare, T. H.

    2010-12-01

    and saturation remained very low. In the subsequent drainage cycle, similar behavior in the primary drainage, i.e., rapid drainage in the pockets as soon as the air reaches the coarse-fine interface was observed. During precipitation, water bypassed through the fine sand and saturation in the pockets, although increased very slowly, remained very low. These observations suggest that a pocket of soil that is coarser than the background soil can keep the air trapped during wetting/precipitation or artificial water spraying that lead to anomalies in soil moisture imagery. Furthermore, as soil moisture controls thermal conductivity of soil, anomalies in soil moisture can result in those in temperature distribution. Finally, when modeling local water flow and retention in pockets of coarse soils, the single-phase approach using Richard’s equation breaks down suggesting that the air pressure variations can not be neglected. A better prediction based on two-phase flow approach can ultimately improve the prediction of soil moisture variations at high spatial resolutions.

  10. The role of a novel auxiliary pocket in bacterial phenylalanyl-tRNA synthetase druggability.

    Science.gov (United States)

    Abibi, Ayome; Ferguson, Andrew D; Fleming, Paul R; Gao, Ning; Hajec, Laurel I; Hu, Jun; Laganas, Valerie A; McKinney, David C; McLeod, Sarah M; Prince, D Bryan; Shapiro, Adam B; Buurman, Ed T

    2014-08-01

    The antimicrobial activity of phenyl-thiazolylurea-sulfonamides against Staphylococcus aureus PheRS are dependent upon phenylalanine levels in the extracellular fluids. Inhibitor efficacy in animal models of infection is substantially diminished by dietary phenylalanine intake, thereby reducing the perceived clinical utility of this inhibitor class. The search for novel antibacterial compounds against Gram-negative pathogens led to a re-evaluation of this phenomenon, which is shown here to be unique to S. aureus. Inhibition of macromolecular syntheses and characterization of novel resistance mutations in Escherichia coli demonstrate that antimicrobial activity of phenyl-thiazolylurea-sulfonamides is mediated by PheRS inhibition, validating this enzyme as a viable drug discovery target for Gram-negative pathogens. A search for novel inhibitors of PheRS yielded three novel chemical starting points. NMR studies were used to confirm direct target engagement for phenylalanine-competitive hits. The crystallographic structure of Pseudomonas aeruginosa PheRS defined the binding modes of these hits and revealed an auxiliary hydrophobic pocket that is positioned adjacent to the phenylalanine binding site. Three viable inhibitor-resistant mutants were mapped to this pocket, suggesting that this region is a potential liability for drug discovery. PMID:24936059

  11. An in silico algorithm for identifying stabilizing pockets in proteins: test case, the Y220C mutant of the p53 tumor suppressor protein.

    Science.gov (United States)

    Bromley, Dennis; Bauer, Matthias R; Fersht, Alan R; Daggett, Valerie

    2016-09-01

    The p53 tumor suppressor protein performs a critical role in stimulating apoptosis and cell cycle arrest in response to oncogenic stress. The function of p53 can be compromised by mutation, leading to increased risk of cancer; approximately 50% of cancers are associated with mutations in the p53 gene, the majority of which are in the core DNA-binding domain. The Y220C mutation of p53, for example, destabilizes the core domain by 4 kcal/mol, leading to rapid denaturation and aggregation. The associated loss of tumor suppressor functionality is associated with approximately 75 000 new cancer cases every year. Destabilized p53 mutants can be 'rescued' and their function restored; binding of a small molecule into a pocket on the surface of mutant p53 can stabilize its wild-type structure and restore its function. Here, we describe an in silico algorithm for identifying potential rescue pockets, including the algorithm's integration with the Dynameomics molecular dynamics data warehouse and the DIVE visual analytics engine. We discuss the results of the application of the method to the Y220C p53 mutant, entailing finding a putative rescue pocket through MD simulations followed by an in silico search for stabilizing ligands that dock into the putative rescue pocket. The top three compounds from this search were tested experimentally and one of them bound in the pocket, as shown by nuclear magnetic resonance, and weakly stabilized the mutant.

  12. CIED infection with either pocket or systemic infection presentation

    DEFF Research Database (Denmark)

    Ihlemann, Nikolaj; Møller-Hansen, Michael; Salado-Rasmussen, Kirsten;

    2016-01-01

    OBJECTIVE: Cardiovascular implantable electronic device (CIED) infections are increasing in numbers. The objective was to review the clinical presentation and outcome in patients affected with CIED infections with either local pocket or systemic presentation. DESIGN: All device removals due to CIED...... infection during the period from 2005 to 2012 were retrospectively reviewed. CIED infections were categorized as systemic or pocket infections. Treatment included complete removal of the device, followed by antibiotic treatment of six weeks. RESULTS: Seventy-one device removals due to infection (32 systemic......-up no relapses and two cases of new infections were noted (2.8%). CONCLUSIONS: CIED infection with systemic or pocket infection was difficult to distinguish in clinical presentation and outcome. Complete device removal and antibiotic treatment of long duration was safe and without relapses....

  13. Ethics pocket cards: an educational tool for busy clinicians.

    Science.gov (United States)

    Volpe, Rebecca L; Levi, Benjamin H; Blackhall, George F; Green, Michael J

    2014-01-01

    The adage "an ounce of prevention is worth a pound of cure" is widely used in healthcare settings and can be applied to the work of institutional clinical ethics committees. The model of clinical ethics consultation, however, is inherently reactive: a crisis or question emerges, and ethics experts are called to help. In an effort to employ a proactive component to the model of clinical ethics consultation (as well as to standardize our educational interventions), we developed ethics pocket cards. The purpose of this article is to: (1) describe the rationale for using ethics pocket cards, (2) provide examples of our cards, and (3) begin a dialogue about the potential uses of ethics pocket cards. In doing so, we hope to explore how such portable, economical devices can advance the goals of ethics consultation as well as the educational aims of ethics committees.

  14. Apache 2 Pocket Reference For Apache Programmers & Administrators

    CERN Document Server

    Ford, Andrew

    2008-01-01

    Even if you know the Apache web server inside and out, you still need an occasional on-the-job reminder -- especially if you're moving to the newer Apache 2.x. Apache 2 Pocket Reference gives you exactly what you need to get the job done without forcing you to plow through a cumbersome, doorstop-sized reference. This Book provides essential information to help you configure and maintain the server quickly, with brief explanations that get directly to the point. It covers Apache 2.x, giving web masters, web administrators, and programmers a quick and easy reference solution. This pocket r

  15. UML 2.0 Pocket Reference UML Syntax and Usage

    CERN Document Server

    Pilone, Dan

    2006-01-01

    Globe-trotting travelers have long resorted to handy, pocket-size dictionaries as an aid to communicating across the language barrier. Dan Pilone's UML 2.0 Pocket Reference is just such an aid for on-the-go developers who need to converse in the Unified Modeling Language (UML). Use this book to decipher the many UML diagrams you'll encounter on the path to delivering a modern software system. Updated to cover the very latest in UML, you'll find coverage of the following UML 2.0 diagram types: Class diagramsComponent diagrams*Sequence diagrams*Communication diagrams*Timing diagrams*Interactio

  16. Microflora cultivable from minocycline strips placed in persisting periodontal pockets

    OpenAIRE

    Leung, WK; Jin, L; Yau, JYY; Q. Sun; Corbet, EF

    2005-01-01

    The microflora that develops on minocycline strips, used as an adjunct in non-surgical periodontal therapy was studied. Minocycline (1.4 mg in polycaprolactone vehicle) and control strips were applied into all residual pockets (PD ≥ 5 mm, ≥2 pockets/subject) of patients with chronic periodontitis 1 month after a course of non-surgical periodontal therapy. Strips were inserted and retained for 3 days, changed to new strips for 3 more days and then removed. Strips were recovered from 14 (eight ...

  17. Why not to ''pocket shoot'': Radiology of intravenous drug abuse

    International Nuclear Information System (INIS)

    Our large population of intravenous drug abusers has increasingly resorted to supraclavicular central venous injection for vascular access. Few reports of complications associated with the practice of supraclavicular ''pocket'' injection have appeared in the radiologic literature. The authors describe the complications associated with this practice, including pneumothorax, mycotic aneurysm, arteriovenous fistula, jugular vein thrombosis, cellulitis, foreign body reaction, and neck abscess. In addition, the authors provide examples of sternoclavicular osteomyelitis. The anatomy of the ''pocket,'' and the pathophysiology and radiographic manifestations of these complications, are reviewed

  18. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain.

    Science.gov (United States)

    Mistry, Pragnesh; Laird, Michelle H W; Schwarz, Ryan S; Greene, Shannon; Dyson, Tristan; Snyder, Greg A; Xiao, Tsan Sam; Chauhan, Jay; Fletcher, Steven; Toshchakov, Vladimir Y; MacKerell, Alexander D; Vogel, Stefanie N

    2015-04-28

    Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. PMID:25870276

  19. Conformational control of the binding of diatomic gases to cytochrome c'.

    Science.gov (United States)

    Manole, Andreea; Kekilli, Demet; Svistunenko, Dimitri A; Wilson, Michael T; Dobbin, Paul S; Hough, Michael A

    2015-06-01

    The cytochromes c' (CYTcp) are found in denitrifying, methanotrophic and photosynthetic bacteria. These proteins are able to form stable adducts with CO and NO but not with O2. The binding of NO to CYTcp currently provides the best structural model for the NO activation mechanism of soluble guanylate cyclase. Ligand binding in CYTcps has been shown to be highly dependent on residues in both the proximal and distal heme pockets. Group 1 CYTcps typically have a phenylalanine residue positioned close to the distal face of heme, while for group 2, this residue is typically leucine. We have structurally, spectroscopically and kinetically characterised the CYTcp from Shewanella frigidimarina (SFCP), a protein that has a distal phenylalanine residue and a lysine in the proximal pocket in place of the more common arginine. Each monomer of the SFCP dimer folds as a 4-alpha-helical bundle in a similar manner to CYTcps previously characterised. SFCP exhibits biphasic binding kinetics for both NO and CO as a result of the high level of steric hindrance from the aromatic side chain of residue Phe 16. The binding of distal ligands is thus controlled by the conformation of the phenylalanine ring. Only a proximal 5-coordinate NO adduct, confirmed by structural data, is observed with no detectable hexacoordinate distal NO adduct.

  20. 5-Aza-2'-deoxycytidine reactivates gene expression via degradation of pRb pocket proteins.

    Science.gov (United States)

    Zheng, Zhixing; Li, Lian; Liu, Xiangyu; Wang, Donglai; Tu, Bo; Wang, Lina; Wang, Haiying; Zhu, Wei-Guo

    2012-01-01

    Not only does 5-aza-2'-deoxycytidine (5-aza-CdR) induce the reexpression of silenced genes through the demethylation of CpG islands, but it increases the expression of unmethylated genes. However, the mechanism by which 5-aza-CdR activates the expression of genes is not completely understood. Here, we report that the pRb pocket proteins pRb, p107, and p130 were degraded in various cancer cell lines in response to 5-aza-CdR treatment, and this effect was dependent on the proteasome pathway. Mouse double minute 2 (MDM2) played a critical role in this 5-aza-CdR-induced degradation of pRb. Furthermore, PP2A phosphatase-induced MDM2 dephosphorylation at S260 was found to be essential for MDM2 binding to pRb in the presence of 5-aza-CdR. pRb degradation resulted in the significant reexpression of several genes, including methylated CDKN2A, RASFF1A, and unmethylated CDKN2D. Finally, knockdown of pRb pocket proteins by either RNAi or 5-aza-CdR treatment induced a significant decrease in the recruitment of SUV39H1 and an increase in the enrichment of KDM3B and KDM4A to histones around the promoter of RASFF1A and thus reduced H3K9 di- and trimethylation, by which RASFF1A expression is activated. Our data reveal a novel mechanism by which 5-aza-CdR induces the expression of both methylated and unmethylated genes by degrading pRb pocket proteins.

  1. Structural analyses of the Slm1-PH domain demonstrate ligand binding in the non-canonical site.

    Directory of Open Access Journals (Sweden)

    Kanchan Anand

    Full Text Available BACKGROUND: Pleckstrin homology (PH domains are common membrane-targeting modules and their best characterized ligands are a set of important signaling lipids that include phosphatidylinositol phosphates (PtdInsPs. PH domains recognize PtdInsPs through two distinct mechanisms that use different binding pockets on opposite sides of the β-strands 1 and 2: i a canonical binding site delimited by the β1-β2 and β3-β4loops and ii a non-canonical binding site bordered by the β1-β2 and β5-β6loops. The PH domain-containing protein Slm1 from budding yeast Saccharomyces cerevisiae is required for actin cytoskeleton polarization and cell growth. We recently reported that this PH domain binds PtdInsPs and phosphorylated sphingolipids in a cooperative manner. PRINCIPAL FINDINGS: To study the structural basis for the Slm1-PH domain (Slm1-PH specificity, we co-crystallized this domain with different soluble compounds that have structures analogous to anionic lipid head groups of reported Slm1 ligands: inositol 4-phosphate, which mimics phosphatidylinositol-4-phosphate (PtdIns(4P, and phosphoserine as a surrogate for dihydrosphingosine 1-phosphate (DHS1-P. We found electron densities for the ligands within the so-called non-canonical binding site. An additional positively charged surface that contacts a phosphate group was identified next to the canonical binding site. CONCLUSIONS: Our results suggest that Slm1-PH utilizes a non-canonical binding site to bind PtdInsPs, similar to that described for the PH domains of β-spectrin, Tiam1 and ArhGAP9. Additionally, Slm1-PH may have retained an active canonical site. We propose that the presence of both a canonical and a non-canonical binding pocket in Slm1-PH may account for the cooperative binding to PtdInsPs and DHS-1P.

  2. Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant.

    Science.gov (United States)

    Park, Jiyong; McDonald, Joseph J; Petter, Russell C; Houk, K N

    2016-04-12

    Epidermal growth factor receptor (EGFR) inhibitors interrupt EGFR-dependent cellular signaling pathways that lead to accelerated tumor growth and proliferation. Mutation of a threonine in the inhibitor binding pocket, known as the "gatekeeper", to methionine (T790M) confers acquired resistance to several EGFR-selective inhibitors. We studied interactions between EGFR inhibitors and the gatekeeper residues of the target protein. Thermodynamic integration (TI) with Amber14 indicates that the binding energies of gefitinib and AEE788 to the active state of the T790M mutant EGFR is 3 kcal/mol higher than to the wild type (WT), whereas ATP binding energy to the mutant is similar to the WT. Using metadynamics MD simulations with NAMD v2.9, the conformational equilibrium between the inactive resting state and the catalytically competent activate state was determined for the WT EGFR. When combined with the results obtained by Sutto and Gervasio, our simulations showed that the T790M point mutation lowers the free energy of the active state by 5 kcal/mol relative to the inactive state of the enzyme. Relative to the WT, the T790M mutant binds gefitinib more strongly. The T790M mutation is nevertheless resistant due to its increased binding of ATP. By contrast, the binding of AEE788 to the active state causes a conformational change in the αC-helix adjacent to the inhibitor binding pocket, that results in a 2 kcal/mol energy penalty. The energy penalty explains why the binding of AEE788 to the T790M mutant is unfavorable relative to binding to WT EGFR. These results establish the role of the gatekeeper mutation on inhibitor selectivity. Additional molecular dynamics (MD) simulations, TI, and metadynamics MD simulations reveal the origins of the changes in binding energy of WT and mutants. PMID:27010480

  3. Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket

    DEFF Research Database (Denmark)

    Höpner, Sabine; Dickhaut, Katharina; Hofstätter, Maria;

    2006-01-01

    immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated......, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly(beta86) pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl......Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify...

  4. Slicing Recognition of Aircraft Integral Panel Generalized Pocket

    Institute of Scientific and Technical Information of China (English)

    Yu Fangfang; Du Baorui; Ren Wenjie; Zheng Guolei; Chu Hongzhen

    2008-01-01

    To automatically obtain a machining area in numerical control (NC) programming, a data model of generalized pocket is estab-lished by analyzing aireraft integral panel characteristics, and a feature recognition approach is proposed. First, by reference to the prao- tieal slice-machining process of an aircraft integral panel, both the part and the blank are sliced in the Z-axis direction; hence a feature profile is created acceding to the slicing planes and the contours are formed by the intersection of the slicing planes with the part and its blanK. Second, the auxiliary features of the generalized pocket are also determined based on the face type and the position, to correct the profile of the pocket. Finally, the generalized pocket feature relationship tree is constructed by matching the vertical relationships among the features. Machining feature information produced by using this method can be directly used to calculate the cutter path. The validity and practicability of the method is verified by NC programming for aircraft panels.

  5. The pocket epithelium: a light- and electronmicroscopic study.

    Science.gov (United States)

    Müller-Glauser, W; Schroeder, H E

    1982-03-01

    The POCKET epithelium is important for the pathogenesis of gingivitis and periodontitis. However, this epithelial variant has never been adequately described. The bioptic material with supraalveolar pockets originated from previous studies in which cotton floss ligatures were placed around the crowns of premolars in eight dogs. After periods of 4 to 21 days or up to 5 months, block biopsies comprising dental and gingival tissues were taken on the buccal side. The tissues were processed for light- and electron microscopic examination. The observations revealed that the pocket epithelium (1) does not attach to the tooth, (2) forms irregular ridges and, over connective tissue papillae, thin coverings which occasionally ulcerate, (3) consists of cells only some of which show a tendency to differentiate, (4) presents a basal lamina complex with discontinuities and multiplications, and (5) is infiltrated mainly by lymphocytes, T- and B-blasts and plasma cells, and is transmigrated by neutrophilic granulocytes. It is concluded that the mosaic-like structure of the pocket epithelium reflects the heterogeneity of the adjacent plaque, that this structure together with the absence of membrane coating granules is the basis for an extremely high permeability, and that epithelial ridges may conduct and collect foreign substances which thereby become more easily recognizable for leukocytes.

  6. Australian Vocational Education and Training Statistics Pocket Guide, Issued 2011

    Science.gov (United States)

    National Centre for Vocational Education Research (NCVER), 2011

    2011-01-01

    This handy, pocket-sized booklet summarises information from the National Centre for Vocational Education Research's (NCVER's) current statistical publications. It presents statistics about: Australia's public vocational education and training (VET) system (which includes activity undertaken at technical and further education [TAFE] institutes,…

  7. Australian Vocational Education and Training Statistics Pocket Guide, Issued 2012

    Science.gov (United States)

    National Centre for Vocational Education Research (NCVER), 2012

    2012-01-01

    This pocket guide presents statistics about: (1) the public vocational education and training (VET) system, which includes activity undertaken at technical and further education (TAFE) institutes, other government providers, community education providers and publicly funded delivery by private providers; (2) apprentices and trainees, who are…

  8. A pocket aide-memoire on drug interactions.

    Science.gov (United States)

    Stockley, I H

    1975-04-01

    A pocket size "slide-rule" type device designed to be used by physicians, pharmacists and nurses as a memory aid on potential drug-drug interactions is described. Color-coded symbols on the device indicate both the type and clinical significance of the potential interactions involving 56 drugs or groups of drugs.

  9. Crystal structure of cyclic nucleotide-binding-like protein from Brucella abortus.

    Science.gov (United States)

    He, Zheng; Gao, Yuan; Dong, Jing; Ke, Yuehua; Li, Xuemei; Chen, Zeliang; Zhang, Xuejun C

    2015-12-25

    The cyclic nucleotide-binding (CNB)-like protein (CNB-L) from Brucella abortus shares sequence homology with CNB domain-containing proteins. We determined the crystal structure of CNB-L at 2.0 Å resolution in the absence of its C-terminal helix and nucleotide. The 3D structure of CNB-L is in a two-fold symmetric form. Each protomer shows high structure similarity to that of cGMP-binding domain-containing proteins, and likely mimics their nucleotide-free conformation. A key residue, Glu17, mediates the dimerization and prevents binding of cNMP to the canonical ligand-pocket. The structurally observed dimer of CNB-L is stable in solution, and thus is likely to be biologically relevant.

  10. Computational characterization of TTHA0379: A potential glycerophosphocholine binding protein of Ugp ATP-binding cassette transporter.

    Science.gov (United States)

    Chandravanshi, Monika; Gogoi, Prerana; Kanaujia, Shankar Prasad

    2016-11-01

    For the de novo biosynthesis of phospholipids, byproducts such as sn-glycerol-3-phosphate (G3P) and glycerophosphocholine (GPC) of glycerophospholipid metabolic pathway are imported inside the cell by an ATP-binding cassette (ABC) transporter known as UgpABCE. Of which, UgpA and UgpE constitutes the transmembrane domains (TMDs), UgpC forms the dimer of ATP-hydrolyzing component and UgpB is the periplasmic substrate binding protein. Structurally, UgpABCE transporter displays similarity to the maltose ABC transporter of Escherichia coli; thus, has been grouped into the CUT1 (Carbohydrate Uptake Transporter-1) family of bacterial ABC transporters. Being a member of CUT1 family, several Ugp (Uptake glycerol phosphate) protein sequences in biological database(s) exhibit sequence and structure similarity to sugar ABC transporters and have been annotated as sugar binding proteins; one of such proteins is TTHA0379 from Thermus thermophilus HB8. Here, in this study, we used computational method(s) to distinguish UgpB and sugar binding proteins based on their primary and tertiary structure features. A comprehensive analysis of these proteins indicates that they are evolutionarily related to each other having common conserved features at their primary and tertiary structure levels. However, they display differences at their active sites owing to the dissimilarity in their ligand preferences. In addition, phylogenetic analysis of TTHA0379 along with UgpB and sugar binding proteins reveals that both the groups of proteins forms two distinct clades and TTHA0379 groups with UgpB proteins. Furthermore, analysis of the ligand binding pocket shows that all the essential features of glycerophosphocholine binding protein i.e. UgpB, are conserved in TTHA0379 as well. Combining these features, here, we designate TTHA0379 to be a GPC binding protein.

  11. Fragment Binding Can Be Either More Enthalpy-Driven or Entropy-Driven: Crystal Structures and Residual Hydration Patterns Suggest Why.

    Science.gov (United States)

    Rühmann, Eggert; Betz, Michael; Heine, Andreas; Klebe, Gerhard

    2015-09-10

    In lead optimization, small, enthalpically advantaged fragments have been suggested to be superior, as an entropic component will be added inevitably during late-stage optimization. Determination of thermodynamic signatures of weak-binding fragments is essential to support the decision-making process, to decide which fragment to take to further optimization. High-resolution crystal structures of six fragments binding to the S1 pocket of thrombin were determined and analyzed with respect to their thermodynamic profile. The two most potent fragments exhibiting an amidine-type scaffold are not the most enthalpic binders; instead a chloro-thiophene fragment binds more enthalpically. Two chemically very similar chloro-aromatic fragments differ strongly in their potency (430 μM vs 10 mM); their binding modes are related, but the surrounding residual water network differs. The more potent one recruits a water molecule and involves Glu192 in binding, thus succeeding in firmly capping the S1 pocket. Fragments exhibiting a rather perfect solvation pattern in their binding mode also experience the highest potency.

  12. Liver fatty acid-binding protein binds monoacylglycerol in vitro and in mouse liver cytosol.

    Science.gov (United States)

    Lagakos, William S; Guan, Xudong; Ho, Shiu-Ying; Sawicki, Luciana Rodriguez; Corsico, Betina; Kodukula, Sarala; Murota, Kaeko; Stark, Ruth E; Storch, Judith

    2013-07-01

    Liver fatty acid-binding protein (LFABP; FABP1) is expressed both in liver and intestinal mucosa. Mice null for LFABP were recently shown to have altered metabolism of not only fatty acids but also monoacylglycerol, the two major products of dietary triacylglycerol hydrolysis (Lagakos, W. S., Gajda, A. M., Agellon, L., Binas, B., Choi, V., Mandap, B., Russnak, T., Zhou, Y. X., and Storch, J. (2011) Am. J. Physiol. Gastrointest. Liver Physiol. 300, G803-G814). Nevertheless, the binding and transport of monoacylglycerol (MG) by LFABP are uncertain, with conflicting reports in the literature as to whether this single chain amphiphile is in fact bound by LFABP. In the present studies, gel filtration chromatography of liver cytosol from LFABP(-/-) mice shows the absence of the low molecular weight peak of radiolabeled monoolein present in the fractions that contain LFABP in cytosol from wild type mice, indicating that LFABP binds sn-2 MG in vivo. Furthermore, solution-state NMR spectroscopy demonstrates two molecules of sn-2 monoolein bound in the LFABP binding pocket in positions similar to those found for oleate binding. Equilibrium binding affinities are ∼2-fold lower for MG compared with fatty acid. Finally, kinetic studies examining the transfer of a fluorescent MG analog show that the rate of transfer of MG is 7-fold faster from LFABP to phospholipid membranes than from membranes to membranes and occurs by an aqueous diffusion mechanism. These results provide strong support for monoacylglycerol as a physiological ligand for LFABP and further suggest that LFABP functions in the efficient intracellular transport of MG. PMID:23658011

  13. Liver Fatty Acid-binding Protein Binds Monoacylglycerol in Vitro and in Mouse Liver Cytosol*

    Science.gov (United States)

    Lagakos, William S.; Guan, Xudong; Ho, Shiu-Ying; Sawicki, Luciana Rodriguez; Corsico, Betina; Kodukula, Sarala; Murota, Kaeko; Stark, Ruth E.; Storch, Judith

    2013-01-01

    Liver fatty acid-binding protein (LFABP; FABP1) is expressed both in liver and intestinal mucosa. Mice null for LFABP were recently shown to have altered metabolism of not only fatty acids but also monoacylglycerol, the two major products of dietary triacylglycerol hydrolysis (Lagakos, W. S., Gajda, A. M., Agellon, L., Binas, B., Choi, V., Mandap, B., Russnak, T., Zhou, Y. X., and Storch, J. (2011) Am. J. Physiol. Gastrointest. Liver Physiol. 300, G803–G814). Nevertheless, the binding and transport of monoacylglycerol (MG) by LFABP are uncertain, with conflicting reports in the literature as to whether this single chain amphiphile is in fact bound by LFABP. In the present studies, gel filtration chromatography of liver cytosol from LFABP−/− mice shows the absence of the low molecular weight peak of radiolabeled monoolein present in the fractions that contain LFABP in cytosol from wild type mice, indicating that LFABP binds sn-2 MG in vivo. Furthermore, solution-state NMR spectroscopy demonstrates two molecules of sn-2 monoolein bound in the LFABP binding pocket in positions similar to those found for oleate binding. Equilibrium binding affinities are ∼2-fold lower for MG compared with fatty acid. Finally, kinetic studies examining the transfer of a fluorescent MG analog show that the rate of transfer of MG is 7-fold faster from LFABP to phospholipid membranes than from membranes to membranes and occurs by an aqueous diffusion mechanism. These results provide strong support for monoacylglycerol as a physiological ligand for LFABP and further suggest that LFABP functions in the efficient intracellular transport of MG. PMID:23658011

  14. Ligand binding-dependent functions of the lipocalin NLaz: an in vivo study in Drosophila.

    Science.gov (United States)

    Ruiz, Mario; Ganfornina, Maria D; Correnti, Colin; Strong, Roland K; Sanchez, Diego

    2014-04-01

    Lipocalins are small extracellular proteins mostly described as lipid carriers. The Drosophila lipocalin NLaz (neural Lazarillo) modulates the IIS pathway and regulates longevity, stress resistance, and behavior. Here, we test whether a native hydrophobic pocket structure is required for NLaz to perform its functions. We use a point mutation altering the binding pocket (NLaz(L130R)) and control mutations outside NLaz binding pocket. Tryptophan fluorescence titration reveals that NLaz(L130R) loses its ability to bind ergosterol and the pheromone 7(z)-tricosene but retains retinoic acid binding. Using site-directed transgenesis in Drosophila, we test the functionality of the ligand binding-altered lipocalin at the organism level. NLaz-dependent life span reduction, oxidative stress and starvation sensitivity, aging markers accumulation, and deficient courtship are rescued by overexpression of NLaz(WT), but not of NLaz(L130R). Transcriptional responses to aging and oxidative stress show a large set of age-responsive genes dependent on the integrity of NLaz binding pocket. Inhibition of IIS activity and modulation of oxidative stress and infection-responsive genes are binding pocket-dependent processes. Control of energy metabolites on starvation appears to be, however, insensitive to the modification of the NLaz binding pocket.

  15. Gas pockets in a wastewater rising main: a case study.

    Science.gov (United States)

    Pozos-Estrada, Oscar; Fuentes-Mariles, Oscar A; Pozos-Estrada, Adrian

    2012-01-01

    This paper presents a case study of an existing wastewater rising main (WWRM) in which an extreme transient event produced by simultaneous power failure of the pumps caused the rupture of a 1.2 m (48 in) prestressed concrete cylinder pipe (PCCP), causing an important leakage of sewage. The event and the methodology followed in order to validate the diagnostics of the failure are described. The detail study included in situ observation of the system, experimental investigation in a setup, hydraulic analysis, as well as details of the structural strength of the WWRM. After the extensive investigation and several simulations of fluid transients for different scenarios and flow conditions, it was found that stationary small gas pockets accumulated at high points of the WWRM were identified as the principal contributory factor of the failure. This case study serves as clear warning of the consequences of operating a WWRM with gas pockets at its high points. PMID:22949261

  16. Pocket PC-based portable gamma-ray spectrometer

    Directory of Open Access Journals (Sweden)

    Kamontip Ploykrachang

    2011-04-01

    Full Text Available A portable gamma-ray spectrometer based on a Pocket PC has been developed. A 12-bit pipeline analog-to-digitalconverter (ADC associated with an implemented pulse height histogram function on field programmable gate array (FPGAoperating at 15 MHz is employed for pulse height analysis from built-in pulse amplifier. The system, which interfaces withthe Pocket PC via an enhanced RS-232 serial port under the microcontroller facilitation, is utilized for spectrum acquisition,display and analysis. The pulse height analysis capability of the system was tested and it was found that the ADC integralnonlinearity of ±0.45% was obtained with the throughput rate at 160 kcps. The overall system performance was tested usinga PIN photodiode-CsI(Tl crystal coupled scintillation detector and gamma standard radioactive sources of Cs-137 andCo-60. Low cost and the compact system size as a result of the implemented logical function are also discussed.

  17. Health Promoting Pocket Parks in a Landscape Architectural Perspective

    DEFF Research Database (Denmark)

    Peschardt, Karin Kragsig

    This thesis presents how the health potential of pocket parks can be improved through design from a landscape architectural perspective. In developed countries, the densification of cities is a wide-spread tendency which often results in a compact city planning structure. People who live in dense...... cities have become detached from nature and live most of their daily life indoors where sedentary work and physical inactivity characterise everyday life. It has been suggested that this inactivity has resulted in a rapid increase in a number of lifestyle diseases. Urban green spaces (UGS) have been...... shown to have a positive influence on preventing lifestyle related diseases, although only limited research suggests how the various green spaces in the urban green infrastructure (UGI) can benefit health. Especially knowledge about the role of pocket parks is lacking. The study evaluates the health...

  18. Excerpts from THE ROMANCE OF SIAM: A POCKET GUIDE

    OpenAIRE

    Ravine, Jai Arun

    2016-01-01

    These pieces are excerpts from the forthcoming book THE ROMANCE OF SIAM: A POCKET GUIDE, which is a subverted travel guide that interrogates the desire White people have to lose and reinvent themselves in Thailand. I track how this “White love” manifests in the tourism industry, popular American media and the western imaginary in order to reveal the connections between tourism and colonization.

  19. Pocket computers: a new aid to nutritional support.

    OpenAIRE

    1985-01-01

    A program has been written to run on a pocket computer (Sharp PC-1500) that can be used at the bedside to predict the nutritional requirements of patients with a wide range of clinical conditions. The predictions of the program showed good correlation with measured values for energy and nitrogen requirements. The program was used, with good results, in the management of over 100 patients needing nutritional support. The calculation of nutritional requirements for each patient individually fac...

  20. Newnes circuit calculations pocket book with computer programs

    CERN Document Server

    Davies, Thomas J

    2013-01-01

    Newnes Circuit Calculations Pocket Book: With Computer Programs presents equations, examples, and problems in circuit calculations. The text includes 300 computer programs that help solve the problems presented. The book is comprised of 20 chapters that tackle different aspects of circuit calculation. The coverage of the text includes dc voltage, dc circuits, and network theorems. The book also covers oscillators, phasors, and transformers. The text will be useful to electrical engineers and other professionals whose work involves electronic circuitry.

  1. Pocket-book for the fuel trade 1982/83

    Energy Technology Data Exchange (ETDEWEB)

    Temming, D.

    1982-01-01

    The 'Pocket-book for the fuel trade 82/83' has been planned as a compendium of the fuel trade and as a buyer's guide for the fuel tradesman. It contains beside technical and economical informations about solid and liquid fuels indications to legal questions (competition, price and cartel laws, labor and social laws, responsability questions) and taxes and duties. A comprehensive list of the trade organizations of the fuel trade is also included.

  2. Design of 50nm Vertical MOSFET Incorporating a Dielectric Pocket

    OpenAIRE

    Donaghy, D; Hall, S.; De Groot, C. H. (Kees); Kunz, V. D.; Ashburn, P.

    2004-01-01

    A new architecture for a vertical MOS transistor is proposed that incorporates a so-calle dielectric pocket (DP) for suppression of short channel effects and bulk punch-through. We outline the advantages that the DP brings and propose a basic fabrication process to realize the device. The design issues of a 50-nm channel device are addressed by numerical simulation. The gate delay of an associated CMOS inverter is assessed in the context of the International Technology Roadmap for Semiconduct...

  3. 24 CFR 570.466 - Additional application submission requirements for Pockets of Poverty-employment opportunities.

    Science.gov (United States)

    2010-04-01

    ... requirements for Pockets of Poverty-employment opportunities. 570.466 Section 570.466 Housing and Urban... application submission requirements for Pockets of Poverty—employment opportunities. Applicants for Action Grants under the Pockets of Poverty provision must describe the number and, to the extent possible,...

  4. Intraperiodontal pocket: An ideal route for local antimicrobial drug delivery

    Directory of Open Access Journals (Sweden)

    Sreeja C Nair

    2012-01-01

    Full Text Available Periodontal pockets act as a natural reservoir filled with gingival crevicular fluid for the controlled release delivery of antimicrobials directly. This article reflects the present status of nonsurgical controlled local intrapocket delivery of antimicrobials in the treatment of periodontitis. These sites have specialty in terms of anatomy, permeability, and their ability to retain a delivery system for a desired length of time. A number of antimicrobial products and the composition of the delivery systems, its use, clinical results, and their release are summarized. The goal in using an intrapocket device for the delivery of an antimicrobial agent is the achievement and maintenance of therapeutic drug concentration for the desired period of time. Novel controlled drug delivery system are capable of improving patient compliance as well as therapeutic efficacy with precise control of the rate by which a particular drug dosage is released from a delivery system without the need for frequent administration. These are considered superior drug delivery system because of low cost, greater stability, non-toxicity, biocompatibility, non-immunogenicity, and are biodegradable in nature. This review also focus on the importance and ideal features of periodontal pockets as a drug delivery platform for designing a suitable dosage form along with its potential advantage and limitations. The microbes in the periodontal pocket could destroy periodontal tissues, and a complete knowledge of these as well as an ideal treatment strategy could be helpful in treating this disease.

  5. Performance of vintage direct reading pocket ionization chambers.

    Science.gov (United States)

    Bergen, Robert J; Harvey, John A; Kearfott, Kimberlee J

    2010-05-01

    The linearity, accuracy, and precision of each of two groups of vintage 51.6 microC-kg-1 maximum scale passive direct reading pocket ionization chambers, each from a different manufacturer and all aged at least 50 years since manufacture, were tested. The pocket ionization chambers were suspended on a phantom and exposed using a 137Cs source. Variations from trial to trial were smaller than variations from chamber to chamber. The average percent standard deviations ranged from 5.7% to 14% across all exposures. The accuracy of the dosimeter readings increased as the exposure level increased. Percent error from known exposure values decreased as exposure increased. An independent samples t test indicated there was a statistically significant difference between the two groups only at a delivered exposure of 6.45 microC-kg-1. Testing was performed in a 222Rn drum to determine the effect of Rn on the pocket ionization chambers. Exposure of five chambers to an average Rn level of 4.70 kBq m-3 and thirty chambers to 3.86 kBq m-3 over a 7-d period produced abnormally high readings at least three times background in eight of the 35 chambers tested.

  6. Rosetta and the Design of Ligand Binding Sites.

    Science.gov (United States)

    Moretti, Rocco; Bender, Brian J; Allison, Brittany; Meiler, Jens

    2016-01-01

    Proteins that bind small molecules (ligands) can be used as biosensors, signal modulators, and sequestering agents. When naturally occurring proteins for a particular target ligand are not available, artificial proteins can be computationally designed. We present a protocol based on RosettaLigand to redesign an existing protein pocket to bind a target ligand. Starting with a protein structure and the structure of the ligand, Rosetta can optimize both the placement of the ligand in the pocket and the identity and conformation of the surrounding sidechains, yielding proteins that bind the target compound. PMID:27094285

  7. Pocketome: an encyclopedia of small-molecule binding sites in 4D.

    Science.gov (United States)

    Kufareva, Irina; Ilatovskiy, Andrey V; Abagyan, Ruben

    2012-01-01

    The importance of binding site plasticity in protein-ligand interactions is well-recognized, and so are the difficulties in predicting the nature and the degree of this plasticity by computational means. To assist in understanding the flexible protein-ligand interactions, we constructed the Pocketome, an encyclopedia of about one thousand experimentally solved conformational ensembles of druggable binding sites in proteins, grouped by location and consistent chain/cofactor composition. The multiplicity of pockets within the ensembles adds an extra, fourth dimension to the Pocketome entry data. Within each ensemble, the pockets were carefully classified by the degree of their pairwise similarity and compatibility with different ligands. The core of the Pocketome is derived regularly and automatically from the current releases of the Protein Data Bank and the Uniprot Knowledgebase; this core is complemented by entries built from manually provided seed ligand locations. The Pocketome website (www.pocketome.org) allows searching for the sites of interest, analysis of conformational clusters, important residues, binding compatibility matrices and interactive visualization of the ensembles using the ActiveICM web browser plugin. The Pocketome collection can be used to build multi-conformational docking and 3D activity models as well as to design cross-docking and virtual ligand screening benchmarks.

  8. Spectroscopic characterization of mutations at the Phe41 position in the distal haem pocket of horseradish peroxidase C: structural and functional consequences.

    Science.gov (United States)

    Heering, Hendrik A; Smith, Andrew T; Smulevich, Giulietta

    2002-05-01

    Three mutants of horseradish peroxidase isoenzyme C (HRPC) have been constructed in which the conserved distal aromatic residue Phe(41) has been substituted by Trp, Val or Ala and the properties of the mutant proteins have been compared with that of the wild-type. The ferric and ferrous states have been studied by resonance Raman, electronic absorption and Fourier-transform infrared spectroscopies, together with their respective fluoride and CO complexes as probes for the integrity of the distal haem-pocket hydrogen-bonding network. The catalytic properties of the mutants, most notably the HRPC-mutant Phe(41)-->Trp (F41W) variant, were also affected. Structural modelling suggests that the bulky indole group of the F41W mutant blocks the distal cavity, inhibiting the binding of fluoride and CO to the haem iron, severely impairing the reaction of the enzyme with H(2)O(2) to form Compound I. Substitution with the smaller side-chain residues Val or Ala resulted in a 2-fold increase in the affinity of the mutants for the aromatic donor benzhydroxamic acid (BHA) compared with the wild-type, whereas the sterically hindered F41W mutant was not able to bind BHA at all. All the mutations studied increased the amount of a ferric six-coordinate aquo-high-spin species. On the other hand, the similarity in the Fe-Im stretching frequencies of the mutants and wild-type protein suggests that the distal haem-pocket mutations do not cause any substantive changes on the proximal side of the haem. Spectra of the HRPC mutant Phe(41)-->Ala-CO and the HRPC mutant Phe(41)-->Val-CO complexes strongly suggested a weakening of the interaction between CO and Arg(38) due to a secondary rearrangement of the haem relative to helix B. The effects observed for these HRP mutants were somewhat different from those noted recently for the analogous Coprinus cinereus peroxidase (CIP) mutants, particularly the Trp mutant. These differences can be reconciled in part as being due to the smaller size of the

  9. Biphenyl/diphenyl ether renin inhibitors: filling the S1 pocket of renin via the S3 pocket.

    Science.gov (United States)

    Yuan, Jing; Simpson, Robert D; Zhao, Wei; Tice, Colin M; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M; Scott, Boyd B; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P; Harrison, Richard K; McGeehan, Gerard M; Singh, Suresh B; Dillard, Lawrence W; Baldwin, John J; Claremon, David A

    2011-08-15

    Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.

  10. TGF-β Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium

    Directory of Open Access Journals (Sweden)

    Christian Alexandro Clement

    2013-06-01

    Full Text Available Transforming growth factor β (TGF-β signaling is regulated by clathrin-dependent endocytosis (CDE for the control of cellular processes during development and in tissue homeostasis. The primary cilium coordinates several signaling pathways, and the pocket surrounding the base and proximal part of the cilium is a site for CDE. We report here that TGF-β receptors localize to the ciliary tip and endocytic vesicles at the ciliary base in fibroblasts and that TGF-β stimulation increases receptor localization and activation of SMAD2/3 and ERK1/2 at the ciliary base. Inhibition of CDE reduced TGF-β-mediated signaling at the cilium, and TGF-β signaling and CDE activity are reduced at stunted primary cilia in Tg737orpk fibroblasts. Similarly, TGF-β signaling during cardiomyogenesis correlated with accumulation of TGF-β receptors and activation of SMAD2/3 at the ciliary base. Our results indicate that the primary cilium regulates TGF-β signaling and that the ciliary pocket is a compartment for CDE-dependent regulation of signal transduction.

  11. Analysis of Pocket Double Gate Tunnel FET for Low Stand by Power Logic Circuits

    Directory of Open Access Journals (Sweden)

    Kamal K. Jha

    2013-12-01

    Full Text Available For low power circuits downscaling of MOSFET has a major issue of scaling of voltage which has ceased after 1V. This paper highlights comparative study and analysis of pocket double gate tunnel FET (DGTFET with MOSFET for low standby power logic circuits. The leakage current of pocket DGTFET and MOSFET have been studied and the analysis results shows that the pocket DGTFET gives the lower leakage current than the MOSFET. Further a pocket DGTFET inverter circuit is design in 32 nm technology node at VDD =0.6 V. The pocket DGTFET inverter shows the significant improvement on the leakage power than multi-threshold CMOS (MTCMOS inverter. The leakage power of pocket DGFET and MTCMOS inverter are 0.116 pW and 1.83 pW respectively. It is found that, the pocket DGTFET can replace the MOSFET for low standby power circuits.

  12. Methods and systems for identifying ligand-protein binding sites

    KAUST Repository

    Gao, Xin

    2016-05-06

    The invention provides a novel integrated structure and system-based approach for drug target prediction that enables the large-scale discovery of new targets for existing drugs Novel computer-readable storage media and computer systems are also provided. Methods and systems of the invention use novel sequence order-independent structure alignment, hierarchical clustering, and probabilistic sequence similarity techniques to construct a probabilistic pocket ensemble (PPE) that captures even promiscuous structural features of different binding sites for a drug on known targets. The drug\\'s PPE is combined with an approximation of the drug delivery profile to facilitate large-scale prediction of novel drug- protein interactions with several applications to biological research and drug development.

  13. Theoretical investigation on the diatomic ligand migration process and ligand binding properties in non-O2-binding H-NOX domain.

    Science.gov (United States)

    Zhang, Yuebin; Liu, Li; Wu, Lei; Li, Shuai; Li, Fei; Li, Zhengqiang

    2013-08-01

    The Nostoc sp (Ns) H-NOX (heme-nitric oxide or OXygen-binding) domain shares 35% sequence identity with soluble guanylate cyclase (sGC) and exhibits similar ligand binding property with the sGC. Previously, our molecular dynamic (MD) simulation work identified that there exists a Y-shaped tunnel system hosted in the Ns H-NOX interior, which servers for ligand migration. The tunnels were then confirmed by Winter et al. [PNAS 2011;108(43):E 881-889] recently using x-ray crystallography with xenon pressured conditions. In this work, to further investigate how the protein matrix of Ns H-NOX modulates the ligand migration process and how the distal residue composition affects the ligand binding prosperities, the free energy profiles for nitric oxide (NO), carbon monooxide (CO), and O2 migration are explored using the steered MDs simulation and the ligand binding energies are calculated using QM/MM schemes. The potential of mean force profiles suggest that the longer branch of the tunnel would be the most favorable route for NO migration and a second NO trapping site other than the distal heme pocket along this route in the Ns H-NOX was identified. On the contrary, CO and O2 would prefer to diffuse via the shorter branch of the tunnel. The QM/MM (quantum mechanics/molecular mechanics) calculations suggest that the hydrophobic distal pocket of Ns H-NOX would provide an approximately vacuum environment and the ligand discrimination would be determined by the intrinsic binding properties of the diatomic gas ligand to the heme group. PMID:23504767

  14. Practical Pocket PC Application w/Biometric Security

    Science.gov (United States)

    Logan, Julian

    2004-01-01

    I work in the Flight Software Engineering Branch, where we provide design and development of embedded real-time software applications for flight and supporting ground systems to support the NASA Aeronautics and Space Programs. In addition, this branch evaluates, develops and implements new technologies for embedded real-time systems, and maintains a laboratory for applications of embedded technology. The majority of microchips that are used in modern society have been programmed using embedded technology. These small chips can be found in microwaves, calculators, home security systems, cell phones and more. My assignment this summer entails working with an iPAQ HP 5500 Pocket PC. This top-of-the-line hand-held device is one of the first mobile PC's to introduce biometric security capabilities. Biometric security, in this case a fingerprint authentication system, is on the edge of technology as far as securing information. The benefits of fingerprint authentication are enormous. The most significant of them are that it is extremely difficult to reproduce someone else's fingerprint, and it is equally difficult to lose or forget your own fingerprint as opposed to a password or pin number. One of my goals for this summer is to integrate this technology with another Pocket PC application. The second task for the summer is to develop a simple application that provides an Astronaut EVA (Extravehicular Activity) Log Book capability. The Astronaut EVA Log Book is what an astronaut would use to report the status of field missions, crew physical health, successes, future plans, etc. My goal is to develop a user interface into which these data fields can be entered and stored. The applications that I am developing are created using eMbedded Visual C++ 4.0 with the Pocket PC 2003 Software Development Kit provided by Microsoft.

  15. Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase

    OpenAIRE

    Mondal, Jagannath; Friesner, Richard A.; Berne, B. J.

    2014-01-01

    Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The sim...

  16. Windows® Group Policy Administrators Pocket Consultant

    CERN Document Server

    Stanek, William

    2009-01-01

    Portable and precise, this pocket-sized guide delivers ready answers for the day-to-day administration of Group Policy. Zero in on core support and maintenance tasks using quick-reference tables, instructions, and lists. You'll get the focused information you need to solve problems and get the job done-whether at your desk or in the field! Get fast facts to: Configure Local GPOs and Active Directory®-based GPOsManage policy preferences and settingsModel policy changes through the consoleMigrate and maintain the SYSVOLDiagnose and troubleshoot replication issuesKnow when to enforce, block,

  17. Windows® Small Business Server 2008 Administrator's Pocket Consultant

    CERN Document Server

    Zacker, Craig

    2009-01-01

    Portable and precise, this pocket-sized guide delivers ready answers for administering Windows Small Business Server 2008. Zero in on core support tasks and tools using quick-reference tables, instructions, and lists. You'll get the focused information you need to solve problems and get the job done-whether at your desk or in the field. Get fast facts to: Plan, install, and configure a small business network Navigate the Windows SBS Console toolCreate and administer user and group accounts Manage automatic updates, disk storage, and shared printersConfigure mail settings and customize inte

  18. Newnes audio and Hi-Fi engineer's pocket book

    CERN Document Server

    Capel, Vivian

    2013-01-01

    Newnes Audio and Hi-Fi Engineer's Pocket Book, Second Edition provides concise discussion of several audio topics. The book is comprised of 10 chapters that cover different audio equipment. The coverage of the text includes microphones, gramophones, compact discs, and tape recorders. The book also covers high-quality radio, amplifiers, and loudspeakers. The book then reviews the concepts of sound and acoustics, and presents some facts and formulas relevant to audio. The text will be useful to sound engineers and other professionals whose work involves sound systems.

  19. Leukocyte integrin αLβ2 headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops.

    Science.gov (United States)

    Sen, Mehmet; Springer, Timothy A

    2016-03-15

    High-resolution crystal structures of the headpiece of lymphocyte function-associated antigen-1 (integrin αLβ2) reveal how the αI domain interacts with its platform formed by the α-subunit β-propeller and β-subunit βI domains. The αLβ2 structures compared with αXβ2 structures show that the αI domain, tethered through its N-linker and a disulfide to a stable β-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between αL and αX subunits. Rerefined β2 integrin structures reveal details including pyroglutamic acid at the β2 N terminus and bending within the EGF1 domain. Allostery is relayed to the αI domain by an internal ligand that binds to a pocket at the interface between the β-propeller and βI domains. Marked differences between the αL and αX subunit β-propeller domains concentrate near the binding pocket and αI domain interfaces. Remarkably, movement in allostery in the βI domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand.

  20. GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors

    Directory of Open Access Journals (Sweden)

    Ranghino Graziella

    2008-06-01

    Full Text Available Abstract Background GPR17 is a G-protein-coupled receptor located at intermediate phylogenetic position between two distinct receptor families: the P2Y and CysLT receptors for extracellular nucleotides and cysteinyl-LTs, respectively. We previously showed that GPR17 can indeed respond to both classes of endogenous ligands and to synthetic compounds active at the above receptor families, thus representing the first fully characterized non-peptide "hybrid" GPCR. In a rat brain focal ischemia model, the selective in vivo knock down of GPR17 by anti-sense technology or P2Y/CysLT antagonists reduced progression of ischemic damage, thus highlighting GPR17 as a novel therapeutic target for stroke. Elucidation of the structure of GPR17 and of ligand binding mechanisms are the necessary steps to obtain selective and potent drugs for this new potential target. On this basis, a 3-D molecular model of GPR17 embedded in a solvated phospholipid bilayer and refined by molecular dynamics simulations has been the first aim of this study. To explore the binding mode of the "purinergic" component of the receptor, the endogenous agonist UDP and two P2Y receptor antagonists demonstrated to be active on GPR17 (MRS2179 and cangrelor were then modeled on the receptor. Results Molecular dynamics simulations suggest that GPR17 nucleotide binding pocket is similar to that described for the other P2Y receptors, although only one of the three basic residues that have been typically involved in ligand recognition is conserved (Arg255. The binding pocket is enclosed between the helical bundle and covered at the top by EL2. Driving interactions are H-bonds and salt bridges between the 6.55 and 6.52 residues and the phosphate moieties of the ligands. An "accessory" binding site in a region formed by the EL2, EL3 and the Nt was also found. Conclusion Nucleotide binding to GPR17 occurs on the same receptor regions identified for already known P2Y receptors. Agonist

  1. Annealing condition influences thermal hysteresis of fungal type ice-binding proteins.

    Science.gov (United States)

    Xiao, Nan; Hanada, Yuichi; Seki, Haruhiko; Kondo, Hidemasa; Tsuda, Sakae; Hoshino, Tamotsu

    2014-02-01

    The Antarctic sea ice diatom Navicular glaciei produced ice-binding protein (NagIBP) that is similar to the antifreeze protein (TisAFP) from snow mold Typhula ishikariensis. In the thermal hysteresis range of NagIBP, ice growth was completely inhibited. At the freezing point, the ice grew in a burst to 6 direction perdicular to the c-axis of ice crystal. This burst pattern is similar to TisAFP and other hyperactive AFPs. The thermal hysteresis of NagIBP and TisAFP could be increased by decreasing a cooling rate to allow more time for the proteins to bind ice. This suggests the possible second binding of proteins occurs on the ice surface, which might increase the hysteresises to a sufficient level to prevent freezing of the brine pockets which habitat of N. glaciei. The secondary ice binding was described as that after AFP molecules bind onto the flat ice plane irreversibly, which was based on adsorption-inhibition mechanism model at the ice-water interface, convex ice front was formed and overgrew during normal TH measurement (no annealing) until uncontrolled growth at the nonequilibrium freezing point. The results suggested that NagIBP is a hyperactive AFP that is expressed for freezing avoidance.

  2. SambVca 2. A Web Tool for Analyzing Catalytic Pockets with Topographic Steric Maps

    KAUST Repository

    Falivene, Laura

    2016-06-27

    Developing more efficient catalysts remains one of the primary targets of organometallic chemists. To accelerate reaching this goal, effective molecular descriptors and visualization tools can represent a remarkable aid. Here, we present a Web application for analyzing the catalytic pocket of metal complexes using topographic steric maps as a general and unbiased descriptor that is suitable for every class of catalysts. To show the broad applicability of our approach, we first compared the steric map of a series of transition metal complexes presenting popular mono-, di-, and tetracoordinated ligands and three classic zirconocenes. This comparative analysis highlighted similarities and differences between totally unrelated ligands. Then, we focused on a recently developed Fe(II) catalyst that is active in the asymmetric transfer hydrogenation of ketones and imines. Finally, we expand the scope of these tools to rationalize the inversion of enantioselectivity in enzymatic catalysis, achieved by point mutation of three amino acids of mononuclear p-hydroxymandelate synthase.

  3. TGF-β Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium

    DEFF Research Database (Denmark)

    Clement, Christian Alexandro; Ajbro, Katrine Dalsgaard; Koefoed, Karen;

    2013-01-01

    Transforming growth factor β (TGF-β) signaling is regulated by clathrin-dependent endocytosis (CDE) for the control of cellular processes during development and in tissue homeostasis. The primary cilium coordinates several signaling pathways, and the pocket surrounding the base and proximal part...... of the cilium is a site for CDE. We report here that TGF-β receptors localize to the ciliary tip and endocytic vesicles at the ciliary base in fibroblasts and that TGF-β stimulation increases receptor localization and activation of SMAD2/3 and ERK1/2 at the ciliary base. Inhibition of CDE reduced TGF......-β-mediated signaling at the cilium, and TGF-β signaling and CDE activity are reduced at stunted primary cilia in Tg737(orpk) fibroblasts. Similarly, TGF-β signaling during cardiomyogenesis correlated with accumulation of TGF-β receptors and activation of SMAD2/3 at the ciliary base. Our results indicate...

  4. Detection of the amoeba Entamoeba gingivalis in periodontal pockets

    Directory of Open Access Journals (Sweden)

    Bonner Mark

    2014-01-01

    Full Text Available Periodontitis is a public health issue, being one of the most prevalent diseases worldwide. However, the aetiology of the disease is still unclear: genetics of patients cannot explain the dispersed or isolated localisation of gingival pockets, while bacteria-based models are insufficient to distinguish gingivitis and periodontitis. The possible role of parasites in the establishment of periodontitis has been poorly studied until now. The aim of this project was to study a potential link between colonisation of gingival crevices by the amoeba Entamoeba gingivalis and periodontitis. In eight different dental clinics in France, samples were taken in periodontal pockets (72 or healthy sites (33, and submitted to microscopic observation and molecular identification by PCR with a new set of primers designed to specifically detect E. gingivalis. This blind sample analysis showed the strong sensitivity of PCR compared with clinical diagnosis (58/72 = 81%, and microscopy (51/65 = 78%. The results of this work show that the parasites detected by microscopy mainly – if not exclusively – belong to the species E. gingivalis and that the presence of the parasite is correlated with periodontitis.

  5. Response of ionization chamber based pocket dosimeter to beta radiation.

    Science.gov (United States)

    Kumar, Munish; Gupta, Anil; Pradhan, S M; Bakshi, A K; Chougaonkar, M P; Babu, D A R

    2013-12-01

    Quantitative estimate of the response of ionization chamber based pocket dosimeters (DRDs) to various beta sources was performed. It has been established that the ionization chamber based pocket dosimeters do not respond to beta particles having energy (Emax)1 MeV, the DRDs exhibit measureable response and the values are ~8%, ~14% and ~27% per mSv for natural uranium, (90)Sr/(90)Y and (106)Ru/(106)Rh beta sources respectively. As the energy of the beta particles increases, the response also increases. The response of DRDs to beta particles having energy>1 MeV arises due to the fact that the thickness of the chamber walls is less than the maximum range of beta particles. This may also be one of the reasons for disparity between doses measured with passive/legal dosimeters (TLDs) and DRDs in those situations in which radiation workers are exposed to mixed field of gamma photons and beta particles especially at uranium processing plants, nuclear (power and research) reactors, waste management facilities and fuel reprocessing plants etc. The paper provides the reason (technical) for disparity between the doses recorded by TLDs and DRDs in mixed field of photons and beta particles.

  6. Detection of the amoeba Entamoeba gingivalis in periodontal pockets.

    Science.gov (United States)

    Bonner, Mark; Amard, Véronique; Bar-Pinatel, Charlotte; Charpentier, Frédéric; Chatard, Jean-Michel; Desmuyck, Yvan; Ihler, Serge; Rochet, Jean-Pierre; Roux de La Tribouille, Véronique; Saladin, Luc; Verdy, Marion; Gironès, Núria; Fresno, Manuel; Santi-Rocca, Julien

    2014-01-01

    Periodontitis is a public health issue, being one of the most prevalent diseases worldwide. However, the aetiology of the disease is still unclear: genetics of patients cannot explain the dispersed or isolated localisation of gingival pockets, while bacteria-based models are insufficient to distinguish gingivitis and periodontitis. The possible role of parasites in the establishment of periodontitis has been poorly studied until now. The aim of this project was to study a potential link between colonisation of gingival crevices by the amoeba Entamoeba gingivalis and periodontitis. In eight different dental clinics in France, samples were taken in periodontal pockets (72) or healthy sites (33), and submitted to microscopic observation and molecular identification by PCR with a new set of primers designed to specifically detect E. gingivalis. This blind sample analysis showed the strong sensitivity of PCR compared with clinical diagnosis (58/72 = 81%), and microscopy (51/65 = 78%). The results of this work show that the parasites detected by microscopy mainly - if not exclusively - belong to the species E. gingivalis and that the presence of the parasite is correlated with periodontitis.

  7. Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane

    DEFF Research Database (Denmark)

    Bach, Tinna Brøbech; Jensen, Anders A.; Petersen, Jette G.;

    2015-01-01

    X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protr...

  8. Rasp21 sequences opposite the nucleotide binding pocket are required for GRF-mediated nucleotide release

    DEFF Research Database (Denmark)

    Leonardsen, L; DeClue, J E; Lybaek, H;

    1996-01-01

    , the sensitivity of H-Ras to GRF was abolished when residues 130-139 were replaced by proline-aspartic acid-glutamine, whereas substitution of the entire loop 8 (residues 123-130 replaced by leucine-isoleucine-arginine) had no effect on the stimulation of guanine nucleotide release by GRF. Substrate activity...

  9. Adjusting the binding thermodynamics, kinetics, and orientation of guests within large synthetic hydrophobic pockets

    OpenAIRE

    Gibb, C. L. D.; Li, X.; Gibb, B C.

    2002-01-01

    Kinetic analysis of the host guest complexation of a large, open molecular basket and a highly complementary adamantoid guest reveals that for these types of systems a dissociative mechanism is in operation. Hence, the resident adamantyl guest must completely vacate the cavity before another guest molecule can move in to replace it. As a result of the rigid nature of the host, the energy barrier to this process is relatively high, about 16 kcal mol−1 at room temperature. ...

  10. The structure of haemoglobin bound to the haemoglobin receptor IsdH from Staphylococcus aureus shows disruption of the native α-globin haem pocket.

    Science.gov (United States)

    Dickson, Claire F; Jacques, David A; Clubb, Robert T; Guss, J Mitchell; Gell, David A

    2015-06-01

    Staphylococcus aureus is a common and serious cause of infection in humans. The bacterium expresses a cell-surface receptor that binds to, and strips haem from, human haemoglobin (Hb). The binding interface has previously been identified; however, the structural changes that promote haem release from haemoglobin were unknown. Here, the structure of the receptor-Hb complex is reported at 2.6 Å resolution, which reveals a conformational change in the α-globin F helix that disrupts the haem-pocket structure and alters the Hb quaternary interactions. These features suggest potential mechanisms by which the S. aureus Hb receptor induces haem release from Hb.

  11. Exploitation of pocket gophers and their food caches by grizzly bears

    Science.gov (United States)

    Mattson, D.J.

    2004-01-01

    I investigated the exploitation of pocket gophers (Thomomys talpoides) by grizzly bears (Ursus arctos horribilis) in the Yellowstone region of the United States with the use of data collected during a study of radiomarked bears in 1977-1992. My analysis focused on the importance of pocket gophers as a source of energy and nutrients, effects of weather and site features, and importance of pocket gophers to grizzly bears in the western contiguous United States prior to historical extirpations. Pocket gophers and their food caches were infrequent in grizzly bear feces, although foraging for pocket gophers accounted for about 20-25% of all grizzly bear feeding activity during April and May. Compared with roots individually excavated by bears, pocket gopher food caches were less digestible but more easily dug out. Exploitation of gopher food caches by grizzly bears was highly sensitive to site and weather conditions and peaked during and shortly after snowmelt. This peak coincided with maximum success by bears in finding pocket gopher food caches. Exploitation was most frequent and extensive on gently sloping nonforested sites with abundant spring beauty (Claytonia lanceolata) and yampah (Perdieridia gairdneri). Pocket gophers are rare in forests, and spring beauty and yampah roots are known to be important foods of both grizzly bears and burrowing rodents. Although grizzly bears commonly exploit pocket gophers only in the Yellowstone region, this behavior was probably widespread in mountainous areas of the western contiguous United States prior to extirpations of grizzly bears within the last 150 years.

  12. Burden of out-of-pocket expenditure for road traffic injuries in urban India

    Directory of Open Access Journals (Sweden)

    Kumar G

    2012-08-01

    Full Text Available Abstract Background Road traffic injuries (RTI are an increasing public health problem in India where out-of-pocket (OOP expenditures on health are among the highest in the world. We estimated the OOP expenses for RTI in a large city in India. Methods Information on medical and non-medical expenditure was documented for RTI cases of all ages that reported alive or dead to the emergency departments of two public hospitals and a large private hospital in Hyderabad. Differential risk of catastrophic OOP total expenditure (COPE-T and medical expenditure (COPE-M, and distress financing was assessed for 723 RTI cases that arrived alive at the study hospitals with multiple logistic regression. Catastrophic expenditure was defined as expenditure > 25% of the RTI patient’s annual household income. Variation in intensity of COPE-M in RTI was assessed using multiple classification analysis (MCA. Results The median OOP medical and non-medical expenditure was USD 169 and USD 163, respectively. The prevalence of COPE-M and COPE-T was 21.9% (95% CI 18.8-24.9 and 46% (95% CI 42–49.3, respectively. Only 22% had access to medical insurance. Being admitted to a private hospital (OR 5.2, 95% CI 2.7–9.9 and not having access to insurance (OR 3.8, 95% CI 1.9–7.6 were significantly associated with risk of having COPE – M. Similar results were seen for COPE - T. MCA analysis showed that the burden of OOP medical expenditure was mainly associated with in-patient days in hospital (Eta =0.191. Prevalence of distress financing was 69% (95% CI 65.5-72.3 with it being significantly higher for those reporting to the public hospitals (OR 2.8, 95% CI 1.7-4.6, those belonging to the lowest per capita annual household income quartile (OR 7.0, 95% CI 3.7-13.3, and for those without insurance access (OR 3.4, 95% CI 2.0-5.7. Conclusions This paper has outlined the high burden of out-of-pocket medical and total expenditure associated with RTI in India. These data

  13. Relating the shape of protein binding sites to binding affinity profiles: is there an association?

    Directory of Open Access Journals (Sweden)

    Bitter István

    2010-10-01

    Full Text Available Abstract Background Various pattern-based methods exist that use in vitro or in silico affinity profiles for classification and functional examination of proteins. Nevertheless, the connection between the protein affinity profiles and the structural characteristics of the binding sites is still unclear. Our aim was to investigate the association between virtual drug screening results (calculated binding free energy values and the geometry of protein binding sites. Molecular Affinity Fingerprints (MAFs were determined for 154 proteins based on their molecular docking energy results for 1,255 FDA-approved drugs. Protein binding site geometries were characterized by 420 PocketPicker descriptors. The basic underlying component structure of MAFs and binding site geometries, respectively, were examined by principal component analysis; association between principal components extracted from these two sets of variables was then investigated by canonical correlation and redundancy analyses. Results PCA analysis of the MAF variables provided 30 factors which explained 71.4% of the total variance of the energy values while 13 factors were obtained from the PocketPicker descriptors which cumulatively explained 94.1% of the total variance. Canonical correlation analysis resulted in 3 statistically significant canonical factor pairs with correlation values of 0.87, 0.84 and 0.77, respectively. Redundancy analysis indicated that PocketPicker descriptor factors explain 6.9% of the variance of the MAF factor set while MAF factors explain 15.9% of the total variance of PocketPicker descriptor factors. Based on the salient structures of the factor pairs, we identified a clear-cut association between the shape and bulkiness of the drug molecules and the protein binding site descriptors. Conclusions This is the first study to investigate complex multivariate associations between affinity profiles and the geometric properties of protein binding sites. We found that

  14. Development of a pocket multi-channel analyzer

    International Nuclear Information System (INIS)

    A pocket Multi-Channel Analyzer, which is based on 20 pin SMT micro-controller, Serial Peripheral Interfaced ADC and FRAM, and MCU on chip timer/counter acting as de-dead-time clock, was developed and introduced in this paper. Pulse peak hold circuit, MCA timing, micro-controller application techniques, and a reliable simple schematic for peak detection was described as well. The protocol MCA is housed in 110 60 23 mm3. The analyzing resolution can be up to 16384 channels. The dead time is 17 μs when the resolution is programmed to be 1024 channels. It is powered from a single +5V supply, and the power consumption is 360 mW. It can be well embedded in various portable multi-channel spectrum equipments. (authors)

  15. Pocket data mining big data on small devices

    CERN Document Server

    Gaber, Mohamed Medhat; Gomes, Joao Bartolo

    2014-01-01

    Owing to continuous advances in the computational power of handheld devices like smartphones and tablet computers, it has become possible to perform Big Data operations including modern data mining processes onboard these small devices. A decade of research has proved the feasibility of what has been termed as Mobile Data Mining, with a focus on one mobile device running data mining processes. However, it is not before 2010 until the authors of this book initiated the Pocket Data Mining (PDM) project exploiting the seamless communication among handheld devices performing data analysis tasks that were infeasible until recently. PDM is the process of collaboratively extracting knowledge from distributed data streams in a mobile computing environment. This book provides the reader with an in-depth treatment on this emerging area of research. Details of techniques used and thorough experimental studies are given. More importantly and exclusive to this book, the authors provide detailed practical guide on the depl...

  16. The Six-Inch Lunar Atlas A Pocket Field Guide

    CERN Document Server

    Spain, Don

    2009-01-01

    The Six-Inch Lunar Atlas has been designed specifically for use in the field by lunar observers so it’s perfect for fitting into an observer’s pocket! The author’s own lunar photographs were taken with a 6-inch (150mm) telescope and CCD camera, and closely match the visual appearance of the Moon when viewed through 3-inch to 8-inch telescopes. Each picture is shown oriented "as the Moon really is" when viewed from the northern hemisphere, and is supplemented by exquisite computer sketches that list the main features. Two separate computer sketches are provided to go with each photograph, one oriented to appear as seen through an SCT telescope (e.g. the Meade and Celestron ranges), the other oriented for Newtonian and refracting telescopes. Observers using the various types telescopes will find it extremely helpful to identify lunar features as the human brain is very poor at making "mirror-image" visual translations.

  17. MARTINDALE'S DRUGS RESTRICTED IN SPORT POCKET COMPANION 2009

    Directory of Open Access Journals (Sweden)

    Sean C. Sweetman

    2009-06-01

    Full Text Available Over 500 drugs restricted in sport presented in alphabetical order. To inform and alert the athlete about the potential problem of drug taking for any kind of reasons on and off during training and competition.A comprehensive index of drug names, synonyms, medical usage, single and multi-ingredient preparations and trade (on occasion street names of drugs from 40 countries worldwide (Martindale data. The classification of World Anti-Doping Agency (WADA is added to the explanation of drugs limitation in sport in and out of competition. A glossary of common medical terms is also included.This pocket publication is a must-have list of restricted drugs for athletes, trainers, sports medicine professionals, in short for anyone in exercise physiology and human performance fields.

  18. Pocket pathologist: A mobile application for rapid diagnostic surgical pathology consultation

    Directory of Open Access Journals (Sweden)

    Douglas J Hartman

    2014-01-01

    Full Text Available Introduction: Telepathology allows the digital transmission of images for rapid access to pathology experts. Recent technologic advances in smartphones have allowed them to be used to acquire and transmit digital images of the glass slide, representing cost savings and efficiency gains over traditional forms of telepathology. We report our experience with developing an iPhone application (App - Pocket Pathologist to facilitate rapid diagnostic pathology teleconsultation utilizing a smartphone. Materials and Methods: A secure, web-based portal (http://pathconsult.upmc.com/ was created to facilitate remote transmission of digital images for teleconsultation. The App augments functionality of the web-based portal and allows the user to quickly and easily upload digital images for teleconsultation. Image quality of smartphone cameras was evaluated by capturing images using different adapters that directly attach phones to a microscope ocular lens. Results: The App was launched in August 2013. The App facilitated easy submission of cases for teleconsultation by limiting the number of data entry fields for users and enabling uploading of images from their smartphone′s gallery wirelessly. Smartphone cameras properly attached to a microscope create static digital images of similar quality to a commercial digital microscope camera. Conclusion: Smartphones have great potential to support telepathology because they are portable, provide ubiquitous internet connectivity, contain excellent digital cameras, and can be easily attached to a microscope. The Pocket Pathologist App represents a significant reduction in the cost of creating digital images and submitting them for teleconsultation. The iPhone App provides an easy solution for global users to submit digital pathology images to pathology experts for consultation.

  19. Study of Application Software Based on Pocket PC Database%基POCKET PC数据库应用程序的研究

    Institute of Scientific and Technical Information of China (English)

    詹捷; 陆玲; 程志梅; 张爱华

    2005-01-01

    本文主要是对在Windows CE 3.0平台下,利用EVC软件开发Pocket PC数据库应用程序的基本方法进行研究,其中重点探讨了在POCKET PC中如何利用EVC对数据库进行各种操作.

  20. Biogenicity of terrestrial oncoids formed in soil pockets, Cayman Brac, British West Indies

    Science.gov (United States)

    Jones, Brian

    2011-05-01

    Terrestrial oncoids, up to 85 mm long, are common in some of the soil-filled pockets found in the finely crystalline dolostones of the Cayman Formation on Cayman Brac. Each of these coated grains has a nucleus formed of a white, finely crystalline dolostone lithoclast (derived from the Cayman Formation) that is encased by a light brown to tan cortex that is formed largely of micrite and minimicrite, is vaguely laminated, and lacks obvious biogenic structures. The cortex, typically microbiota that includes various reticulate filaments that are typically < 1 μm in diameter, cocci, some large-diameter collapsed and calcified filaments, sporangia-like structures, and locally, exopolysaccharides (EPS). In the subsurface parts of the cortices, however, filaments are very rare and there are only scattered cocci. Evidence derived from the surface microbes indicates that they played an active role in the growth of the cortical laminae by binding material to their surfaces, calcification of the microbes, providing substrates on which calcite was precipitated, and forming cavities in which calcite cement was later precipitated. In stark contrast, it is difficult to ascribe a biotic influence to the formation of the subsurface laminae because of the paucity of preserved microbes. The lack of microbes, however, probably reflects the fact that the formative microbes were destroyed during diagenesis. This example clearly demonstrates that the lack of preserved microbes cannot be taken as an indication that the grains formed as a result of abiogenic processes.

  1. Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins.

    Science.gov (United States)

    Vilas, Jéssica M; Ferreirós, Alba; Carneiro, Carmen; Morey, Lluis; Da Silva-Álvarez, Sabela; Fernandes, Tânia; Abad, María; Di Croce, Luciano; García-Caballero, Tomás; Serrano, Manuel; Rivas, Carmen; Vidal, Anxo; Collado, Manuel

    2015-02-20

    Cellular reprogramming to iPSCs has uncovered unsuspected links between tumor suppressors and pluripotency factors. Using this system, it was possible to identify tumor suppressor p27 as a repressor of Sox2 during differentiation. This led to the demonstration that defects in the repression of Sox2 can contribute to tumor development. The members of the retinoblastoma family of pocket proteins, pRb, p107 and p130, are negative regulators of the cell cycle with tumor suppressor activity and with roles in differentiation. In this work we studied the relative contribution of the retinoblastoma family members to the regulation of Sox2 expression. We found that deletion of Rb or p130 leads to impaired repression of Sox2, a deffect amplified by inactivation of p53. We also identified binding of pRb and p130 to an enhancer with crucial regulatory activity on Sox2 expression. Using cellular reprogramming we tested the impact of the defective repression of Sox2 and confirmed that Rb deficiency allows the generation of iPSCs in the absence of exogenous Sox2. Finally, partial depletion of Sox2 positive cells reduced the pituitary tumor development initiated by Rb loss in vivo. In summary, our results show that Sox2 repression by pRb is a relevant mechanism of tumor suppression.

  2. Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins

    Science.gov (United States)

    Carneiro, Carmen; Morey, Lluis; Silva-Álvarez, Sabela Da; Fernandes, Tânia; Abad, María; Croce, Luciano Di; García-Caballero, Tomás; Serrano, Manuel; Rivas, Carmen; Vidal, Anxo; Collado, Manuel

    2015-01-01

    Cellular reprogramming to iPSCs has uncovered unsuspected links between tumor suppressors and pluripotency factors. Using this system, it was possible to identify tumor suppressor p27 as a repressor of Sox2 during differentiation. This led to the demonstration that defects in the repression of Sox2 can contribute to tumor development. The members of the retinoblastoma family of pocket proteins, pRb, p107 and p130, are negative regulators of the cell cycle with tumor suppressor activity and with roles in differentiation. In this work we studied the relative contribution of the retinoblastoma family members to the regulation of Sox2 expression. We found that deletion of Rb or p130 leads to impaired repression of Sox2, a deffect amplified by inactivation of p53. We also identified binding of pRb and p130 to an enhancer with crucial regulatory activity on Sox2 expression. Using cellular reprogramming we tested the impact of the defective repression of Sox2 and confirmed that Rb deficiency allows the generation of iPSCs in the absence of exogenous Sox2. Finally, partial depletion of Sox2 positive cells reduced the pituitary tumor development initiated by Rb loss in vivo. In summary, our results show that Sox2 repression by pRb is a relevant mechanism of tumor suppression. PMID:25576924

  3. Protein contacts and ligand binding in the inward-facing model of human P-glycoprotein.

    Science.gov (United States)

    Pajeva, Ilza K; Hanl, Markus; Wiese, Michael

    2013-05-01

    The primary aim of this work was to analyze the contacts between residues in the nucleotide binding domains (NBDs) and at the interface between the transmembrane domains (TMDs) and the NBDs in the inward-open homology model of human P-glycoprotein (P-gp). The analysis revealed communication nets through hydrogen bonding in the NBD and at the NBD-TMD interface of each half involving residues from the adenosine triphosphate (ATP) motifs and the coupling helices of the intracellular loops. Similar networks have been identified in P-gp conformations generated by molecular dynamics simulation. Differences have been recorded in the networking between both halves of P-gp. Many of the residue contacts have also been observed in the X-ray crystal structures of other ATP binding cassette (ABC) transporters, which confirms their validity. Next, possible binding pockets involving residues of importance for the TMD-NBD communication were identified. By studying these pockets, binding sites were suggested for rhodamine 123 (R-site) and prazosin (regulatory site) at the NBD-TMD interface that agreed with the experimental data on their location. Additionally, one more R-site in the protein cavity was proposed, in accordance with the available biochemical data. Together with the previously suggested Hoechst 33342 site (H-site), all sites were interpreted with respect to their effects on the protein ATPase activity, in correspondence with the experimental observations. Several residues involved in key contacts in the P-gp NBDs were proposed for further targeted mutagenesis experiments. PMID:23564544

  4. 78 FR 54214 - Endangered and Threatened Wildlife and Plants; Removing Five Subspecies of Mazama Pocket Gopher...

    Science.gov (United States)

    2013-09-03

    ...We, the U.S. Fish and Wildlife Service (Service), remove five subspecies of Mazama pocket gopher (Tacoma, Brush Prairie, Shelton, Olympic, and Cathlamet) from the list of candidates for listing as threatened or endangered species under the Endangered Species Act of 1973, as amended. After review of the best available scientific and commercial information, we find that the Tacoma pocket gopher......

  5. The Harpoon Security System for Helper Programs on a Pocket Companion

    NARCIS (Netherlands)

    Smit, Gerard J.M.; Havinga, Paul J.M.; Os, van Daniel

    1997-01-01

    We present a security framework for executing foreign programs, called helpers, on a Pocket Companion: a wireless hand-held computer. A helper program as proposed in this paper is a service program that can migrate once from a server to a Pocket Companion or vice-versa. A helper program is convenien

  6. Unusual Siderite-Bearing Dendrites in Melt Pockets of the Elga IIE Iron

    Science.gov (United States)

    Teplyakova, S. N.; Artemov, V. V.; Vasiliev, A. L.

    2012-03-01

    The Elga iron contains melt pockets with dedritic texture not only inside Fe,Ni-metal but also inside silicate inclusions (SI). The unusual siderite-bearing melt pockets inside SIs has never been previously observed in any types of meteorites.

  7. The Role of Electronic Pocket Dictionaries as an English Learning Tool among Chinese Students

    Science.gov (United States)

    Jian, Hua-Li; Sandnes, Frode Eika; Law, Kris M. Y.; Huang, Yo-Ping; Huang, Yueh-Min

    2009-01-01

    This study addressed the role of electronic pocket dictionaries as a language learning tool among university students in Hong Kong and Taiwan. The target groups included engineering and humanities students at both undergraduate and graduate level. Speed of reference was found to be the main motivator for using an electronic pocket dictionary.…

  8. Microbiological characteristics of the contents of periodontal pockets of patients with periodontitis adolescents

    Directory of Open Access Journals (Sweden)

    Morgunova V.M.

    2011-03-01

    Full Text Available In this paper we present a study of the contents of periodontal pocket in patients with a diagnosis of chronic generalized periodontitis mild, moderate and severe. Defined genera and species affiliation of anaerobic bacteria by various methods of diagnosis. We found a decreasing trend in the number of associations of microorganisms in periodontal pockets, as the weighting of the pathological process

  9. Microbiological characteristics of the contents of periodontal pockets of patients with periodontitis adolescents

    OpenAIRE

    Morgunova V.M.

    2011-01-01

    In this paper we present a study of the contents of periodontal pocket in patients with a diagnosis of chronic generalized periodontitis mild, moderate and severe. Defined genera and species affiliation of anaerobic bacteria by various methods of diagnosis. We found a decreasing trend in the number of associations of microorganisms in periodontal pockets, as the weighting of the pathological process

  10. Divergent evolution of vitamin B9 binding underlies Juno-mediated adhesion of mammalian gametes.

    Science.gov (United States)

    Han, Ling; Nishimura, Kaoru; Sadat Al Hosseini, Hamed; Bianchi, Enrica; Wright, Gavin J; Jovine, Luca

    2016-02-01

    The interaction between egg and sperm is the first necessary step of fertilization in all sexually reproducing organisms. A decade-long search for a protein pair mediating this event in mammals culminated in the identification of the glycosylphosphatidylinositol (GPI)-anchored glycoprotein Juno as the egg plasma membrane receptor of sperm Izumo1 [1,2]. The Juno-Izumo1 interaction was shown to be essential for fertilization since mice lacking either gene exhibit sex-specific sterility, making these proteins promising non-hormonal contraceptive targets [1,3]. No structural information is available on how gamete membranes interact at fertilization, and it is unclear how Juno - which was previously named folate receptor (FR) 4, based on sequence similarity considerations - triggers membrane adhesion by binding Izumo1. Here, we report the crystal structure of Juno and find that the overall fold is similar to that of FRα and FRβ but with significant flexibility within the area that corresponds to the rigid ligand-binding site of these bona fide folate receptors. This explains both the inability of Juno to bind vitamin B9/folic acid [1], and why mutations within the flexible region can either abolish or change the species specificity of this interaction. Furthermore, structural similarity between Juno and the cholesterol-binding Niemann-Pick disease type C1 protein (NPC1) suggests how the modified binding surface of Juno may recognize the helical structure of the amino-terminal domain of Izumo1. As Juno appears to be a mammalian innovation, our study indicates that a key evolutionary event in mammalian reproduction originated from the neofunctionalization of the vitamin B9-binding pocket of an ancestral folate receptor molecule. PMID:26859261

  11. Textual Spatial Cosine Similarity

    OpenAIRE

    Crocetti, Giancarlo

    2015-01-01

    When dealing with document similarity many methods exist today, like cosine similarity. More complex methods are also available based on the semantic analysis of textual information, which are computationally expensive and rarely used in the real time feeding of content as in enterprise-wide search environments. To address these real-time constraints, we developed a new measure of document similarity called Textual Spatial Cosine Similarity, which is able to detect similitude at the semantic ...

  12. Structural fold, conservation and Fe(II) binding of the intracellular domain of prokaryote FeoB

    Energy Technology Data Exchange (ETDEWEB)

    Hung, Kuo-Wei; Chang, Yi-Wei; Eng, Edward T.; Chen, Jai-Hui; Chen, Yi-Chung; Sun, Yuh-Ju; Hsiao, Chwan-Deng; Dong, Gang; Spasov, Krasimir A.; Unger, Vinzenz M.; Huang, Tai-huang (Yale-MED); (Perutz Lab); (AS); (NTHU-Taiwan)

    2010-09-17

    FeoB is a G-protein coupled membrane protein essential for Fe(II) uptake in prokaryotes. Here, we report the crystal structures of the intracellular domain of FeoB (NFeoB) from Klebsiella pneumoniae (KpNFeoB) and Pyrococcus furiosus (PfNFeoB) with and without bound ligands. In the structures, a canonical G-protein domain (G domain) is followed by a helical bundle domain (S-domain), which despite its lack of sequence similarity between species is structurally conserved. In the nucleotide-free state, the G-domain's two switch regions point away from the binding site. This gives rise to an open binding pocket whose shallowness is likely to be responsible for the low nucleotide-binding affinity. Nucleotide binding induced significant conformational changes in the G5 motif which in the case of GMPPNP binding was accompanied by destabilization of the switch I region. In addition to the structural data, we demonstrate that Fe(II)-induced foot printing cleaves the protein close to a putative Fe(II)-binding site at the tip of switch I, and we identify functionally important regions within the S-domain. Moreover, we show that NFeoB exists as a monomer in solution, and that its two constituent domains can undergo large conformational changes. The data show that the S-domain plays important roles in FeoB function.

  13. The Use of Pocket Electronic Dictionaries by Thai University Students

    Directory of Open Access Journals (Sweden)

    Atipat Boonmoh

    2011-10-01

    Full Text Available

    ABSTRACT: This article reports on a small-scale study of Thai-speaking learners using pocket electronic dictionaries (PEDs to read an English news article. It investigates how the subjects use their PEDs for reading comprehension. Thirty-nine undergraduate students completed a questionnaire survey. Of these, four were chosen to participate in the experiment. Observations and interviews were utilized to ascertain how the subjects used their PEDs. The findings showed superficial and partial reading of the dictionary entries. It also revealed several factors that may hinder dictionary look-up success. On the basis of this research, guidelines for buying PEDs and for teaching PED skills are proposed.

    OPSOMMING: Die gebruik van sak- elektroniese woordeboeke deur Thaise universiteitstudente. Hierdie artikel doen verslag van 'n kleinskaalse studie van Thaisprekende aanleerders wat sak- elektroniese woordeboeke (SEW's gebruik om 'n Engelse nuusartikel te lees. Dit ondersoek hoe die proefpersone hul SAW's gebruik vir leesbegrip. Nege-en-dertig voorgraadse studente het 'n vraelysopname voltooi. Uit hulle is vier gekies om aan die eksperiment deel te neem. Waarnemings en onderhoude is aangewend om te bepaal hoe die proefpersone hul SEW's gebruik het. Die bevindings het oppervlakkige en gedeeltelike lees van die woordeboekinskrywings getoon. Dit het ook verskeie faktore uitgewys wat woordeboekopsoeksukses mag belemmer. Op grond van hierdie navorsing word riglyne vir die koop van SEW's en vir die onderrig van SEWvaardighede voorgestel.

    Sleutelwoorde: WOORDEBOEKGEBRUIK, SAK- ELEKTRONIESE WOORDEBOEK, WOORDEBOEKRAADPLEGING, EENTALIGE WOORDEBOEK, TWEETALIGE WOORDEBOEK

  14. Inertial Pocket Navigation System: Unaided 3D Positioning.

    Science.gov (United States)

    Diaz, Estefania Munoz

    2015-01-01

    Inertial navigation systems use dead-reckoning to estimate the pedestrian's position. There are two types of pedestrian dead-reckoning, the strapdown algorithm and the step-and-heading approach. Unlike the strapdown algorithm, which consists of the double integration of the three orthogonal accelerometer readings, the step-and-heading approach lacks the vertical displacement estimation. We propose the first step-and-heading approach based on unaided inertial data solving 3D positioning. We present a step detector for steps up and down and a novel vertical displacement estimator. Our navigation system uses the sensor introduced in the front pocket of the trousers, a likely location of a smartphone. The proposed algorithms are based on the opening angle of the leg or pitch angle. We analyzed our step detector and compared it with the state-of-the-art, as well as our already proposed step length estimator. Lastly, we assessed our vertical displacement estimator in a real-world scenario. We found that our algorithms outperform the literature step and heading algorithms and solve 3D positioning using unaided inertial data. Additionally, we found that with the pitch angle, five activities are distinguishable: standing, sitting, walking, walking up stairs and walking down stairs. This information complements the pedestrian location and is of interest for applications, such as elderly care. PMID:25897501

  15. Micro-Pocket Fission Detectors (MPFD) For Fuel Assembly Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Troy Unruh; Michael Reichenberger; Phillip Ugorowski

    2013-09-01

    Neutron sensors capable of real-time measurement of thermal flux, fast flux, and temperature in a single miniaturized probe are needed in irradiation tests required to demonstrate the performance of candidate new fuels, and cladding materials. In-core ceramic-based miniature neutron detectors or “Micro-Pocket Fission Detectors” (MPFDs) have been studied at Kansas State University (KSU). The first MPFD prototypes were tested in various neutron fields at the KSU TRIGA research reactor with successful results. Currently, a United States Department of Energy-sponsored joint KSU/Idaho National Laboratory (INL) effort is underway to develop a high-temperature, high-pressure version of the MPFD using radiation-resistant, high temperature materials, which would be capable of withstanding irradiation test conditions in high performance material and test reactors (MTRs). Ultimately, this more compact, more accurate, and longer lifetime flux sensor for critical mock-ups, existing and advanced reactor designs, high performance MTRs, and transient test reactors has the potential to lead to higher accuracy and resolution data from irradiation testing, more detailed core flux measurements and enhanced fuel assembly processing. Prior evaluations by KSU indicate that these sensors could also be used to monitor burn-up of nuclear fuel. If integrated into nuclear fuel assemblies, MPFDs offer several advantages to current spent fuel management systems.

  16. Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein.

    Science.gov (United States)

    Rodina, Anna; Patel, Pallav D; Kang, Yanlong; Patel, Yogita; Baaklini, Imad; Wong, Michael J H; Taldone, Tony; Yan, Pengrong; Yang, Chenghua; Maharaj, Ronnie; Gozman, Alexander; Patel, Maulik R; Patel, Hardik J; Chirico, William; Erdjument-Bromage, Hediye; Talele, Tanaji T; Young, Jason C; Chiosis, Gabriela

    2013-12-19

    Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70. PMID:24239008

  17. Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif

    OpenAIRE

    Jehle, Katja; Cato, Laura; Neeb, Antje; Muhle-Goll, Claudia; Jung, Nicole; Smith, Emmanuel W.; Buzon, Victor; Carbó, Laia R.; Estébanez-Perpiñá, Eva; Schmitz, Katja; Fruk, Ljiljana; Luy, Burkhard; Chen, Yu; Cox, Marc B.; Bräse, Stefan

    2014-01-01

    The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the rec...

  18. Combining docking and comparative molecular similarity indices analysis (COMSIA) to predict estrogen activity and probe molecular mechanisms of estrogen activity for estrogen compounds

    Institute of Scientific and Technical Information of China (English)

    YANG XuShu; WANG XiaoDong; JI Li; LI Rong; SUN Cheng; WANG LianSheng

    2008-01-01

    Estrogen compounds are suspected of disrupting endocrine functions by mimicking natural hormones,and such compounds may pose a serious threat to the health of humans and wildlife. Close attention has been paid to the prediction and molecular mechanisms of estrogen activity for estrogen compounds. In this article, estrogen receptor a subtype (Era) -based comparative molecular similarity indices analysis (COMSIA) was performed on 44 estrogen compounds with structural diversity to find out the structural relationship with the activity and to predict the activity. The model with the significant correlation and the best predictive power (R2 = 0.965, (Q2LOO = 0.599, R2pred = 0.825) was achieved. The COMSIA and docking results revealed the structural features for estrogen activity and key amino acid residues in binding pocket, and provided an insight into the interaction between the ligands and these amino acid residues.

  19. Sonographic assessment of predictors of depth of the corner pocket for ultrasound-guided supraclavicular brachial plexus block

    Directory of Open Access Journals (Sweden)

    Naveen Yadav

    2016-01-01

    Conclusion: Prescanning of supraclavicular region for estimating depth of corner pocket should be done before choosing an appropriate size needle. Furthermore, the needle should not be advanced more than the predicted corner pocket depth.

  20. Structure of the RNA-Binding Domain of Telomerase: Implications For RNA Recognition and Binding

    Energy Technology Data Exchange (ETDEWEB)

    Rouda,S.; Skordalakes, E.

    2007-01-01

    Telomerase, a ribonucleoprotein complex, replicates the linear ends of eukaryotic chromosomes, thus taking care of the 'end of replication problem.' TERT contains an essential and universally conserved domain (TRBD) that makes extensive contacts with the RNA (TER) component of the holoenzyme, and this interaction is thought to facilitate TERT/TER assembly and repeat-addition processivity. Here, we present a high-resolution structure of TRBD from Tetrahymena thermophila. The nearly all-helical structure comprises a nucleic acid-binding fold suitable for TER binding. An extended pocket on the surface of the protein, formed by two conserved motifs (CP and T motifs) comprises TRBD's RNA-binding pocket. The width and the chemical nature of this pocket suggest that it binds both single- and double-stranded RNA, possibly stem I, and the template boundary element (TBE). Moreover, the structure provides clues into the role of this domain in TERT/TER stabilization and telomerase repeat-addition processivity.

  1. Approximate similarity search

    OpenAIRE

    Amato, Giuseppe

    2000-01-01

    Similarity searching is fundamental in various application areas. Recently it has attracted much attention in the database community because of the growing need to deal with large volume of data. Consequently, efficiency has become a matter of concern in design. Although much has been done to develop structures able to perform fast similarity search, results are still not satisfactory, and more research is needed. The performance of similarity search for complex features deteriorates and does...

  2. Identifying features of pocket parks that may be related to health promoting use

    DEFF Research Database (Denmark)

    Peschardt, Karin Kragsig; Stigsdotter, Ulrika K.; Schipperijn, Jasper

    2016-01-01

    Urban green spaces have been shown to promote health and well-being and recent research indicates that the two primary potentially health promoting uses of pocket parks are ‘rest and restitution’ and ‘socialising’. The aim of this study is to identify features in pocket parks that may support...... these uses. The relationship between the two types of use and the shape, size, noise level, greenness, as well as ‘elements’ (paved and unpaved trails, café, historical feature, table, other seating than benches, flowerbeds, view outside park, playground) in nine pocket parks in Copenhagen were analysed...

  3. Technical Tip for Proximal Release During Open Carpal Tunnel Release Using a Subcutaneous Pocket.

    Science.gov (United States)

    Nikkhah, Dariush; Sadr, Amir H; Akhavani, Mohammed Ali

    2016-06-01

    Technical steps to avoid incomplete proximal release of the carpal tunnel are described. Local anaesthesia is infiltrated as a subcutaneous bleb over the distal wrist crease and extending 2-3 cm over the forearm fascia. Tumescence of local anaesthesia into the subcutaneous plane helps create a pocket between the forearm fascia and subcutaneous tissues. Intraoperatively a subcutaneous pocket is made above the transverse carpal ligament and antebrachial fascia with blunt dissection. A retractor is placed under the pocket, which facilitates optimal visualization to allow reliable complete proximal release of compression.The authors have found that this technique is reproducible and reliable across their collective experience. PMID:27454649

  4. α-Hemoglobin-stabilizing Protein (AHSP) Perturbs the Proximal Heme Pocket of Oxy-α-hemoglobin and Weakens the Iron-Oxygen Bond*

    Science.gov (United States)

    Dickson, Claire F.; Rich, Anne M.; D'Avigdor, William M. H.; Collins, Daniel A. T.; Lowry, Jason A.; Mollan, Todd L.; Khandros, Eugene; Olson, John S.; Weiss, Mitchell J.; Mackay, Joel P.; Lay, Peter A.; Gell, David A.

    2013-01-01

    α-Hemoglobin (αHb)-stabilizing protein (AHSP) is a molecular chaperone that assists hemoglobin assembly. AHSP induces changes in αHb heme coordination, but how these changes are facilitated by interactions at the αHb·AHSP interface is not well understood. To address this question we have used NMR, x-ray absorption spectroscopy, and ligand binding measurements to probe αHb conformational changes induced by AHSP binding. NMR chemical shift analyses of free CO-αHb and CO-αHb·AHSP indicated that the seven helical elements of the native αHb structure are retained and that the heme Fe(II) remains coordinated to the proximal His-87 side chain. However, chemical shift differences revealed alterations of the F, G, and H helices and the heme pocket of CO-αHb bound to AHSP. Comparisons of iron-ligand geometry using extended x-ray absorption fine structure spectroscopy showed that AHSP binding induces a small 0.03 Å lengthening of the Fe-O2 bond, explaining previous reports that AHSP decreases αHb O2 affinity roughly 4-fold and promotes autooxidation due primarily to a 3–4-fold increase in the rate of O2 dissociation. Pro-30 mutations diminished NMR chemical shift changes in the proximal heme pocket, restored normal O2 dissociation rate and equilibrium constants, and reduced O2-αHb autooxidation rates. Thus, the contacts mediated by Pro-30 in wild-type AHSP promote αHb autooxidation by introducing strain into the proximal heme pocket. As a chaperone, AHSP facilitates rapid assembly of αHb into Hb when βHb is abundant but diverts αHb to a redox resistant holding state when βHb is limiting. PMID:23696640

  5. α-Hemoglobin-stabilizing protein (AHSP) perturbs the proximal heme pocket of oxy-α-hemoglobin and weakens the iron-oxygen bond.

    Science.gov (United States)

    Dickson, Claire F; Rich, Anne M; D'Avigdor, William M H; Collins, Daniel A T; Lowry, Jason A; Mollan, Todd L; Khandros, Eugene; Olson, John S; Weiss, Mitchell J; Mackay, Joel P; Lay, Peter A; Gell, David A

    2013-07-01

    α-Hemoglobin (αHb)-stabilizing protein (AHSP) is a molecular chaperone that assists hemoglobin assembly. AHSP induces changes in αHb heme coordination, but how these changes are facilitated by interactions at the αHb·AHSP interface is not well understood. To address this question we have used NMR, x-ray absorption spectroscopy, and ligand binding measurements to probe αHb conformational changes induced by AHSP binding. NMR chemical shift analyses of free CO-αHb and CO-αHb·AHSP indicated that the seven helical elements of the native αHb structure are retained and that the heme Fe(II) remains coordinated to the proximal His-87 side chain. However, chemical shift differences revealed alterations of the F, G, and H helices and the heme pocket of CO-αHb bound to AHSP. Comparisons of iron-ligand geometry using extended x-ray absorption fine structure spectroscopy showed that AHSP binding induces a small 0.03 Å lengthening of the Fe-O2 bond, explaining previous reports that AHSP decreases αHb O2 affinity roughly 4-fold and promotes autooxidation due primarily to a 3-4-fold increase in the rate of O2 dissociation. Pro-30 mutations diminished NMR chemical shift changes in the proximal heme pocket, restored normal O2 dissociation rate and equilibrium constants, and reduced O2-αHb autooxidation rates. Thus, the contacts mediated by Pro-30 in wild-type AHSP promote αHb autooxidation by introducing strain into the proximal heme pocket. As a chaperone, AHSP facilitates rapid assembly of αHb into Hb when βHb is abundant but diverts αHb to a redox resistant holding state when βHb is limiting.

  6. Similarity transformations of MAPs

    Directory of Open Access Journals (Sweden)

    Andersen Allan T.

    1999-01-01

    Full Text Available We introduce the notion of similar Markovian Arrival Processes (MAPs and show that the event stationary point processes related to two similar MAPs are stochastically equivalent. This holds true for the time stationary point processes too. We show that several well known stochastical equivalences as e.g. that between the H 2 renewal process and the Interrupted Poisson Process (IPP can be expressed by the similarity transformations of MAPs. In the appendix the valid region of similarity transformations for two-state MAPs is characterized.

  7. Structural insights into parasite eIF4E binding specificity for m7G and m2,2,7G mRNA caps.

    Science.gov (United States)

    Liu, Weizhi; Zhao, Rui; McFarland, Craig; Kieft, Jeffrey; Niedzwiecka, Anna; Jankowska-Anyszka, Marzena; Stepinski, Janusz; Darzynkiewicz, Edward; Jones, David N M; Davis, Richard E

    2009-11-01

    The eukaryotic translation initiation factor eIF4E recognizes the mRNA cap, a key step in translation initiation. Here we have characterized eIF4E from the human parasite Schistosoma mansoni. Schistosome mRNAs have either the typical monomethylguanosine (m(7)G) or a trimethylguanosine (m(2,2,7)G) cap derived from spliced leader trans-splicing. Quantitative fluorescence titration analyses demonstrated that schistosome eIF4E has similar binding specificity for both caps. We present the first crystal structure of an eIF4E with similar binding specificity for m(7)G and m(2,2,7)G caps. The eIF4E.m(7)GpppG structure demonstrates that the schistosome protein binds monomethyl cap in a manner similar to that of single specificity eIF4Es and exhibits a structure similar to other known eIF4Es. The structure suggests an alternate orientation of a conserved, key Glu-90 in the cap-binding pocket that may contribute to dual binding specificity and a position for mRNA bound to eIF4E consistent with biochemical data. Comparison of NMR chemical shift perturbations in schistosome eIF4E on binding m(7)GpppG and m(2,2,7)GpppG identified key differences between the two complexes. Isothermal titration calorimetry demonstrated significant thermodynamics differences for the binding process with the two caps (m(7)G versus m(2,2,7)G). Overall the NMR and isothermal titration calorimetry data suggest the importance of intrinsic conformational flexibility in the schistosome eIF4E that enables binding to m(2,2,7)G cap. PMID:19710013

  8. Clustering by Pattern Similarity

    Institute of Scientific and Technical Information of China (English)

    Hai-xun Wang; Jian Pei

    2008-01-01

    The task of clustering is to identify classes of similar objects among a set of objects. The definition of similarity varies from one clustering model to another. However, in most of these models the concept of similarity is often based on such metrics as Manhattan distance, Euclidean distance or other Lp distances. In other words, similar objects must have close values in at least a set of dimensions. In this paper, we explore a more general type of similarity. Under the pCluster model we proposed, two objects are similar if they exhibit a coherent pattern on a subset of dimensions. The new similarity concept models a wide range of applications. For instance, in DNA microarray analysis, the expression levels of two genes may rise and fall synchronously in response to a set of environmental stimuli. Although the magnitude of their expression levels may not be close, the patterns they exhibit can be very much alike. Discovery of such clusters of genes is essential in revealing significant connections in gene regulatory networks. E-commerce applications, such as collaborative filtering, can also benefit from the new model, because it is able to capture not only the closeness of values of certain leading indicators but also the closeness of (purchasing, browsing, etc.) patterns exhibited by the customers. In addition to the novel similarity model, this paper also introduces an effective and efficient algorithm to detect such clusters, and we perform tests on several real and synthetic data sets to show its performance.

  9. New Similarity Functions

    DEFF Research Database (Denmark)

    Yazdani, Hossein; Ortiz-Arroyo, Daniel; Kwasnicka, Halina

    2016-01-01

    In data science, there are important parameters that affect the accuracy of the algorithms used. Some of these parameters are: the type of data objects, the membership assignments, and distance or similarity functions. This paper discusses similarity functions as fundamental elements in membership...

  10. Pocket atlas of sectional anatomy: computed tomography and magnetic resonance imaging. Vol. 3. Spine, extremities, joints

    Energy Technology Data Exchange (ETDEWEB)

    Moeller, T.B.; Reif, E. [Caritas Hospital, Dillingen (Germany). Dept. of Radiology

    2007-07-01

    Magnetic resonance imaging (MRI) of the musculoskeletal system is an established and important component in the diagnosis of diseases of the joints, soft tissues, bones, and bone marrow. We are therefore pleased to collect together images of the joints and the spinal column in a separate volume on the musculoskeletal system. Demonstrating the growing importance of new developments in MRI in recent years, with ever-increasing resolution, many images were acquired with 3-tesla units. We are deeply grateful to the manufacturers, Siemens and Philips, for making this possible. We believe that colored atlases are the ideal medium to represent the highly detailed images achieved nowadays with improved resolution techniques. Volume 3 of the Pocket Atlas of Sectional Anatomay provides a color illustration facing each magnetic resonance image, as in the preceding volumes on the skull, thorax, and abdomen. To ensure the greatest possible precision in details, we still produce these illustrations ourselves. Each is accompanied by a sectional image and an orientation aid. Uniform color schemes ensure optimal clarity, as similar structures, such as arteries, veins, nerves, tendons, etc., are consistently represented in the same color. Individual muscle groups are represented uniformly, but differentiated from other muscle groups, so that classification is possible even when numerous groups of muscles are shown in the same image. Maximal lucidity prevails even in highly detailed representations. This is made possible by the high quality of the production and printing process that are characteristic of Thieme International. (orig.)

  11. Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis

    Science.gov (United States)

    Figliuzzi, Michele Mario; Giudice, Amerigo; Pileggi, Settimia; Scordamaglia, Francesco; Marrelli, Massimo; Tatullo, Marco; Fortunato, Leonzio

    2016-01-01

    Summary Aim Hydroxyapatite (PA) has a chemical composition and physical structure very similar to natural bone and therefore it has been considered to be the ideal biomaterial able to ensure a biomimetic scaffold to use in bone tissue engineering. The aim of this study is to clinically test hydroxyapatite used as osteoconductive biomaterial in the treatment of periodontal bone defects. Clinical and radiological evaluations were conducted at 6, 12 and 18 months after the surgery. Materials and methods Forty patients with 2- and 3-wall intrabony pockets were enrolled in this study. PPD, CAL, radiographic depth (RD) and angular defects were preoperatively measured. After surgery, patients were re-evaluated every 6 months for 18 months. Statistical analyses were also performed to investigate any differences between preoperative and postoperative measurements. Results Paired t-test samples conducted on the data obtained at baseline and 18 months after, showed significant (p<0.01) differences in each measurement performed. The role of preoperative RD was demonstrated to be a significant key factor (p<0.01). A relevant correlation between preoperative PPD and CAL gain was also found. Conclusions Within the limitations of this study, the absence of anatomical variables, except the morphology of the bone defect, emphasizes the importance of the proper surgical approach and the graft material used. PMID:27486507

  12. Complex home care: Part 2- family annual income, insurance premium, and out-of-pocket expenses.

    Science.gov (United States)

    Piamjariyakul, Ubolrat; Yadrich, Donna Macan; Ross, Vicki M; Smith, Carol E; Clements, Faye; Williams, Arthur R

    2010-01-01

    Annual costs paid by families for intravenous infusion of home parenteral nutrition (HPN) health insurance premiums, deductibles, co-payments for health services, and the wide range of out-of-pocket home health care expenses are significant. The costs of managing complex chronic care at home cannot be completely understood until all out-of-pocket costs have been defined, described, and tabulated. Non-reimbursed and out-of-pocket costs paid by families over years for complex chronic care negatively impact the financial stability of families. National health care reform must take into account the long-term financial burdens of families caring for those with complex home care. Any changes that may increase the out-of-pocket costs or health insurance costs to these families can also have a negative long-term impact on society when greater numbers of patients declare bankruptcy or qualify for medical disability. PMID:21158253

  13. Yeasts associated with the infrabuccal pocket and colonies of the carpenter ant Camponotus vicinus.

    Science.gov (United States)

    Mankowski, M E; Morrell, J J

    2004-01-01

    After scanning electron microscopy indicated that the infrabuccal pockets of carpenter ants (Camponotus vicinus) contained numerous yeast-like cells, yeast associations were examined in six colonies of carpenter ants from two locations in Benton County in western Oregon. Samples from the infrabuccal-pocket contents and worker ant exoskeletons, interior galleries of each colony, and detritus and soil around the colonies were plated on yeast-extract/ malt-extract agar augmented with 1 M hydrochloric acid and incubated at 25 C. Yeasts were identified on the basis of morphological characteristics and physiological attributes with the BIOLOG(®) microbial identification system. Yeast populations from carpenter ant nest material and material surrounding the nest differed from those obtained from the infrabuccal pocket. Debaryomyces polymorphus was isolated more often from the infrabuccal pocket than from other material. This species has also been isolated from other ant species, but its role in colony nutrition is unknown. PMID:21148849

  14. Optimal design of Tilting-Pad Thrust Bearings with High Pressure Injection Pockets

    DEFF Research Database (Denmark)

    Heinrichson, Niels; Santos, Ilmar

    2006-01-01

    to move towards the leading edge of the pads as the pocket size is increased. A large pocket is seen to negatively influence the performance with respect to friction loss at most operating conditions while at some operating conditions it has a small positive influence. The small pocket has a slight...... positive influence on the friction loss at most operating conditions. Moderate thermal crowning is shown to have a positive effect on performance, reducing friction loss.......A thermo-elasto-hydrodynamic(TEHD) model based on the Reynolds equation has been used to study the effect of oil injection pockets on the performance of tilting pad thrust bearings. The optimal position of the pivot both with respect to load carrying capacity and minimal power consumption is seen...

  15. Yeasts associated with the infrabuccal pocket and colonies of the carpenter ant Camponotus vicinus.

    Science.gov (United States)

    Mankowski, M E; Morrell, J J

    2004-01-01

    After scanning electron microscopy indicated that the infrabuccal pockets of carpenter ants (Camponotus vicinus) contained numerous yeast-like cells, yeast associations were examined in six colonies of carpenter ants from two locations in Benton County in western Oregon. Samples from the infrabuccal-pocket contents and worker ant exoskeletons, interior galleries of each colony, and detritus and soil around the colonies were plated on yeast-extract/ malt-extract agar augmented with 1 M hydrochloric acid and incubated at 25 C. Yeasts were identified on the basis of morphological characteristics and physiological attributes with the BIOLOG(®) microbial identification system. Yeast populations from carpenter ant nest material and material surrounding the nest differed from those obtained from the infrabuccal pocket. Debaryomyces polymorphus was isolated more often from the infrabuccal pocket than from other material. This species has also been isolated from other ant species, but its role in colony nutrition is unknown.

  16. Focused surveys for the Pacific Pocket Mouse in Orange County, California

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — The purpose of this report is to document the results of confirmation trapping surveys for the Pacific Pocket Mouse performed by the San Diego Natural History...

  17. Surgical management of retraction pockets of the pars tensa with cartilage and perichondrial grafts.

    Science.gov (United States)

    Spielmann, P; Mills, R

    2006-09-01

    Stable, self-cleansing retraction pockets of the pars tensa are common incidental findings and require no treatment. In other cases, recurrent discharge occurs and there may also be associated conductive hearing loss. In a minority of cases, cholesteatoma may develop. This paper presents the results of surgery using a graft composed of cartilage and perichondrium for retraction pockets involving the posterior half of the tympanic membrane, as well as early results using a larger graft designed to manage retraction of the entire tympanic membrane. Data on 51 patients with posterior retraction pockets are presented. Forty-two (82 per cent) patients had no aural discharge one year following surgery and the tympanic membrane was not retracted in 43 (84 per cent). The larger 'Mercedes-Benz' graft was used in four patients and the results obtained suggested that it may prove a successful technique for extensive retraction pockets. PMID:16740207

  18. Similar component analysis

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hong; WANG Xin; LI Junwei; CAO Xianguang

    2006-01-01

    A new unsupervised feature extraction method called similar component analysis (SCA) is proposed in this paper. SCA method has a self-aggregation property that the data objects will move towards each other to form clusters through SCA theoretically,which can reveal the inherent pattern of similarity hidden in the dataset. The inputs of SCA are just the pairwise similarities of the dataset,which makes it easier for time series analysis due to the variable length of the time series. Our experimental results on many problems have verified the effectiveness of SCA on some engineering application.

  19. Role of a Hydrophobic Pocket in Polyamine Interactions with the Polyspecific Organic Cation Transporter OCT3.

    Science.gov (United States)

    Li, Dan C; Nichols, Colin G; Sala-Rabanal, Monica

    2015-11-13

    Organic cation transporter 3 (OCT3, SLC22A3) is a polyspecific, facilitative transporter expressed in astrocytes and in placental, intestinal, and blood-brain barrier epithelia, and thus elucidating the molecular mechanisms underlying OCT3 substrate recognition is critical for the rational design of drugs targeting these tissues. The pharmacology of OCT3 is distinct from that of other OCTs, and here we investigated the role of a hydrophobic cavity tucked within the translocation pathway in OCT3 transport properties. Replacement of an absolutely conserved Asp by charge reversal (D478E), neutralization (D478N), or even exchange (D478E) abolished MPP(+) uptake, demonstrating this residue to be obligatory for OCT3-mediated transport. Mutations at non-conserved residues lining the putative binding pocket of OCT3 to the corresponding residue in OCT1 (L166F, F450L, and E451Q) reduced the rate of MPP(+) transport, but recapitulated the higher sensitivity pharmacological profile of OCT1. Thus, interactions of natural polyamines (putrescine, spermidine, spermine) and polyamine-like potent OCT1 blockers (1,10-diaminodecane, decamethonium, bistriethylaminodecane, and 1,10-bisquinuclidinedecane) with wild-type OCT3 were weak, but were significantly potentiated in the mutant OCT3s. Conversely, a reciprocal mutation in OCT1 (F161L) shifted the polyamine-sensitivity phenotype toward that of OCT3. Further analysis indicated that OCT1 and OCT3 can recognize essentially the same substrates, but the strength of substrate-transporter interactions is weaker in OCT3, as informed by the distinct makeup of the hydrophobic cleft. The residues identified here are key contributors to both the observed differences between OCT3 and OCT1 and to the mechanisms of substrate recognition by OCTs in general.

  20. Out-of-pocket expenditures for pharmaceuticals: Lessons from the Austrian household budget survey

    OpenAIRE

    Sanwald, Alice; Theurl, Engelbert

    2015-01-01

    BACKGROUND: Paying pharmaceuticals out-of-pocket is an important source of financing pharmaceutical consumption. Only limited empirical knowledge is available on the determinants of these expenditures. OBJECTIVES: In this paper we analyze which characteristics of private households influence out-of-pocket pharmaceutical expenditure (OOPPE) in Austria. DESIGN & METHODS: We use cross-sectional information on OOPPE and on household characteristics provided by the Austrian household budget survey...

  1. NEET Micro-Pocket Fission Detector -- FY 2012 Status Report

    Energy Technology Data Exchange (ETDEWEB)

    Troy Unruh; Joy Rempe; Douglas McGregor; Philip Ugorowski; Michael Reichenberger

    2012-09-01

    A research program has been initiated by the NEET program for developing and testing compact miniature fission chambers capable of simultaneously measuring thermal neutron flux, fast neutron flux and temperature within a single package. When implemented, these sensors will significantly advance flux detection capabilities for irradiation tests in US Materials Test Reactors (MTRs).Ultimately, evaluations may lead to a more compact, more accurate, and longer lifetime flux sensor for critical mock-ups, high performance reactors and commercial nuclear power plants. Deployment of Micro-Pocket Fission Detectors (MPFDs) in US DOE-NE program irradiation tests will address several challenges: Current fission chamber technologies do not offer the ability to measure fast flux, thermal flux and temperature within a single compact probe, MPFDs offer this option. MPFD construction is very different then current fission chamber construction; the use of high temperature materials allow MPFDs to be specifically tailored to survive harsh conditions in typical high performance MTR irradiation tests. New high-fidelity reactor physics codes will need a small, accurate, multipurpose in-core sensor to validate the codes without perturbing the validation experiment; MPFDs fill this requirement. MPFDs can be built with variable sensitivities to survive the lifetime of an experiment or fuel assembly in some MTRs; allowing for more efficient and cost effective power monitoring. The small size of the MPFDs allows multiple sensors to be simultaneously deployed; obtaining data required to visualize the reactor flux and temperature profiles. This report summarizes the research progress for year 1 of this 3 year project. An updated design of the MPFD has been developed, materials and tools to support the new design have been procured, construction methods to support the new design have been initiated at INL’s HTTL and KSU’s SMART Laboratory, plating methods are being updated at KSU, new

  2. NEET Micro-Pocket Fission Detector. Final Project report

    Energy Technology Data Exchange (ETDEWEB)

    Unruh, T.; Rempe, Joy; McGregor, Douglas; Ugorowski, Philip; Reichenberger, Michael; Ito, Takashi; Villard, J.-F.

    2014-09-01

    A collaboration between the Idaho National Laboratory (INL), the Kansas State University (KSU), and the French Alternative Energies and Atomic Energy Commission, Commissariat à l'Énergie Atomique et aux Energies Alternatives, (CEA), is funded by the Nuclear Energy Enabling Technologies (NEET) program to develop and test Micro-Pocket Fission Detectors (MPFDs), which are compact fission chambers capable of simultaneously measuring thermal neutron flux, fast neutron flux and temperature within a single package. When deployed, these sensors will significantly advance flux detection capabilities for irradiation tests in US Material Test Reactors (MTRs). Ultimately, evaluations may lead to a more compact, more accurate, and longer lifetime flux sensor for critical mock-ups, and high performance reactors, allowing several Department of Energy Office of Nuclear Energy (DOE-NE) programs to obtain higher accuracy/higher resolution data from irradiation tests of candidate new fuels and materials. Specifically, deployment of MPFDs will address several challenges faced in irradiations performed at MTRs: Current fission chamber technologies do not offer the ability to measure fast flux, thermal flux and temperature within a single compact probe; MPFDs offer this option. MPFD construction is very different than current fission chamber construction; the use of high temperature materials allow MPFDs to be specifically tailored to survive harsh conditions encountered in-core of high performance MTRs. The higher accuracy, high fidelity data available from the compact MPFD will significantly enhance efforts to validate new high-fidelity reactor physics codes and new multi-scale, multi-physics codes. MPFDs can be built with variable sensitivities to survive the lifetime of an experiment or fuel assembly in some MTRs, allowing for more efficient and cost effective power monitoring. The small size of the MPFDs allows multiple sensors to be deployed, offering the potential to

  3. Gender similarities and differences.

    Science.gov (United States)

    Hyde, Janet Shibley

    2014-01-01

    Whether men and women are fundamentally different or similar has been debated for more than a century. This review summarizes major theories designed to explain gender differences: evolutionary theories, cognitive social learning theory, sociocultural theory, and expectancy-value theory. The gender similarities hypothesis raises the possibility of theorizing gender similarities. Statistical methods for the analysis of gender differences and similarities are reviewed, including effect sizes, meta-analysis, taxometric analysis, and equivalence testing. Then, relying mainly on evidence from meta-analyses, gender differences are reviewed in cognitive performance (e.g., math performance), personality and social behaviors (e.g., temperament, emotions, aggression, and leadership), and psychological well-being. The evidence on gender differences in variance is summarized. The final sections explore applications of intersectionality and directions for future research.

  4. Gender similarities and differences.

    Science.gov (United States)

    Hyde, Janet Shibley

    2014-01-01

    Whether men and women are fundamentally different or similar has been debated for more than a century. This review summarizes major theories designed to explain gender differences: evolutionary theories, cognitive social learning theory, sociocultural theory, and expectancy-value theory. The gender similarities hypothesis raises the possibility of theorizing gender similarities. Statistical methods for the analysis of gender differences and similarities are reviewed, including effect sizes, meta-analysis, taxometric analysis, and equivalence testing. Then, relying mainly on evidence from meta-analyses, gender differences are reviewed in cognitive performance (e.g., math performance), personality and social behaviors (e.g., temperament, emotions, aggression, and leadership), and psychological well-being. The evidence on gender differences in variance is summarized. The final sections explore applications of intersectionality and directions for future research. PMID:23808917

  5. Directed evolution of the Escherichia coli cAMP receptor protein at the cAMP pocket.

    Science.gov (United States)

    Gunasekara, Sanjiva M; Hicks, Matt N; Park, Jin; Brooks, Cory L; Serate, Jose; Saunders, Cameron V; Grover, Simranjeet K; Goto, Joy J; Lee, Jin-Won; Youn, Hwan

    2015-10-30

    The Escherichia coli cAMP receptor protein (CRP) requires cAMP binding to undergo a conformational change for DNA binding and transcriptional regulation. Two CRP residues, Thr(127) and Ser(128), are known to play important roles in cAMP binding through hydrogen bonding and in the cAMP-induced conformational change, but the connection between the two is not completely clear. Here, we simultaneously randomized the codons for these two residues and selected CRP mutants displaying high CRP activity in a cAMP-producing E. coli. Many different CRP mutants satisfied the screening condition for high CRP activity, including those that cannot form any hydrogen bonds with the incoming cAMP at the two positions. In vitro DNA-binding analysis confirmed that these selected CRP mutants indeed display high CRP activity in response to cAMP. These results indicate that the hydrogen bonding ability of the Thr(127) and Ser(128) residues is not critical for the cAMP-induced CRP activation. However, the hydrogen bonding ability of Thr(127) and Ser(128) was found to be important in attaining high cAMP affinity. Computational analysis revealed that most natural cAMP-sensing CRP homologs have Thr/Ser, Thr/Thr, or Thr/Asn at positions 127 and 128. All of these pairs are excellent hydrogen bonding partners and they do not elevate CRP activity in the absence of cAMP. Taken together, our analyses suggest that CRP evolved to have hydrogen bonding residues at the cAMP pocket residues 127 and 128 for performing dual functions: preserving high cAMP affinity and keeping CRP inactive in the absence of cAMP.

  6. Cognitive residues of similarity

    OpenAIRE

    OToole, Stephanie; Keane, Mark T.

    2013-01-01

    What are the cognitive after-effects of making a similarity judgement? What, cognitively, is left behind and what effect might these residues have on subsequent processing? In this paper, we probe for such after-effects using a visual search task, performed after a task in which pictures of real-world objects were compared. So, target objects were first presented in a comparison task (e.g., rate the similarity of this object to another) thus, presumably, modifying some of their features befor...

  7. Characterization of molecular determinants of the conformational stability of macrophage migration inhibitory factor: leucine 46 hydrophobic pocket.

    Directory of Open Access Journals (Sweden)

    Farah El-Turk

    Full Text Available Macrophage Migration Inhibitory Factor (MIF is a key mediator of inflammatory responses and innate immunity and has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. The oligomerization of MIF, more specifically trimer formation, is essential for its keto-enol tautomerase activity and probably mediates several of its interactions and biological activities, including its binding to its receptor CD74 and activation of certain signaling pathways. Therefore, understanding the molecular factors governing the oligomerization of MIF and the role of quaternary structure in modulating its structural stability and multifunctional properties is crucial for understanding the function of MIF in health and disease. Herein, we describe highly conserved intersubunit interactions involving the hydrophobic packing of the side chain of Leu46 onto the β-strand β3 of one monomer within a hydrophobic pocket from the adjacent monomer constituted by residues Arg11, Val14, Phe18, Leu19, Val39, His40, Val41, Val42, and Pro43. To elucidate the structural significance of these intersubunit interactions and their relative contribution to MIF's trimerization, structural stability and catalytic activity, we generated three point mutations where Leu46 was replaced by glycine (L46G, alanine (L46A and phenylalanine (L46F, and their structural properties, stability, oligomerization state, and catalytic activity were characterized using a battery of biophysical methods and X-ray crystallography. Our findings provide new insights into the role of the Leu46 hydrophobic pocket in stabilizing the conformational state of MIF in solution. Disrupting the Leu46 hydrophobic interaction perturbs the secondary and tertiary structure of the protein but has no effect on its oligomerization state.

  8. The human fatty acid-binding protein family: Evolutionary divergences and functions

    Directory of Open Access Journals (Sweden)

    Smathers Rebecca L

    2011-03-01

    Full Text Available Abstract Fatty acid-binding proteins (FABPs are members of the intracellular lipid-binding protein (iLBP family and are involved in reversibly binding intracellular hydrophobic ligands and trafficking them throughout cellular compartments, including the peroxisomes, mitochondria, endoplasmic reticulum and nucleus. FABPs are small, structurally conserved cytosolic proteins consisting of a water-filled, interior-binding pocket surrounded by ten anti-parallel beta sheets, forming a beta barrel. At the superior surface, two alpha-helices cap the pocket and are thought to regulate binding. FABPs have broad specificity, including the ability to bind long-chain (C16-C20 fatty acids, eicosanoids, bile salts and peroxisome proliferators. FABPs demonstrate strong evolutionary conservation and are present in a spectrum of species including Drosophila melanogaster, Caenorhabditis elegans, mouse and human. The human genome consists of nine putatively functional protein-coding FABP genes. The most recently identified family member, FABP12, has been less studied.

  9. The Qualitative Similarity Hypothesis

    Science.gov (United States)

    Paul, Peter V.; Lee, Chongmin

    2010-01-01

    Evidence is presented for the qualitative similarity hypothesis (QSH) with respect to children and adolescents who are d/Deaf or hard of hearing. The primary focus is on the development of English language and literacy skills, and some information is provided on the acquisition of English as a second language. The QSH is briefly discussed within…

  10. Similarity of molecular shape.

    Science.gov (United States)

    Meyer, A Y; Richards, W G

    1991-10-01

    The similarity of one molecule to another has usually been defined in terms of electron densities or electrostatic potentials or fields. Here it is expressed as a function of the molecular shape. Formulations of similarity (S) reduce to very simple forms, thus rendering the computerised calculation straightforward and fast. 'Elements of similarity' are identified, in the same spirit as 'elements of chirality', except that the former are understood to be variable rather than present-or-absent. Methods are presented which bypass the time-consuming mathematical optimisation of the relative orientation of the molecules. Numerical results are presented and examined, with emphasis on the similarity of isomers. At the extreme, enantiomeric pairs are considered, where it is the dissimilarity (D = 1 - S) that is of consequence. We argue that chiral molecules can be graded by dissimilarity, and show that D is the shape-analog of the 'chirality coefficient', with the simple form of the former opening up numerical access to the latter. PMID:1770379

  11. Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

    Energy Technology Data Exchange (ETDEWEB)

    Ida, Tomoyo [Osaka University, Toyonaka, Osaka 560-0043 (Japan); Suzuki, Hideyuki [Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan); Fukuyama, Keiichi [Osaka University, Toyonaka, Osaka 560-0043 (Japan); Hiratake, Jun [Kyoto University, Uji, Kyoto 611-0011 (Japan); Wada, Kei, E-mail: keiwada@med.miyazaki-u.ac.jp [University of Miyazaki, Miyazaki 889-1692 (Japan); Osaka University, Toyonaka, Osaka 560-0043 (Japan)

    2014-02-01

    The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.

  12. Binding of a fluorescence reporter and a ligand to an odorant-binding protein of the yellow fever mosquito, Aedes aegypti [v2; ref status: indexed, http://f1000r.es/4yp

    Directory of Open Access Journals (Sweden)

    Gabriel M. Leal

    2015-01-01

    Full Text Available Odorant-binding proteins (OBPs, also named pheromone-binding proteins when the odorant is a pheromone, are essential for insect olfaction. They solubilize odorants that reach the port of entry of the olfactory system, the pore tubules in antennae and other olfactory appendages. Then, OBPs transport these hydrophobic compounds through an aqueous sensillar lymph to receptors embedded on dendritic membranes of olfactory receptor neurons. Structures of OBPs from mosquito species have shed new light on the mechanism of transport, although there is considerable debate on how they deliver odorant to receptors. An OBP from the southern house mosquito, Culex quinquefasciatus, binds the hydrophobic moiety of a mosquito oviposition pheromone (MOP on the edge of its binding cavity. Likewise, it has been demonstrated that the orthologous protein from the malaria mosquito binds the insect repellent DEET on a similar edge of its binding pocket. A high school research project was aimed at testing whether the orthologous protein from the yellow fever mosquito, AaegOBP1, binds DEET and other insect repellents, and MOP was used as a positive control. Binding assays using the fluorescence reporter N-phenyl-1-naphtylamine (NPN were inconclusive. However, titration of NPN fluorescence emission in AaegOBP1 solution with MOP led to unexpected and intriguing results. Quenching was observed in the initial phase of titration, but addition of higher doses of MOP led to a stepwise increase in fluorescence emission coupled with a blue shift, which can be explained at least in part by formation of MOP micelles to house stray NPN molecules.

  13. Limiting Similarity Revisited

    OpenAIRE

    Szabo, P; Meszena, G.

    2005-01-01

    We reinvestigate the validity of the limiting similarity principle via numerical simulations of the Lotka-Volterra model. A Gaussian competition kernel is employed to describe decreasing competition with increasing difference in a one-dimensional phenotype variable. The simulations are initiated by a large number of species, evenly distributed along the phenotype axis. Exceptionally, the Gaussian carrying capacity supports coexistence of all species, initially present. In case of any other, d...

  14. Compression-based similarity

    OpenAIRE

    Vitányi, Paul

    2011-01-01

    First we consider pair-wise distances for literal objects consisting of finite binary files. These files are taken to contain all of their meaning, like genomes or books. The distances are based on compression of the objects concerned, normalized, and can be viewed as similarity distances. Second, we consider pair-wise distances between names of objects, like "red" or "christianity." In this case the distances are based on searches of the Internet. Such a search can be performed by any search...

  15. RECOGNITION OF STRUCTURE SIMILARITIES IN PROTEINS

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Protein fold structure is more conserved than its amino acid sequence and closely associated with biological function,so calculating the similarity of protein structures is a fundamental problem in structural biology and plays a key role in protein fold classification,fold function inference,and protein structure prediction.Large progress has been made in recent years in this field and many methods for considering structural similarity have been proposed,including methods for protein structure compar-ison,retrieval of protein structures from databases,and ligand binding site comparison.Most of those methods can be available on the World Wide Web,but evaluation of all the methods is still a hard problem.This paper summarizes some popular methods and latest methods for structure similarities,including structure alignment,protein structure retrieval,and ligand binding site alignment.

  16. Iranian Households’ Payments on Food and Health Out-of-Pocket Expenditures: Evidence of Inequality

    Directory of Open Access Journals (Sweden)

    Hesam GHIASVAND

    2015-10-01

    Full Text Available Background: Inequality in households’ payments on food and health expenditures presents the accessibility and utili-zation patterns between them. This study investigated the Iranian rural and urban households’ inequality in payments on food and Out-of-Pocket health expenditures from 1998 to 2012.Methods: This descriptive study was conducted through the analysis of Iranian Statistics Centre data on Iranian households’ income and expenditures. The Gini Coefficients, Concentration and Kakwani indices have been calculat-ed for Iranian rural and urban households’ Out-of-Pocket health and food expenditures.Results: The means of Iranian rural and urban total consumption expenditures inequality were 0.48 and 0.48, respec-tively. The means of concentration index of food expenditures for rural and urban regions were 0.35 and 0.34, respec-tively. The means of Out-of-Pocket payments for health services for rural and urban regions were 0.51 and 0.5, re-spectively. Finally the means of Kakwani index of Out-of-Pocket health payments in rural and urban households were -0.005 and -0.018, respectively.Conclusion: There are relative high levels of inequality in Iranian households’ payments on food and Out-of-Pocket health expenditures.

  17. Medicare Advantage Members’ Expected Out-Of-Pocket Spending For Inpatient And Skilled Nursing Facility Services

    Science.gov (United States)

    Keohane, Laura M.; Grebla, Regina C.; Mor, Vincent; Trivedi, Amal N.

    2015-01-01

    Inpatient and skilled nursing facility (SNF) cost sharing in Medicare Advantage (MA) plans may reduce unnecessary use of these services. However, large out-of-pocket expenses potentially limit access to care and encourage beneficiaries at high risk of needing inpatient and postacute care to avoid or leave MA plans. In 2011 new federal regulations restricted inpatient and skilled nursing facility cost sharing and mandated limits on out-of-pocket spending in MA plans. After these regulations, MA members in plans with low premiums averaged $1,758 in expected out-of-pocket spending for an episode of seven hospital days and twenty skilled nursing facility days. Among members with the same low-premium plan in 2010 and 2011, 36 percent of members belonged to plans that added an out-of-pocket spending limit in 2011. However, these members also had a $293 increase in average cost sharing for an inpatient and skilled nursing facility episode, possibly to offset plans’ expenses in financing out-of-pocket limits. Some MA beneficiaries may still have difficulty affording acute and postacute care despite greater regulation of cost sharing. PMID:26056208

  18. Medicare Advantage Members' Expected Out-Of-Pocket Spending For Inpatient And Skilled Nursing Facility Services.

    Science.gov (United States)

    Keohane, Laura M; Grebla, Regina C; Mor, Vincent; Trivedi, Amal N

    2015-06-01

    Inpatient and skilled nursing facility (SNF) cost sharing in Medicare Advantage (MA) plans may reduce unnecessary use of these services. However, large out-of-pocket expenses potentially limit access to care and encourage beneficiaries at high risk of needing inpatient and postacute care to avoid or leave MA plans. In 2011 new federal regulations restricted inpatient and skilled nursing facility cost sharing and mandated limits on out-of-pocket spending in MA plans. After these regulations, MA members in plans with low premiums averaged $1,758 in expected out-of-pocket spending for an episode of seven hospital days and twenty skilled nursing facility days. Among members with the same low-premium plan in 2010 and 2011, 36 percent of members belonged to plans that added an out-of-pocket spending limit in 2011. However, these members also had a $293 increase in average cost sharing for an inpatient and skilled nursing facility episode, possibly to offset plans' expenses in financing out-of-pocket limits. Some MA beneficiaries may still have difficulty affording acute and postacute care despite greater regulation of cost sharing.

  19. Three Dimensional Flow and Pressure Patterns in a Single Pocket of a Hydrostatic Journal Bearing

    Science.gov (United States)

    Braun, M. Jack; Dzodzo, Milorad B.

    1996-01-01

    The flow in a hydrostatic pocket is described by a mathematical model that uses the three dimensional Navier-Stokes equations written in terms of the primary variables, u, v, w, and p. Using a conservative formulation, a finite volume multi-block method is applied through a collocated, body fitted grid. The flow is simulated in a shallow pocket with a depth/length ratio of 0.02. The flow structures obtained and described by the authors in their previous two dimensional models are made visible in their three dimensional aspect for the Couette flow. It has been found that the flow regimes formed central and secondary vortical cells with three dimensional corkscrew-like structures that lead the fluid on an outward bound path in the axial direction of the pocket. The position of the central vortical cell center is at the exit region of the capillary restrictor feedline. It has also been determined that a fluid turn around zone occupies all the upstream space between the floor of the pocket and the runner, thus preventing any flow exit through the upstream port. The corresponding pressure distribution under the shaft presented as well. It was clearly established that for the Couette dominated case the pressure varies significantly in the pocket in the circumferential direction, while its variation is less pronounced axially.

  20. Treatment of Fingertip Amputation in Adults by Palmar Pocketing of the Amputated Part

    Directory of Open Access Journals (Sweden)

    Mi Sun Jung

    2012-07-01

    Full Text Available Background First suggested by Brent in 1979, the pocket principle is an alternative methodfor patients for whom a microsurgical replantation is not feasible. We report the successfulresults of a modified palmar pocket method in adults.Methods Between 2004 and 2008, we treated 10 patients by nonmicrosurgical replantationusing palmar pocketing. All patients were adults who sustained a complete fingertip amputationfrom the tip to lunula in a digits. In all of these patients, the amputation occurred due to a crushor avulsion-type injury, and a microsurgical replantation was not feasible. We used the palmarpocketing method following a composite graft in these patients and prepared the pocket in thesubcutaneous layer of the ipsilateral palm.Results Of a total of 10 cases, nine had complete survival of the replantation and one had20% partial necrosis. All of the cases were managed to conserve the fingernails, which led toacceptable cosmetic results.Conclusions A composite graft and palmar pocketing in adult cases of fingertip injuryconstitute a simple, reliable operation for digital amputation extending from the tip to thelunula. These methods had satisfactory results.

  1. On the specificity of heparin/heparan sulfate binding to proteins. Anion-binding sites on antithrombin and thrombin are fundamentally different.

    Directory of Open Access Journals (Sweden)

    Philip D Mosier

    Full Text Available BACKGROUND: The antithrombin-heparin/heparan sulfate (H/HS and thrombin-H/HS interactions are recognized as prototypic specific and non-specific glycosaminoglycan (GAG-protein interactions, respectively. The fundamental structural basis for the origin of specificity, or lack thereof, in these interactions remains unclear. The availability of multiple co-crystal structures facilitates a structural analysis that challenges the long-held belief that the GAG binding sites in antithrombin and thrombin are essentially similar with high solvent exposure and shallow surface characteristics. METHODOLOGY: Analyses of solvent accessibility and exposed surface areas, gyrational mobility, symmetry, cavity shape/size, conserved water molecules and crystallographic parameters were performed for 12 X-ray structures, which include 12 thrombin and 16 antithrombin chains. Novel calculations are described for gyrational mobility and prediction of water loci and conservation. RESULTS: The solvent accessibilities and gyrational mobilities of arginines and lysines in the binding sites of the two proteins reveal sharp contrasts. The distribution of positive charges shows considerable asymmetry in antithrombin, but substantial symmetry for thrombin. Cavity analyses suggest the presence of a reasonably sized bifurcated cavity in antithrombin that facilitates a firm 'hand-shake' with H/HS, but with thrombin, a weaker 'high-five'. Tightly bound water molecules were predicted to be localized in the pentasaccharide binding pocket of antithrombin, but absent in thrombin. Together, these differences in the binding sites explain the major H/HS recognition characteristics of the two prototypic proteins, thus affording an explanation of the specificity of binding. This provides a foundation for understanding specificity of interaction at an atomic level, which will greatly aid the design of natural or synthetic H/HS sequences that target proteins in a specific manner.

  2. Similar dissection of sets

    CERN Document Server

    Akiyama, Shigeki; Okazaki, Ryotaro; Steiner, Wolfgang; Thuswaldner, Jörg

    2010-01-01

    In 1994, Martin Gardner stated a set of questions concerning the dissection of a square or an equilateral triangle in three similar parts. Meanwhile, Gardner's questions have been generalized and some of them are already solved. In the present paper, we solve more of his questions and treat them in a much more general context. Let $D\\subset \\mathbb{R}^d$ be a given set and let $f_1,...,f_k$ be injective continuous mappings. Does there exist a set $X$ such that $D = X \\cup f_1(X) \\cup ... \\cup f_k(X)$ is satisfied with a non-overlapping union? We prove that such a set $X$ exists for certain choices of $D$ and $\\{f_1,...,f_k\\}$. The solutions $X$ often turn out to be attractors of iterated function systems with condensation in the sense of Barnsley. Coming back to Gardner's setting, we use our theory to prove that an equilateral triangle can be dissected in three similar copies whose areas have ratio $1:1:a$ for $a \\ge (3+\\sqrt{5})/2$.

  3. Co-current air-water flow in downward sloping pipes: Transport of capacity reducing gas pockets in wastewater mains

    OpenAIRE

    Pothof, I.W.M.

    2011-01-01

    Air-water flow is an undesired condition in many systems for the transportation of water or wastewater. Air in storm water tunnels may get trapped and negatively affect the system. Air pockets in hydropower tunnels or sewers may cause blow-back events and inadmissible pressure spikes. Water pipes and wastewater pressure mains in particular are subject to air pocket formation in downward-sloping reaches, such as inverted siphons or terrain slopes. Air pocket accumulation causes energy losses a...

  4. The $^{13}C$-pockets in AGB Stars and Their Fingerprints in Mainstream SiC Grains

    CERN Document Server

    Liu, Nan; Gallino, Roberto; Savina, Michael R; Bisterzo, Sara; Gyngard, Frank; Pellin, Michael J; Dauphas, Nicolas

    2015-01-01

    We identify three isotopic tracers that can be used to constrain the $^{13}C$-pocket and show the correlated isotopic ratios of Sr and Ba in single mainstream presolar SiC grains. These newly measured data can be explained by postprocess AGB model calculations with large $^{13}C$-pockets with a range of relatively low $^{13}C$ concentrations, which may suggest that multiple mixing processes contributed to the $^{13}C$-pocket formation in parent AGB stars.

  5. Half-bow sliding knot: modified suture technique for scleral fixation using the corneoscleral pocket.

    Science.gov (United States)

    Chee, Soon-Phaik

    2011-09-01

    A modified suture technique for precise knot placement in the Hoffman corneoscleral pocket technique of scleral fixation is described. Both loops of the polypropylene suture passing from the intraocular device through the sclera and conjunctiva are retrieved from the pocket. A loop of suture is pulled through 3 suture throws made using the second suture loop, forming a half bow. Centration of the intraocular lens (IOL)-capsular bag is checked. If the suture tension is too tight, the surgeon can easily undo the knot of the half-bow knot by pulling it free and can then retie the sliding knot. When the IOL-capsular bag is centered, the suture loop is cut and the free end removed. The second suture end is retrieved from the pocket, and knot tying is completed without further adjustment to the tension. Posterior pressure on the intraocular device centers it and settles the knot within the sclera at the fixation point.

  6. 趁热打铁——联想Pocket Yoga Netbook

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    闹得沸沸扬扬的联想新款上网本PocketYoga不管是外观还是尺寸都像极了索尼VAIOP系列,造型与标准的商务信封差不多,难道是想趁着VAIOP市场火爆的东风也热闹一把?与VAIOP不同的是,PocketYoga的显示屏可以360度旋转,从而变成平板电脑。PocketYoga拥有奢华的皮革外壳,还安装了一个超广角触摸屏和边角齐平的按键。从以上方面来看,

  7. SMAP-WS: a parallel web service for structural proteome-wide ligand-binding site comparison.

    Science.gov (United States)

    Ren, Jingyuan; Xie, Lei; Li, Wilfred W; Bourne, Philip E

    2010-07-01

    The proteome-wide characterization and analysis of protein ligand-binding sites and their interactions with ligands can provide pivotal information in understanding the structure, function and evolution of proteins and for designing safe and efficient therapeutics. The SMAP web service (SMAP-WS) meets this need through parallel computations designed for 3D ligand-binding site comparison and similarity searching on a structural proteome scale. SMAP-WS implements a shape descriptor (the Geometric Potential) that characterizes both local and global topological properties of the protein structure and which can be used to predict the likely ligand-binding pocket [Xie,L. and Bourne,P.E. (2007) A robust and efficient algorithm for the shape description of protein structures and its application in predicting ligand-binding sites. BMC bioinformatics, 8 (Suppl. 4.), S9.]. Subsequently a sequence order independent profile-profile alignment (SOIPPA) algorithm is used to detect and align similar pockets thereby finding protein functional and evolutionary relationships across fold space [Xie, L. and Bourne, P.E. (2008) Detecting evolutionary relationships across existing fold space, using sequence order-independent profile-profile alignments. Proc. Natl Acad. Sci. USA, 105, 5441-5446]. An extreme value distribution model estimates the statistical significance of the match [Xie, L., Xie, L. and Bourne, P.E. (2009) A unified statistical model to support local sequence order independent similarity searching for ligand-binding sites and its application to genome-based drug discovery. Bioinformatics, 25, i305-i312.]. These algorithms have been extensively benchmarked and shown to outperform most existing algorithms. Moreover, several predictions resulting from SMAP-WS have been validated experimentally. Thus far SMAP-WS has been applied to predict drug side effects, and to repurpose existing drugs for new indications. SMAP-WS provides both a user-friendly web interface and

  8. Structural analysis of the synthetic Duffy Binding Protein (DBP antigen DEKnull relevant for Plasmodium vivax malaria vaccine design.

    Directory of Open Access Journals (Sweden)

    Edwin Chen

    2015-03-01

    Full Text Available The Plasmodium vivax vaccine candidate Duffy Binding Protein (DBP is a protein necessary for P. vivax invasion of reticulocytes. The polymorphic nature of DBP induces strain-specific immune responses that pose unique challenges for vaccine development. DEKnull is a synthetic DBP based antigen that has been engineered through mutation to enhance induction of blocking inhibitory antibodies. We determined the x-ray crystal structure of DEKnull to identify if any conformational changes had occurred upon mutation. Computational and experimental analyses assessed immunogenicity differences between DBP and DEKnull epitopes. Functional binding assays with monoclonal antibodies were used to interrogate the available epitopes in DEKnull. We demonstrate that DEKnull is structurally similar to the parental Sal1 DBP. The DEKnull mutations do not cause peptide backbone shifts within the polymorphic loop, or at either the DBP dimerization interface or DARC receptor binding pockets, two important structurally conserved protective epitope motifs. All B-cell epitopes, except for the mutated DEK motif, are conserved between DEKnull and DBP. The DEKnull protein retains binding to conformationally dependent inhibitory antibodies. DEKnull is an iterative improvement of DBP as a vaccine candidate. DEKnull has reduced immunogenicity to polymorphic regions responsible for strain-specific immunity while retaining conserved protein folds necessary for induction of strain-transcending blocking inhibitory antibodies.

  9. Self Similar Optical Fiber

    Science.gov (United States)

    Lai, Zheng-Xuan

    This research proposes Self Similar optical fiber (SSF) as a new type of optical fiber. It has a special core that consists of self similar structure. Such a structure is obtained by following the formula for generating iterated function systems (IFS) in Fractal Theory. The resulted SSF can be viewed as a true fractal object in optical fibers. In addition, the method of fabricating SSF makes it possible to generate desired structures exponentially in numbers, whereas it also allows lower scale units in the structure to be reduced in size exponentially. The invention of SSF is expected to greatly ease the production of optical fiber when a large number of small hollow structures are needed in the core of the optical fiber. This dissertation will analyze the core structure of SSF based on fractal theory. Possible properties from the structural characteristics and the corresponding applications are explained. Four SSF samples were obtained through actual fabrication in a laboratory environment. Different from traditional conductive heating fabrication system, I used an in-house designed furnace that incorporated a radiation heating method, and was equipped with automated temperature control system. The obtained samples were examined through spectrum tests. Results from the tests showed that SSF does have the optical property of delivering light in a certain wavelength range. However, SSF as a new type of optical fiber requires a systematic research to find out the theory that explains its structure and the associated optical properties. The fabrication and quality of SSF also needs to be improved for product deployment. As a start of this extensive research, this dissertation work opens the door to a very promising new area in optical fiber research.

  10. PROSTAGLANDIN E2 LEVEL IN GINGIVAL CREVICULAR FLUID AND ITS RELATION TO THE PERIODONTAL POCKET DEPTH IN PATIENTS WITH PERIODONTITIS

    Institute of Scientific and Technical Information of China (English)

    周坚; 邹石莹; 赵戚; 赵玉霞

    1994-01-01

    Prostaglandin E2(PGE2)levels in gingival crevicular fluid (GCF)of 46 normal controls and 90 patients suf-fering from periodontitis with different periodontal pocket depths were measured by radioimmunoassay (RIA).The results demonstrated that PGE2 levels in the periodontal pockets are higher in patients with peri-odontitis.The PGE2 level rises as the periodontal pocket deepens,especially in casses where the periodontal pocket depth exceeds 6 mm.This study shows that PGE2 level is significantly related to the severity of bone destruc-tion in periodontitis.

  11. How the Proximal Pocket May Influence the Enantiospecificities of Chloroperoxidase-Catalyzed Epoxidations of Olefins

    Science.gov (United States)

    Morozov, Alexander N.; Chatfield, David C.

    2016-01-01

    Chloroperoxidase-catalyzed enantiospecific epoxidations of olefins are of significant biotechnological interest. Typical enantiomeric excesses are in the range of 66%–97% and translate into free energy differences on the order of 1 kcal/mol. These differences are generally attributed to the effect of the distal pocket. In this paper, we show that the influence of the proximal pocket on the electron transfer mechanism in the rate-limiting event may be just as significant for a quantitatively accurate account of the experimentally-measured enantiospecificities. PMID:27517911

  12. Compact DC-DC Converter for Pocket Micro-Controller Systems

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    Novel compact DC-C converters for pocket micro-controller systems are discussed in the paper,which are based on switched capcotprs and inductorless,consequently are more suitable for being hybridized.The new converters enable the pocket microcontroller system to be powered by only one+12V source,while+5V and -12V are converted from the +12V source.The basic principle,voltage ratio,efficiency and ripples are analysed.Experiment and SPICE simulation are also given,which show positive results.

  13. Coarse-grained molecular dynamics simulations of protein-ligand binding.

    Science.gov (United States)

    Negami, Tatsuki; Shimizu, Kentaro; Terada, Tohru

    2014-09-30

    Coarse-grained molecular dynamics (CGMD) simulations with the MARTINI force field were performed to reproduce the protein-ligand binding processes. We chose two protein-ligand systems, the levansucrase-sugar (glucose or sucrose), and LinB-1,2-dichloroethane systems, as target systems that differ in terms of the size and shape of the ligand-binding pocket and the physicochemical properties of the pocket and the ligand. Spatial distributions of the Coarse-grained (CG) ligand molecules revealed potential ligand-binding sites on the protein surfaces other than the real ligand-binding sites. The ligands bound most strongly to the real ligand-binding sites. The binding and unbinding rate constants obtained from the CGMD simulation of the levansucrase-sucrose system were approximately 10 times greater than the experimental values; this is mainly due to faster diffusion of the CG ligand in the CG water model. We could obtain dissociation constants close to the experimental values for both systems. Analysis of the ligand fluxes demonstrated that the CG ligand molecules entered the ligand-binding pockets through specific pathways. The ligands tended to move through grooves on the protein surface. Thus, the CGMD simulations produced reasonable results for the two different systems overall and are useful for studying the protein-ligand binding processes.

  14. Influence of length and flexibility of spacers on the binding affinity of divalent ligands

    Directory of Open Access Journals (Sweden)

    Susanne Liese

    2015-05-01

    Full Text Available We present a quantitative model for the binding of divalent ligand–receptor systems. We study the influence of length and flexibility of the spacers on the overall binding affinity and derive general rules for the optimal ligand design. To this end, we first compare different polymeric models and determine the probability to simultaneously bind to two neighboring receptor binding pockets. In a second step the binding affinity of divalent ligands in terms of the IC50 value is derived. We find that a divalent ligand has the potential to bind more efficiently than its monovalent counterpart only, if the monovalent dissociation constant is lower than a critical value. This critical monovalent dissociation constant depends on the ligand-spacer length and flexibility as well as on the size of the receptor. Regarding the optimal ligand-spacer length and flexibility, we find that the average spacer length should be equal or slightly smaller than the distance between the receptor binding pockets and that the end-to-end spacer length fluctuations should be in the same range as the size of a receptor binding pocket.

  15. Influence of length and flexibility of spacers on the binding affinity of divalent ligands.

    Science.gov (United States)

    Liese, Susanne; Netz, Roland R

    2015-01-01

    We present a quantitative model for the binding of divalent ligand-receptor systems. We study the influence of length and flexibility of the spacers on the overall binding affinity and derive general rules for the optimal ligand design. To this end, we first compare different polymeric models and determine the probability to simultaneously bind to two neighboring receptor binding pockets. In a second step the binding affinity of divalent ligands in terms of the IC50 value is derived. We find that a divalent ligand has the potential to bind more efficiently than its monovalent counterpart only, if the monovalent dissociation constant is lower than a critical value. This critical monovalent dissociation constant depends on the ligand-spacer length and flexibility as well as on the size of the receptor. Regarding the optimal ligand-spacer length and flexibility, we find that the average spacer length should be equal or slightly smaller than the distance between the receptor binding pockets and that the end-to-end spacer length fluctuations should be in the same range as the size of a receptor binding pocket.

  16. Binding Procurement

    Science.gov (United States)

    Rao, Gopalakrishna M.; Vaidyanathan, Hari

    2007-01-01

    This viewgraph presentation reviews the use of the binding procurement process in purchasing Aerospace Flight Battery Systems. NASA Engineering and Safety Center (NESC) requested NASA Aerospace Flight Battery Systems Working Group to develop a set of guideline requirements document for Binding Procurement Contracts.

  17. Profiling Protein Kinases and Other ATP Binding Proteins in Arabidopsis Using Acyl-ATP Probes*

    OpenAIRE

    Villamor, J. G.; Kaschani, F.; Colby, T; Oeljeklaus, J.; Zhao, D; Kaiser, M.; Patricelli, M. P.; R. A. L. van der Hoorn

    2013-01-01

    Many protein activities are driven by ATP binding and hydrolysis. Here, we explore the ATP binding proteome of the model plant Arabidopsis thaliana using acyl-ATP (AcATP)1 probes. These probes target ATP binding sites and covalently label lysine residues in the ATP binding pocket. Gel-based profiling using biotinylated AcATP showed that labeling is dependent on pH and divalent ions and can be competed by nucleotides. The vast majority of these AcATP-labeled proteins are known ATP binding prot...

  18. Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy.

    Science.gov (United States)

    Tsutsui, Yuko; Deredge, Daniel; Wintrode, Patrick L; Hays, Franklin A

    2016-01-01

    Imatinib (Gleevec), a non-receptor tyrosine kinase inhibitor (nRTKI), is one of the most successful anti-neoplastic drugs in clinical use. However, imatinib-resistant mutations are increasingly prevalent in patient tissues and driving development of novel imatinib analogs. We present a detailed study of the conformational dynamics, in the presence and absence of bound imatinib, for full-length human c-Src using hydrogen-deuterium exchange and mass spectrometry. Our results demonstrate that imatinib binding to the kinase domain effects dynamics of proline-rich or phosphorylated peptide ligand binding sites in distal c-Src SH3 and SH2 domains. These dynamic changes in functional regulatory sites, distal to the imatinib binding pocket, show similarities to structural transitions involved in kinase activation. These data also identify imatinib-sensitive, and imatinib-resistant, mutation sites. Thus, the current study identifies novel c-Src allosteric sites associated with imatinib binding and kinase activation and provide a framework for follow-on development of TKI binding modulators. PMID:27480221

  19. Structural and functional insights into the ligand-binding domain of a nonduplicated retinoid X nuclear receptor from the invertebrate chordate amphioxus.

    Science.gov (United States)

    Tocchini-Valentini, Giuseppe D; Rochel, Natacha; Escriva, Hector; Germain, Pierre; Peluso-Iltis, Carole; Paris, Mathilde; Sanglier-Cianferani, Sarah; Van Dorsselaer, Alain; Moras, Dino; Laudet, Vincent

    2009-01-16

    Retinoid X nuclear receptors (RXRs), as well as their insect orthologue, ultraspiracle protein (USP), play an important role in the transcription regulation mediated by the nuclear receptors as the common partner of many other nuclear receptors. Phylogenetic and structural studies have shown that the several evolutionary shifts have modified the ligand binding ability of RXRs. To understand the vertebrate-specific character of RXRs, we have studied the RXR ligand-binding domain of the cephalochordate amphioxus (Branchiostoma floridae), an invertebrate chordate that predates the genome duplication that produced the three vertebrates RXRs (alpha, beta, and gamma). Here we report the crystal structure of a novel apotetramer conformation of the AmphiRXR ligand-binding domain, which shows some similarity with the structures of the arthropods RXR/USPs. AmphiRXR adopts an apo antagonist conformation with a peculiar conformation of helix H11 filling the binding pocket. In contrast to the arthropods RXR/USPs, which cannot be activated by any RXR ligands, our functional data show that AmphiRXR, like the vertebrates/mollusk RXRs, is able to bind and be activated by RXR ligands but less efficiently than vertebrate RXRs. Our data suggest that amphioxus RXR is, functionally, an intermediate between arthropods RXR/USPs and vertebrate RXRs. PMID:18986992

  20. Characterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca2+ pumps: a computational study.

    KAUST Repository

    Di Marino, Daniele

    2015-03-01

    Despite the investments in malaria research, an effective vaccine has not yet been developed and the causative parasites are becoming increasingly resistant to most of the available drugs. PfATP6, the sarco/endoplasmic reticulum Ca2+ pump (SERCA) of P. falciparum, has been recently genetically validated as a potential antimalarial target and cyclopiazonic acid (CPA) has been found to be a potent inhibitor of SERCAs in several organisms, including P. falciparum. In position 263, PfATP6 displays a leucine residue, whilst the corresponding position in the mammalian SERCA is occupied by a glutamic acid. The PfATP6 L263E mutation has been studied in relation to the artemisinin inhibitory effect on P. falciparum and recent studies have provided evidence that the parasite with this mutation is more susceptible to CPA. Here, we characterized, for the first time, the interaction of CPA with PfATP6 and its mammalian counterpart to understand similarities and differences in the mode of binding of the inhibitor to the two Ca2+ pumps. We found that, even though CPA does not directly interact with the residue in position 263, the presence of a hydrophobic residue in this position in PfATP6 rather than a negatively charged one, as in the mammalian SERCA, entails a conformational arrangement of the binding pocket which, in turn, determines a relaxation of CPA leading to a different binding mode of the compound. Our findings highlight differences between the plasmodial and human SERCA CPA-binding pockets that may be exploited to design CPA derivatives more selective toward PfATP6.

  1. Mechanism of RecO recruitment to DNA by single-stranded DNA binding protein.

    Science.gov (United States)

    Ryzhikov, Mikhail; Koroleva, Olga; Postnov, Dmitri; Tran, Andrew; Korolev, Sergey

    2011-08-01

    RecO is a recombination mediator protein (RMP) important for homologous recombination, replication repair and DNA annealing in bacteria. In all pathways, the single-stranded (ss) DNA binding protein, SSB, plays an inhibitory role by protecting ssDNA from annealing and recombinase binding. Conversely, SSB may stimulate each reaction through direct interaction with RecO. We present a crystal structure of Escherichia coli RecO bound to the conserved SSB C-terminus (SSB-Ct). SSB-Ct binds the hydrophobic pocket of RecO in a conformation similar to that observed in the ExoI/SSB-Ct complex. Hydrophobic interactions facilitate binding of SSB-Ct to RecO and RecO/RecR complex in both low and moderate ionic strength solutions. In contrast, RecO interaction with DNA is inhibited by an elevated salt concentration. The SSB mutant lacking SSB-Ct also inhibits RecO-mediated DNA annealing activity in a salt-dependent manner. Neither RecO nor RecOR dissociates SSB from ssDNA. Therefore, in E. coli, SSB recruits RMPs to ssDNA through SSB-Ct, and RMPs are likely to alter the conformation of SSB-bound ssDNA without SSB dissociation to initiate annealing or recombination. Intriguingly, Deinococcus radiodurans RecO does not bind SSB-Ct and weakly interacts with the peptide in the presence of RecR, suggesting the diverse mechanisms of DNA repair pathways mediated by RecO in different organisms. PMID:21504984

  2. Mechanism of RecO recruitment to DNA by single-stranded DNA binding protein

    Energy Technology Data Exchange (ETDEWEB)

    Ryzhikov, Mikhail; Koroleva, Olga; Postnov, Dmitri; Tran, Andrew; Korolev, Sergey (St. Louis-MED)

    2011-08-25

    RecO is a recombination mediator protein (RMP) important for homologous recombination, replication repair and DNA annealing in bacteria. In all pathways, the single-stranded (ss) DNA binding protein, SSB, plays an inhibitory role by protecting ssDNA from annealing and recombinase binding. Conversely, SSB may stimulate each reaction through direct interaction with RecO. We present a crystal structure of Escherichia coli RecO bound to the conserved SSB C-terminus (SSB-Ct). SSB-Ct binds the hydrophobic pocket of RecO in a conformation similar to that observed in the ExoI/SSB-Ct complex. Hydrophobic interactions facilitate binding of SSB-Ct to RecO and RecO/RecR complex in both low and moderate ionic strength solutions. In contrast, RecO interaction with DNA is inhibited by an elevated salt concentration. The SSB mutant lacking SSB-Ct also inhibits RecO-mediated DNA annealing activity in a salt-dependent manner. Neither RecO nor RecOR dissociates SSB from ssDNA. Therefore, in E. coli, SSB recruits RMPs to ssDNA through SSB-Ct, and RMPs are likely to alter the conformation of SSB-bound ssDNA without SSB dissociation to initiate annealing or recombination. Intriguingly, Deinococcus radiodurans RecO does not bind SSB-Ct and weakly interacts with the peptide in the presence of RecR, suggesting the diverse mechanisms of DNA repair pathways mediated by RecO in different organisms.

  3. Adaptation of a pocket PC for use as a wearable voice dosimeter

    NARCIS (Netherlands)

    Popolo, PS; Svec, Jan G.; Titze, Ingo R.

    2005-01-01

    This article deals with the adaptation of a commercially available Pocket PC for use a wearable device that measures the vocal dose of teachers as a voice dosimeter, or other individuals on the job, at home, and elsewhere during the course of an entire day. An engineering approach for designing a vo

  4. Investigation of dielectric pocket induced variations in tunnel field effect transistor

    Science.gov (United States)

    Upasana; Narang, Rakhi; Saxena, Manoj; Gupta, Mridula

    2016-04-01

    The performance of conventional Tunnel FETs struggling from ambipolar issues, insufficient on-current, lower transconductance value, higher delay and lower cut off frequency has been improved by introducing several material and device engineering concepts in past few years. Keeping this in view, another interesting and reliable option i.e. Dielectric Pocket TFET (featuring a dielectric pocket placement near tunneling junction) has been comprehensively and qualitatively demonstrated using ATLAS device simulator. The architecture has been explored in terms of various device electrostatic parameters such as potential, energy band profile, electron and hole concentration, electric field variation and band to band generation rate (GBTB) near the tunneling junction where the Dielectric Pocket (DP) has been introduced. Subsequently, a detailed investigation by changing the position and dielectric constant of pocket at respective junctions has been made where DP induced variations in drain current, transconductance and parasitic capacitance have been examined. The work highlights major improvements over conventional TFET in terms of lower subthreshold swing and threshold voltage, higher drain current and transconductance, improved on-to-off current ratio, suppressed ambipolar conduction and improved dynamic power dissipation issues for low voltage analog and digital applications.

  5. A Mobile Computing Solution for Collecting Functional Analysis Data on a Pocket PC

    Science.gov (United States)

    Jackson, James; Dixon, Mark R.

    2007-01-01

    The present paper provides a task analysis for creating a computerized data system using a Pocket PC and Microsoft Visual Basic. With Visual Basic software and any handheld device running the Windows MOBLE operating system, this task analysis will allow behavior analysts to program and customize their own functional analysis data-collection…

  6. Adaptation of a Pocket PC for Use as a Wearable Voice Dosimeter

    Science.gov (United States)

    Popolo, Peter S.; Svec, Jan G.; Titze, Ingo R.

    2005-01-01

    This article deals with the adaptation of a commercially available Pocket PC for use as a voice dosimeter, a wearable device that measures the vocal dose of teachers or other individuals on the job, at home, and elsewhere during the course of an entire day. An engineering approach for designing a voice dosimeter is described, and design data are…

  7. The Single Needle Lockstitch Machine. [Constructing and Setting Pockets.] Module 9.

    Science.gov (United States)

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This module on constructing and setting pockets, one in a series on the single needle lockstitch sewing machine for student self-study, contains three sections. Each section includes the following parts: an introduction, directions, an objective, learning activities, student information, student self-check, check-out activities, and an…

  8. Pocket proteins pRb and p107 are required for cortical lamination independent of apoptosis.

    Science.gov (United States)

    Svoboda, D S; Paquin, A; Park, D S; Slack, R S

    2013-12-01

    Pocket proteins (pRb, p107 and p130) are well studied in their role of regulating cell cycle progression. Increasing evidence suggests that these proteins also control early differentiation and even later stages of cell maturation, such as migration. However, pocket proteins also regulate apoptosis, and many of the developmental defects in knock out models have been attributed to increased cell death. Here, we eliminate ectopic apoptosis in the developing brain through the deletion of Bax, and show that pocket proteins are required for radial migration independent of their role in cell death regulation. Following loss of pRb and p107, a population of cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and this migration defect cannot be rescued by eliminating ectopic cell death. In addition, we show that pRb and p107 regulate radial migration through a cell autonomous mechanism since pRb/p107 deficient neurons fail to migrate to the correct cortical layer within a wild type brain. These results define a novel role of pocket proteins in regulating cortical lamination through a cell autonomous mechanism independent of their role in apoptosis.

  9. ENVIRONMENTAL TECHNOLOGY VERIFICATION REPORT: PAINT OVERSPRAY ARRESTOR, COLUMBUS INDUSTRIES, INC., SL-90B 8 POCKET BAG

    Science.gov (United States)

    The report gives results of March 23-24, 1999, tests of Columbus Industries Inc's SL-90B 8 Pocket Bag paint overspray arrestor (POA) as part of an evaluation of POAs by EPA's Air Pollution Control Technology (APCT) Environmental Technology Verification (ETV) Program. The basic pe...

  10. Out-of-Pocket Net Price for College. Data Point. NCES 2014-902

    Science.gov (United States)

    Horn, Laura; Paslov, Jonathan

    2014-01-01

    This Data Point uses data from four administrations of the National Postsecondary Student Aid Study (NPSAS:2000, NPSAS:04, NPSAS:08, and NPSAS:12) to briefly present trends in out-of-pocket net price for college, the amount that students and their families must pay to attend college after subtracting grants, loans, work-study, and all other…

  11. 利用EVC实现Pocket PC和工控机串行通信%Implementation of serial communication software between pocket PC and industry control computer based on EVC

    Institute of Scientific and Technical Information of China (English)

    张军; 蒋铁登

    2006-01-01

    串口通信广泛应用于工业控制领域,PocketPC利用自身串口通信功能和使用方便的特点,使得它具有广泛的应用范围和良好的应用前景.为了实现PocketPC对工业控制系统的现场控制,通过对eMbedded visual C++(EVC)3.0在PocketPC2002操作系统平台和LabWindows/CVI在Windows操作系统平台上的串口通信软件的关键技术进行了研究,实现了PocketPC和工控机之间的串口通信,从而利用Pocket PC实现对工业设备的现场控制.

  12. Steered Molecular Dynamics Simulation on the Binding of NNRTI to HIV-1 RT

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Lingling; Shen, Jianhua; Luo, Xiaomin; Cheng, Feng; Xu, Yechun; Chen, Kaixian; Arnold, Edward; Ding, Jianping; Jiang, Hualiang

    2003-06-01

    HIV-1 reverse transcriptase (RT) is the primary target for anti-AIDS chemotherapy. Nonnucleoside RT inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 RT. The binding and unbinding processes of alpha-APA, an NNRTI, have been studied using nanosecond conventional molecular dynamics and steered molecular dynamics simulations. The simulation results show that the unbinding process of alpha-APA consists of three phases based on the position of alpha-APA in relation to the entrance of the binding pocket. When alpha-APA is bound in the binding pocket, the hydrophobic interactions between HIV-1 RT and alpha-APA dominate the binding; however, the hydrophilic interactions (both direct and water-bridged hydrogen bonds) also contribute to the stabilizing forces. Whereas Tyr-181 makes significant hydrophobic interactions with alpha-APA, Tyr-188 forms a strong hydrogen bond with the acylamino group (N14) of alpha-APA. These two residues have very flexible side chains and appear to act as two ''flexible clamps'' discouraging alpha-APA to dissociate from the binding pocket. At the pocket entrance, two relatively inflexible residues, Val-179 and Leu-100, gauge the openness of the entrance and form the bottleneck of the inhibitor-unbinding pathway. Two special water molecules at the pocket entrance appear to play important roles in inhibitor recognition of binding and unbinding. These water molecules form water bridges between the polar groups of the inhibitor and the residues around the entrance, and between the polar groups of the inhibitor themselves. The water-bridged interactions not only induce the inhibitor to adopt an energetically favorable conformation so the inhibitor can pass through the pocket entrance, but also stabilize the binding of the inhibitor in the pocket to prevent the inhibitor's dissociation. The complementary steered molecular dynamics and conventional molecular dynamics

  13. The function and three-dimensional structure of a thromboxane A2/cysteinyl leukotriene-binding protein from the saliva of a mosquito vector of the malaria parasite.

    Directory of Open Access Journals (Sweden)

    Patricia H Alvarenga

    Full Text Available The highly expressed D7 protein family of mosquito saliva has previously been shown to act as an anti-inflammatory mediator by binding host biogenic amines and cysteinyl leukotrienes (CysLTs. In this study we demonstrate that AnSt-D7L1, a two-domain member of this group from Anopheles stephensi, retains the CysLT binding function seen in the homolog AeD7 from Aedes aegypti but has lost the ability to bind biogenic amines. Unlike any previously characterized members of the D7 family, AnSt-D7L1 has acquired the important function of binding thromboxane A(2 (TXA(2 and its analogs with high affinity. When administered to tissue preparations, AnSt-D7L1 abrogated Leukotriene C(4 (LTC(4-induced contraction of guinea pig ileum and contraction of rat aorta by the TXA(2 analog U46619. The protein also inhibited platelet aggregation induced by both collagen and U46619 when administered to stirred platelets. The crystal structure of AnSt-D7L1 contains two OBP-like domains and has a structure similar to AeD7. In AnSt-D7L1, the binding pocket of the C-terminal domain has been rearranged relative to AeD7, making the protein unable to bind biogenic amines. Structures of the ligand complexes show that CysLTs and TXA(2 analogs both bind in the same hydrophobic pocket of the N-terminal domain. The TXA(2 analog U46619 is stabilized by hydrogen bonding interactions of the ω-5 hydroxyl group with the phenolic hydroxyl group of Tyr 52. LTC(4 and occupies a very similar position to LTE(4 in the previously determined structure of its complex with AeD7. As yet, it is not known what, if any, new function has been acquired by the rearranged C-terminal domain. This article presents, to our knowledge, the first structural characterization of a protein from mosquito saliva that inhibits collagen mediated platelet activation.

  14. Health care consumers’ opinions on different variants of out-of-pocket payments. A cross-sectional questionnaire study .

    NARCIS (Netherlands)

    Reitsma, M.; Jong, J. de

    2014-01-01

    Background: Health care expenditures are rising faster than the resources in many countries. One of the tools to reduce this expenditures is by introducing out-of-pocket payments. With these payments insured have to pay (part of) the costs of health care themselves. One of the aims of out-of pocket

  15. Ondansetron and Granisetron Binding Orientation in the 5-HT3 Receptor Determined by Unnatural Amino Acid Mutagenesis

    Science.gov (United States)

    Duffy, Noah H.; Lester, Henry A.; Dougherty, Dennis A.

    2012-01-01

    The serotonin type 3 receptor (5-HT3R) is a ligand-gated ion channel that mediates fast synaptic transmission in the central and peripheral nervous systems. The 5-HT3R is a therapeutic target, and the clinically available drugs ondansetron and granisetron inhibit receptor activity. Their inhibitory action is through competitive binding to the native ligand binding site, although the binding orientation of the drugs at the receptor has been a matter of debate. Here we heterologously express mouse 5-HT3A receptors in Xenopus oocytes and use unnatural amino acid mutagenesis to establish a cation-π interaction for both ondansetron and granisetron to tryptophan 183 in the ligand binding pocket. This cation-π interaction establishes a binding orientation for both ondansetron and granisetron within the binding pocket. PMID:22873819

  16. Enhanced performance of GeSn source-pocket tunnel field-effect transistors for low-power applications

    Science.gov (United States)

    Liu, Lei; Liang, Renrong; Wang, Jing; Xu, Jun

    2016-07-01

    Germanium–tin (GeSn) source-pocket tunnel field-effect transistors (TFETs) are comprehensively investigated by numerical device simulations at low supply voltages. Device configurations with homo- and hetero-tunneling junctions (TJ) are analyzed and compared. It is shown that direct-gap GeSn alloys are favorable for increasing the source-pocket tunneling rate. Increasing the source Sn composition of the device may aid the on-state current increase, but the subthreshold swing (SS) is degraded because of the reduced band gap. At ultrascaled supply voltages, the GeSn hetero-TJ TFET with higher pocket Sn composition exhibits the best performance and SS, and the device performance can be further improved by increasing the Sn composition in the pocket region. These simulation results could be used to understand and optimize the performance of GeSn source-pocket TFETs, which are very promising electronic devices for low-power applications.

  17. Chicken avidin-related proteins show altered biotin-binding and physico-chemical properties as compared with avidin.

    Science.gov (United States)

    Laitinen, Olli H; Hytönen, Vesa P; Ahlroth, Mervi K; Pentikäinen, Olli T; Gallagher, Ciara; Nordlund, Henri R; Ovod, Vladimir; Marttila, Ari T; Porkka, Eevaleena; Heino, Sanna; Johnson, Mark S; Airenne, Kari J; Kulomaa, Markku S

    2002-01-01

    Chicken avidin and bacterial streptavidin are proteins familiar from their use in various (strept)avidin-biotin technological applications. Avidin binds the vitamin biotin with the highest affinity known for non-covalent interactions found in nature. The gene encoding avidin (AVD) has homologues in chicken, named avidin-related genes (AVRs). In the present study we used the AVR genes to produce recombinant AVR proteins (AVRs 1, 2, 3, 4/5, 6 and 7) in insect cell cultures and characterized their biotin-binding affinity and biochemical properties. Amino acid sequence analysis and molecular modelling were also used to predict and explain the properties of the AVRs. We found that the AVR proteins are very similar to avidin, both structurally and functionally. Despite the numerous amino acid substitutions in the subunit interface regions, the AVRs form extremely stable tetramers similar to those of avidin. Differences were found in some physico-chemical properties of the AVRs as compared with avidin, including lowered pI, increased glycosylation and, most notably, reversible biotin binding for two AVRs (AVR1 and AVR2). Molecular modelling showed how the replacement Lys(111)-->isoleucine in AVR2 alters the shape of the biotin-binding pocket and thus results in reversible binding. Both modelling and biochemical analyses showed that disulphide bonds can form and link monomers in AVR4/5, a property not found in avidin. These, together with the other properties of the AVRs described in the present paper, may offer advantages over avidin and streptavidin, making the AVRs applicable for improved avidin-biotin technological applications. PMID:11964162

  18. β-Subunit Binding Is Sufficient for Ligands to Open the Integrin αIIbβ3 Headpiece.

    Science.gov (United States)

    Lin, Fu-Yang; Zhu, Jianghai; Eng, Edward T; Hudson, Nathan E; Springer, Timothy A

    2016-02-26

    The platelet integrin αIIbβ3 binds to a KQAGDV motif at the fibrinogen γ-chain C terminus and to RGD motifs present in loops in many extracellular matrix proteins. These ligands bind in a groove between the integrin α and β-subunits; the basic Lys or Arg side chain hydrogen bonds to the αIIb-subunit, and the acidic Asp side chain coordinates to a metal ion held by the β3-subunit. Ligand binding induces headpiece opening, with conformational change in the β-subunit. During this opening, RGD slides in the ligand-binding pocket toward αIIb, with movement of the βI-domain β1-α1 loop toward αIIb, enabling formation of direct, charged hydrogen bonds between the Arg side chain and αIIb. Here we test whether ligand interactions with β3 suffice for stable ligand binding and headpiece opening. We find that the AGDV tetrapeptide from KQAGDV binds to the αIIbβ3 headpiece with affinity comparable with the RGDSP peptide from fibronectin. AGDV induced complete headpiece opening in solution as shown by increase in hydrodynamic radius. Soaking of AGDV into closed αIIbβ3 headpiece crystals induced intermediate states similarly to RGDSP. AGDV has very little contact with the α-subunit. Furthermore, as measured by epitope exposure, AGDV, like the fibrinogen γ C-terminal peptide and RGD, caused integrin extension on the cell surface. Thus, pushing by the β3-subunit on Asp is sufficient for headpiece opening and ligand sliding, and no pulling by the αIIb subunit on Arg is required.

  19. IQGAP Proteins Reveal an Atypical Phosphoinositide (aPI) Binding Domain with a Pseudo C2 Domain Fold

    Energy Technology Data Exchange (ETDEWEB)

    Dixon, Miles J.; Gray, Alexander; Schenning, Martijn; Agacan, Mark; Tempel, Wolfram; Tong, Yufeng; Nedyalkova, Lyudmila; Park, Hee-Won; Leslie, Nicholas R.; van Aalten, Daan M.F.; Downes, C. Peter; Batty, Ian H. (Toronto); (Dundee)

    2012-10-16

    Class I phosphoinositide (PI) 3-kinases act through effector proteins whose 3-PI selectivity is mediated by a limited repertoire of structurally defined, lipid recognition domains. We describe here the lipid preferences and crystal structure of a new class of PI binding modules exemplified by select IQGAPs (IQ motif containing GTPase-activating proteins) known to coordinate cellular signaling events and cytoskeletal dynamics. This module is defined by a C-terminal 105-107 amino acid region of which IQGAP1 and -2, but not IQGAP3, binds preferentially to phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3). The binding affinity for PtdInsP3, together with other, secondary target-recognition characteristics, are comparable with those of the pleckstrin homology domain of cytohesin-3 (general receptor for phosphoinositides 1), an established PtdInsP3 effector protein. Importantly, the IQGAP1 C-terminal domain and the cytohesin-3 pleckstrin homology domain, each tagged with enhanced green fluorescent protein, were both re-localized from the cytosol to the cell periphery following the activation of PI 3-kinase in Swiss 3T3 fibroblasts, consistent with their common, selective recognition of endogenous 3-PI(s). The crystal structure of the C-terminal IQGAP2 PI binding module reveals unexpected topological similarity to an integral fold of C2 domains, including a putative basic binding pocket. We propose that this module integrates select IQGAP proteins with PI 3-kinase signaling and constitutes a novel, atypical phosphoinositide binding domain that may represent the first of a larger group, each perhaps structurally unique but collectively dissimilar from the known PI recognition modules.

  20. Pairing symmetries of several iron-based superconductor families and some similarities with cuprates and heavy-fermions

    Directory of Open Access Journals (Sweden)

    Das Tanmoy

    2012-03-01

    Full Text Available We show that, by using the unit-cell transformation between 1 Fe per unit cell to 2 Fe per unit cell, one can qualitatively understand the pairing symmetry of several families of iron-based superconductors. In iron-pnictides and iron-chalcogenides, the nodeless s±-pairing and the resulting magnetic resonance mode transform nicely between the two unit cells, while retaining all physical properties unchanged. However, when the electron-pocket disappears from the Fermi surface with complete doping in KFe2As2, we find that the unit-cell invariant requirement prohibits the occurrence of s±-pairing symmetry (caused by inter-hole-pocket nesting. However, the intra-pocket nesting is compatible here, which leads to a nodal d-wave pairing. The corresponding Fermi surface topology and the pairing symmetry are similar to Ce-based heavy-fermion superconductors. Furthermore, when the Fermi surface hosts only electron-pockets in KyFe2-xSe2, the inter-electron-pocket nesting induces a nodeless and isotropic d-wave pairing. This situation is analogous to the electron-doped cuprates, where the strong antiferromagnetic order creates similar disconnected electron-pocket Fermi surface, and hence nodeless d-wave pairing appears. The unit-cell transformation in KyFe2-xSe2 exhibits that the d-wave pairing breaks the translational symmetry of the 2 Fe unit cell, and thus cannot be realized unless a vacancy ordering forms to compensate for it. These results are consistent with the coexistence picture of a competing order and nodeless d-wave superconductivity in both cuprates and KyFe1.6Se2.

  1. Out-of-pocket healthcare payments on chronic conditions impoverish urban poor in Bangalore, India

    Directory of Open Access Journals (Sweden)

    Bhojani Upendra

    2012-11-01

    Full Text Available Abstract Background The burden of chronic conditions is on the rise in India, necessitating long-term support from healthcare services. Healthcare, in India, is primarily financed through out-of-pocket payments by households. Considering scarce evidence available from India, our study investigates whether and how out-of-pocket payments for outpatient care affect individuals with chronic conditions. Methods A large census covering 9299 households was conducted in Bangalore, India. Of these, 3202 households that reported presence of chronic condition were further analysed. Data was collected using a structured household-level questionnaire. Out-of-pocket payments, catastrophic healthcare expenditure, and the resultant impoverishment were measured using a standard technique. Results The response rate for the census was 98.5%. Overall, 69.6% (95%CI=68.0-71.2 of households made out-of-pocket payments for outpatient care spending a median of 3.2% (95%CI=3.0-3.4 of their total income. Overall, 16% (95%CI=14.8-17.3 of households suffered financial catastrophe by spending more than 10% of household income on outpatient care. Occurrence and intensity of financial catastrophe were inequitably high among poor. Low household income, use of referral hospitals as place for consultation, and small household size were associated with a greater likelihood of incurring financial catastrophe. The out-of-pocket spending on chronic conditions doubled the number of people living below the poverty line in one month, with further deepening of their poverty. In order to cope, households borrowed money (4.2% instances, and sold or mortgaged their assets (0.4% instances. Conclusions This study provides evidence from India that the out-of-pocket payment for chronic conditions, even for outpatient care, pushes people into poverty. Our findings suggest that improving availability of affordable medications and diagnostics for chronic conditions, as well as strengthening the

  2. Estimating similarity of XML Schemas using path similarity measure

    Directory of Open Access Journals (Sweden)

    Veena Trivedi

    2012-07-01

    Full Text Available In this paper, an attempt has been made to develop an algorithm which estimates the similarity for XML Schemas using multiple similarity measures. For performing the task, the XML Schema element information has been represented in the form of string and four different similarity measure approaches have been employed. To further improve the similarity measure, an overall similarity measure has also been calculated. The approach used in this paper is a distinguished one, as it calculates the similarity between two XML schemas using four approaches and gives an integrated values for the similarity measure. Keywords-componen

  3. Enthalpy/entropy compensation effects from cavity desolvation underpin broad ligand binding selectivity for rat odorant binding protein 3.

    Science.gov (United States)

    Portman, Katherine L; Long, Jed; Carr, Stephen; Briand, Loïc; Winzor, Donald J; Searle, Mark S; Scott, David J

    2014-04-15

    Evolution has produced proteins with exquisite ligand binding specificity, and manipulating this effect has been the basis for much of modern rational drug design. However, there are general classes of proteins with broader ligand selectivity linked to function, the origin of which is poorly understood. The odorant binding proteins (OBPs) sequester volatile molecules for transportation to the olfactory receptors. Rat OBP3, which we characterize by X-ray crystallography and NMR, binds a homologous series of aliphatic γ-lactones within its aromatic-rich hydrophobic pocket with remarkably little variation in affinity but extensive enthalpy/entropy compensation effects. We show that the binding energetics are modulated by two desolvation processes with quite different thermodynamic signatures. Ligand desolvation follows the classical hydrophobic effect; however, cavity desolvation is consistent with the liberation of "high energy" water molecules back into bulk solvent with a strong, but compensated, enthalpic contribution, which together underpin the origins of broad ligand binding selectivity.

  4. Crystallographic analysis reveals the structural basis of the high-affinity binding of iophenoxic acid to human serum albumin

    Directory of Open Access Journals (Sweden)

    Chung Chun-wa

    2011-04-01

    Full Text Available Abstract Background Iophenoxic acid is an iodinated radiocontrast agent that was withdrawn from clinical use because of its exceptionally long half-life in the body, which was due in part to its high-affinity binding to human serum albumin (HSA. It was replaced by Iopanoic acid, which has an amino rather than a hydroxyl group at position 3 on the iodinated benzyl ring and, as a result, binds to albumin with lower affinity and is excreted more rapidly from the body. To understand how iophenoxic acid binds so tightly to albumin, we wanted to examine the structural basis of its interaction with HSA. Results We have determined the co-crystal structure of HSA in complex with iophenoxic acid at 2.75 Å resolution, revealing a total of four binding sites, two of which - in drugs sites 1 and 2 on the protein - are likely to be occupied at clinical doses. High-affinity binding of iophenoxic acid occurs at drug site 1. The structure reveals that polar and apolar groups on the compound are involved in its interactions with drug site 1. In particular, the 3-hydroxyl group makes three hydrogen bonds with the side-chains of Tyr 150 and Arg 257. The mode of binding to drug site 2 is similar except for the absence of a binding partner for the hydroxyl group on the benzyl ring of the compound. Conclusions The HSA-iophenoxic acid structure indicates that high-affinity binding to drug site 1 is likely to be due to extensive desolvation of the compound, coupled with the ability of the binding pocket to provide a full set of salt-bridging or hydrogen bonding partners for its polar groups. Consistent with this interpretation, the structure also suggests that the lower-affinity binding of iopanoic acid arises because replacement of the 3-hydroxyl by an amino group eliminates hydrogen bonding to Arg 257. This finding underscores the importance of polar interactions in high-affinity binding to albumin.

  5. Reconstitution of a surface transferrin binding complex in insect form Trypanosoma brucei.

    OpenAIRE

    Ligtenberg, M.J.; Bitter, W.; Kieft, R.; Steverding, D; Janssen, H.; Calafat, J.; Borst, P

    1994-01-01

    In the bloodstream of the mammalian host, Trypanosoma brucei takes up host transferrin by means of a high-affinity uptake system, presumably a transferrin receptor. Transferrin-binding activity is seen in the flagellar pocket and is absent in insect form trypanosomes. By transfection we have reconstituted a transferrin-binding complex in insect form trypanosomes. Formation of this complex requires the products of two genes that are part of a variant surface glycoprotein expression site, expre...

  6. Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites

    DEFF Research Database (Denmark)

    Kaae, Birgitte Høiriis; Harpsøe, Kasper; Kastrup, Jette Sandholm Jensen;

    2007-01-01

    have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2...... subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites....

  7. The use of pocket-size imaging devices: a position statement of the European Association of Echocardiography.

    Science.gov (United States)

    Sicari, Rosa; Galderisi, Maurizio; Voigt, Jens-Uwe; Habib, Gilbert; Zamorano, Jose L; Lancellotti, Patrizio; Badano, Luigi P

    2011-02-01

    Pocket-size imaging devices are a completely new type of echo machines which have recently reached the market. They are very cheap, smartphone-size hand-held echo machines with limited technical capabilities. The aim of this European Association of Echocardiography (EAE) position paper is to provide recommendations on the use of pocket-size imaging devices in the clinical arena by profiling the educational needs of potential users other than cardiologists experts in echo. EAE recommendations about pocket-size imaging devices can be summarized in: (1) pocket-size imaging devices do not provide a complete diagnostic echocardiographic examination. The range of indications for their use is therefore limited. (2) Imaging assessment with pocket-size imaging devices should be reported as part of the physical examination of the patient. Image data should be stored according to the applicable national rules for technical examinations. (3) With the exception of cardiologists who are certified for transthoracic echocardiography according to national legislation, specific training and certification is recommended for all users. The certification should be limited to the clinical questions that can potentially be answered by pocket-size devices. (4) The patient has to be informed that an examination with the current generation of pocket-size imaging devices does not replace a complete echocardiogram. PMID:21216764

  8. The Impact of Health Insurance Programs on Out-of-Pocket Expenditures in Indonesia: An Increase or a Decrease?

    Directory of Open Access Journals (Sweden)

    Aurelia Souares

    2013-07-01

    Full Text Available We used panel data from the Indonesian Family Life Survey to investigate the impact of health insurance programs on reducing out-of-pocket expenditures. We employed three linear panel data models, two of which accounted for endogeneity: pooled ordinary least squares (OLS, pooled two-stage least squares (2SLS for instrumental variable (IV, and fixed effects (FE. The study revealed that two health insurance programs had a significantly negative impact on out-of-pocket expenditures by using IV estimates. In the IV model, Askeskin decreased out-of-pocket expenditures by 34% and Askes by 55% compared with non-Askeskin and non-Askes, respectively, while Jamsostek was found to bear a nonsignificant effect on out-of-pocket expenditures. In the FE model, only Askeskin had a significant negative effect with an 11% reduction on out-of-pocket expenditures. This study showed that two large existing health insurance programs in Indonesia, Askeskin and Askes, effectively reduced household out-of-pocket expenditures. The ability of programs to offer financial protection by reducing out-of-pocket expenditures is likely to be a direct function of their benefits package and co-payment policies.

  9. The binding sites for cocaine and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L;

    2008-01-01

    T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive...

  10. Modulated Degradation of Transient Electronic Devices through Multilayer Silk Fibroin Pockets.

    Science.gov (United States)

    Brenckle, Mark A; Cheng, Huanyu; Hwang, Sukwon; Tao, Hu; Paquette, Mark; Kaplan, David L; Rogers, John A; Huang, Yonggang; Omenetto, Fiorenzo G

    2015-09-16

    The recent introduction of transient, bioresorbable electronics into the field of electronic device design offers promise for the areas of medical implants and environmental monitors, where programmed loss of function and environmental resorption are advantageous characteristics. Materials challenges remain, however, in protecting the labile device components from degradation at faster than desirable rates. Here we introduce an indirect passivation strategy for transient electronic devices that consists of encapsulation in multiple air pockets fabricated from silk fibroin. This approach is investigated through the properties of silk as a diffusional barrier to water penetration, coupled with the degradation of magnesium-based devices in humid air. Finally, silk pockets are demonstrated to be useful for controlled modulation of device lifetime. This approach may provide additional future opportunities for silk utility due to the low immunogenicity of the material and its ability to stabilize labile biotherapeutic dopants. PMID:26305434

  11. Pocket PC基于XML的异构数据库同步

    Institute of Scientific and Technical Information of China (English)

    王璐

    2011-01-01

    在嵌入式数据库领域,世界各大数据库厂商都有各自的移动解决方案,但每种数据同步方案都针对自己的数据库,不能兼容其他的数据库产品。该文介绍的是Pocket PC在微软的Windows mobile操作系统平台下,通过XML方式进行的一种跨平台的数据库同步方法。文中介绍了Pocket PC以XML方式分别对PC服务器中的Microsoft SQL Server数据库和Microsoft Access数据库的同步过程,并对比RDA,提出了优势和局限所在。

  12. Characterization of vertical strain silicon MOSFET incorporating dielectric pocket (SDP-VMOSFET)

    Energy Technology Data Exchange (ETDEWEB)

    Napiah, Z. A. F. M., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com; Makhtar, N., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com; Othman, M. A., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com; Idris, M. I., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com; Arith, F., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com; Yasin, N. Y. M., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com; Taib, S. N., E-mail: zulatfyi@utem.edu.my, E-mail: nazirah6969@gmail.com, E-mail: azlishah@utem.edu.my, E-mail: idzdihar@utem.edu.my, E-mail: faiz.arith@utem.edu.my, E-mail: yashidar@yahoo.com, E-mail: sitinabilahtaib@gmail.com [Centre for Telecommunication Research and Innovation (CeTRI), Faculty of Electronic and Computer Engineering, Universiti Teknikal Malaysia Melaka, Hang Tuah Jaya, 76100 Durian Tunggal, Melaka (Malaysia)

    2014-02-24

    The vertical Metal-Oxide-Semiconductor Field-Effect-Transistor (MOSFET) leads to a double channel width that can increase the packaging density. The strained silicon MOSFET was introduced to modify the carrier transport properties of silicon in order to enhance transport of both electrons and holes within strained layer. Dielectric pocket was act to control encroachment of the drain doping into the channel and reduce short channel effects (SCE). SDP-VMOSFET which was a combination of those advantages was proposed to overcome the SCE in term of leakage current, threshold voltage roll-off also Drain Induce Barrier Lowering (DIBL). As a result, SDP-VMOSFET produces a better threshold voltage and DIBL compared to related structures. Meanwhile, it gives slightly increased for leakage current compared to Vertical MOSFET Incorporating Dielectric Pocket. The characteristics of the SDP-VMOSFET are analyzed in order to optimize the performance of the device and leading to the next generation of IC technology.

  13. Pars tensa retraction pockets in children: treatment by excision and ventilation tube insertion.

    Science.gov (United States)

    Srinivasan, V; Banhegyi, G; O'Sullivan, G; Sherman, I W

    2000-08-01

    Tympanic membrane retraction pockets involving the pars tensa are not uncommon in clinical practice. Recurrent infections, ossicular erosion and cholesteatoma are the recognized sequelae. The management options include surveillance, medical treatment and surgery. The surgical procedures range from grommet insertion to extensive tympanoplasty procedures. We report our experience with simple excision and grommet insertion, performed in 31 ears in 26 patients as day cases. The follow-up ranged from 8 to 34 months with a mean of 16 months. The procedure was successful in 23 ears (success rate of 74%). Recurrence of retraction occurred in seven ears and in one ear there was a persistent perforation. Age, previous grommet insertion and severity of retraction did not have a statistically significant influence on the final outcome. We conclude that excision and grommet insertion is a simple, safe and efficient procedure for the management of tympanic membrane retraction pockets and can be considered in preference to extensive tympanoplasty. PMID:10971530

  14. Triple Point Collision and Origin of Unburned Gas Pockets in Irregular Detonations

    OpenAIRE

    Mahmoudi, Yasser; Mazaheri, Kiumars

    2014-01-01

    The turbulent structure of an irregular detonation is studied through very high resolution numerical simulations of 600 points per half reaction length. The aim is to explore the nature of the transverse waves during the collision and reflection processes of the triple point with the channel walls. Consequently the formation and consumption mechanism of unreacted gas pockets is studied. Results show that as the triple point collides with the wall, the transverse shock interacts with the unrea...

  15. Focused Cardiac Ultrasound Using a Pocket-Size Device in the Emergency Room

    OpenAIRE

    Mancuso, Frederico José Neves; Siqueira, Vicente Nicoliello; Moisés, Valdir Ambrósio; Gois, Aécio Flavio Teixeira; de Paola, Angelo Amato Vincenzo; Carvalho, Antonio Carlos Camargo; Campos, Orlando

    2014-01-01

    Background Cardiovascular urgencies are frequent reasons for seeking medical care. Prompt and accurate medical diagnosis is critical to reduce the morbidity and mortality of these conditions. Objective To evaluate the use of a pocket-size echocardiography in addition to clinical history and physical exam in a tertiary medical emergency care. Methods One hundred adult patients without known cardiac or lung diseases who sought emergency care with cardiac complaints were included. Patients with ...

  16. Out-of-pocket health spending by poor and near-poor elderly Medicare beneficiaries.

    OpenAIRE

    Gross, D J; Alecxih, L; Gibson, M J; Corea, J; Caplan, C; Brangan, N

    1999-01-01

    OBJECTIVE: To estimate out-of-pocket health care spending by lower-income Medicare beneficiaries, and to examine spending variations between those who receive Medicaid assistance and those who do not receive such aid. DATA SOURCES AND COLLECTION: 1993 Medicare Current Beneficiary Survey (MCBS) Cost and Use files, supplemented with data from the Bureau of the Census (Current Population Survey); the Congressional Budget Office; the Health Care Financing Administration, Office of the Actuary (Na...

  17. Young Adult Insurance Coverage And Out-Of-Pocket Spending: Long-Term Patterns.

    Science.gov (United States)

    Berk, Marc L; Fang, Zhengyi

    2016-04-01

    The Affordable Care Act appears to have improved health insurance coverage for young adults (ages 18-30). But data from twenty national surveys conducted between 1977 and 2013 paint a more complex picture, showing coverage rates lower in 2013 than they were thirty-six years earlier. Racial and ethnic disparities in coverage have declined recently, while out-of-pocket expenditures remain low for most young adults. PMID:27008855

  18. Morphological adaptations for digging and climate-impacted soil properties define pocket gopher (Thomomys spp. distributions.

    Directory of Open Access Journals (Sweden)

    Ariel E Marcy

    Full Text Available Species ranges are mediated by physiology, environmental factors, and competition with other organisms. The allopatric distribution of five species of northern Californian pocket gophers (Thomomys spp. is hypothesized to result from competitive exclusion. The five species in this environmentally heterogeneous region separate into two subgenera, Thomomys or Megascapheus, which have divergent digging styles. While all pocket gophers dig with their claws, the tooth-digging adaptations of subgenus Megascapheus allow access to harder soils and climate-protected depths. In a Northern Californian locality, replacement of subgenus Thomomys with subgenus Megascapheus occurred gradually during the Pleistocene-Holocene transition. Concurrent climate change over this transition suggests that environmental factors--in addition to soil--define pocket gopher distributional limits. Here we show 1 that all pocket gophers occupy the subset of less energetically costly soils and 2 that subgenera sort by percent soil clay, bulk density, and shrink-swell capacity (a mineralogical attribute. While clay and bulk density (without major perturbations stay constant over decades to millennia, low precipitation and high temperatures can cause shrink-swell clays to crack and harden within days. The strong yet underappreciated interaction between soil and moisture on the distribution of vertebrates is rarely considered when projecting species responses to climatic change. Furthermore, increased precipitation alters the weathering processes that create shrink-swell minerals. Two projected outcomes of ongoing climate change--higher temperatures and precipitation--will dramatically impact hardness of soil with shrink-swell minerals. Current climate models do not include factors controlling soil hardness, despite its impact on all organisms that depend on a stable soil structure.

  19. Cytological analysis of the periodontal pocket in patients with aggressive periodontitis and chronic periodontitis

    OpenAIRE

    E Castro Cecilia; A Koss Myriam; E López María

    2014-01-01

    Background: Oral exfoliative cytology includes the study and interpretation of the features cells exfoliated from the oral mucosa. The aim of this study was to analyze cytological changes in the periodontal pocket of patients with different clinical stages of aggressive periodontitis (AP) and chronic periodontitis (CP). Materials and Methods: Patients aged 24-54 years, of whom 41 were diagnosed with AP, 40 with CP, sub-classified as mild, moderate and severe periodontitis, and 40 healthy indi...

  20. Characterization of polymer release from the flagellar pocket of Leishmania mexicana promastigotes

    OpenAIRE

    1994-01-01

    Trypanosomatids contain a unique compartment, the flagellar pocket, formed by an invagination of the plasma membrane at the base of the flagellum, which is considered to be the sole cellular site for endocytosis and exocytosis of macromolecules. The culture supernatant of Leishmania mexicana promastigotes, the insect stage of this protozoan parasite, contains two types of polymers: a filamentous acid phosphatase (sAP) composed of a 100-kD phosphoglycoprotein with non- covalently associated pr...

  1. Primary cutaneous anaplastic large cell lymphoma successfully treated with local thermotherapy using pocket hand warmers.

    Science.gov (United States)

    Honma, Masaru; Hashimoto, Makoto; Iwasaki, Takeshi; Iinuma, Shin; Takahashi, Hidetoshi; Ishida-Yamamoto, Akemi; Iizuka, Hajime

    2008-11-01

    Apart from for cutaneous deep fungal or mycobacterial infections, thermotherapy has been used for various malignant tumors. We report a case of primary cutaneous anaplastic large cell lymphoma, which responded quite well to topical thermotherapy using chemical pocket hand warmers. The treatment resulted in an immediate tumor regression without recurrence. This method is simple and might be a useful tool against solitary cutaneous lymphoma, especially of elderly patients with poor performance status or with various systemic complications. PMID:19120772

  2. Multiple Fermi pockets revealed by Shubnikov-de Haas oscillations in WTe2

    OpenAIRE

    Xiang, Fei-Xiang; Veldhorst, Menno; Dou, Shi-Xue; Wang, Xiao-lin

    2015-01-01

    We use magneto-transport measurements to investigate the electronic structure of WTe2 single crystals. A non-saturating and parabolic magnetoresistance is observed in the temperature range between 2.5 to 200 K and magnetic fields up to 8 T. Shubnikov - de Haas oscillations with beating patterns are observed. The fast Fourier transform of the SdH oscillations reveals three oscillation frequencies, corresponding to three pairs of Fermi pockets with comparable effective masses , m* ~ 0.31 me. By...

  3. A mollusk retinoic acid receptor (RAR) ortholog sheds light on the evolution of ligand binding.

    Science.gov (United States)

    Gutierrez-Mazariegos, Juliana; Nadendla, Eswar Kumar; Lima, Daniela; Pierzchalski, Keely; Jones, Jace W; Kane, Maureen; Nishikawa, Jun-Ichi; Hiromori, Youhei; Nakanishi, Tsuyoshi; Santos, Miguel M; Castro, L Filipe C; Bourguet, William; Schubert, Michael; Laudet, Vincent

    2014-11-01

    Nuclear receptors are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors because they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NlRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with retinoid X receptor. Surprisingly, we also find that NlRAR does not bind all-trans retinoic acid or any other retinoid we tested. Furthermore, NlRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit coactivators in the presence of these compounds. Three-dimensional modeling of the ligand-binding domain of NlRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NlRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether our data suggest that, in mollusks, RAR has lost its affinity for all-trans retinoic acid, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of nuclear receptors validated by millions of years of evolution that were impossible to reveal in model organisms. PMID:25116705

  4. Multivariate Time Series Similarity Searching

    OpenAIRE

    Jimin Wang; Yuelong Zhu; Shijin Li; Dingsheng Wan; Pengcheng Zhang

    2014-01-01

    Multivariate time series (MTS) datasets are very common in various financial, multimedia, and hydrological fields. In this paper, a dimension-combination method is proposed to search similar sequences for MTS. Firstly, the similarity of single-dimension series is calculated; then the overall similarity of the MTS is obtained by synthesizing each of the single-dimension similarity based on weighted BORDA voting method. The dimension-combination method could use the existing similarity searchin...

  5. The influence of Injection Pockets on the Performance of Tilting-Pad Thrust Bearings: Part I - Theory

    DEFF Research Database (Denmark)

    Heinrichson, Niels; Santos, Ilmar; Fuerst, Axel

    2006-01-01

    This is Part I of a two-part series of papers describing the effects of high pressure injection pockets on the operating conditions of tilting-pad thrust bearings. A numerical model based on the Reynolds equation is developed extending the three dimensional thermo-elasto-hydrodynamic (TEHD......) analysis of tilting-pad thrust bearings to include the effects of high pressure injection and recesses in the bearing pad. The model is applied to the analysis of an existing bearing of large dimensions and the influence of the pocket is analyzed. It is shown that a shallow pocket positively influences...

  6. Structural Analysis of Papain-Like NlpC/P60 Superfamily Enzymes with a Circularly Permuted Topology Reveals Potential Lipid Binding Sites

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Qingping; Rawlings, Neil D.; Chiu, Hsiu-Ju; Jaroszewski, Lukasz; Klock, Heath E.; Knuth, Mark W.; Miller, Mitchell D.; Elsliger, Marc-Andre; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A. (SG); (Wellcome)

    2012-07-11

    NlpC/P60 superfamily papain-like enzymes play important roles in all kingdoms of life. Two members of this superfamily, LRAT-like and YaeF/YiiX-like families, were predicted to contain a catalytic domain that is circularly permuted such that the catalytic cysteine is located near the C-terminus, instead of at the N-terminus. These permuted enzymes are widespread in virus, pathogenic bacteria, and eukaryotes. We determined the crystal structure of a member of the YaeF/YiiX-like family from Bacillus cereus in complex with lysine. The structure, which adopts a ligand-induced, 'closed' conformation, confirms the circular permutation of catalytic residues. A comparative analysis of other related protein structures within the NlpC/P60 superfamily is presented. Permutated NlpC/P60 enzymes contain a similar conserved core and arrangement of catalytic residues, including a Cys/His-containing triad and an additional conserved tyrosine. More surprisingly, permuted enzymes have a hydrophobic S1 binding pocket that is distinct from previously characterized enzymes in the family, indicative of novel substrate specificity. Further analysis of a structural homolog, YiiX (PDB 2if6) identified a fatty acid in the conserved hydrophobic pocket, thus providing additional insights into possible function of these novel enzymes.

  7. Cytological analysis of the periodontal pocket in patients with aggressive periodontitis and chronic periodontitis

    Directory of Open Access Journals (Sweden)

    E Castro Cecilia

    2014-01-01

    Full Text Available Background: Oral exfoliative cytology includes the study and interpretation of the features cells exfoliated from the oral mucosa. The aim of this study was to analyze cytological changes in the periodontal pocket of patients with different clinical stages of aggressive periodontitis (AP and chronic periodontitis (CP. Materials and Methods: Patients aged 24-54 years, of whom 41 were diagnosed with AP, 40 with CP, sub-classified as mild, moderate and severe periodontitis, and 40 healthy individuals who were the control group. Samples of the epithelium of the periodontal pocket were taken for the cytological study. Results: Superficial and intermediate cell values were significantly greater in patients with AP than in patients with CP or the control group. Histiocyte number was higher in patients with CP than in those with AP, and differed significantly in both types of periodontitis compared to the control group. There were significant differences in polymorphonuclear neutrophil leukocytes when both types of periodontitis were compared to the control group. Microbial flora was statistically higher in patients with CP, and there were differences between patients with periodontitis and the control group. Conclusions: The cytological study demonstrated that patients with AP had greater tissue damage, shown by the increase in intermediate and superficial cells of the epithelium of the periodontal pocket compared to the group of healthy subjects and to a lesser extent, to patients with CP. Only superficial cells made it possible to differentiate the sub-stages of the disease.

  8. Fermi pockets and quantum oscillations of the Hall coefficient in high-temperature superconductors

    Science.gov (United States)

    Chakravarty, Sudip; Kee, Hae-Young

    2008-01-01

    Recent quantum oscillation measurements in high-temperature superconductors in high magnetic fields and low temperatures have ushered in a new era. These experiments explore the normal state from which superconductivity arises and provide evidence of a reconstructed Fermi surface consisting of electron and hole pockets in a regime in which such a possibility was previously considered to be remote. More specifically, the Hall coefficient has been found to oscillate according to the Onsager quantization condition, involving only fundamental constants and the areas of the pockets, but with a sign that is negative. Here, we explain the observations with the theory that the alleged normal state exhibits a hidden order, the d-density wave, which breaks symmetries signifying time reversal, translation by a lattice spacing, and a rotation by an angle π/2, while the product of any two symmetry operations is preserved. The success of our analysis underscores the importance of spontaneous breaking of symmetries, Fermi surface reconstruction, and conventional quasiparticles. We primarily focus on the version of the order that is commensurate with the underlying crystalline lattice, but we also touch on the consequences if the order were to incommensurate. It is shown that whereas commensurate order results in two independent oscillation frequencies as a function of the inverse of the applied magnetic field, incommensurate order leads to three independent frequencies. The oscillation amplitudes, however, are determined by the mobilities of the charge carriers comprising the Fermi pockets. PMID:18577585

  9. Mutations in the CRE pocket of bacterial RNA polymerase affect multiple steps of transcription.

    Science.gov (United States)

    Petushkov, Ivan; Pupov, Danil; Bass, Irina; Kulbachinskiy, Andrey

    2015-07-13

    During transcription, the catalytic core of RNA polymerase (RNAP) must interact with the DNA template with low-sequence specificity to ensure efficient enzyme translocation and RNA extension. Unexpectedly, recent structural studies of bacterial promoter complexes revealed specific interactions between the nontemplate DNA strand at the downstream edge of the transcription bubble (CRE, core recognition element) and a protein pocket formed by core RNAP (CRE pocket). We investigated the roles of these interactions in transcription by analyzing point amino acid substitutions and deletions in Escherichia coli RNAP. The mutations affected multiple steps of transcription, including promoter recognition, RNA elongation and termination. In particular, we showed that interactions of the CRE pocket with a nontemplate guanine immediately downstream of the active center stimulate RNA-hairpin-dependent transcription pausing but not other types of pausing. Thus, conformational changes of the elongation complex induced by nascent RNA can modulate CRE effects on transcription. The results highlight the roles of specific core RNAP-DNA interactions at different steps of RNA synthesis and suggest their importance for transcription regulation in various organisms.

  10. Multiple Fermi pockets revealed by Shubnikov-de Haas oscillations in WTe2

    Science.gov (United States)

    Xiang, Fei-Xiang; Veldhorst, Menno; Dou, Shi-Xue; Wang, Xiao-Lin

    2015-11-01

    The recently discovered non-saturating and parabolic magnetoresistance and the pressure-induced superconductivity at low temperature in WTe2 imply its rich electronic structure and possible practical applications. Here we use magnetotransport measurements to investigate the electronic structure of WTe2 single crystals. A non-saturating and parabolic magnetoresistance is observed from low temperature to high temperature up to 200 K with magnetic fields up to 8 T. Shubnikov-de Haas (SdH) oscillations with beating patterns are observed, the fast Fourier transform of which reveals three oscillation frequencies, corresponding to three pairs of Fermi pockets with comparable effective masses, m* ∼ 0.31~me . By fitting the Hall resistivity, we infer that they can be attributed to one pair of electron pockets and two pairs of hole pockets, together with nearly perfect compensation of the electron-hole carrier concentration. These magnetotransport measurements reveal the complex electronic structure in WTe2, explaining the non-saturating magnetoresistance.

  11. Molecular Mechanisms of Pharmaceutical Drug Binding into Calsequestrin

    Directory of Open Access Journals (Sweden)

    ChulHee Kang

    2012-11-01

    Full Text Available Calsequestrin (CASQ is a major Ca2+-storage/buffer protein present in the sarcoplasmic reticulum of both skeletal (CASQ1 and cardiac (CASQ2 muscles. CASQ has significant affinity for a number of pharmaceutical drugs with known muscular toxicities. Our approach, with in silico molecular docking, single crystal X-ray diffraction, and isothermal titration calorimetry (ITC, identified three distinct binding pockets on the surface of CASQ2, which overlap with 2-methyl-2,4-pentanediol (MPD binding sites observed in the crystal structure. Those three receptor sites based on canine CASQ1 crystal structure gave a high correlation (R2 = 0.80 to our ITC data. Daunomycin, doxorubicin, thioridazine, and trifluoperazine showed strong affinity to the S1 site, which is a central cavity formed between three domains of CASQ2. Some of the moderate-affinity drugs and some high-affinity drugs like amlodipine and verapamil displayed their binding into S2 sites, which are the thioredoxin-like fold present in each CASQ domain. Docking predictions combined with dissociation constants imply that presence of large aromatic cores and less flexible functional groups determines the strength of binding affinity to CASQ. In addition, the predicted binding pockets for both caffeine and epigallocatechin overlapped with the S1 and S2 sites, suggesting competitive inhibition by these natural compounds as a plausible explanation for their antagonistic effects on cardiotoxic side effects.

  12. Quantitative dissection of the binding contributions of ligand lysines of the receptor-associated protein (RAP) to the low density lipoprotein receptor-related protein (LRP1).

    Science.gov (United States)

    Dolmer, Klavs; Campos, Andres; Gettins, Peter G W

    2013-08-16

    Although lysines are known to be critical for ligand binding to LDL receptor family receptors, relatively small reductions in affinity have been found when such lysines have been mutated. To resolve this paradox, we have examined the specific binding contributions of four lysines, Lys-253, Lys-256, Lys-270, and Lys-289, in the third domain (D3) of receptor-associated protein (RAP), by eliminating all other lysine residues. Using D3 variants containing lysine subsets, we examined binding to the high affinity fragment CR56 from LRP1. With this simplification, we found that elimination of the lysine pairs Lys-253/Lys-256 and Lys-270/Lys-289 resulted in increases in Kd of 1240- and 100,000-fold, respectively. Each pair contributed additively to overall affinity, with 61% from Lys-270/Lys-289 and 39% from Lys-253/Lys-256. Furthermore, the Lys-270/Lys-289 pair alone could bind different single CR domains with similar affinity. Within the pairs, binding contributions of Lys-270 ≫ Lys-256 > Lys-253 ∼ Lys-289 were deduced. Importantly, however, Lys-289 could significantly compensate for the loss of Lys-270, thus explaining how previous studies have underestimated the importance of Lys-270. Calorimetry showed that favorable enthalpy, from Lys-256 and Lys-270, overwhelmingly drives binding, offset by unfavorable entropy. Our findings support a mode of ligand binding in which a proximal pair of lysines engages the negatively charged pocket of a CR domain, with two such pairs of interactions (requiring two CR domains), appropriately separated, being alone sufficient to provide the low nanomolar affinity found for most protein ligands of LDL receptor family members.

  13. Out-Of-Pocket Expenditure on Institutional Delivery in Rural Lucknow

    Directory of Open Access Journals (Sweden)

    Mukesh Shukla

    2015-06-01

    Full Text Available AbstractIntroduction: Promotion of reproductive health through institutional delivery has been adopted by government as a strategy for reducing maternal mortality rate but still about half of the deliveries have been conducted at home. Cost barrier is one of the major cause for preferring home delivery instead of institutional delivery. Not only the direct costs responsible for low institutional delivery but also indirect costs too accountable for less number of institutional births in the country. Aims & Objectives: To estimate the out of pocket expenditure incurred by households during delivery and its determinants. Materials and methods: A community based cross sectional study was conducted during which a total 272 households having women who had recently delivered in government institutions were interviewed. Result: The mean out of pocket expenditure was found to be Rs. 1406.04 ± 103.27 including spending’s on drugs, travel, pathological tests and unofficial payments. Low socioeconomic class, residence outside the catchment area of delivery point, tertiary and secondary health care facilities as place of delivery and low literacy status of head of the family below high school  were found to be significantly associated with out of pocket expenditure bivariate analysis (p<0.05. On multivariate analysis low socioeconomic (OR 22.40; 95% CI 9.44-53.15; p = 0.01   and residence (OR 13.07; 95% CI (1.58-116.55; p = 0.03  outside the catchment area of delivery point were found to be independent predictors of catastrophic out of pocket expenditure during delivery. Conclusions: Although government has been running lot of schemes for availing free of cost health services but still one has to pay from their pocket as medical expenses. In order to bear these expenses, they have to borrow money, sell their assets and securities due to which households suffer a lot. In the present study, unofficial payment was found prevalent in public institutions

  14. Acoustic Similarity and Dichotic Listening.

    Science.gov (United States)

    Benson, Peter

    1978-01-01

    An experiment tests conjectures that right ear advantage (REA) has an auditory origin in competition or interference between acoustically similar stimuli and that feature-sharing effect (FSE) has its origin in assignment of features of phonetically similar stimuli. No effect on the REA for acoustic similarity, and a clear effect of acoustic…

  15. Functional Similarity and Interpersonal Attraction.

    Science.gov (United States)

    Neimeyer, Greg J.; Neimeyer, Robert A.

    1981-01-01

    Students participated in dyadic disclosure exercises over a five-week period. Results indicated members of high functional similarity dyads evidenced greater attraction to one another than did members of low functional similarity dyads. "Friendship" pairs of male undergraduates displayed greater functional similarity than did "nominal" pairs from…

  16. Residues accessible in the binding-site crevice of transmembrane helix 6 of the CB2 cannabinoid receptor.

    Science.gov (United States)

    Nebane, Ntsang M; Hurst, Dow P; Carrasquer, Carl A; Qiao, Zhuanhong; Reggio, Patricia H; Song, Zhao-Hui

    2008-12-30

    We have used the substituted-cysteine accessibility method (SCAM) to map the residues in the sixth membrane-spanning segment of the CB2 cannabinoid receptor that contribute to the surface of the water-accessible binding-site crevice. Using a background of the mutant C2.59S which is relatively insensitive to the methanethiosulfonate (MTS) reagents, we mutated to cysteine, one at a time, 34 consecutive residues in TMH6 of the CB2 receptor. These mutant receptors were then expressed in HEK293 cells. By incubating HEK293 cells stably transfected with CB2 receptors with the small, charged, hydrophilic, thiol-specific reagent methanethiosulfonate ethylammonium (MTSEA), [(3)H]CP55940 binding was significantly inhibited for six mutant receptors. All six of the mutants that reacted with MTSEA were protected from the reaction when pretreated with the cannabinoid agonist WIN55212-2, suggesting that MTSEA modification occurred within the binding crevice. Therefore, the side chains of the residues at these reactive loci (V6.51, L6.52, L6.54, M6.55, L6.59, and T6.62) are on the water-accessible surface of the binding-site crevice. These residues are extracellular to the TMH6 CWXP hinge motif. The pattern of accessibility is consistent with a alpha-helical conformation for this segment of TMH6. Molecular modeling studies performed in the context of the CB2 model show that V6.51, L6.52, L6.54, M6.55, L6.59, and T6.62 face into the CB2 binding pocket, further confirming our SCAM results. These results are similar to the accessibility patterns determined by SCAM studies of TMH6 in the opioid and dopamine D2 receptors. PMID:19053233

  17. Use of an active fixation lead and a subpectoral pacemaker pocket may not avoid Twiddler′s syndrome

    Directory of Open Access Journals (Sweden)

    Floris E A Udink ten Cate

    2012-01-01

    Full Text Available Manipulation of a pacemaker with consequent malfunction of the device has been called Twiddler′s syndrome. Use of active-fixation leads and subpectoral pacemaker pockets has been considered to help in avoiding this problem. We describe a child in whom twiddling was not prevented despite implantation of a lumenless atrial lead and insertion of the pacemaker generator in a subpectoral pocket.

  18. Nuclear pockets and clefts in the lymphoid cell population of bone marrow and blood of children with acute lymphoblastic leukemia.

    OpenAIRE

    Schuurmans Stekhoven, J. H.; Holland, R.

    1986-01-01

    Ultrastructural investigation of the nuclei of the lymphoid cell population of bone marrow and blood of children with acute lymphoblastic leukemia regularly shows the presence of two types of nuclear pockets and nuclear clefts. The incidences of these nuclear features decrease significantly during cytostatic therapy. The pockets consist of either a cytoplasmic segment enclosed by a nuclear heterochromatin bridge or a nuclear segment enclosed by an intranuclear cleft. One type of nuclear cleft...

  19. Improving structural similarity based virtual screening using background knowledge

    OpenAIRE

    Girschick, Tobias; Puchbauer, Lucia; Kramer, Stefan

    2013-01-01

    Background Virtual screening in the form of similarity rankings is often applied in the early drug discovery process to rank and prioritize compounds from a database. This similarity ranking can be achieved with structural similarity measures. However, their general nature can lead to insufficient performance in some application cases. In this paper, we provide a link between ranking-based virtual screening and fragment-based data mining methods. The inclusion of binding-relevant background k...

  20. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1.

    Science.gov (United States)

    de Vera, Ian Mitchelle S; Giri, Pankaj K; Munoz-Tello, Paola; Brust, Richard; Fuhrmann, Jakob; Matta-Camacho, Edna; Shang, Jinsai; Campbell, Sean; Wilson, Henry D; Granados, Juan; Gardner, William J; Creamer, Trevor P; Solt, Laura A; Kojetin, Douglas J

    2016-07-15

    Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsaturated fatty acids, including arachidonic acid and docosahexaenoic acid (DHA), that interact with the ligand-binding domain (LBD) of a related orphan receptor, Nur77/NR4A1. However, the binding location and whether these ligands bind other NR4A receptors were not defined. Here, we show that unsaturated fatty acids also interact with the Nurr1 LBD, and solution NMR spectroscopy reveals the binding epitope of DHA at its putative ligand-binding pocket. Biochemical assays reveal that DHA-bound Nurr1 interacts with high affinity with a peptide derived from PIASγ, a protein that interacts with Nurr1 in cellular extracts, and DHA also affects cellular Nurr1 transactivation. This work is the first structural report of a natural ligand binding to a canonical NR4A ligand-binding pocket and indicates a natural ligand can bind and affect Nurr1 function. PMID:27128111

  1. LAMP using a disposable pocket warmer for anthrax detection, a highly mobile and reliable method for anti-bioterrorism.

    Science.gov (United States)

    Hatano, Ben; Maki, Takayuki; Obara, Takeyuki; Fukumoto, Hitomi; Hagisawa, Kohsuke; Matsushita, Yoshitaro; Okutani, Akiko; Bazartseren, Boldbaastar; Inoue, Satoshi; Sata, Tetsutaro; Katano, Harutaka

    2010-01-01

    A quick, reliable detection system is necessary to deal with bioterrorism. Loop-mediated isothermal amplification (LAMP) is a DNA amplification method that can amplify specific DNA fragments in isothermal conditions. We developed a new highly mobile and practical LAMP anthrax detection system that uses a disposable pocket warmer without the need for electricity (pocket-warmer LAMP). In our tests, the detection limit of the pocket-warmer LAMP was 1,000 copies of Bacillus anthracis pag and capB gene fragments per tube. The pocket-warmer LAMP also detected B. anthracis genes from DNA extracted from 0.1 volume of a B. anthracis colony. The lower detection limit of the pocket-warmer LAMP was not significantly different from that of a conventional LAMP using a heat block, and was not changed under cold (4 degrees C) or warm (37 degrees C) conditions in a Styrofoam box. The pocket-warmer LAMP could be useful against bioterrorism, and as a sensitive, reliable detection tool in areas with undependable electricity infrastructures. PMID:20093760

  2. Classification of a Haemophilus influenzae ABC transporter HI1470/71 through its cognate molybdate periplasmic binding protein, MolA

    OpenAIRE

    Tirado-Lee, Leidamarie; Lee, Allen; Rees, Douglas C.; Pinkett, Heather W.

    2011-01-01

    molA(HI1472) from H. influenzae encodes a periplasmic binding protein (PBP) that delivers substrate to the ABC transporter MolB2C2 (formerly HI1470/71). The structures of MolA with molybdate and tungstate in the binding pocket were solved to 1.6 and 1.7-Å resolution, respectively. The MolA binding protein binds molybdate and tungstate but not other oxyanions such as sulfate and phosphate, making it the first class III molybdate binding protein structurally solved. The ~100 μM binding affinity...

  3. Learning Multi-modal Similarity

    CERN Document Server

    McFee, Brian

    2010-01-01

    In many applications involving multi-media data, the definition of similarity between items is integral to several key tasks, e.g., nearest-neighbor retrieval, classification, and recommendation. Data in such regimes typically exhibits multiple modalities, such as acoustic and visual content of video. Integrating such heterogeneous data to form a holistic similarity space is therefore a key challenge to be overcome in many real-world applications. We present a novel multiple kernel learning technique for integrating heterogeneous data into a single, unified similarity space. Our algorithm learns an optimal ensemble of kernel transfor- mations which conform to measurements of human perceptual similarity, as expressed by relative comparisons. To cope with the ubiquitous problems of subjectivity and inconsistency in multi- media similarity, we develop graph-based techniques to filter similarity measurements, resulting in a simplified and robust training procedure.

  4. Roget's Thesaurus and Semantic Similarity

    OpenAIRE

    Jarmasz, Mario; Szpakowicz, Stan

    2012-01-01

    We have implemented a system that measures semantic similarity using a computerized 1987 Roget's Thesaurus, and evaluated it by performing a few typical tests. We compare the results of these tests with those produced by WordNet-based similarity measures. One of the benchmarks is Miller and Charles' list of 30 noun pairs to which human judges had assigned similarity measures. We correlate these measures with those computed by several NLP systems. The 30 pairs can be traced back to Rubenstein ...

  5. Incidence of pocket hematoma after electrophysiological device placement:dual antiplatelet therapy versus low-molecular-weight heparin regimen

    Institute of Scientific and Technical Information of China (English)

    Yan CHEN; Xin-Cun YANG; Kang MENG; Yun-Tao LI; Ming-Dong GAO; Ze-Chun ZENG; Jin-Rong ZHANG; Hong-Liang CONG; Yin LIU; Ru ZHAO; Le-Feng WANG

    2014-01-01

    Background Given the increasing number of patients who require dual antiplatelet (DAP) therapy and electrophysiological device (EPD) placement, perioperative antiplatelet management is a current challenge. In this study, we investigated the incidence of pocket hema-toma formation after EPD placement in patients undergoing DAP therapy or an alternative low-molecular-weight heparin (LMWH) regimen. Methods This clinical observational study was performed from July 2010 to July 2012. In total, 171 patients were enrolled in the analysis after meeting the inclusion criteria. These patients were divided into two groups: 86 patients were treated with DAP therapy at the time of device implantation, and the DAP therapy was discontinued for 5 to 7 days and replaced with enoxaparin before device implantation in the other 85 patients. Adenosine phosphate (ADP)-mediated platelet aggregation and arachidonic acid-induced platelet aggregation were tested preoperatively. We compared the incidence of pocket hematoma between the two groups and the association of pocket hematoma develop-ment with ADP-mediated platelet aggregation and arachidonic acid-induced platelet aggregation.Results The incidence of pocket hema-toma in the patients who continued DAP was lower than that in the patients who replaced the dual antiplatelet regimen with LMWH (3.49%vs. 16.47%, respectively;X2 = 6.66,P < 0.01). Among the patients who continued DAP therapies, the rate of ADP-mediated platelet aggre-gation inhibition in patients with pocket hematomas was higher than that in patients without pocket hematomas. None of the patients under-going DAP or enoxaparin therapy developed pocket infection, thromboembolic events, or other serious complications. Multiple logistic re-gression analysis revealed that LMWH therapy was an independent risk factor for the development of pocket hematoma (RR = 0.054, 95%CI = 0.012-0.251). Furthermore, patients undergoing LMWH therapy were 5.1-fold more likely to develop pocket

  6. vi and Vim Editors Pocket Reference Support for every text editing task

    CERN Document Server

    Robbins, Arnold

    2011-01-01

    Many Unix, Linux, and Mac OS X geeks enjoy using the powerful, platform-agnostic text editors vi and Vim, but there are far too many commands for anyone to remember. Author Arnold Robbins has chosen the most valuable commands for vi, Vim, and vi's main clones-vile, elvis, and nvi-and packed them into this easy-to-browse pocket reference. You'll find commands for all kinds of editing tasks, such as programming, modifying system files, and writing and marking up articles. This second edition includes: Command-line optionsvi commands and set optionsInput mode shortcutsSubstitution and regular e

  7. Landscape of protein-small ligand binding modes.

    Science.gov (United States)

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    Elucidating the mechanisms of specific small-molecule (ligand) recognition by proteins is a long-standing conundrum. While the structures of these molecules, proteins and ligands, have been extensively studied, protein-ligand interactions, or binding modes, have not been comprehensively analyzed. Although methods for assessing similarities of binding site structures have been extensively developed, the methods for the computational treatment of binding modes have not been well established. Here, we developed a computational method for encoding the information about binding modes as graphs, and assessing their similarities. An all-against-all comparison of 20,040 protein-ligand complexes provided the landscape of the protein-ligand binding modes and its relationships with protein- and chemical spaces. While similar proteins in the same SCOP Family tend to bind relatively similar ligands with similar binding modes, the correlation between ligand and binding similarities was not very high (R(2)  = 0.443). We found many pairs with novel relationships, in which two evolutionally distant proteins recognize dissimilar ligands by similar binding modes (757,474 pairs out of 200,790,780 pairs were categorized into this relationship, in our dataset). In addition, there were an abundance of pairs of homologous proteins binding to similar ligands with different binding modes (68,217 pairs). Our results showed that many interesting relationships between protein-ligand complexes are still hidden in the structure database, and our new method for assessing binding mode similarities is effective to find them.

  8. Landscape of protein-small ligand binding modes.

    Science.gov (United States)

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    Elucidating the mechanisms of specific small-molecule (ligand) recognition by proteins is a long-standing conundrum. While the structures of these molecules, proteins and ligands, have been extensively studied, protein-ligand interactions, or binding modes, have not been comprehensively analyzed. Although methods for assessing similarities of binding site structures have been extensively developed, the methods for the computational treatment of binding modes have not been well established. Here, we developed a computational method for encoding the information about binding modes as graphs, and assessing their similarities. An all-against-all comparison of 20,040 protein-ligand complexes provided the landscape of the protein-ligand binding modes and its relationships with protein- and chemical spaces. While similar proteins in the same SCOP Family tend to bind relatively similar ligands with similar binding modes, the correlation between ligand and binding similarities was not very high (R(2)  = 0.443). We found many pairs with novel relationships, in which two evolutionally distant proteins recognize dissimilar ligands by similar binding modes (757,474 pairs out of 200,790,780 pairs were categorized into this relationship, in our dataset). In addition, there were an abundance of pairs of homologous proteins binding to similar ligands with different binding modes (68,217 pairs). Our results showed that many interesting relationships between protein-ligand complexes are still hidden in the structure database, and our new method for assessing binding mode similarities is effective to find them. PMID:27327045

  9. Dynamic similarity in erosional processes

    Science.gov (United States)

    Scheidegger, A.E.

    1963-01-01

    A study is made of the dynamic similarity conditions obtaining in a variety of erosional processes. The pertinent equations for each type of process are written in dimensionless form; the similarity conditions can then easily be deduced. The processes treated are: raindrop action, slope evolution and river erosion. ?? 1963 Istituto Geofisico Italiano.

  10. Personalized recommendation with corrected similarity

    International Nuclear Information System (INIS)

    Personalized recommendation has attracted a surge of interdisciplinary research. Especially, similarity-based methods in applications of real recommendation systems have achieved great success. However, the computations of similarities are overestimated or underestimated, in particular because of the defective strategy of unidirectional similarity estimation. In this paper, we solve this drawback by leveraging mutual correction of forward and backward similarity estimations, and propose a new personalized recommendation index, i.e., corrected similarity based inference (CSI). Through extensive experiments on four benchmark datasets, the results show a greater improvement of CSI in comparison with these mainstream baselines. And a detailed analysis is presented to unveil and understand the origin of such difference between CSI and mainstream indices. (paper)

  11. Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies

    OpenAIRE

    Li, Jing; Du, Yun; Liu, Xian; Shen, Qian-cheng; Huang, Ai-Long; Zheng, Ming-Yue; Luo, Xiao-Min; Jiang, Hua-liang

    2012-01-01

    Aim: To investigate the molecular mechanisms underlying the influence of DNA polymerase from different genotypes of hepatitis B virus (HBV) on the binding affinity of adefovir (ADV). Methods: Computational approaches, including homology modeling, docking, MD simulation and MM/PBSA free energy analyses were used. Results: Sequence analyses revealed that residue 238 near the binding pocket was not only a polymorphic site but also a genotype-specific site (His238 in genotype B; Asn238 in genotyp...

  12. Using remote substituents to control solution structure and anion binding in lanthanide complexes

    DEFF Research Database (Denmark)

    Tropiano, Manuel; Blackburn, Octavia A.; Tilney, James A.;

    2013-01-01

    of the molecule, at a substantial distance from the binding pocket. Herein, we explore these remote substituent effects and explain the observed behaviour through discussion of the way in which remote substituents can influence and control the global structure of a molecule through their demands upon...... conformational space. Peripheral modifications to a binuclear lanthanide motif derived from α,α'-bis(DO3 Ayl)-m-xylene are shown to result in dramatic changes to the binding constant for isophthalate. In this system, the parent compound displays considerable conformational flexibility, yet can be assumed to bind...

  13. Compare local pocket and global protein structure models by small structure patterns

    KAUST Repository

    Cui, Xuefeng

    2015-09-09

    Researchers proposed several criteria to assess the quality of predicted protein structures because it is one of the essential tasks in the Critical Assessment of Techniques for Protein Structure Prediction (CASP) competitions. Popular criteria include root mean squared deviation (RMSD), MaxSub score, TM-score, GDT-TS and GDT-HA scores. All these criteria require calculation of rigid transformations to superimpose the the predicted protein structure to the native protein structure. Yet, how to obtain the rigid transformations is unknown or with high time complexity, and, hence, heuristic algorithms were proposed. In this work, we carefully design various small structure patterns, including the ones specifically tuned for local pockets. Such structure patterns are biologically meaningful, and address the issue of relying on a sufficient number of backbone residue fragments for existing methods. We sample the rigid transformations from these small structure patterns; and the optimal superpositions yield by these small structures are refined and reported. As a result, among 11; 669 pairs of predicted and native local protein pocket models from the CASP10 dataset, the GDT-TS scores calculated by our method are significantly higher than those calculated by LGA. Moreover, our program is computationally much more efficient. Source codes and executables are publicly available at http://www.cbrc.kaust.edu.sa/prosta/

  14. Focused Cardiac Ultrasound Using a Pocket-Size Device in the Emergency Room

    Energy Technology Data Exchange (ETDEWEB)

    Mancuso, Frederico José Neves, E-mail: frederico.mancuso@grupofleury.com.br [Disciplina de Cardiologia - Escola Paulista de Medicina - Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil); Disciplina de Medicina de Urgência - Escola Paulista de Medicina - Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil); Siqueira, Vicente Nicoliello; Moisés, Valdir Ambrósio [Disciplina de Cardiologia - Escola Paulista de Medicina - Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil); Gois, Aécio Flavio Teixeira [Disciplina de Medicina de Urgência - Escola Paulista de Medicina - Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil); Paola, Angelo Amato Vincenzo de; Carvalho, Antonio Carlos Camargo; Campos, Orlando [Disciplina de Cardiologia - Escola Paulista de Medicina - Universidade Federal de São Paulo (Unifesp), São Paulo, SP (Brazil)

    2014-12-15

    Cardiovascular urgencies are frequent reasons for seeking medical care. Prompt and accurate medical diagnosis is critical to reduce the morbidity and mortality of these conditions. To evaluate the use of a pocket-size echocardiography in addition to clinical history and physical exam in a tertiary medical emergency care. One hundred adult patients without known cardiac or lung diseases who sought emergency care with cardiac complaints were included. Patients with ischemic changes in the electrocardiography or fever were excluded. A focused echocardiography with GE Vscan equipment was performed after the initial evaluation in the emergency room. Cardiac chambers dimensions, left and right ventricular systolic function, intracardiac flows with color, pericardium, and aorta were evaluated. The mean age was 61 ± 17 years old. The patient complaint was chest pain in 51 patients, dyspnea in 32 patients, arrhythmia to evaluate the left ventricular function in ten patients, hypotension/dizziness in five patients and edema in one patient. In 28 patients, the focused echocardiography allowed to confirm the initial diagnosis: 19 patients with heart failure, five with acute coronary syndrome, two with pulmonary embolism and two patients with cardiac tamponade. In 17 patients, the echocardiography changed the diagnosis: ten with suspicious of heart failure, two with pulmonary embolism suspicious, two with hypotension without cause, one suspicious of acute coronary syndrome, one of cardiac tamponade and one of aortic dissection. The focused echocardiography with pocket-size equipment in the emergency care may allow a prompt diagnosis and, consequently, an earlier initiation of the therapy.

  15. The PocketSpacecraft.com Integrated eXploration Environment (PIXE)

    Science.gov (United States)

    Johnson, Michael

    2015-04-01

    The PocketSpacecraft.com Integrated eXploration Environment (PIXE) is an integrated generic spacecraft design, simulation, manufacturing, and operations system for the low cost mass exploration of space by amateur and professional Principle Investigators (PIs). PIs use an online tool to design Thin-Film Spacecraft/Lander/Rovers (TF-SLRs) using a library of predefined spacecraft and mission components to specify TF-SLRs in quantities ranging from one to thousands per mission, each with a typical mass cost per TF-SLR. TF-SLR designs and missions are verified by simulation, automatically manufactured using a hybrid printed electronics process, and integrated for launch into 0.5-3U Interplanetary CubeSat motherships capable of being qualified to COSPAR Planetary Protection Category IVa or better. The Interplanetary CubeSat is launched on a standard CubeSat rideshare to an orbit suitable for deploying the TF-SLRs, and acts as a communications relay until its end of life. Data is received on earth using adapted radio telescopes and CCSDS compliant ground stations, and forwarded to a central data warehouse for download by the PI. Individual elements of the concept have been demonstrated on earth and in orbit during 2013 and 2014. A full proof of concept mission 'Pocket Spacecraft: Mission to the Moon' has been traditionally and crowd funded and is being prepared for flight with the goal of achieving low lunar orbit in 2016.

  16. Utilizing Wireless PocketPC's in Earth System Science Lectures to Expand Discourse

    Science.gov (United States)

    Samson, P. J.; van der Pluijm, B.

    2004-12-01

    Introductory science teaching, including otherwise engaging topics such as climate change and natural hazards, traditionally relies on static textbooks and/or course packs, and presentation is often delivered as a monologue in front of a passive audience. Add to this the advent of extensive lecture notes on the Internet and the students are left with little incentive to attend class, much less participate. Clearly this model does not provide much opportunity for students to critically think through the arguments being developed. In order to address this issue, we are experimenting with the use of interactive spatial concept challenges utilizing wireless PocketPC computers in Earth Systems classes at the University of Michigan. The tools being developed have the goal of involving students in their own learning during lecture and focusing their attention on underlying concepts. Following Mazur (1997) students respond to spatial questions offered through the PocketPC and formulate their own answers; followed by an in-class discussion in small groups, attempting to reach consensus on the best answer. Successful implementation of this approach in climate change offers new opportunities to engage students in discourse and improved learning through peer and interactive instruction. Eric Mazur, 1997: Peer Instruction: A User's Manual, Prentice-Hall, Upper Saddle River, NJ.

  17. Focused Cardiac Ultrasound Using a Pocket-Size Device in the Emergency Room

    International Nuclear Information System (INIS)

    Cardiovascular urgencies are frequent reasons for seeking medical care. Prompt and accurate medical diagnosis is critical to reduce the morbidity and mortality of these conditions. To evaluate the use of a pocket-size echocardiography in addition to clinical history and physical exam in a tertiary medical emergency care. One hundred adult patients without known cardiac or lung diseases who sought emergency care with cardiac complaints were included. Patients with ischemic changes in the electrocardiography or fever were excluded. A focused echocardiography with GE Vscan equipment was performed after the initial evaluation in the emergency room. Cardiac chambers dimensions, left and right ventricular systolic function, intracardiac flows with color, pericardium, and aorta were evaluated. The mean age was 61 ± 17 years old. The patient complaint was chest pain in 51 patients, dyspnea in 32 patients, arrhythmia to evaluate the left ventricular function in ten patients, hypotension/dizziness in five patients and edema in one patient. In 28 patients, the focused echocardiography allowed to confirm the initial diagnosis: 19 patients with heart failure, five with acute coronary syndrome, two with pulmonary embolism and two patients with cardiac tamponade. In 17 patients, the echocardiography changed the diagnosis: ten with suspicious of heart failure, two with pulmonary embolism suspicious, two with hypotension without cause, one suspicious of acute coronary syndrome, one of cardiac tamponade and one of aortic dissection. The focused echocardiography with pocket-size equipment in the emergency care may allow a prompt diagnosis and, consequently, an earlier initiation of the therapy

  18. Radial-firing optical fiber tip containing conical-shaped air-pocket for biomedical applications.

    Science.gov (United States)

    Lee, Seung Ho; Ryu, Yong-Tak; Son, Dong Hoon; Jeong, Seongmook; Kim, Youngwoong; Ju, Seongmin; Kim, Bok Hyeon; Han, Won-Taek

    2015-08-10

    We report a novel radial-firing optical fiber tip containing a conical-shaped air-pocket fabricated by deforming a hollow optical fiber using electric arc-discharge process. The hollow optical fiber was fusion spliced with a conventional optical fiber, simultaneously deforming into the intagliated conical-shaped region along the longitudinal fiber-axis of the fiber due to the gradual collapse of the cavity of the hollow optical fiber. Then the distal-end of the hollow optical fiber was sealed by the additional arc-discharge in order to obstruct the inflow of an external bio-substance or liquid to the inner air surface during the surgical operations, resulting in the formation of encased air-pocket in the silica glass fiber. Due to the total internal reflection of the laser beam at the conical-shaped air surface, the laser beam (λ = 632.8 nm) was deflected to the circumferential direction up to 87 degree with respect to the fiber-axis. PMID:26367974

  19. Studies on development of controlled delivery of combination drug(s to periodontal pocket

    Directory of Open Access Journals (Sweden)

    Tiwari Gaurav

    2010-01-01

    Full Text Available Aim: The aim of this study to develop the controlled delivery of combination drug(s to periodontal pocket. Materials and Methods: In the present investigation mucoadhesive gel formulations were prepared using carboxy methylcellulose (CMC, methylcellulose (MC, hydroxyethylcellulose (HEC, polyvinylpirrolidone (PVP, polycarbophil (PC, and poloxamer. Each formulation was characterized in terms of polarizing light microscopy, gelation, gel melting, hardness, compressibility, adhesiveness, cohesiveness, syringeability, adhesion to a mucin disk, rheological studies, drug release, and antibacterial activities. Addition of CMC and PVP to the gel favored hexagonal phase formation. The gelation temperature was decreased linearly with an increasing concentration of drug(s, whereas, the melting temperature increased with the concentration of drug(s. Increasing the concentrations of each polymeric component significantly increased formulation hardness, compressibility, adhesiveness, mucoadhesion, and syringeability, yet a decreased cohesiveness. Increased time of contact between the formulation and mucin significantly increased the required force of detachment. Drug release from all formulations was non-diffusion controlled and significantly decreased as the concentration of the polymer was increased, due to the concomitant increased viscosity of the formulations and the swelling kinetics of PC, following contact with the dissolution fluid. Result: Antibacterial studies revealed that a gel with 30% HEC had a growth inhibition zone on agar with all three strains. Conclusion: Formulations containing HEC exhibited superior physical characteristics for improved drug delivery to the periodontal pocket and are now the subject of long-term clinical investigations.

  20. Single reconstructed Fermi surface pocket in an underdoped single-layer cuprate superconductor.

    Science.gov (United States)

    Chan, M K; Harrison, N; McDonald, R D; Ramshaw, B J; Modic, K A; Barišić, N; Greven, M

    2016-01-01

    The observation of a reconstructed Fermi surface via quantum oscillations in hole-doped cuprates opened a path towards identifying broken symmetry states in the pseudogap regime. However, such an identification has remained inconclusive due to the multi-frequency quantum oscillation spectra and complications accounting for bilayer effects in most studies. We overcome these impediments with high-resolution measurements on the structurally simpler cuprate HgBa2CuO4+δ (Hg1201), which features one CuO2 plane per primitive unit cell. We find only a single oscillatory component with no signatures of magnetic breakdown tunnelling to additional orbits. Therefore, the Fermi surface comprises a single quasi-two-dimensional pocket. Quantitative modelling of these results indicates that a biaxial charge density wave within each CuO2 plane is responsible for the reconstruction and rules out criss-crossed charge stripes between layers as a viable alternative in Hg1201. Lastly, we determine that the characteristic gap between reconstructed pockets is a significant fraction of the pseudogap energy.

  1. Single reconstructed Fermi surface pocket in an underdoped single-layer cuprate superconductor.

    Science.gov (United States)

    Chan, M K; Harrison, N; McDonald, R D; Ramshaw, B J; Modic, K A; Barišić, N; Greven, M

    2016-01-01

    The observation of a reconstructed Fermi surface via quantum oscillations in hole-doped cuprates opened a path towards identifying broken symmetry states in the pseudogap regime. However, such an identification has remained inconclusive due to the multi-frequency quantum oscillation spectra and complications accounting for bilayer effects in most studies. We overcome these impediments with high-resolution measurements on the structurally simpler cuprate HgBa2CuO4+δ (Hg1201), which features one CuO2 plane per primitive unit cell. We find only a single oscillatory component with no signatures of magnetic breakdown tunnelling to additional orbits. Therefore, the Fermi surface comprises a single quasi-two-dimensional pocket. Quantitative modelling of these results indicates that a biaxial charge density wave within each CuO2 plane is responsible for the reconstruction and rules out criss-crossed charge stripes between layers as a viable alternative in Hg1201. Lastly, we determine that the characteristic gap between reconstructed pockets is a significant fraction of the pseudogap energy. PMID:27448102

  2. Child Wasting in Emergency Pockets: A Meta-Analysis of Small-Scale Surveys from Ethiopia.

    Science.gov (United States)

    Altare, Chiara; Delbiso, Tefera Darge; Guha-Sapir, Debarati

    2016-02-01

    Child undernutrition is a major public health concern in Ethiopia (stunting national prevalence: 44%; wasting: 10%), despite the overall improvement in child health status during the last decade. Hundreds of small-scale surveys are conducted in Ethiopia's emergency pockets under ENCU's supervision. We reviewed the evidence from small-scale surveys conducted between 2008 and 2013 with two objectives: to provide a summary estimate of wasting prevalence from emergency pockets and to examine reasons for variation in prevalence estimates. We created a dataset by combining data from the Complex Emergency Database, the Famine Early Warning System Network and the Armed Conflict Location Event Data. We conducted a meta-analysis of small-scale surveys using a random effects model with known within-study heterogeneity. The influence of survey covariates on estimated prevalence was investigated with meta-regression techniques. We included 158 surveys in the analysis. A high degree of heterogeneity among surveys was observed. The overall estimate of wasting prevalence was 10.6% (95% CI 9.8-11.4), with differences among regions and between residents and refugees. Meta-regression results showed that vaccination coverage, child mortality, diarrhea prevalence and food insecurity are significantly associated with wasting prevalence. Child care and displacement status were not. Aggregated analysis of small-scale surveys provides insights into the prevalence of wasting and factors explaining its variation. It can also guide survey planning towards areas with limited data availability. PMID:26828512

  3. Triple Point Collision and Origin of Unburned Gas Pockets in Irregular Detonations

    CERN Document Server

    Mahmoudi, Yasser

    2014-01-01

    The turbulent structure of an irregular detonation is studied through very high resolution numerical simulations of 600 points per half reaction length. The aim is to explore the nature of the transverse waves during the collision and reflection processes of the triple point with the channel walls. Consequently the formation and consumption mechanism of unreacted gas pockets is studied. Results show that as the triple point collides with the wall, the transverse shock interacts with the unreacted pocket. After reflection of the triple point off the wall, the transverse wave interacts with the wall. The structure found to be of a double Mach configuration and does not change before and after reflection. In the second half of the detonation cell the triple point and the transverse wave collide simultaneously with the wall. The strong transverse wave switches from a primary triple point before collision to a new one after reflection. After some time a weak triple point reflects off the wall and hence the structu...

  4. Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors.

    Science.gov (United States)

    Wagner, Florence F; Weïwer, Michel; Steinbacher, Stefan; Schomburg, Adrian; Reinemer, Peter; Gale, Jennifer P; Campbell, Arthur J; Fisher, Stewart L; Zhao, Wen-Ning; Reis, Surya A; Hennig, Krista M; Thomas, Méryl; Müller, Peter; Jefson, Martin R; Fass, Daniel M; Haggarty, Stephen J; Zhang, Yan-Ling; Holson, Edward B

    2016-09-15

    The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications. PMID:27377864

  5. Similarity of samples and trimming

    CERN Document Server

    Álvarez-Esteban, Pedro C; Cuesta-Albertos, Juan A; Matrán, Carlos; 10.3150/11-BEJ351

    2012-01-01

    We say that two probabilities are similar at level $\\alpha$ if they are contaminated versions (up to an $\\alpha$ fraction) of the same common probability. We show how this model is related to minimal distances between sets of trimmed probabilities. Empirical versions turn out to present an overfitting effect in the sense that trimming beyond the similarity level results in trimmed samples that are closer than expected to each other. We show how this can be combined with a bootstrap approach to assess similarity from two data samples.

  6. Self-similar aftershock rates

    CERN Document Server

    Davidsen, Jörn

    2016-01-01

    In many important systems exhibiting crackling noise --- intermittent avalanche-like relaxation response with power-law and, thus, self-similar distributed event sizes --- the "laws" for the rate of activity after large events are not consistent with the overall self-similar behavior expected on theoretical grounds. This is in particular true for the case of seismicity and a satisfying solution to this paradox has remained outstanding. Here, we propose a generalized description of the aftershock rates which is both self-similar and consistent with all other known self-similar features. Comparing our theoretical predictions with high resolution earthquake data from Southern California we find excellent agreement, providing in particular clear evidence for a unified description of aftershocks and foreshocks. This may offer an improved way of time-dependent seismic hazard assessment and earthquake forecasting.

  7. Self-similar aftershock rates

    Science.gov (United States)

    Davidsen, Jörn; Baiesi, Marco

    2016-08-01

    In many important systems exhibiting crackling noise—an intermittent avalanchelike relaxation response with power-law and, thus, self-similar distributed event sizes—the "laws" for the rate of activity after large events are not consistent with the overall self-similar behavior expected on theoretical grounds. This is particularly true for the case of seismicity, and a satisfying solution to this paradox has remained outstanding. Here, we propose a generalized description of the aftershock rates which is both self-similar and consistent with all other known self-similar features. Comparing our theoretical predictions with high-resolution earthquake data from Southern California we find excellent agreement, providing particularly clear evidence for a unified description of aftershocks and foreshocks. This may offer an improved framework for time-dependent seismic hazard assessment and earthquake forecasting.

  8. How the ACA's Health Insurance Expansions Have Affected Out-of-Pocket Cost-Sharing and Spending on Premiums.

    Science.gov (United States)

    Glied, Sherry; Solís-Román, Claudia; Parikh, Shivani

    2016-09-01

    One important benefit gained by the millions of Americans with health insurance through the Affordable Care Act (ACA) is protection from high out-of-pocket health spending. While Medicaid unambiguously reduces out-of-pocket premium and medical costs for low-income people, it is less certain that marketplace coverage and other types of insurance purchased to comply with the law's individual mandate also protect from high health spending. Goal: To compare out-of-pocket spending in 2014 to spending in 2013; assess how this spending changed in states where many people enrolled in the marketplaces relative to states where few people enrolled; and project the decline in the percentage of people paying high amounts out-of-pocket. Methods: Linear regression models were used to estimate whether people under age 65 spent above certain thresholds. Key findings and conclusions: The probability of incurring high out-of-pocket costs and premium expenses declined as marketplace enrollment increased. The percentage reductions were greatest among those with incomes between 250 percent and 399 percent of poverty, those who were eligible for premium subsidies, and those who previously were uninsured or had very limited nongroup coverage. These effects appear largely attributable to marketplace enrollment rather than to other ACA provisions or to economic trends.

  9. Community Detection by Neighborhood Similarity

    Institute of Scientific and Technical Information of China (English)

    LIU Xu; XIE Zheng; YI Dong-Yun

    2012-01-01

    Detection of the community structure in a network is important for understanding the structure and dynamics of the network.By exploring the neighborhood of vertices,a local similarity metric is proposed,which can be quickly computed.The resulting similarity matrix retains the same support as the adjacency matrix.Based on local similarity,an agglomerative hierarchical clustering algorithm is proposed for community detection.The algorithm is implemented by an efficient max-heap data structure and runs in nearly linear time,thus is capable of dealing with large sparse networks with tens of thousands of nodes.Experiments on synthesized and real-world networks demonstrate that our method is efficient to detect community structures,and the proposed metric is the most suitable one among all the tested similarity indices.%Detection of the community structure in a network is important for understanding the structure and dynamics of the network. By exploring the neighborhood of vertices, a local similarity metric is proposed, which can be quickly computed. The resulting similarity matrix retains the same support as the adjacency matrix. Based on local similarity, an agglomerative hierarchical clustering algorithm is proposed for community detection. The algorithm is implemented by an efficient max-heap data structure and runs in nearly linear time, thus is capable of dealing with large sparse networks with tens of thousands of nodes. Experiments on synthesized and real-world networks demonstrate that our method is efficient to detect community structures, and the proposed metric is the most suitable one among all the tested similarity indices.

  10. SELF-SIMILAR TRAFFIC GENERATOR

    OpenAIRE

    Linawati Linawati; I Made Suartika

    2009-01-01

    Network traffic generator can be produced using OPNET. OPNET generates the traffic as explicit traffic or background traffic. This paper demonstrates generating traffic in OPNET 7.0 as background traffic. The traffi generator that was simulated is self-similar traffic with different Hurst parameter. The simulation results proved that OPNET with background traffic function can be as a qualified self-similar traffic generator. These results can help in investigating and analysing network perfor...

  11. Similarity measures for protein ensembles

    DEFF Research Database (Denmark)

    Lindorff-Larsen, Kresten; Ferkinghoff-Borg, Jesper

    2009-01-01

    Analyses of similarities and changes in protein conformation can provide important information regarding protein function and evolution. Many scores, including the commonly used root mean square deviation, have therefore been developed to quantify the similarities of different protein conformations...... a synthetic example from molecular dynamics simulations. We then apply the algorithms to revisit the problem of ensemble averaging during structure determination of proteins, and find that an ensemble refinement method is able to recover the correct distribution of conformations better than standard single...

  12. Self-Similar Isentropic Implosions

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez, M.; Amable, L.

    1980-07-01

    The self-similar compression of an isentropic spherical gas pellet Is analyzed for large values of the ratio of the final to initial densities. An asymptotic analysis provides the solution corresponding to a prescribed value of the final density when it is high. In addition an approximate solution is given when the specific heat ratio is not constant. The time evolution of the pressure on the outer surface leading to the self-similar solutions, is calculated for large density ratios. (Author)

  13. Molecular similarity of MDR inhibitors

    OpenAIRE

    Simon Gibbons; Mire Zloh

    2004-01-01

    Abstract: The molecular similarity of multidrug resistance (MDR) inhibitors was evaluated using the point centred atom charge approach in an attempt to find some common features of structurally unrelated inhibitors. A series of inhibitors of bacterial MDR were studied and there is a high similarity between these in terms of their shape, presence and orientation of aromatic ring moieties. A comparison of the lipophilic properties of these molecules has also been conducted suggesting that this ...

  14. Representation is representation of similarities.

    Science.gov (United States)

    Edelman, S

    1998-08-01

    Advanced perceptual systems are faced with the problem of securing a principled (ideally, veridical) relationship between the world and its internal representation. I propose a unified approach to visual representation, addressing the need for superordinate and basic-level categorization and for the identification of specific instances of familiar categories. According to the proposed theory, a shape is represented internally by the responses of a small number of tuned modules, each broadly selective for some reference shape, whose similarity to the stimulus it measures. This amounts to embedding the stimulus in a low-dimensional proximal shape space spanned by the outputs of the active modules. This shape space supports representations of distal shape similarities that are veridical as Shepard's (1968) second-order isomorphisms (i.e., correspondence between distal and proximal similarities among shapes, rather than between distal shapes and their proximal representations). Representation in terms of similarities to reference shapes supports processing (e.g., discrimination) of shapes that are radically different from the reference ones, without the need for the computationally problematic decomposition into parts required by other theories. Furthermore, a general expression for similarity between two stimuli, based on comparisons to reference shapes, can be used to derive models of perceived similarity ranging from continuous, symmetric, and hierarchical ones, as in multidimensional scaling (Shepard 1980), to discrete and nonhierarchical ones, as in the general contrast models (Shepard & Arabie 1979; Tversky 1977). PMID:10097019

  15. Thermodynamic evaluation and modeling of proton and water exchange associated with benzamidine and berenil binding to ß-trypsin

    Directory of Open Access Journals (Sweden)

    M.T. Pereira

    2005-11-01

    Full Text Available Serine-proteases are involved in vital processes in virtually all species. They are important targets for researchers studying the relationships between protein structure and activity, for the rational design of new pharmaceuticals. Trypsin was used as a model to assess a possible differential contribution of hydration water to the binding of two synthetic inhibitors. Thermodynamic parameters for the association of bovine ß-trypsin (homogeneous material, observed 23,294.4 ± 0.2 Da, theoretical 23,292.5 Da with the inhibitors benzamidine and berenil at pH 8.0, 25ºC and with 25 mM CaCl2, were determined using isothermal titration calorimetry and the osmotic stress method. The association constant for berenil was about 12 times higher compared to the one for benzamidine (binding constants are K = 596,599 ± 25,057 and 49,513 ± 2,732 M-1, respectively; the number of binding sites is the same for both ligands, N = 0.99 ± 0.05. Apparently the driving force responsible for this large difference of affinity is not due to hydrophobic interactions because the variation in heat capacity (DCp, a characteristic signature of these interactions, was similar in both systems tested (-464.7 ± 23.9 and -477.1 ± 86.8 J K-1 mol-1 for berenil and benzamidine, respectively. The results also indicated that the enzyme has a net gain of about 21 water molecules regardless of the inhibitor tested. It was shown that the difference in affinity could be due to a larger number of interactions between berenil and the enzyme based on computational modeling. The data support the view that pharmaceuticals derived from benzamidine that enable hydrogen bond formation outside the catalytic binding pocket of ß-trypsin may result in more effective inhibitors.

  16. Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif.

    Science.gov (United States)

    Jehle, Katja; Cato, Laura; Neeb, Antje; Muhle-Goll, Claudia; Jung, Nicole; Smith, Emmanuel W; Buzon, Victor; Carbó, Laia R; Estébanez-Perpiñá, Eva; Schmitz, Katja; Fruk, Ljiljana; Luy, Burkhard; Chen, Yu; Cox, Marc B; Bräse, Stefan; Brown, Myles; Cato, Andrew C B

    2014-03-28

    The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.

  17. Social Values as Arguments: Similar is Convincing

    Directory of Open Access Journals (Sweden)

    Gregory R Maio

    2014-08-01

    Full Text Available Politicians, philosophers, and rhetors engage in co-value argumentation: appealing to one value in order to support another value (e.g., equality leads to freedom. Across four experiments in the United Kingdom and India, we found that the psychological relatedness of values affects the persuasiveness of the arguments that bind them. Experiment 1 found that participants were more persuaded by arguments citing values that fulfilled similar motives than by arguments citing opposing values. Experiments 2 and 3 replicated this result using a wider variety of values, while finding that the effect is stronger among people higher in need for cognition and that the effect is mediated by the greater plausibility of co-value arguments that link motivationally compatible values. Experiment 4 extended the effect to real-world arguments taken from political propaganda and replicated the mediating effect of argument plausibility. The findings highlight the importance of value relatedness in argument persuasiveness.

  18. Polypharmacology within CXCR4: Multiple binding sites and allosteric behavior

    Science.gov (United States)

    Planesas, Jesús M.; Pérez-Nueno, Violeta I.; Borrell, José I.; Teixidó, Jordi

    2014-10-01

    CXCR4 is a promiscuous receptor, which binds multiple diverse ligands. As usual in promiscuous proteins, CXCR4 has a large binding site, with multiple subsites, and high flexibility. Hence, it is not surprising that it is involved in the phenomenon of allosteric modulation. However, incomplete knowledge of allosteric ligand-binding sites has hampered an in-depth molecular understanding of how these inhibitors work. For example, it is known that lipidated fragments of intracellular GPCR loops, so called pepducins, such as pepducin ATI-2341, modulate CXCR4 activity using an agonist allosteric mechanism. Nevertheless, there are also examples of small organic molecules, such as AMD11070 and GSK812397, which may act as antagonist allosteric modulators. Here, we give new insights into this issue by proposing the binding interactions between the CXCR4 receptor and the above-mentioned allosteric modulators. We propose that CXCR4 has minimum two topographically different allosteric binding sites. One allosteric site would be in the intracellular loop 1 (ICL1) where pepducin ATI-2341 would bind to CXCR4, and the second one, in the extracellular side of CXCR4 in a subsite into the main orthosteric binding pocket, delimited by extracellular loops n° 1, 2, and the N-terminal end, where antagonists AMD11070 and GSK812397 would bind. Prediction of allosteric interactions between CXCR4 and pepducin ATI-2341 were studied first by rotational blind docking to determine the main binding region and a subsequent refinement of the best pose was performed using flexible docking methods and molecular dynamics. For the antagonists AMD11070 and GSK812397, the entire CXCR4 protein surface was explored by blind docking to define the binding region. A second docking analysis by subsites of the identified binding region was performed to refine the allosteric interactions. Finally, we identified the binding residues that appear to be essential for CXCR4 (agonists and antagonists) allosteric

  19. Health service use, out-of-pocket payments and catastrophic health expenditure among older people in India

    DEFF Research Database (Denmark)

    Brinda, Ethel Mary; Kowal, Paul; Attermann, Jørn;

    2015-01-01

    BACKGROUND: Healthcare financing through out-of-pocket payments and inequities in healthcare utilisation are common in low and middle income countries (LMICs). Given the dearth of pertinent studies on these issues among older people in LMICs, we investigated the determinants of health service use......, out-of-pocket and catastrophic health expenditures among older people in one LMIC, India. METHODS: We accessed data from a nationally representative, multistage sample of 2414 people aged 65 years and older from the WHO's Study on global Ageing and adult health in India. Sociodemographic...... the number of health visits and out-of-pocket health expenditures. The prevalence of catastrophic health expenditure among older people in India was 7% (95% CI 6% to 8%). Older men and individuals with chronic diseases were at higher risk of catastrophic health expenditure, while access to health insurance...

  20. GeoPad and GeoPocket: GIS-Enabled Field Science Education

    Science.gov (United States)

    Knoop, P. A.; van der Pluijm, B.

    2005-12-01

    Over the past three years we have successfully incorporated and evaluated the use of field-based information technology in introductory through senior-level field courses offered at the University of Michigan's Camp Davis Geology Field Station, near Jackson, WY. The use of GeoPads (field-durable Tablet PCs) and GeoPockets (field-durable Pocket PCs) -- both equipped with GIS, GPS, wireless networking, electronic notebook and other pertinent software -- have significantly enhanced our field exercises and excursions, for both students and instructors. In addition to describing our on-going work, the results of an external, independent review of GeoPad-curriculum integration are presented. For example, using GeoPads to teach field mapping not only supports the traditional approaches and advantages of field instruction, but also offers important benefits in the development of students' spatial reasoning skills. Students are able to record observations and directly create geologic maps in the field, using a combination of an electronic field notebook (Microsoft OneNote) tightly integrated with intuitive, pen-enabled GIS software (ArcGIS-ArcMap). Specifically, this arrangement permits students to analyze and manipulate their data in multiple contexts and representations -- while still in the field -- using both traditional 2-D map views, as well as richer 3-D contexts. Such enhancements provide students with powerful exploratory tools that aid the development of spatial reasoning skills, allowing more intuitive interactions with 2-D representations of our 3-D world. Additionally, field-based GIS mapping enables better error-detection, through immediate interaction with current observations in the context of both supporting data (e.g., topographic maps, aerial photos, magnetic surveys) and students' ongoing observations. GeoPockets provide instructional staff with a more portable, though less feature-rich device, which is highly suitable to the role of "electronic

  1. A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site.

    Science.gov (United States)

    Duffy, Caroline M; Hilbert, Brendan J; Kelch, Brian A

    2016-03-27

    The eukaryotic DNA polymerase sliding clamp, proliferating cell nuclear antigen or PCNA, is a ring-shaped protein complex that surrounds DNA to act as a sliding platform for increasing processivity of cellular replicases and for coordinating various cellular pathways with DNA replication. A single point mutation, Ser228Ile, in the human PCNA gene was recently identified to cause a disease whose symptoms resemble those of DNA damage and repair disorders. The mutation lies near the binding site for most PCNA-interacting proteins. However, the structural consequences of the S228I mutation are unknown. Here, we describe the structure of the disease-causing variant, which reveals a large conformational change that dramatically transforms the binding pocket for PCNA client proteins. We show that the mutation markedly alters the binding energetics for some client proteins, while another, p21(CIP1), is only mildly affected. Structures of the disease variant bound to peptides derived from two PCNA partner proteins reveal that the binding pocket can adjust conformation to accommodate some ligands, indicating that the binding site is dynamic and pliable. Our work has implications for the plasticity of the binding site in PCNA and reveals how a disease mutation selectively alters interactions to a promiscuous binding site that is critical for DNA metabolism.

  2. Similarity measures for face recognition

    CERN Document Server

    Vezzetti, Enrico

    2015-01-01

    Face recognition has several applications, including security, such as (authentication and identification of device users and criminal suspects), and in medicine (corrective surgery and diagnosis). Facial recognition programs rely on algorithms that can compare and compute the similarity between two sets of images. This eBook explains some of the similarity measures used in facial recognition systems in a single volume. Readers will learn about various measures including Minkowski distances, Mahalanobis distances, Hansdorff distances, cosine-based distances, among other methods. The book also summarizes errors that may occur in face recognition methods. Computer scientists "facing face" and looking to select and test different methods of computing similarities will benefit from this book. The book is also useful tool for students undertaking computer vision courses.

  3. Design of a Novel Low Cost Point of Care Tampon (POCkeT Colposcope for Use in Resource Limited Settings.

    Directory of Open Access Journals (Sweden)

    Christopher T Lam

    Full Text Available Current guidelines by WHO for cervical cancer screening in low- and middle-income countries involves visual inspection with acetic acid (VIA of the cervix, followed by treatment during the same visit or a subsequent visit with cryotherapy if a suspicious lesion is found. Implementation of these guidelines is hampered by a lack of: trained health workers, reliable technology, and access to screening facilities. A low cost ultra-portable Point of Care Tampon based digital colposcope (POCkeT Colposcope for use at the community level setting, which has the unique form factor of a tampon, can be inserted into the vagina to capture images of the cervix, which are on par with that of a state of the art colposcope, at a fraction of the cost. A repository of images to be compiled that can be used to empower front line workers to become more effective through virtual dynamic training. By task shifting to the community setting, this technology could potentially provide significantly greater cervical screening access to where the most vulnerable women live. The POCkeT Colposcope's concentric LED ring provides comparable white and green field illumination at a fraction of the electrical power required in commercial colposcopes. Evaluation with standard optical imaging targets to assess the POCkeT Colposcope against the state of the art digital colposcope and other VIAM technologies.Our POCkeT Colposcope has comparable resolving power, color reproduction accuracy, minimal lens distortion, and illumination when compared to commercially available colposcopes. In vitro and pilot in vivo imaging results are promising with our POCkeT Colposcope capturing comparable quality images to commercial systems.The POCkeT Colposcope is capable of capturing images suitable for cervical lesion analysis. Our portable low cost system could potentially increase access to cervical cancer screening in limited resource settings through task shifting to community health workers.

  4. Improved cardiovascular diagnostic accuracy by pocket size imaging device in non-cardiologic outpatients: the NaUSiCa (Naples Ultrasound Stethoscope in Cardiology study

    Directory of Open Access Journals (Sweden)

    Schiattarella Pier

    2010-11-01

    Full Text Available Abstract Miniaturization has evolved in the creation of a pocket-size imaging device which can be utilized as an ultrasound stethoscope. This study assessed the additional diagnostic power of pocket size device by both experts operators and trainees in comparison with physical examination and its appropriateness of use in comparison with standard echo machine in a non-cardiologic population. Three hundred four consecutive non cardiologic outpatients underwent a sequential assessment including physical examination, pocket size imaging device and standard Doppler-echo exam. Pocket size device was used by both expert operators and trainees (who received specific training before the beginning of the study. All the operators were requested to give only visual, qualitative insights on specific issues. All standard Doppler-echo exams were performed by expert operators. One hundred two pocket size device exams were performed by experts and two hundred two by trainees. The time duration of the pocket size device exam was 304 ± 117 sec. Diagnosis of cardiac abnormalities was made in 38.2% of cases by physical examination and in 69.7% of cases by physical examination + pocket size device (additional diagnostic power = 31.5%, p In conclusion, pocket size device showed a relevant additional diagnostic value in comparison with physical examination. Sensitivity and specificity were good in experts and suboptimal in trainees. Specificity was particularly influenced by the level of experience. Training programs are needed for pocket size device users.

  5. BINDING ISOTHERMS SURFACTANT-PROTEINS

    OpenAIRE

    Elena Irina Moater; Cristiana Radulescu; Ionica Ionita

    2011-01-01

    The interactions between surfactants and proteins shows some similarities with interactions between surfactants and polymers, but the hydrophobic amphoteric nature of proteins and their secondary and tertiary structure components make them different from conventional polymer systems. Many studies from the past about surfactant - proteins bonding used the dialysis techniques. Other techniques used to determine the binding isotherm, included ultrafiltration, ultracentrifugation, potentiometry, ...

  6. Similarity Measures for Comparing Biclusterings.

    Science.gov (United States)

    Horta, Danilo; Campello, Ricardo J G B

    2014-01-01

    The comparison of ordinary partitions of a set of objects is well established in the clustering literature, which comprehends several studies on the analysis of the properties of similarity measures for comparing partitions. However, similarity measures for clusterings are not readily applicable to biclusterings, since each bicluster is a tuple of two sets (of rows and columns), whereas a cluster is only a single set (of rows). Some biclustering similarity measures have been defined as minor contributions in papers which primarily report on proposals and evaluation of biclustering algorithms or comparative analyses of biclustering algorithms. The consequence is that some desirable properties of such measures have been overlooked in the literature. We review 14 biclustering similarity measures. We define eight desirable properties of a biclustering measure, discuss their importance, and prove which properties each of the reviewed measures has. We show examples drawn and inspired from important studies in which several biclustering measures convey misleading evaluations due to the absence of one or more of the discussed properties. We also advocate the use of a more general comparison approach that is based on the idea of transforming the original problem of comparing biclusterings into an equivalent problem of comparing clustering partitions with overlapping clusters. PMID:26356865

  7. Sparse Similarity-Based Fisherfaces

    DEFF Research Database (Denmark)

    Fagertun, Jens; Gomez, David Delgado; Hansen, Mads Fogtmann;

    2011-01-01

    intensities are used by Sparse Principal Component Analysis and Fisher Linear Discriminant Analysis to assign a one dimensional subspace projection to each person belonging to a reference data set. Experimental results performed in the AR dataset show that Similarity-based Fisherfaces in a sparse version can...

  8. Influence of a mutation in the ATP-binding region of Ca2+/calmodulin-dependent protein kinase II on its interaction with peptide substrates.

    Science.gov (United States)

    Praseeda, Mullasseril; Pradeep, Kurup K; Krupa, Ananth; Krishna, S Sri; Leena, Suseela; Kumar, R Rajeev; Cheriyan, John; Mayadevi, Madhavan; Srinivasan, Narayanaswamy; Omkumar, Ramakrishnapillai V

    2004-03-01

    CaMKII (Ca2+/calmodulin-dependent protein kinase II) is expressed in high concentrations in the brain and is found enriched in the postsynaptic densities. The enzyme is activated by the binding of calmodulin to the autoregulatory domain in the presence of high levels of intracellular Ca2+, which causes removal of auto-inhibition from the N-terminal catalytic domain. Knowledge of the 3D (three-dimensional) structure of this enzyme at atomic resolution is restricted to the association domain, a region at the extreme C-terminus. The catalytic domain of CaMKII shares high sequence similarity with CaMKI. The 3D structure of the catalytic core of CaMKI comprises ATP- and substrate-binding regions in a cleft between two distinct lobes, similar to the structures of all protein kinases solved to date. Mutation of Glu-60, a residue in the ATP-binding region of CaMKII, to glycine exerts different effects on phosphorylation of two peptide substrates, syntide and NR2B ( N -methyl-D-aspartate receptor subunit 2B) 17-mer. Although the mutation caused increases in the Km values for phosphorylation for both the peptide substrates, the effect on the kcat values for each was different. The kcat value decreased in the case of syntide, whereas it increased in the case of the NR2B peptide as a result of the mutation. This resulted in a significant decrease in the apparent kcat/Km value for syntide, but the change was minimal for the NR2B peptide. These results indicate that different catalytic mechanisms are employed by the kinase for the two peptides. Molecular modelling suggests structural changes are likely to occur at the peptide-binding pocket in the active state of the enzyme as a consequence of the Glu-60-->Gly mutation. PMID:14558884

  9. Approaching an organic semimetal: Electron pockets at the Fermi level for a p-benzoquinonemonoimine zwitterion

    Energy Technology Data Exchange (ETDEWEB)

    Rosa, Luis G.; Velev, Julian [Department of Physics and Electronics, University of Puerto Rico, Humacao (United States); Institute for Functional Nanomaterials, University of Puerto Rico, San Juan (United States); Department of Physics and Astronomy, Nebraska Center for Materials and Nanoscience, University of Nebraska-Lincoln, NE (United States); Zhang, Zhengzheng [Department of Physics, University of Puerto Rico, Rio Piedras, San Juan (United States); Alvira, Jose; Vega, Omar; Diaz, Gerson [Department of Physics and Electronics, University of Puerto Rico, Humacao (United States); Routaboul, Lucie; Braunstein, Pierre [Laboratoire de Chimie de Coordination, Institut de Chimie (UMR 7177 CNRS), Universite de Strasbourg (France); Doudin, Bernard [Institut de Physique, Applique de Physique et Chimie des Materiaux de Strasbourg, Universite Louis Pasteur Strasbourg (France); Losovyj, Yaroslav B. [Institute for Functional Nanomaterials, University of Puerto Rico, San Juan (United States); J. Bennett Johnston Sr. Center for Advanced Microstructures and Devices, Louisiana State Univ., Baton Rouge, LA (United States); Dowben, Peter A. [Institute for Functional Nanomaterials, University of Puerto Rico, San Juan (United States)

    2012-08-15

    There is compelling evidence of electron pockets, at the Fermi level, in the band structure for an organic zwitterion molecule of the p-benzoquinonemonoimine type. The electronic structure of the zwitterion molecular film has a definite, although small, density of states evident at the Fermi level as well as a nonzero inner potential and thus is very different from a true insulator. In spite of a small Brillouin zone, significant band width is observed in the intermolecular band dispersion. The results demonstrate that Bloch's theorem applies to the wave vector dependence of the electronic band structure formed from the molecular orbitals of adjacent molecules in a molecular thin film of a p-benzoquinonemonoimine type zwitterion. (Copyright copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  10. Out of pocket payments and social health insurance for private hospital care: Evidence from Greece.

    Science.gov (United States)

    Grigorakis, Nikolaos; Floros, Christos; Tsangari, Haritini; Tsoukatos, Evangelos

    2016-08-01

    The Greek state has reduced their funding on health as part of broader efforts to limit the large fiscal deficits and rising debt ratios to GDP. Benefits cuts and limitations of Social Health Insurance (SHI) reimbursements result in substantial Out of Pocket (OOP) payments in the Greek population. In this paper, we examine social health insurance's risk pooling mechanisms and the catastrophic impact that OOP payments may have on insured's income and well-being. Using data collected from a cross sectional survey in Greece, we find that the OOP payments for inpatient care in private hospitals have a positive relationship with SHI funding. Moreover, we show that the SHI funding is inadequate to total inpatient financing. We argue that the Greek health policy makers have to give serious consideration to the perspective of a SHI system which should be supplemented by the Private Health Insurance (PHI) sector. PMID:27421172

  11. Highly sensitive resistive type single-axis tactile sensor with liquid pocket

    Science.gov (United States)

    Kim, Seonggi; Kim, Baek-chul; Jung, Jiyeon; Koo, Ja Choon; Choi, Hyouk Ryeol; Moon, Hyungpil

    2014-03-01

    In this paper, we propose the resistive type tactile sensor with a liquid pocket. The tactile sensor with polymer substrate has two components which are the sensing element and the structural part. The sensing part is surrounded by PDMS (Sylgard 184) which is relatively solid. To make the sensor more sensitive, we design the upper part of the sensing element in a shape of half-sphere filled with a liquid (silicone oil). When the force is applied to the sensor, the liquid pressure increases and evenly presses down the sensing element to deform. The size of sensor is 7 x 3 x 1 mm including the wiring part. The good sensitivity (0.012 S/kPa-1) of the fabricated sensor is experimentally verified.

  12. Low-Level Laser Therapy (LLLT) for periodontal pockets: a review

    Science.gov (United States)

    Pribac, Valentin; Todea, Carmen; Duma, Virgil-Florin

    2016-03-01

    The applications of lasers in medicine, both in the field of diagnosis and treatment are gaining momentum. In dentistry in particular, numerous types of lasers with a wide range of characteristics are being utilized in all fields. In consequence, a lot of experience and knowledge has been gained in the last two decades in this domain; this resulted in the development of novel technologies and devices. A brief overview is made in the first part of this article on these topics. The treatment of periodontal disease with laser therapy is pointed out, as well as the photodynamic therapy which is using LLLT for the activation of the sensitizing gel that is introduced in the periodontal pockets. This paper reviews also the application of photodynamic therapy in clinical trials which have different results; a standardization of the protocol utilized for this procedure is concluded to be necessary.

  13. HOW DISSIMILARLY SIMILAR ARE BIOSIMILARS?

    Directory of Open Access Journals (Sweden)

    Ramshankar Vijayalakshmi

    2012-05-01

    Full Text Available Recently Biopharmaceuticals are the new chemotherapeutical agents that are called as “Biosimilars” or “follow on protein products” by the European Medicines Agency (EMA and the American regulatory agencies (Food and Drug Administration respectively. Biosimilars are extremely similar to the reference molecule but not identical, however close their similarities may be. A regulatory framework is therefore in place to assess the application for marketing authorisation of biosimilars. When a biosimilar is similar to the reference biopharmaceutical in terms of safety, quality, and efficacy, it can be registered. It is important to document data from clinical trials with a view of similar safety and efficacy. If the development time for a generic medicine is around 3 years, a biosimilar takes about 6-9 years. Generic medicines need to demonstrate bioequivalence only unlike biosimilars that need to conduct phase I and Phase III clinical trials. In this review, different biosimilars that are already being used successfully in the field on Oncology is discussed. Their similarity, differences and guidelines to be followed before a clinically informed decision to be taken, is discussed. More importantly the regulatory guidelines that are operational in India with a work flow of making a biosimilar with relevant dos and dont’s are discussed. For a large populous country like India, where with improved treatments in all sectors including oncology, our ageing population is increasing. For the health care of this sector, we need more newer, cheaper and effective biosimilars in the market. It becomes therefore important to understand the regulatory guidelines and steps to come up with more biosimilars for the existing population and also more information is mandatory for the practicing clinicians to translate these effectively into clinical practice.

  14. GeoPad and GeoPocket: Information Technology for Field Science Education

    Science.gov (United States)

    Knoop, P. A.; van der Pluijm, B.

    2006-12-01

    Over the past four years we have successfully incorporated and evaluated the use of field-based Information Technology (IT) in introductory through senior-level field courses offered at the University of Michigan's Camp Davis Geology Field Station, near Jackson, WY. The use of GeoPads (field-durable Tablet PCs) and GeoPockets (field-durable Pocket PCs) -- both equipped with GIS, GPS, wireless networking, electronic notebook and other pertinent software -- have significantly enhanced our field exercises and excursions, for both students and instructors. We have focused on three main applications: (1) Mapping facilitating the development of spatial reasoning skills via powerful, intuitive capabilities for in-the-field data entry, visualization, analysis, and interpretation in both 2-D and 3-D representations; (2) Field-Trips enriching the overall experience by providing in-the-field access to a broad, relevant collection of supplemental materials, such as papers, figures, maps, photos, thin section images, etc.; and, (3) Field-Based Exercises enhancing the learning opportunities afforded by field-based exercises by supporting data analysis and interpretation, while still in the context in which the data was gathered. This IT-based approach to field education utilizes standard, off-the-shelf hardware and software, and provides students with experience using tools that are increasingly relevant to their future academic or professional careers. Furthermore, this approach is generally applicable to education and research in many traditionally non-IT-savvy science domains, in addition to geology, such as archeology, biology, sociology, and natural resources.

  15. Using wireless (Pocket)PCs in Large Introductory Courses to Expand Discourse and Interactivity

    Science.gov (United States)

    van der Pluijm, B. A.; Knoop, P. A.; Samson, P. J.; Teasley, S. D.

    2005-12-01

    Teaching methods in introductory, undergraduate courses traditionally rely on static textbooks and/or course packs, with presentation delivered as a monologue in front of a mostly passive, large audience. The concepts presented in class are often best illustrated using visualizations and/or demonstrations, but even the most stunning of images or spectacular exhibits, while motivating, offer students only passive participation in the learning process. Add to this the advent of course websites with lecture notes and PowerPoint presentations and the students are left with little incentive to attend, much less participate. Clearly this model does not provide much opportunity or motivation for today's students to learn and think more critically about the arguments being developed. What is needed is a coupling of the rich imagery of many fields with advances in technology and in learning, toward revitalizing pedagogical approaches in survey-level courses and student-instructor interaction. Our IT-enhanced classroom project couples the use of peer instruction techniques in large classes (as originally described by Mazur, 1997) with the use of interactive spatial concept challenges, utilizing wireless PocketPCs (handhelds) or student-owned wireless-enabled laptops. The technologies employed (web, PocketPC/laptop, WiFi) are off-the-shelf technologies and the Peer Instruction technique is increasingly documented in undergraduate science classes. However, the combination is not employed due to its initial cost, wrongly perceived level of effort to implement, availability of engaging activities and modest volume of data on student learning. We'll show our development, implementation and preliminary cognitive assessment efforts of this IT-enhanced classroom experience, involving interactive image quizzes and data manipulation in large introductory classes at the University of Michigan.

  16. Focused Cardiac Ultrasound Using a Pocket-Size Device in the Emergency Room

    Directory of Open Access Journals (Sweden)

    Frederico José Neves Mancuso

    2014-12-01

    Full Text Available Background: Cardiovascular urgencies are frequent reasons for seeking medical care. Prompt and accurate medical diagnosis is critical to reduce the morbidity and mortality of these conditions. Objective: To evaluate the use of a pocket-size echocardiography in addition to clinical history and physical exam in a tertiary medical emergency care. Methods: One hundred adult patients without known cardiac or lung diseases who sought emergency care with cardiac complaints were included. Patients with ischemic changes in the electrocardiography or fever were excluded. A focused echocardiography with GE Vscan equipment was performed after the initial evaluation in the emergency room. Cardiac chambers dimensions, left and right ventricular systolic function, intracardiac flows with color, pericardium, and aorta were evaluated. Results: The mean age was 61 ± 17 years old. The patient complaint was chest pain in 51 patients, dyspnea in 32 patients, arrhythmia to evaluate the left ventricular function in ten patients, hypotension/dizziness in five patients and edema in one patient. In 28 patients, the focused echocardiography allowed to confirm the initial diagnosis: 19 patients with heart failure, five with acute coronary syndrome, two with pulmonary embolism and two patients with cardiac tamponade. In 17 patients, the echocardiography changed the diagnosis: ten with suspicious of heart failure, two with pulmonary embolism suspicious, two with hypotension without cause, one suspicious of acute coronary syndrome, one of cardiac tamponade and one of aortic dissection. Conclusion: The focused echocardiography with pocket-size equipment in the emergency care may allow a prompt diagnosis and, consequently, an earlier initiation of the therapy.

  17. Solute-vacancy binding in aluminum

    International Nuclear Information System (INIS)

    Previous efforts to understand solute-vacancy binding in aluminum alloys have been hampered by a scarcity of reliable, quantitative experimental measurements. Here, we report a large database of solute-vacancy binding energies determined from first-principles density functional calculations. The calculated binding energies agree well with accurate measurements where available, and provide an accurate predictor of solute-vacancy binding in other systems. We find: (i) some common solutes in commercial Al alloys (e.g., Cu and Mg) possess either very weak (Cu), or even repulsive (Mg), binding energies. Hence, we assert that some previously reported large binding energies for these solutes are erroneous. (ii) Large binding energies are found for Sn, Cd and In, confirming the proposed mechanism for the reduced natural aging in Al-Cu alloys containing microalloying additions of these solutes. (iii) In addition, we predict that similar reduction in natural aging should occur with additions of Si, Ge and Au. (iv) Even larger binding energies are found for other solutes (e.g., Pb, Bi, Sr, Ba), but these solutes possess essentially no solubility in Al. (v) We have explored the physical effects controlling solute-vacancy binding in Al. We find that there is a strong correlation between binding energy and solute size, with larger solute atoms possessing a stronger binding with vacancies. (vi) Most transition-metal 3d solutes do not bind strongly with vacancies, and some are even energetically strongly repelled from vacancies, particularly for the early 3d solutes, Ti and V

  18. Drug binding properties of neonatal albumin

    DEFF Research Database (Denmark)

    Brodersen, R; Honoré, B

    1989-01-01

    Neonatal and adult albumin was isolated by gel chromatography on Sephacryl S-300, from adult and umbilical cord serum, respectively. Binding of monoacetyl-diamino-diphenyl sulfone, warfarin, sulfamethizole, and diazepam was studied by means of equilibrium dialysis and the binding data were analyzed...... by the method of several acceptable fitted curves. It was found that the binding affinity to neonatal albumin is less than to adult albumin for monoacetyl-diamino-diphenyl sulfone and warfarin. Sulfamethizole binding to the neonatal protein is similarly reduced when more than one molecule of the drug...... is bound per albumin molecule, and binding of the first sulfamethizole molecule is possibly reduced as well. Diazepam binds with equal affinity to the fetal and adult proteins. Among the two main albumin drug-binding functions, for warfarin and diazepam, the former is thus compromised in the newborn...

  19. Evaluating the binding efficiency of pheromone binding protein with its natural ligand using molecular docking and fluorescence analysis

    Science.gov (United States)

    Ilayaraja, Renganathan; Rajkumar, Ramalingam; Rajesh, Durairaj; Muralidharan, Arumugam Ramachandran; Padmanabhan, Parasuraman; Archunan, Govindaraju

    2014-06-01

    Chemosignals play a crucial role in social and sexual communication among inter- and intra-species. Chemical cues are bound with protein that is present in the pheromones irrespective of sex are commonly called as pheromone binding protein (PBP). In rats, the pheromone compounds are bound with low molecular lipocalin protein α2u-globulin (α2u). We reported farnesol is a natural endogenous ligand (compound) present in rat preputial gland as a bound volatile compound. In the present study, an attempt has been made through computational method to evaluating the binding efficiency of α2u with the natural ligand (farnesol) and standard fluorescent molecule (2-naphthol). The docking analysis revealed that the binding energy of farnesol and 2-naphthol was almost equal and likely to share some binding pocket of protein. Further, to extrapolate the results generated through computational approach, the α2u protein was purified and subjected to fluorescence titration and binding assay. The results showed that the farnesol is replaced by 2-naphthol with high hydrophobicity of TYR120 in binding sites of α2u providing an acceptable dissociation constant indicating the binding efficiency of α2u. The obtained results are in corroboration with the data made through computational approach.

  20. Retrieval of similar chess positions

    OpenAIRE

    Ganguly, Debasis; LEVELING, JOHANNES; Jones, Gareth J.F.

    2014-01-01

    We address the problem of retrieving chess game positions similar to a given query position from a collection of archived chess games. We investigate this problem from an information retrieval (IR) perspective. The advantage of our proposed IR-based approach is that it allows using the standard inverted organization of stored chess positions, leading to an ecient retrieval. Moreover, in contrast to retrieving exactly identical board positions, the IR-based approach is able to provide approxim...