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Sample records for binding sitesin multiple

  1. MONKEY: Identifying conserved transcription-factor binding sitesin multiple alignments using a binding site-specific evolutionarymodel

    Energy Technology Data Exchange (ETDEWEB)

    Moses, Alan M.; Chiang, Derek Y.; Pollard, Daniel A.; Iyer, VenkyN.; Eisen, Michael B.

    2004-10-28

    We introduce a method (MONKEY) to identify conserved transcription-factor binding sites in multispecies alignments. MONKEY employs probabilistic models of factor specificity and binding site evolution, on which basis we compute the likelihood that putative sites are conserved and assign statistical significance to each hit. Using genomes from the genus Saccharomyces, we illustrate how the significance of real sites increases with evolutionary distance and explore the relationship between conservation and function.

  2. Cooperative binding: a multiple personality.

    Science.gov (United States)

    Martini, Johannes W R; Diambra, Luis; Habeck, Michael

    2016-06-01

    Cooperative binding has been described in many publications and has been related to or defined by several different properties of the binding behavior of the ligand to the target molecule. In addition to the commonly used Hill coefficient, other characteristics such as a sigmoidal shape of the overall titration curve in a linear plot, a change of ligand affinity of the other binding sites when a site of the target molecule becomes occupied, or complex roots of the binding polynomial have been used to define or to quantify cooperative binding. In this work, we analyze how the different properties are related in the most general model for binding curves based on the grand canonical partition function and present several examples which highlight differences between the cooperativity characterizing properties which are discussed. Our results mainly show that among the presented definitions there are not two which fully coincide. Moreover, this work poses the question whether it can make sense to distinguish between positive and negative cooperativity based on the macroscopic binding isotherm only. This article shall emphasize that scientists who investigate cooperative effects in biological systems could help avoiding misunderstandings by stating clearly which kind of cooperativity they discuss.

  3. 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

  4. Alcohol Binding to the Odorant Binding Protein LUSH: Multiple Factors Affecting Binding Affinities

    OpenAIRE

    Ader, Lauren; Jones, David N. M.; Lin, Hai

    2010-01-01

    Density function theory (DFT) calculations have been carried out to investigate the binding of alcohols to the odorant binding protein LUSH from Drosophila melanogaster. LUSH is one of the few proteins known to bind to ethanol at physiologically relevant concentrations and where high-resolution structural information is available for the protein bound to alcohol at these concentrations. The structures of the LUSH–alcohol complexes identify a set of specific hydrogen-bonding interactions as cr...

  5. The Multiple Carbohydrate Binding Specificities of Helicobacter pylori

    Science.gov (United States)

    Teneberg, Susann

    Persistent colonization of the human stomach by Helicobacter pylori is a risk factor for the development of peptic ulcer disease and gastric cancer. Adhesion of microbes to the target tissue is an important determinant for successful initiation, establishment and maintenance of infection, and a variety of different candidate carbohydrate receptors for H. pylori have been identified. Here the different the binding specifities, and their potential role in adhesion to human gastric epithelium are described. Finally, recent findings on the roles of sialic acid binding SabA adhesin in interactions with human neutrophils and erythrocytes are discussed.

  6. A calmodulin-binding/CGCG box DNA-binding protein family involved in multiple signaling pathways in plants

    Science.gov (United States)

    Yang, Tianbao; Poovaiah, B. W.

    2002-01-01

    We reported earlier that the tobacco early ethylene-responsive gene NtER1 encodes a calmodulin-binding protein (Yang, T., and Poovaiah, B. W. (2000) J. Biol. Chem. 275, 38467-38473). Here we demonstrate that there is one NtER1 homolog as well as five related genes in Arabidopsis. These six genes are rapidly and differentially induced by environmental signals such as temperature extremes, UVB, salt, and wounding; hormones such as ethylene and abscisic acid; and signal molecules such as methyl jasmonate, H(2)O(2), and salicylic acid. Hence, they were designated as AtSR1-6 (Arabidopsis thaliana signal-responsive genes). Ca(2+)/calmodulin binds to all AtSRs, and their calmodulin-binding regions are located on a conserved basic amphiphilic alpha-helical motif in the C terminus. AtSR1 targets the nucleus and specifically recognizes a novel 6-bp CGCG box (A/C/G)CGCG(G/T/C). The multiple CGCG cis-elements are found in promoters of genes such as those involved in ethylene signaling, abscisic acid signaling, and light signal perception. The DNA-binding domain in AtSR1 is located on the N-terminal 146 bp where all AtSR1-related proteins share high similarity but have no similarity to other known DNA-binding proteins. The calmodulin-binding nuclear proteins isolated from wounded leaves exhibit specific CGCG box DNA binding activities. These results suggest that the AtSR gene family encodes a family of calmodulin-binding/DNA-binding proteins involved in multiple signal transduction pathways in plants.

  7. Multiple approaches to assess pectin binding to galectin-3.

    Science.gov (United States)

    Zhang, Tao; Zheng, Yi; Zhao, Dongyang; Yan, Jingmin; Sun, Chongliang; Zhou, Yifa; Tai, Guihua

    2016-10-01

    Although several approaches have been used to evaluate binding of carbohydrates to lectins, results are not always comparable, especially with larger polysaccharides. Here, we quantitatively assessed and compared binding of pectin-derived polysaccharides to galectin-3 (Gal-3) using five methods: surface plasmon resonance (SPR), bio-layer interferometry (BLI), fluorescence polarization (FP), competitive fluorescence-linked immunosorbance (cFLISA), and the well-known cell-based hemagglutination assay (G3H). Our studies revealed that whereas Gal-3-pectin binding parameters determined by SPR and BLI were comparable and correlated with inhibitory potencies from the G3H assay, results using FP and cFLISA assays were highly variable and depended greatly on the probe and mass of the polysaccharide. In the cFLISA assay, for example, pectins showed no inhibition when using the DTAF-labeled asialofetuin probe, but did when using a DTAF-labeled pectin probe. And the FP approach with the DTAF-lactose probe did not work on polysaccharides and large galactan chains, although it did work well with smaller galactans. Nevertheless, even though results derived from all of these methods are in general agreement, derived KD, IC50, and MIC values do differ. Our results reflect the variability using various techniques and therefore will be useful to investigators who are developing pectin-derived Gal-3 antagonists as anti-cancer agents. PMID:27328612

  8. The TRPV5/6 calcium channels contain multiple calmodulin binding sites with differential binding properties.

    NARCIS (Netherlands)

    Kovalevskaya, N.V.; Bokhovchuk, F.M.; Vuister, G.W.

    2012-01-01

    The epithelial Ca(2+) channels TRPV5/6 (transient receptor potential vanilloid 5/6) are thoroughly regulated in order to fine-tune the amount of Ca(2+) reabsorption. Calmodulin has been shown to be involved into calcium-dependent inactivation of TRPV5/6 channels by binding directly to the distal C-t

  9. Multiple binding of bilirubin to human serum albumin and cobinding with laurate

    DEFF Research Database (Denmark)

    Sato, H; Honoré, B; Brodersen, R

    1988-01-01

    Numerical analysis of multiple binding of two ligands to one carrier has been accomplished, using the principle of several sets of acceptable binding constants, with bilirubin-laurate-albumin as an example. Binding of bilirubin to defatted human serum albumin was investigated by a spectroscopic...... method, based upon a difference of light absorption spectrum for free and bound bilirubin. The observations were supplemented with previous data from an independent technique, measurement of oxidation rates of free bilirubin with hydrogen peroxide and peroxidase. A continuous isotherm was obtained......, showing binding of at least 4 mol bilirubin per mole albumin with the following stoichiometric binding constants, 1.11 X 10(8), 1.7 X 10(7), 8 X 10(5), and 4 X 10(4) M-1 at pH 8.2, ionic strength 0.15 M, 25 degrees C. The binding is anticooperative at all steps. A saturation level was not reached...

  10. Multiple antigen peptide dendrimer elicits antibodies for detecting rat and mouse growth hormone binding proteins

    OpenAIRE

    Aguilar, Roberto M.; Talamantes, Frank J.; Bustamante, Juan J.; Muñoz, Jesus; Treviño, Lisa R.; Martinez, Andrew O.; Haro, Luis S.

    2009-01-01

    The membrane-bound rat growth hormone receptor (GH-R) and an alternatively spliced isoform, the soluble rat GH binding protein (GH-BP), are comprised of identical N-terminal GH binding domains, however, their C-terminal sequences differ. Immunological reagents are needed to distinguish between the two isoforms in order to understand their respective roles in mediating the actions of GH. Accordingly, a tetravalent multiple antigen peptide (MAP) dendrimer with four identical branches of a C-ter...

  11. An intermolecular binding mechanism involving multiple LysM domains mediates carbohydrate recognition by an endopeptidase

    DEFF Research Database (Denmark)

    Wong, Jaslyn E M M; Midtgaard, Søren Roi; Gysel, Kira;

    2015-01-01

    of multiple LysM domains in substrate binding has so far lacked support from high-resolution structures of ligand-bound complexes. Here, a structural study of the Thermus thermophilus NlpC/P60 endopeptidase containing two LysM domains is presented. The crystal structure and small-angle X-ray scattering...

  12. Zinc-induced oligomerization of zinc α2 glycoprotein reveals multiple fatty acid-binding sites.

    Science.gov (United States)

    Zahid, Henna; Miah, Layeque; Lau, Andy M; Brochard, Lea; Hati, Debolina; Bui, Tam T T; Drake, Alex F; Gor, Jayesh; Perkins, Stephen J; McDermott, Lindsay C

    2016-01-01

    Zinc α2 glycoprotein (ZAG) is an adipokine with a class I MHC protein fold and is associated with obesity and diabetes. Although its intrinsic ligand remains unknown, ZAG binds the dansylated C11 fatty acid 11-(dansylamino)undecanoic acid (DAUDA) in the groove between the α1 and α2 domains. The surface of ZAG has approximately 15 weak zinc-binding sites deemed responsible for precipitation from human plasma. In the present study the functional significance of these metal sites was investigated. Analytical ultracentrifugation (AUC) and CD showed that zinc, but not other divalent metals, causes ZAG to oligomerize in solution. Thus ZAG dimers and trimers were observed in the presence of 1 and 2 mM zinc. Molecular modelling of X-ray scattering curves and sedimentation coefficients indicated a progressive stacking of ZAG monomers, suggesting that the ZAG groove may be occluded in these. Using fluorescence-detected sedimentation velocity, these ZAG-zinc oligomers were again observed in the presence of the fluorescent boron dipyrromethene fatty acid C16-BODIPY (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-hexadecanoic acid). Fluorescence spectroscopy confirmed that ZAG binds C16-BODIPY. ZAG binding to C16-BODIPY, but not to DAUDA, was reduced by increased zinc concentrations. We conclude that the lipid-binding groove in ZAG contains at least two distinct fatty acid-binding sites for DAUDA and C16-BODIPY, similar to the multiple lipid binding seen in the structurally related immune protein CD1c. In addition, because high concentrations of zinc occur in the pancreas, the perturbation of these multiple lipid-binding sites by zinc may be significant in Type 2 diabetes where dysregulation of ZAG and zinc homoeostasis occurs.

  13. Multiple opioid receptor binding in dissociated intact guinea pig brain cells

    International Nuclear Information System (INIS)

    Dissociated intact guinea pig brain cells were prepared by the method of Rogers and El-Fakahany. Over 95% of these cells are viable as demonstrated by their exclusion of the dye trypan blue. Opioid receptor binding assays were performed in a modified Kreb-Ringers physiological buffer. The following radiolabeled ligands and conditions were used to selectively labeled multiple opioid receptors: mu binding, 1 nM [3H]naloxone + 20 nM DADLE + 300 nM U50,488H; kappa binding, 4 nM (-)-[3H]-EKC + 100 nM DAGO + 500 nM DADLE; delta binding, 2 nM [3H]-DADLE + 100 nM DAGO + 300 nM U50,488H; sigma binding, 4 nM (+)-[3H]SKF 10,047. The intact brain cells in physiological buffer demonstrated specific binding for mu, kappa, delta, and sigma receptors. The relative binding potency of naloxone for each of the receptor types is arbitrarily set at 1

  14. Single-stranded DNA-binding proteins: multiple domains for multiple functions.

    Science.gov (United States)

    Dickey, Thayne H; Altschuler, Sarah E; Wuttke, Deborah S

    2013-07-01

    The recognition of single-stranded DNA (ssDNA) is integral to myriad cellular functions. In eukaryotes, ssDNA is present stably at the ends of chromosomes and at some promoter elements. Furthermore, it is formed transiently by several cellular processes including telomere synthesis, transcription, and DNA replication, recombination, and repair. To coordinate these diverse activities, a variety of proteins have evolved to bind ssDNA in a manner specific to their function. Here, we review the recognition of ssDNA through the analysis of high-resolution structures of proteins in complex with ssDNA. This functionally diverse set of proteins arises from a limited set of structural motifs that can be modified and arranged to achieve distinct activities, including a range of ligand specificities. We also investigate the ways in which these domains interact in the context of large multidomain proteins/complexes. These comparisons reveal the structural features that define the range of functions exhibited by these proteins.

  15. Multiple ETS family proteins regulate PF4 gene expression by binding to the same ETS binding site.

    Directory of Open Access Journals (Sweden)

    Yoshiaki Okada

    Full Text Available In previous studies on the mechanism underlying megakaryocyte-specific gene expression, several ETS motifs were found in each megakaryocyte-specific gene promoter. Although these studies suggested that several ETS family proteins regulate megakaryocyte-specific gene expression, only a few ETS family proteins have been identified. Platelet factor 4 (PF4 is a megakaryocyte-specific gene and its promoter includes multiple ETS motifs. We had previously shown that ETS-1 binds to an ETS motif in the PF4 promoter. However, the functions of the other ETS motifs are still unclear. The goal of this study was to investigate a novel functional ETS motif in the PF4 promoter and identify proteins binding to the motif. In electrophoretic mobility shift assays and a chromatin immunoprecipitation assay, FLI-1, ELF-1, and GABP bound to the -51 ETS site. Expression of FLI-1, ELF-1, and GABP activated the PF4 promoter in HepG2 cells. Mutation of a -51 ETS site attenuated FLI-1-, ELF-1-, and GABP-mediated transactivation of the promoter. siRNA analysis demonstrated that FLI-1, ELF-1, and GABP regulate PF4 gene expression in HEL cells. Among these three proteins, only FLI-1 synergistically activated the promoter with GATA-1. In addition, only FLI-1 expression was increased during megakaryocytic differentiation. Finally, the importance of the -51 ETS site for the activation of the PF4 promoter during physiological megakaryocytic differentiation was confirmed by a novel reporter gene assay using in vitro ES cell differentiation system. Together, these data suggest that FLI-1, ELF-1, and GABP regulate PF4 gene expression through the -51 ETS site in megakaryocytes and implicate the differentiation stage-specific regulation of PF4 gene expression by multiple ETS factors.

  16. SH3 domain-peptide binding energy calculations based on structural ensemble and multiple peptide templates.

    Directory of Open Access Journals (Sweden)

    Seungpyo Hong

    Full Text Available SH3 domains mediate signal transduction by recognizing short peptides. Understanding of the driving forces in peptide recognitions will help us to predict the binding specificity of the domain-peptide recognition and to understand the molecular interaction networks of cells. However, accurate calculation of the binding energy is a tough challenge. In this study, we propose three ideas for improving our ability to predict the binding energy between SH3 domains and peptides: (1 utilizing the structural ensembles sampled from a molecular dynamics simulation trajectory, (2 utilizing multiple peptide templates, and (3 optimizing the sequence-structure mapping. We tested these three ideas on ten previously studied SH3 domains for which SPOT analysis data were available. The results indicate that calculating binding energy using the structural ensemble was most effective, clearly increasing the prediction accuracy, while the second and third ideas tended to give better binding energy predictions. We applied our method to the five SH3 targets in DREAM4 Challenge and selected the best performing method.

  17. STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

    Science.gov (United States)

    Létourneau, Danny; Bédard, Mikaël; Cabana, Jérôme; Lefebvre, Andrée; LeHoux, Jean-Guy; Lavigne, Pierre

    2016-01-01

    START domain proteins are conserved α/β helix-grip fold that play a role in the non-vesicular and intracellular transport of lipids and sterols. The mechanism and conformational changes permitting the entry of the ligand into their buried binding sites is not well understood. Moreover, their functions and the identification of cognate ligands is still an active area of research. Here, we report the solution structure of STARD6 and the characterization of its backbone dynamics on multiple time-scales through 15N spin-relaxation and amide exchange studies. We reveal for the first time the presence of concerted fluctuations in the Ω1 loop and the C-terminal helix on the microsecond-millisecond time-scale that allows for the opening of the binding site and ligand entry. We also report that STARD6 binds specifically testosterone. Our work represents a milestone for the study of ligand binding mechanism by other START domains and the elucidation of the biological function of STARD6. PMID:27340016

  18. Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting

    Science.gov (United States)

    Zhu, Yuanjun; Li, Ruyi; Lin, Yuan; Shui, Mengyang; Liu, Xiaoyan; Chen, Huan; Wang, Yinye

    2016-01-01

    Targeted delivery of antithrombotic drugs centralizes the effects in the thrombosis site and reduces the hemorrhage side effects in uninjured vessels. We have recently reported that the platelet-targeting factor Xa (FXa) inhibitors, constructed by engineering one Arg-Gly-Asp (RGD) motif into Ancylostoma caninum anticoagulant peptide 5 (AcAP5), can reduce the risk of systemic bleeding than non-targeted AcAP5 in mouse arterial injury model. Increasing the number of platelet-binding sites of FXa inhibitors may facilitate their adhesion to activated platelets, and further lower the bleeding risks. For this purpose, we introduced three RGD motifs into AcAP5 to generate a variant NR4 containing three platelet-binding sites. NR4 reserved its inherent anti-FXa activity. Protein-protein docking showed that all three RGD motifs were capable of binding to platelet receptor αIIbβ3. Molecular dynamics simulation demonstrated that NR4 has more opportunities to interact with αIIbβ3 than single-RGD-containing NR3. Flow cytometry analysis and rat arterial thrombosis model further confirmed that NR4 possesses enhanced platelet targeting activity. Moreover, NR4-treated mice showed a trend toward less tail bleeding time than NR3-treated mice in carotid artery endothelium injury model. Therefore, our data suggest that engineering multiple binding sites in one recombinant protein is a useful tool to improve its platelet-targeting efficiency. PMID:27432161

  19. Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting.

    Science.gov (United States)

    Zhu, Yuanjun; Li, Ruyi; Lin, Yuan; Shui, Mengyang; Liu, Xiaoyan; Chen, Huan; Wang, Yinye

    2016-01-01

    Targeted delivery of antithrombotic drugs centralizes the effects in the thrombosis site and reduces the hemorrhage side effects in uninjured vessels. We have recently reported that the platelet-targeting factor Xa (FXa) inhibitors, constructed by engineering one Arg-Gly-Asp (RGD) motif into Ancylostoma caninum anticoagulant peptide 5 (AcAP5), can reduce the risk of systemic bleeding than non-targeted AcAP5 in mouse arterial injury model. Increasing the number of platelet-binding sites of FXa inhibitors may facilitate their adhesion to activated platelets, and further lower the bleeding risks. For this purpose, we introduced three RGD motifs into AcAP5 to generate a variant NR4 containing three platelet-binding sites. NR4 reserved its inherent anti-FXa activity. Protein-protein docking showed that all three RGD motifs were capable of binding to platelet receptor αIIbβ3. Molecular dynamics simulation demonstrated that NR4 has more opportunities to interact with αIIbβ3 than single-RGD-containing NR3. Flow cytometry analysis and rat arterial thrombosis model further confirmed that NR4 possesses enhanced platelet targeting activity. Moreover, NR4-treated mice showed a trend toward less tail bleeding time than NR3-treated mice in carotid artery endothelium injury model. Therefore, our data suggest that engineering multiple binding sites in one recombinant protein is a useful tool to improve its platelet-targeting efficiency. PMID:27432161

  20. Binding of Multiple Rap1 Proteins Stimulates Chromosome Breakage Induction during DNA Replication.

    Directory of Open Access Journals (Sweden)

    Greicy H Goto

    2015-08-01

    Full Text Available Telomeres, the ends of linear eukaryotic chromosomes, have a specialized chromatin structure that provides a stable chromosomal terminus. In budding yeast Rap1 protein binds to telomeric TG repeat and negatively regulates telomere length. Here we show that binding of multiple Rap1 proteins stimulates DNA double-stranded break (DSB induction at both telomeric and non-telomeric regions. Consistent with the role of DSB induction, Rap1 stimulates nearby recombination events in a dosage-dependent manner. Rap1 recruits Rif1 and Rif2 to telomeres, but neither Rif1 nor Rif2 is required for DSB induction. Rap1-mediated DSB induction involves replication fork progression but inactivation of checkpoint kinase Mec1 does not affect DSB induction. Rap1 tethering shortens artificially elongated telomeres in parallel with telomerase inhibition, and this telomere shortening does not require homologous recombination. These results suggest that Rap1 contributes to telomere homeostasis by promoting chromosome breakage.

  1. Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging.

    Science.gov (United States)

    Khan, Shahid; Conte, Ianina; Carter, Tom; Bayer, K Ulrich; Molloy, Justin E

    2016-07-26

    Localization of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIα (α) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIβ (β). The βE' splice variant bound more weakly than α, showing that binding by β depends critically on the interdomain linker. The mutations βT287D and αT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (βK43R and αK42M) or Ca(2+)/calmodulin (βA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the αT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIα isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar

  2. Somitogenesis clock-wave initiation requires differential decay and multiple binding sites for clock protein.

    Directory of Open Access Journals (Sweden)

    Mark Campanelli

    2010-04-01

    Full Text Available Somitogenesis is a process common to all vertebrate embryos in which repeated blocks of cells arise from the presomitic mesoderm (PSM to lay a foundational pattern for trunk and tail development. Somites form in the wake of passing waves of periodic gene expression that originate in the tailbud and sweep posteriorly across the PSM. Previous work has suggested that the waves result from a spatiotemporally graded control protein that affects the oscillation rate of clock-gene expression. With a minimally constructed mathematical model, we study the contribution of two control mechanisms to the initial formation of this gene-expression wave. We test four biologically motivated model scenarios with either one or two clock protein transcription binding sites, and with or without differential decay rates for clock protein monomers and dimers. We examine the sensitivity of wave formation with respect to multiple model parameters and robustness to heterogeneity in cell population. We find that only a model with both multiple binding sites and differential decay rates is able to reproduce experimentally observed waveforms. Our results show that the experimentally observed characteristics of somitogenesis wave initiation constrain the underlying genetic control mechanisms.

  3. Roles of multiple surface sites, long substrate binding clefts, and carbohydrate binding modules in the action of amylolytic enzymes on polysaccharide substrates

    DEFF Research Database (Denmark)

    Nielsen, Morten Munch; Seo, E.S.; Dilokpimol, Adiphol;

    2008-01-01

    Germinating barley seeds contain multiple forms of alpha-amylase, which are subject to both differential gene expression and differential degradation as part of the repertoire of starch-degrading enzymes. The alpha-amylases are endo-acting and possess a long substrate binding cleft with a charact...

  4. Identification of an erythrocyte binding peptide from the erythrocyte binding antigen, EBA-175, which blocks parasite multiplication and induces peptide-blocking antibodies

    DEFF Research Database (Denmark)

    Jakobsen, P H; Heegaard, P M; Koch, C;

    1998-01-01

    A biotinylated peptide covering a sequence of 21 amino acids (aa) from the erythrocyte binding antigen (EBA-175) of Plasmodium falciparum bound to human glycophorin A, an erythrocyte receptor for merozoites, as demonstrated by enzyme-linked immunosorbent assay (ELISA) and to erythrocytes as demon......A biotinylated peptide covering a sequence of 21 amino acids (aa) from the erythrocyte binding antigen (EBA-175) of Plasmodium falciparum bound to human glycophorin A, an erythrocyte receptor for merozoites, as demonstrated by enzyme-linked immunosorbent assay (ELISA) and to erythrocytes...... as demonstrated by flow cytometry analysis. The peptide, EBA(aa1076-96), also bound to desialylated glycophorin A and glycophorin B when tested by ELISA. The peptide blocked parasite multiplication in vitro. The glycophorin A binding sequence was further delineated to a 12-aa sequence, EBA(aa1085-96), by testing...... the binding of a range of truncated peptides to immobilized glycophorin A. Our data indicate that EBA(aa1085-96) is part of a ligand on the merozoite for binding to erythrocyte receptors. This binding suggests that the EBA(aa1085-96) peptide is involved in a second binding step, independent of sialic acid...

  5. Identification of an erythrocyte binding peptide from the erythrocyte binding antigen, EBA-175, which blocks parasite multiplication and induces peptide-blocking antibodies

    DEFF Research Database (Denmark)

    Jakobsen, P.H.; Heegaard, Peter M. H.; Koch, C.;

    1998-01-01

    A biotinylated peptide covering a sequence of 21 amino acids (aa) from the erythrocyte binding antigen (EBA-175) of Plasmodium falciparum bound to human glycophorin A, an erythrocyte receptor for merozoites, as demonstrated by enzyme-linked immunosorbent assay (ELISA) and to erythrocytes as demon......A biotinylated peptide covering a sequence of 21 amino acids (aa) from the erythrocyte binding antigen (EBA-175) of Plasmodium falciparum bound to human glycophorin A, an erythrocyte receptor for merozoites, as demonstrated by enzyme-linked immunosorbent assay (ELISA) and to erythrocytes...... as demonstrated by flow cytometry analysis. The peptide, EBA(aa1076-96), also bound to desialylated glycophorin A and glycophorin B when tested by ELISA, The peptide blocked parasite multiplication in vitro. The glycophorin A binding sequence was further delineated to a 12-aa sequence, EBA(aa1085-96), by testing...... the binding of a range of truncated peptides to immobilized glycophorin A. Our data indicate that EBA(aa1085-96) is part of a ligand on the merozoite for binding to erythrocyte receptors. This binding suggests that the EBA(aa1085-96) peptide is involved in a second binding step, independent of sialic acid...

  6. Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes.

    Science.gov (United States)

    Lin, Clara S; Uboldi, Alessandro D; Epp, Christian; Bujard, Hermann; Tsuboi, Takafumi; Czabotar, Peter E; Cowman, Alan F

    2016-04-01

    Successful invasion of human erythrocytes byPlasmodium falciparummerozoites is required for infection of the host and parasite survival. The early stages of invasion are mediated via merozoite surface proteins that interact with human erythrocytes. The nature of these interactions are currently not well understood, but it is known that merozoite surface protein 1 (MSP1) is critical for successful erythrocyte invasion. Here we show that the peripheral merozoite surface proteins MSP3, MSP6, MSPDBL1, MSPDBL2, and MSP7 bind directly to MSP1, but independently of each other, to form multiple forms of the MSP1 complex on the parasite surface. These complexes have overlapping functions that interact directly with human erythrocytes. We also show that targeting the p83 fragment of MSP1 using inhibitory antibodies inhibits all forms of MSP1 complexes and disrupts parasite growthin vitro.

  7. Probabilistic Inference on Multiple Normalized Signal Profiles from Next Generation Sequencing: Transcription Factor Binding Sites

    KAUST Repository

    Wong, Ka-Chun

    2015-04-20

    With the prevalence of chromatin immunoprecipitation (ChIP) with sequencing (ChIP-Seq) technology, massive ChIP-Seq data has been accumulated. The ChIP-Seq technology measures the genome-wide occupancy of DNA-binding proteins in vivo. It is well-known that different DNA-binding protein occupancies may result in a gene being regulated in different conditions (e.g. different cell types). To fully understand a gene\\'s function, it is essential to develop probabilistic models on multiple ChIP-Seq profiles for deciphering the gene transcription causalities. In this work, we propose and describe two probabilistic models. Assuming the conditional independence of different DNA-binding proteins\\' occupancies, the first method (SignalRanker) is developed as an intuitive method for ChIP-Seq genome-wide signal profile inference. Unfortunately, such an assumption may not always hold in some gene regulation cases. Thus, we propose and describe another method (FullSignalRanker) which does not make the conditional independence assumption. The proposed methods are compared with other existing methods on ENCODE ChIP-Seq datasets, demonstrating its regression and classification ability. The results suggest that FullSignalRanker is the best-performing method for recovering the signal ranks on the promoter and enhancer regions. In addition, FullSignalRanker is also the best-performing method for peak sequence classification. We envision that SignalRanker and FullSignalRanker will become important in the era of next generation sequencing. FullSignalRanker program is available on the following website: http://www.cs.toronto.edu/∼wkc/FullSignalRanker/ © 2015 IEEE.

  8. An intermolecular binding mechanism involving multiple LysM domains mediates carbohydrate recognition by an endopeptidase

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Jaslyn E. M. M. [Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus (Denmark); Midtgaard, Søren Roi [University of Copenhagen, Universitetsparken 5, 2100 Copenhagen (Denmark); Gysel, Kira [Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus (Denmark); Thygesen, Mikkel B.; Sørensen, Kasper K.; Jensen, Knud J. [University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C (Denmark); Stougaard, Jens; Thirup, Søren; Blaise, Mickaël, E-mail: mickael.blaise@cpbs.cnrs.fr [Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus (Denmark)

    2015-03-01

    The crystal and solution structures of the T. thermophilus NlpC/P60 d, l-endopeptidase as well as the co-crystal structure of its N-terminal LysM domains bound to chitohexaose allow a proposal to be made regarding how the enzyme recognizes peptidoglycan. LysM domains, which are frequently present as repetitive entities in both bacterial and plant proteins, are known to interact with carbohydrates containing N-acetylglucosamine (GlcNAc) moieties, such as chitin and peptidoglycan. In bacteria, the functional significance of the involvement of multiple LysM domains in substrate binding has so far lacked support from high-resolution structures of ligand-bound complexes. Here, a structural study of the Thermus thermophilus NlpC/P60 endopeptidase containing two LysM domains is presented. The crystal structure and small-angle X-ray scattering solution studies of this endopeptidase revealed the presence of a homodimer. The structure of the two LysM domains co-crystallized with N-acetyl-chitohexaose revealed a new intermolecular binding mode that may explain the differential interaction between LysM domains and short or long chitin oligomers. By combining the structural information with the three-dimensional model of peptidoglycan, a model suggesting how protein dimerization enhances the recognition of peptidoglycan is proposed.

  9. An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding.

    Directory of Open Access Journals (Sweden)

    Shaun Mahony

    2014-03-01

    Full Text Available Regulatory proteins can bind to different sets of genomic targets in various cell types or conditions. To reliably characterize such condition-specific regulatory binding we introduce MultiGPS, an integrated machine learning approach for the analysis of multiple related ChIP-seq experiments. MultiGPS is based on a generalized Expectation Maximization framework that shares information across multiple experiments for binding event discovery. We demonstrate that our framework enables the simultaneous modeling of sparse condition-specific binding changes, sequence dependence, and replicate-specific noise sources. MultiGPS encourages consistency in reported binding event locations across multiple-condition ChIP-seq datasets and provides accurate estimation of ChIP enrichment levels at each event. MultiGPS's multi-experiment modeling approach thus provides a reliable platform for detecting differential binding enrichment across experimental conditions. We demonstrate the advantages of MultiGPS with an analysis of Cdx2 binding in three distinct developmental contexts. By accurately characterizing condition-specific Cdx2 binding, MultiGPS enables novel insight into the mechanistic basis of Cdx2 site selectivity. Specifically, the condition-specific Cdx2 sites characterized by MultiGPS are highly associated with pre-existing genomic context, suggesting that such sites are pre-determined by cell-specific regulatory architecture. However, MultiGPS-defined condition-independent sites are not predicted by pre-existing regulatory signals, suggesting that Cdx2 can bind to a subset of locations regardless of genomic environment. A summary of this paper appears in the proceedings of the RECOMB 2014 conference, April 2-5.

  10. Multiple ligand simultaneous docking (MLSD): A novel approach to study the effect of inhibitors on substrate binding to PPO.

    Science.gov (United States)

    Raghavendra, S; Aditya Rao, S J; Kumar, Vadlapudi; Ramesh, C K

    2015-12-01

    Multiple ligand simultaneous docking, a computational approach is used to study the concurrent interactions between substrate and the macromolecule binding together in the presence of an inhibitor. The present investigation deals with the study of the effect of different inhibitors on binding of substrate to the protein Polyphenoloxidase (PPO). The protein was isolated from Mucuna pruriens and confirmed as tyrosinases involved in L-DOPA production. The activity was measured using different inhibitors at different concentrations taking catechol as substrate. A high-throughput binding study was conducted to compare the binding orientations of individual ligands and multiple ligands employing Autodock 4.2. The results of single substrate docking showed a better binding of urea with the binding energy of -3.48 kJ mol(-1) and inter molecular energy of -3.48 kJ mol(-1) while the results of MLSD revealed that ascorbic acid combined with the substrate showed better inhibition with a decreased binding energy of -2.37 kJ mol(-1). PMID:26414950

  11. Circulating vitamin D binding protein levels are not associated with relapses or with vitamin D status in multiple sclerosis

    NARCIS (Netherlands)

    Smolders, J.J.F.M.; Peelen, E.; Thewissen, M.; Menheere, P.; Damoiseaux, J.; Hupperts, R.

    2014-01-01

    BACKGROUND: A low vitamin D status has been associated with multiple sclerosis (MS). Most circulating vitamin D metabolites are bound to vitamin D binding protein (DBP). OBJECTIVES: The purpose of this study was to explore whether there is an association between MS and DBP. METHODS: We compared DBP

  12. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients.

    Directory of Open Access Journals (Sweden)

    Liesbeth Bieghs

    Full Text Available Insulin-like growth factor (IGF signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM. In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6, leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17, monoclonal gammopathy of undetermined significance (MGUS (n = 37, and control individuals (n = 15, using ELISA (IGFs and 125I-IGF1 Western Ligand Blotting (IGFBPs. MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold and decrease in intact IGFBP-3 (0.6-0.5 fold in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration.

  13. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients.

    Science.gov (United States)

    Bieghs, Liesbeth; Brohus, Malene; Kristensen, Ida B; Abildgaard, Niels; Bøgsted, Martin; Johnsen, Hans E; Conover, Cheryl A; De Bruyne, Elke; Vanderkerken, Karin; Overgaard, Michael T; Nyegaard, Mette

    2016-01-01

    Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold) and decrease in intact IGFBP-3 (0.6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration. PMID:27111220

  14. Nonspecific recognition is achieved in Pot1pC through the use of multiple binding modes.

    Science.gov (United States)

    Dickey, Thayne H; McKercher, Marissa A; Wuttke, Deborah S

    2013-01-01

    Pot1 is the protein responsible for binding to and protecting the 3' single-stranded DNA (ssDNA) overhang at most eukaryotic telomeres. Here, we present the crystal structure of one of the two oligonucleotide/oligosaccharide-binding folds (Pot1pC) that make up the ssDNA-binding domain in S. pombe Pot1. Comparison with the homologous human domain reveals unexpected structural divergence in the mode of ligand binding that explains the differing ligand requirements between species. Despite the presence of apparently base-specific hydrogen bonds, Pot1pC is able to bind a wide range of ssDNA sequences with thermodynamic equivalence. To address how Pot1pC binds ssDNA with little to no specificity, multiple structures of Pot1pC bound to noncognate ssDNA ligands were solved. These structures reveal that this promiscuity is implemented through new binding modes that thermodynamically compensate for base-substitutions through alternate stacking interactions and new H-bonding networks.

  15. Multiple sup 3 H-oxytocin binding sites in rat myometrial plasma membranes

    Energy Technology Data Exchange (ETDEWEB)

    Crankshaw, D.; Gaspar, V.; Pliska, V. (McMaster Univ., Hamilton, Ontario, (Canada))

    1990-01-01

    The affinity spectrum method has been used to analyse binding isotherms for {sup 3}H-oxytocin to rat myometrial plasma membranes. Three populations of binding sites with dissociation constants (Kd) of 0.6-1.5 x 10(-9), 0.4-1.0 x 10(-7) and 7 x 10(-6) mol/l were identified and their existence verified by cluster analysis based on similarities between Kd, binding capacity and Hill coefficient. When experimental values were compared to theoretical curves constructed using the estimated binding parameters, good fits were obtained. Binding parameters obtained by this method were not influenced by the presence of GTP gamma S (guanosine-5'-O-3-thiotriphosphate) in the incubation medium. The binding parameters agree reasonably well with those found in uterine cells, they support the existence of a medium affinity site and may allow for an explanation of some of the discrepancies between binding and response in this system.

  16. Multiplicity of carbohydrate-binding sites in -prism fold lectins: occurrence and possible evolutionary implications

    Indian Academy of Sciences (India)

    Alok Sharma; Divya Chandran; Desh D Singh; M Vijayan

    2007-09-01

    The -prism II fold lectins of known structure, all from monocots, invariably have three carbohydrate-binding sites in each subunit/domain. Until recently, -prism I fold lectins of known structure were all from dicots and they exhibited one carbohydrate-binding site per subunit/domain. However, the recently determined structure of the -prism fold I lectin from banana, a monocot, has two very similar carbohydrate-binding sites. This prompted a detailed analysis of all the sequences appropriate for two-lectin folds and which carry one or more relevant carbohydrate-binding motifs. The very recent observation of a -prism I fold lectin, griffithsin, with three binding sites in each domain further confirmed the need for such an analysis. The analysis demonstrates substantial diversity in the number of binding sites unrelated to the taxonomical position of the plant source. However, the number of binding sites and the symmetry within the sequence exhibit reasonable correlation. The distribution of the two families of -prism fold lectins among plants and the number of binding sites in them, appear to suggest that both of them arose through successive gene duplication, fusion and divergent evolution of the same primitive carbohydrate-binding motif involving a Greek key. Analysis with sequences in individual Greek keys as independent units lends further support to this conclusion. It would seem that the preponderance of three carbohydrate-binding sites per domain in monocot lectins, particularly those with the -prism II fold, is related to the role of plant lectins in defence.

  17. Multiple determinants of splicing repression activity in the polypyrimidine tract binding proteins, PTBP1 and PTBP2.

    Science.gov (United States)

    Keppetipola, Niroshika M; Yeom, Kyu-Hyeon; Hernandez, Adrian L; Bui, Tessa; Sharma, Shalini; Black, Douglas L

    2016-08-01

    Most human genes generate multiple protein isoforms through alternative pre-mRNA splicing, but the mechanisms controlling alternative splicing choices by RNA binding proteins are not well understood. These proteins can have multiple paralogs expressed in different cell types and exhibiting different splicing activities on target exons. We examined the paralogous polypyrimidine tract binding proteins PTBP1 and PTBP2 to understand how PTBP1 can exhibit greater splicing repression activity on certain exons. Using both an in vivo coexpression assay and an in vitro splicing assay, we show that PTBP1 is more repressive than PTBP2 per unit protein on a target exon. Constructing chimeras of PTBP1 and 2 to determine amino acid features that contribute to their differential activity, we find that multiple segments of PTBP1 increase the repressive activity of PTBP2. Notably, when either RRM1 of PTBP2 or the linker peptide separating RRM2 and RRM3 are replaced with the equivalent PTBP1 sequences, the resulting chimeras are highly active for splicing repression. These segments are distinct from the known region of interaction for the PTBP1 cofactors Raver1 and Matrin3 in RRM2. We find that RRM2 of PTBP1 also increases the repression activity of an otherwise PTBP2 sequence, and that this is potentially explained by stronger binding by Raver1. These results indicate that multiple features over the length of the two proteins affect their ability to repress an exon. PMID:27288314

  18. Non-specific recognition is achieved in Pot1pC through the use of multiple binding modes

    Science.gov (United States)

    Dickey, Thayne H.; McKercher, Marissa A.; Wuttke, Deborah S.

    2012-01-01

    Summary Pot1 is the protein responsible for binding to and protecting the 3’ single-stranded DNA (ssDNA) overhang at most eukaryotic telomeres. Here we present the crystal structure of one of the two OB-folds (Pot1pC) that make up the ssDNA-binding domain in S. pombe Pot1. Comparison with the homologous human domain reveals unexpected structural divergence in the mode of ligand binding that explains the differing ligand requirements between species. Despite the presence of apparently base-specific hydrogen bonds, Pot1pC is able to bind a wide range of ssDNA sequences with thermodynamic equivalence. To address how Pot1pC binds ssDNA with little to no specificity, multiple structures of Pot1pC bound to non-cognate ssDNA ligands were solved. These structures reveal that this promiscuity is implemented through new binding modes that thermodynamically compensate for base-substitutions through alternate stacking interactions and new H-bonding networks. PMID:23201273

  19. Characterization and autoradiographic localization of multiple tachykinin binding sites in gastrointestinal tract and bladder

    Energy Technology Data Exchange (ETDEWEB)

    Burcher, E.; Buck, S.H.; Lovenberg, W.; O' Donohue, T.L.

    1986-03-01

    Binding sites for the (125I)Bolton-Hunter-labeled tachykinins substance K (BHSK), eledoisin (BHE) and substance P (BHSP) were investigated using crude membrane suspensions and autoradiography. In smooth muscle membranes from guinea-pig small intestine and rat duodenum, specific binding of BHSK was saturable and reversible, showing a single class of sites with a KD of 1 to 3 nM and maximum number of specific binding sites of 1 to 2 fmol/mg of wet weight tissue. Pharmacological characterization of this binding revealed a novel receptor site (K) with affinity for substance K greater than kassinin greater than or equal to eledoisin greater than neuromedin K greater than substance P greater than physalaemin. Inhibition of the binding of BHSK in membranes from mouse urinary bladder exhibited a similar K-type pattern. In rat duodenum and mouse bladder membranes, the binding of BHE was inhibited by substance K greater than kassinin greater than eledoisin greater than neuromedin K greater than substance P greater than physalaemin indicating the same receptor site as for BHSK. In rat cerebral cortex membranes BHE binding was inhibited by neuromedin K = kassinin = eledoisin greater than physalaemin greater than substance K greater than substance P indicating a definitive tachykinin E receptor site. The same displacement pattern of BHE binding was also detected in longitudinal muscle membranes from the guinea-pig small intestine. In mouse bladder membranes and in rat and guinea-pig intestine, the binding of BHSP was inhibited by substance P greater than physalaemin greater than substance K greater than or equal to eledoisin = kassinin greater than neuromedin K indicating a definitive tachykinin P receptor site. Autoradiographic binding sites for both BHSK and BHSP were seen in circular muscle of the rat stomach, small intestine and colon and in circular and longitudinal muscle of the guinea-pig small intestine and colon.

  20. Circulating vitamin D binding protein levels are not associated with relapses or with vitamin D status in multiple sclerosis

    OpenAIRE

    Smolders, Joost; Peelen, Evelyn; Thewissen, Marielle; Menheere, Paul; Damoiseaux, Jan; Hupperts, Raymond

    2014-01-01

    Background: A low vitamin D status has been associated with multiple sclerosis (MS). Most circulating vitamin D metabolites are bound to vitamin D binding protein (DBP). Objectives: The purpose of this study was to explore whether there is an association between MS and DBP. Methods: We compared DBP concentrations in blood samples of controls (n = 30) and subjects with relapsing-remitting MS (RRMS) during remission (n = 29) and relapse (n = 15). Furthermore, we explored correlations of DBP wit...

  1. Use of Multiple Peptide-Based SERS Probes Binding to Different Epitopes on a Protein Biomarker To Improve Detection Sensitivity.

    Science.gov (United States)

    Shin, Kayeong; Cho, Jun-Haeng; Yoon, Moon-Young; Chung, Hoeil

    2016-04-01

    We propose an analytical strategy to improve the sensitivity for detecting a protein biomarker through signal multiplication by manipulating multiple peptide-based surface-enhanced Raman scattering (SERS) probes to bind the biomarker. Protective antigen (PA) was used as an Anthrax biomarker in this study. For this purpose, five small peptides selective to various PA epitopes with different binding affinities were chosen and peptide-conjugated Au nanoparticle (AuNP) SERS probes were individually prepared using each peptide. Initially, five different SERS probes were separately used to detect PA and the sensitivities were compared. Next, the possibility of enhancing sensitivity by employing multiple SERS probes was examined. Rather than applying the probes simultaneously, which would induce competitive binding, each probe was added sequentially and an optimal probe-addition sequence was determined to provide maximal sensitivity. Finally, PA samples at seven different concentrations were measured with the optimal sequence. The limit of detection (LOD) was 0.1 aM, and the enhancement was more effective at lower PA concentrations. The proposed scheme can be further applicable to detect other protein biomarkers to diagnose various diseases. PMID:26948277

  2. Screening Mixtures of Small Molecules for Binding to Multiple Sites on the Surface Tetanus Toxin C Fragment by Bioaffinity NMR

    Energy Technology Data Exchange (ETDEWEB)

    Cosman, M; Zeller, L; Lightstone, F C; Krishnan, V V; Balhorn, R

    2002-01-01

    also contains 3-sialyllactose (another predicted site 1 binder) and bisbenzimide 33342 (non-binder). A series of five predicted Site-2 binders were then screened sequentially in the presence of the Site-1 binder doxorubicin. These experiments showed that the compounds lavendustin A and naphthofluorescein-di-({beta}-D-galactopyranoside) binds along with doxorubicin to TetC. Further experiments indicate that doxorubicin and lavendustin are potential candidates to use in preparing a bidendate inhibitor specific for TetC. The simultaneous binding of two different predicted Site-2 ligands to TetC suggests that they may bind multiple sites. Another possibility is that the conformations of the binding sites are dynamic and can bind multiple diverse ligands at a single site depending on the pre-existing conformation of the protein, especially when doxorubicin is already bound.

  3. Multiple individual and cross-specific indiotypes on 13 levan-binding myeloma proteins of BALB/c mice

    Science.gov (United States)

    1975-01-01

    13 leven-binding myeloma proteins (LBMP) of BALB/c origin were classified into two groups with different binding specificities; one group of 11 proteins bound beta2 leads to 1 fructosans, a second group of two proteins bound fructosans probably of beta2 leads to 6 linkage. Anti-idiotypic sera prepared to 10 of the proteins in the appropriate strains of mice identified numerous idiotypic determinants. Each protein used for immunization had its own unique individual idiotypic specificities (IdI) and in addition most of the proteins carried two- nine cross-specific or shared idiotypes (IdX) that were found only among LBMP, and not found in 106 non-LBMP. Most of the IdX determinants and only four of the IdI determinants of the beta2 leads to 1 fructosan binding group were located in the antigen-binding site. The multiplicity of antigenic differences in this functionally related group of immunoglobulins reveals an unexpected degree of heterogeneity in V-regions that appears to be unrelated to binding. PMID:1151286

  4. Identification of multiple binding sites for the THAP domain of the Galileo transposase in the long terminal inverted-repeats.

    Science.gov (United States)

    Marzo, Mar; Liu, Danxu; Ruiz, Alfredo; Chalmers, Ronald

    2013-08-01

    Galileo is a DNA transposon responsible for the generation of several chromosomal inversions in Drosophila. In contrast to other members of the P-element superfamily, it has unusually long terminal inverted-repeats (TIRs) that resemble those of Foldback elements. To investigate the function of the long TIRs we derived consensus and ancestral sequences for the Galileo transposase in three species of Drosophilids. Following gene synthesis, we expressed and purified their constituent THAP domains and tested their binding activity towards the respective Galileo TIRs. DNase I footprinting located the most proximal DNA binding site about 70 bp from the transposon end. Using this sequence we identified further binding sites in the tandem repeats that are found within the long TIRs. This suggests that the synaptic complex between Galileo ends may be a complicated structure containing higher-order multimers of the transposase. We also attempted to reconstitute Galileo transposition in Drosophila embryos but no events were detected. Thus, although the limited numbers of Galileo copies in each genome were sufficient to provide functional consensus sequences for the THAP domains, they do not specify a fully active transposase. Since the THAP recognition sequence is short, and will occur many times in a large genome, it seems likely that the multiple binding sites within the long, internally repetitive, TIRs of Galileo and other Foldback-like elements may provide the transposase with its binding specificity.

  5. Site-directed alkylation of multiple opioid receptors. I. Binding selectivity

    International Nuclear Information System (INIS)

    A method for measuring and expressing the binding selectivity of ligands for mu, delta, and kappa opioid binding sites is reported. Radioligands are used that are partially selective for these sites in combination with membrane preparations enriched in each site. Enrichment was obtained by treatment of membranes with the alkylating agent beta-chlornaltrexamine in the presence of appropriate protecting ligands. After enrichment for mu receptors, [3H] dihydromorphine bound to a single type of site as judged by the slope of competition binding curves. After enrichment for delta or kappa receptors, binding sites for [3H] [D-Ala2, D-Leu5]enkephalin and [3H]ethylketocyclazocine, respectively, were still not homogeneous. There were residual mu sites in delta-enriched membranes but no evidence for residual mu or delta sites in kappa-enriched membranes were found. This method was used to identify ligands that are highly selective for each of the three types of sites

  6. Computational analysis of protein-ligand binding : from single continuous trajectories to multiple parallel simulations

    OpenAIRE

    Thorsteinsdottir, Holmfridur B.

    2010-01-01

    The interaction of proteins with other proteins or small molecules is essential for biological functions. Understanding the molecular basis of protein-ligand binding is of a vast interest for drug discovery, and computational methods to estimate proteinligand binding are starting to play an increasingly important role. In order to apply atomistic computational methods to the drug discovery process it is necessary to have accurate three-dimensional structures of the target prote...

  7. Multiple GTP-binding proteins participate in clathrin-coated vesicle- mediated endocytosis

    OpenAIRE

    1993-01-01

    We have examined the effects of various agonists and antagonists of GTP- binding proteins on receptor-mediated endocytosis in vitro. Stage- specific assays which distinguish coated pit assembly, invagination, and coat vesicle budding have been used to demonstrate requirements for GTP-binding protein(s) in each of these events. Coated pit invagination and coated vesicle budding are both stimulated by addition of GTP and inhibited by GDP beta S. Although coated pit invagination is resistant to ...

  8. Multiple growth hormone-binding proteins are expressed on insulin-producing cells

    DEFF Research Database (Denmark)

    Møldrup, A; Billestrup, N; Thorn, N A;

    1989-01-01

    The insulin-producing rat islet tumor cell line, RIN-5AH, expresses somatogen binding sites and responds to GH by increased proliferation and insulin production. Affinity cross-linking shows that RIN-5AH cells contain two major GH-binding subunits of Mr 100-130K (110K), which appear to exist...... as disulfide-linked multimers of Mr 270-350K (300K). In addition, a minor Mr 180K GH-binding protein is identified which does not appear to be associated with other proteins by disulfide bridges. A plasma membrane-enriched fraction accounts for 86% of the RIN-cell GH-binding activity while cytosol...... and intracellular organelles are low in GH-binding activity. The plasma membrane-bound activity is soluble in Triton X-100 with intact hormone binding characteristics. The apparent KD in detergent solution is estimated to 18 ng/ml (8 x 10(-10) M). 125I-hGH-affinity cross-linking to intact and detergent...

  9. Multiple actin binding domains of Ena/VASP proteins determine actin network stiffening.

    Science.gov (United States)

    Gentry, Brian S; van der Meulen, Stef; Noguera, Philippe; Alonso-Latorre, Baldomero; Plastino, Julie; Koenderink, Gijsje H

    2012-11-01

    Vasodilator-stimulated phosphoprotein (Ena/VASP) is an actin binding protein, important for actin dynamics in motile cells and developing organisms. Though VASP's main activity is the promotion of barbed end growth, it has an F-actin binding site and can form tetramers, and so could additionally play a role in actin crosslinking and bundling in the cell. To test this activity, we performed rheology of reconstituted actin networks in the presence of wild-type VASP or mutants lacking the ability to tetramerize or to bind G-actin and/or F-actin. We show that increasing amounts of wild-type VASP increase network stiffness up to a certain point, beyond which stiffness actually decreases with increasing VASP concentration. The maximum stiffness is 10-fold higher than for pure actin networks. Confocal microscopy shows that VASP forms clustered actin filament bundles, explaining the reduction in network elasticity at high VASP concentration. Removal of the tetramerization site results in significantly reduced bundling and bundle clustering, indicating that VASP's flexible tetrameric structure causes clustering. Removing either the F-actin or the G-actin binding site diminishes VASP's effect on elasticity, but does not eliminate it. Mutating the F-actin and G-actin binding site together, or mutating the F-actin binding site and saturating the G-actin binding site with monomeric actin, eliminates VASP's ability to increase network stiffness. We propose that, in the cell, VASP crosslinking confers only moderate increases in linear network elasticity, and unlike other crosslinkers, VASP's network stiffening activity may be tuned by the local concentration of monomeric actin.

  10. MULTIPLE G PROTEINS COMPETE FOR BINDING WITH THE HUMAN GONADOTROPIN RELEASING HORMONE RECEPTOR

    OpenAIRE

    Knollman, Paul E.; Conn, P. Michael

    2008-01-01

    The GnRH receptor is coupled to G proteins of the families Gq and G11. Gq and G11. Coupling leads to intracellular signaling through the phospholipase C pathway. GnRHR coupling to other G proteins is controversial. This study provides evidence that G protein families Gs, Gi, Gq and G11 complete for binding with the GnRHR. We quantified interactions of over-expressed G proteins with GnRHR by a competitive binding approach, using measurements of second messengers, IP and cAMP. Transient co-tran...

  11. Lynx1 and Aβ1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes

    DEFF Research Database (Denmark)

    Thomsen, Morten S; Arvaniti, Maria; Jensen, Majbrit M;

    2016-01-01

    Lynx1 regulates synaptic plasticity in the brain by regulating nicotinic acetylcholine receptors (nAChRs). It is not known to which extent Lynx1 can bind to endogenous nAChR subunits in the brain or how this interaction is affected by Alzheimer's disease pathology. We apply affinity purification...

  12. EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy.

    Directory of Open Access Journals (Sweden)

    Vito A G Ricigliano

    Full Text Available Epstein-Barr virus (EBV is a non-heritable factor that associates with multiple sclerosis (MS. However its causal relationship with the disease is still unclear. The virus establishes a complex co-existence with the host that includes regulatory influences on gene expression. Hence, if EBV contributes to the pathogenesis of MS it may do so by interacting with disease predisposing genes. To verify this hypothesis we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works by our and other groups have implicated in disease development binding inside MS associated genomic intervals. We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed vs expected overlap [O/E] = 5.392-fold, p < 2.0e-05. This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05, even after controlling for the chromatin accessibility state of shared regions (p <0.001. Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267. Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.

  13. Orthogonal matrix factorization enables integrative analysis of multiple RNA binding proteins

    OpenAIRE

    Stražar, Martin; Žitnik, Marinka; Zupan, Blaž; Ule, Jernej; Curk, Tomaž

    2016-01-01

    Motivation: RNA binding proteins (RBPs) play important roles in post-transcriptional control of gene expression, including splicing, transport, polyadenylation and RNA stability. To model protein–RNA interactions by considering all available sources of information, it is necessary to integrate the rapidly growing RBP experimental data with the latest genome annotation, gene function, RNA sequence and structure. Such integration is possible by matrix factorization, where current approaches hav...

  14. Long-term music training tunes how the brain temporally binds signals from multiple senses

    OpenAIRE

    Lee, Hweeling; Noppeney, Uta

    2011-01-01

    Practicing a musical instrument is a rich multisensory experience involving the integration of visual, auditory, and tactile inputs with motor responses. This combined psychophysics–fMRI study used the musician's brain to investigate how sensory-motor experience molds temporal binding of auditory and visual signals. Behaviorally, musicians exhibited a narrower temporal integration window than nonmusicians for music but not for speech. At the neural level, musicians showed increased audiovisua...

  15. Structural and Functional Characterization of CRM1-Nup214 Interactions Reveals Multiple FG-Binding Sites Involved in Nuclear Export.

    Science.gov (United States)

    Port, Sarah A; Monecke, Thomas; Dickmanns, Achim; Spillner, Christiane; Hofele, Romina; Urlaub, Henning; Ficner, Ralf; Kehlenbach, Ralph H

    2015-10-27

    CRM1 is the major nuclear export receptor. During translocation through the nuclear pore, transport complexes transiently interact with phenylalanine-glycine (FG) repeats of multiple nucleoporins. On the cytoplasmic side of the nuclear pore, CRM1 tightly interacts with the nucleoporin Nup214. Here, we present the crystal structure of a 117-amino-acid FG-repeat-containing fragment of Nup214, in complex with CRM1, Snurportin 1, and RanGTP at 2.85 Å resolution. The structure reveals eight binding sites for Nup214 FG motifs on CRM1, with intervening stretches that are loosely attached to the transport receptor. Nup214 binds to N- and C-terminal regions of CRM1, thereby clamping CRM1 in a closed conformation and stabilizing the export complex. The role of conserved hydrophobic pockets for the recognition of FG motifs was analyzed in biochemical and cell-based assays. Comparative studies with RanBP3 and Nup62 shed light on specificities of CRM1-nucleoporin binding, which serves as a paradigm for transport receptor-nucleoporin interactions. PMID:26489467

  16. Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes.

    Science.gov (United States)

    Hinchliffe, Philip; González, Mariano M; Mojica, Maria F; González, Javier M; Castillo, Valerie; Saiz, Cecilia; Kosmopoulou, Magda; Tooke, Catherine L; Llarrull, Leticia I; Mahler, Graciela; Bonomo, Robert A; Vila, Alejandro J; Spencer, James

    2016-06-28

    Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both l- and d-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Kis of 6-15 µM or 36-84 µM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 µM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the l-BTZ enantiomers exhibit 100-fold lower Kis (0.26-0.36 µM) than d-BTZs (26-29 µM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the l-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. d-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding. PMID:27303030

  17. Long-term music training tunes how the brain temporally binds signals from multiple senses.

    Science.gov (United States)

    Lee, Hweeling; Noppeney, Uta

    2011-12-20

    Practicing a musical instrument is a rich multisensory experience involving the integration of visual, auditory, and tactile inputs with motor responses. This combined psychophysics-fMRI study used the musician's brain to investigate how sensory-motor experience molds temporal binding of auditory and visual signals. Behaviorally, musicians exhibited a narrower temporal integration window than nonmusicians for music but not for speech. At the neural level, musicians showed increased audiovisual asynchrony responses and effective connectivity selectively for music in a superior temporal sulcus-premotor-cerebellar circuitry. Critically, the premotor asynchrony effects predicted musicians' perceptual sensitivity to audiovisual asynchrony. Our results suggest that piano practicing fine tunes an internal forward model mapping from action plans of piano playing onto visible finger movements and sounds. This internal forward model furnishes more precise estimates of the relative audiovisual timings and hence, stronger prediction error signals specifically for asynchronous music in a premotor-cerebellar circuitry. Our findings show intimate links between action production and audiovisual temporal binding in perception. PMID:22114191

  18. Atuoradiographic detection of multiple sclerosis plaques with an ω3 (peripheral type benzodiazepine) binding site radiogland

    International Nuclear Information System (INIS)

    In Multiple Sclerosis (MS), the presence of monocyte-macrophages and microglial cells in active plaques is a constant feature. They are numerous at the border of active lesions where they constiture, with other cell types such as lymphocytes and oligodendrocytes the so-called flial wall. Monocyte-macrophages and microglial cells are thought to be directly involved in the process of demyelination. Some macrophages laden with meylin degradation products are also seen in the center of the plaqie, often located in the perivascular cuffs. In addition, astrocytic gliosis occurs in the center of the plaques. As all these cell types are richly endowed with ω3 sites, the feasibility of using ω3 site autoradiagraphy to detect the demyelination plaques in the brain of post-mortem cases of Multiple Sclerosis has been investigated. (Author). 8 refs

  19. Estimation of individual binding energies in some dimers involving multiple hydrogen bonds using topological properties of electron charge density

    Energy Technology Data Exchange (ETDEWEB)

    Ebrahimi, A., E-mail: Ebrahimi@hamoon.usb.ac.ir [Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan (Iran, Islamic Republic of); Habibi Khorassani, S.M.; Delarami, H. [Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan (Iran, Islamic Republic of)

    2009-11-18

    Individual hydrogen bond (HB) energies have been estimated in several systems involving multiple HBs such as adenine-thymine and guanine-cytosine using electron charge densities calculated at X...H hydrogen bond critical points (HBCPs) by atoms in molecules (AIM) method at B3LYP/6-311++G** and MP2/6-311++G** levels. A symmetrical system with two identical H bonds has been selected to search for simple relations between {rho}{sub HBCP} and individual E{sub HB}. Correlation coefficient between E{sub HB} and {rho}{sub HBCP} in the base of linear, quadratic, and exponential equations are acceptable and equal to 0.95. The estimated individual binding energies E{sub HB} are in good agreement with the results of atom-replacement approach and natural bond orbital analysis (NBO). The E{sub HB} values estimated from {rho} values at H...X BCP are in satisfactory agreement with the main geometrical parameter H...X. With respect to the obtained individual binding energies, the strength of a HB depends on the substituent and the cooperative effects of other HBs.

  20. Phosphatidylethanolamine binding protein 4 (PEBP4) is a secreted protein and has multiple functions.

    Science.gov (United States)

    He, Huan; Liu, Dan; Lin, Hui; Jiang, Shanshan; Ying, Ying; Chun, Shao; Deng, Haiteng; Zaia, Joseph; Wen, Rong; Luo, Zhijun

    2016-07-01

    Phosphatidylethanolamine binding proteins (PEBP) represent a superfamily of proteins that are conserved from bacteria to humans. In mammals, four members have been identified, PEBP1-4. To determine the functional differences among PEBP1-4 and the underlying mechanism for their actions, we performed a sequence alignment and found that PEBP4 contains a signal peptide and potential glycosylation sites, whereas PEBP1-3 are intracellular proteins. To test if PEBP4 is secreted, we made constructs with Myc epitope at the amino (N) terminus or carboxyl (C) terminus to mask the signal sequence or keep it free, respectively. Our data revealed that both mouse and human PEBP4 were secreted when the epitope was tagged at their C-terminus. To our surprise, secretion was dependent upon the C-terminal conserved domain in addition to the N-terminal signal sequence. When the epitope was placed to the N-terminus, the recombinant protein failed to secrete and instead, was retained in the cytoplasm. Mass spectrometry detected asparagine (N)-glycosylation on the secreted PEBP4. Although overexpression of N-terminal tagged PEBP4 resulted in an inhibition of ERK activation by EGF, that with a C-terminal epitope tag did not have such an effect. Likewise, transfection of PEBP4 shRNA did not appear to affect ERK activation, suggesting that PEBP4 does not participate in the regulation of this pathway. In contrast, PEBP4 siRNA suppressed phosphorylation of Act at S473. Therefore, our results suggest that PEBP4 is a multifunctional protein and can be secreted. It will be important to investigate the mechanism by which PEBP4 is secreted and regulates cellular events.

  1. Identification of 2-[125I]iodomelatonin binding sites in the thymus of mice and its significance

    Institute of Scientific and Technical Information of China (English)

    刘志民; 赵瑛; 彭树勋

    1995-01-01

    The melatonin binding sites in membrane preparations of the mouse thymus were demonstratedusing 2-[125I] iodomelatonin as a radioligand.The binding sites were stable,saturable,reversible and of highaffinity.Studies on specificity of 2-[125I] iodomelatonin binding suggested that the 2-[125I] iodomelatonin bindingsites are highly specific for melatonin.These binding sites fulfilled the standard criteria for receptors.Ourwork suggested that melatonin should have direct regulatory action on immune system mediated through themelatonin binding sites.Studies on the circadian rhythm showed that there existed the circadian rhythm in the bind-ing capacity for 2-[125I] iodomelatonin in the mouse thymus with the peak values at 12:00-16:00 andthe trough values between 00:00 and 4:00.The subceUular distribution of 2-[125I] iodomelatonin binding sitesin the mouse thymus was in the following descending order:nuclear>mitochondrial>microsomal>cytosolic frac-tion.There was also an age-related decrease in 2-[125I] iodomelatonin binding in the mouse thymus.This iscorrelated with the involution of the thymus.

  2. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax.

    Science.gov (United States)

    Bajpai, R; Matulis, S M; Wei, C; Nooka, A K; Von Hollen, H E; Lonial, S; Boise, L H; Shanmugam, M

    2016-07-28

    Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM. PMID:26640142

  3. Accumulation of multiple-repeat starch-binding domains (SBD2-SBD5) does not reduce amylose content of potato starch granules

    NARCIS (Netherlands)

    Nazarian, F.; Vincken, J.P.; Ji, Q.; Suurs, L.C.J.M.; Buléon, A.

    2007-01-01

    This study investigates whether it is possible to produce an amylose-free potato starch by displacing the amylose enzyme, granule-bound starch synthase I (GBSSI), from the starch granule by engineered, high-affinity, multiple-repeat family 20 starch-binding domains (SBD2, SBD3, SBD4, and SBD5). The

  4. Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in relapsing and primary progressive multiple sclerosis

    NARCIS (Netherlands)

    Wilczak, N; Ramsaransing, GSM; Mostert, J; Chesik, D; De Keyser, J

    2005-01-01

    Using radioimmunoassay we measured serum levels of insulin- like growth factor ( IGF)- 1 and IGF binding protein ( IGFBP)- 3 in patients with relapsing multiple sclerosis ( MS) and a benign course ( Expanded Disability Status Scale ( EDSS) less than or equal to 3 despite > 10 years disease duration)

  5. Multiple POU-binding motifs, recognized by tissue-specific nuclear factors, are important for Dll1 gene expression in neural stem cells

    International Nuclear Information System (INIS)

    We cloned the 5'-flanking region of the mouse homolog of the Delta gene (Dll1) and demonstrated that the sequence between nucleotide position -514 and -484 in the 5'-flanking region of Dll1 played a critical role in the regulation of its tissue-specific expression in neural stem cells (NSCs). Further, we showed that multiple POU-binding motifs, located within this short sequence of 30 bp, were essential for transcriptional activation of Dll1 and also that multiple tissue-specific nuclear factors recognized these POU-binding motifs in various combinations through differentiation of NSCs. Thus, POU-binding factors may play an important role in Dll1 expression in developing NSCs

  6. Multiple Functions of the RNA-Binding Protein HuR in Cancer Progression, Treatment Responses and Prognosis

    Directory of Open Access Journals (Sweden)

    Baocheng Wang

    2013-05-01

    Full Text Available The human embryonic lethal abnormal vision-like protein, HuR, is a member of the Hu family of RNA-binding proteins. Over the past decade, this ubiquitously expressed protein has been extensively investigated in cancer research because it is involved in the regulation of mRNA stability and translation in many cell types. HuR activity and function is associated with its subcellular distribution, transcriptional regulation, translational and post-translational modifications. HuR regulation of target mRNAs is based on the interaction between the three specific domains of HuR protein and one or several U- or AU-rich elements (AREs in the untranslated region of target mRNAs. A number of cancer-related transcripts containing AREs, including mRNAs for proto-oncogenes, cytokines, growth factors, and invasion factors, have been characterized as HuR targets. It has been proposed that HuR has a central tumorigenic activity by enabling multiple cancer phenotypes. In this review, we comprehensively survey the existing evidence with regard to the diverse functions of HuR in caner development and progression. The current data also suggest that HuR might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation.

  7. Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL

    Directory of Open Access Journals (Sweden)

    Hastie C James

    2006-01-01

    Full Text Available Abstract Background Pim-1, 2 and 3 are a group of enzymes related to the calcium calmodulin family of protein kinases. Over-expression of Pim-1 and Pim-2 in mice promotes the development of lymphomas, and up-regulation of Pim expression has been observed in several human cancers. Results Here we show that the pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. In vitro mapping showed that Pim-2 predominantly phosphorylated Ser112, while Pim-1 phosphorylated Ser112, but also Ser136 and Ser155 at a reduced rate compared to Ser112. Pim-3 was found to be the least specific for Ser112, and the most effective at phosphorylating Ser136 and Ser155. Pim-3 was also able to phosphorylate other sites in Bad in vitro, including Ser170, another potential in vivo site. Mutation of Ser136 to alanine prevented the phosphorylation of Ser112 and Ser155 by Pim kinases in HEK-293 cells, suggesting that this site must be phosphorylated first in order to make the other sites accessible. Pim phosphorylation of Bad was also found to promote the 14-3-3 binding of Bad and block its association with Bcl-XL. Conclusion All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.

  8. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells.

    Science.gov (United States)

    Sutherland, Claire L; Chalupny, N Jan; Schooley, Kenneth; VandenBos, Tim; Kubin, Marek; Cosman, David

    2002-01-15

    The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-gamma production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors. PMID:11777960

  9. Correlation between anti-interferon-β binding and neutralizing antibodies in interferon-β-treated multiple sclerosis patients

    DEFF Research Database (Denmark)

    Jensen, P E H; Sellebjerg, F; Søndergaard, H B;

    2012-01-01

    Measurements of binding antibodies (BAbs), neutralizing antibodies (NAbs) and MX1 mRNA expression are used to analyse the immunological reactions in patients with MS treated with IFN-β. The correlations between these are yet not fully understood....

  10. The Interaction of Integrin αIIbβ3 with Fibrin Occurs through Multiple Binding Sites in the αIIb β-Propeller Domain*

    Science.gov (United States)

    Podolnikova, Nataly P.; Yakovlev, Sergiy; Yakubenko, Valentin P.; Wang, Xu; Gorkun, Oleg V.; Ugarova, Tatiana P.

    2014-01-01

    The currently available antithrombotic agents target the interaction of platelet integrin αIIbβ3 (GPIIb-IIIa) with fibrinogen during platelet aggregation. Platelets also bind fibrin formed early during thrombus growth. It was proposed that inhibition of platelet-fibrin interactions may be a necessary and important property of αIIbβ3 antagonists; however, the mechanisms by which αIIbβ3 binds fibrin are uncertain. We have previously identified the γ370–381 sequence (P3) in the γC domain of fibrinogen as the fibrin-specific binding site for αIIbβ3 involved in platelet adhesion and platelet-mediated fibrin clot retraction. In the present study, we have demonstrated that P3 can bind to several discontinuous segments within the αIIb β-propeller domain of αIIbβ3 enriched with negatively charged and aromatic residues. By screening peptide libraries spanning the sequence of the αIIb β-propeller, several sequences were identified as candidate contact sites for P3. Synthetic peptides duplicating these segments inhibited platelet adhesion and clot retraction but not platelet aggregation, supporting the role of these regions in fibrin recognition. Mutant αIIbβ3 receptors in which residues identified as critical for P3 binding were substituted for homologous residues in the I-less integrin αMβ2 exhibited reduced cell adhesion and clot retraction. These residues are different from those that are involved in the coordination of the fibrinogen γ404–411 sequence and from auxiliary sites implicated in binding of soluble fibrinogen. These results map the binding of fibrin to multiple sites in the αIIb β-propeller and further indicate that recognition specificity of αIIbβ3 for fibrin differs from that for soluble fibrinogen. PMID:24338009

  11. Multiple transport-active binding sites are available for a single substrate on human P-glycoprotein (ABCB1).

    Science.gov (United States)

    Chufan, Eduardo E; Kapoor, Khyati; Sim, Hong-May; Singh, Satyakam; Talele, Tanaji T; Durell, Stewart R; Ambudkar, Suresh V

    2013-01-01

    P-glycoprotein (Pgp, ABCB1) is an ATP-Binding Cassette (ABC) transporter that is associated with the development of multidrug resistance in cancer cells. Pgp transports a variety of chemically dissimilar amphipathic compounds using the energy from ATP hydrolysis. In the present study, to elucidate the binding sites on Pgp for substrates and modulators, we employed site-directed mutagenesis, cell- and membrane-based assays, molecular modeling and docking. We generated single, double and triple mutants with substitutions of the Y307, F343, Q725, F728, F978 and V982 residues at the proposed drug-binding site with cys in a cysless Pgp, and expressed them in insect and mammalian cells using a baculovirus expression system. All the mutant proteins were expressed at the cell surface to the same extent as the cysless wild-type Pgp. With substitution of three residues of the pocket (Y307, Q725 and V982) with cysteine in a cysless Pgp, QZ59S-SSS, cyclosporine A, tariquidar, valinomycin and FSBA lose the ability to inhibit the labeling of Pgp with a transport substrate, [(125)I]-Iodoarylazidoprazosin, indicating these drugs cannot bind at their primary binding sites. However, the drugs can modulate the ATP hydrolysis of the mutant Pgps, demonstrating that they bind at secondary sites. In addition, the transport of six fluorescent substrates in HeLa cells expressing triple mutant (Y307C/Q725C/V982C) Pgp is also not significantly altered, showing that substrates bound at secondary sites are still transported. The homology modeling of human Pgp and substrate and modulator docking studies support the biochemical and transport data. In aggregate, our results demonstrate that a large flexible pocket in the Pgp transmembrane domains is able to bind chemically diverse compounds. When residues of the primary drug-binding site are mutated, substrates and modulators bind to secondary sites on the transporter and more than one transport-active binding site is available for each

  12. Multiple transport-active binding sites are available for a single substrate on human P-glycoprotein (ABCB1.

    Directory of Open Access Journals (Sweden)

    Eduardo E Chufan

    Full Text Available P-glycoprotein (Pgp, ABCB1 is an ATP-Binding Cassette (ABC transporter that is associated with the development of multidrug resistance in cancer cells. Pgp transports a variety of chemically dissimilar amphipathic compounds using the energy from ATP hydrolysis. In the present study, to elucidate the binding sites on Pgp for substrates and modulators, we employed site-directed mutagenesis, cell- and membrane-based assays, molecular modeling and docking. We generated single, double and triple mutants with substitutions of the Y307, F343, Q725, F728, F978 and V982 residues at the proposed drug-binding site with cys in a cysless Pgp, and expressed them in insect and mammalian cells using a baculovirus expression system. All the mutant proteins were expressed at the cell surface to the same extent as the cysless wild-type Pgp. With substitution of three residues of the pocket (Y307, Q725 and V982 with cysteine in a cysless Pgp, QZ59S-SSS, cyclosporine A, tariquidar, valinomycin and FSBA lose the ability to inhibit the labeling of Pgp with a transport substrate, [(125I]-Iodoarylazidoprazosin, indicating these drugs cannot bind at their primary binding sites. However, the drugs can modulate the ATP hydrolysis of the mutant Pgps, demonstrating that they bind at secondary sites. In addition, the transport of six fluorescent substrates in HeLa cells expressing triple mutant (Y307C/Q725C/V982C Pgp is also not significantly altered, showing that substrates bound at secondary sites are still transported. The homology modeling of human Pgp and substrate and modulator docking studies support the biochemical and transport data. In aggregate, our results demonstrate that a large flexible pocket in the Pgp transmembrane domains is able to bind chemically diverse compounds. When residues of the primary drug-binding site are mutated, substrates and modulators bind to secondary sites on the transporter and more than one transport-active binding site is available

  13. Surface plasmon resonance imaging reveals multiple binding modes of Agrobacterium transformation mediator VirE2 to ssDNA.

    Science.gov (United States)

    Kim, Sanghyun; Zbaida, David; Elbaum, Michael; Leh, Hervé; Nogues, Claude; Buckle, Malcolm

    2015-07-27

    VirE2 is the major secreted protein of Agrobacterium tumefaciens in its genetic transformation of plant hosts. It is co-expressed with a small acidic chaperone VirE1, which prevents VirE2 oligomerization. After secretion into the host cell, VirE2 serves functions similar to a viral capsid in protecting the single-stranded transferred DNA en route to the nucleus. Binding of VirE2 to ssDNA is strongly cooperative and depends moreover on protein-protein interactions. In order to isolate the protein-DNA interactions, imaging surface plasmon resonance (SPRi) studies were conducted using surface-immobilized DNA substrates of length comparable to the protein-binding footprint. Binding curves revealed an important influence of substrate rigidity with a notable preference for poly-T sequences and absence of binding to both poly-A and double-stranded DNA fragments. Dissociation at high salt concentration confirmed the electrostatic nature of the interaction. VirE1-VirE2 heterodimers also bound to ssDNA, though by a different mechanism that was insensitive to high salt. Neither VirE2 nor VirE1-VirE2 followed the Langmuir isotherm expected for reversible monomeric binding. The differences reflect the cooperative self-interactions of VirE2 that are suppressed by VirE1. PMID:26044711

  14. Studies of the biogenic amine transporters. IV. Demonstration of a multiplicity of binding sites in rat caudate membranes for the cocaine analog [125I]RTI-55.

    Science.gov (United States)

    Rothman, R B; Cadet, J L; Akunne, H C; Silverthorn, M L; Baumann, M H; Carroll, F I; Rice, K C; de Costa, B R; Partilla, J S; Wang, J B

    1994-07-01

    membranes prepared from rat caudate or COS cells that transiently expressed the cloned cocaine-sensitive DA transporter complementary DNA. Similar experiments also resolved two components of the caudate 5-HT transporter. Viewed collectively, these data provide evidence that [125I]RTI-55 labels multiple binding sites associated with the DA and 5-HT transporters.

  15. Bridged bis(beta-cyclodextrin)s possessing coordinated metal center(s) and their inclusion complexation behavior with model substrates: enhanced molecular binding ability by multiple recognition.

    Science.gov (United States)

    Liu, Y; Chen, Y; Li, L; Zhang, H Y; Liu, S X; Guan, X D

    2001-12-14

    To investigate quantitatively the cooperative binding ability of several beta-cyclodextrin oligomers bearing single or multiligated metal center(s), the inclusion complexation behavior of four bis(beta-cyclodextrin)s (2-5) linked by 2,2'-bipyridine-4,4'-dicarboxy tethers and their copper(II) complexes (6-9) with representative dye guests, i.e., methyl orange (MO), acridine red (AR), rhodamine B (RhB), ammonium 8-anilino-1-naphthalenesulfonic acid (ANS), and sodium 6-(p-toludino)-2-naphthalenesulfonate (TNS), have been examined in aqueous solution at 25 degrees C by means of UV-vis, circular dichroism, fluorescence, and 2D NMR spectroscopy. The results obtained indicate that bis(beta-cyclodextrin)s 2-5 can associate with one or three copper(II) ion(s) producing 2:1 or 2:3 bis(beta-cyclodextrin)-copper(II) complexes. These metal-ligated oligo(beta-cyclodextrin)s can bind two model substrates to form intramolecular 2:2 host-guest inclusion complexes and thus significantly enhance the original binding abilities of parent beta-cyclodextrin and bis(beta-cyclodextrin) toward model substrates through the cooperative binding of two guest molecules by four tethered cyclodextrin moieties, as well as the additional binding effect supplied by ligated metal center(s). Host 6 showed the highest enhancement of the stability constant, up to 38.3 times for ANS as compared with parent beta-cyclodextrin. The molecular binding mode and stability constant of substrates by bridged bis- and oligo(beta-cyclodextrin)s 2-9 are discussed from the viewpoint of the size/shape-fit interaction and molecular multiple recognition between host and guest.

  16. Multiple Transmembrane Binding Sites for p-Trifluoromethyldiazirinyl-etomidate, a Photoreactive Torpedo Nicotinic Acetylcholine Receptor Allosteric Inhibitor*

    OpenAIRE

    Hamouda, Ayman K.; Stewart, Deirdre S.; Husain, S. Shaukat; Cohen, Jonathan B.

    2011-01-01

    Photoreactive derivatives of the general anesthetic etomidate have been developed to identify their binding sites in γ-aminobutyric acid, type A and nicotinic acetylcholine receptors. One such drug, [3H]TDBzl-etomidate (4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzyl-[3H]1-(1-phenylethyl)-1H-imidazole-5-carboxylate), acts as a positive allosteric potentiator of Torpedo nACh receptor (nAChR) and binds to a novel site in the transmembrane domain at the γ-α subunit interface. To extend our unders...

  17. Atomic force microscopy measurements reveal multiple bonds between Helicobacter pylori blood group antigen binding adhesin and Lewis b ligand.

    Science.gov (United States)

    Parreira, P; Shi, Q; Magalhaes, A; Reis, C A; Bugaytsova, J; Borén, T; Leckband, D; Martins, M C L

    2014-12-01

    The strength of binding between the Helicobacter pylori blood group antigen-binding adhesin (BabA) and its cognate glycan receptor, the Lewis b blood group antigen (Le(b)), was measured by means of atomic force microscopy. High-resolution measurements of rupture forces between single receptor-ligand pairs were performed between the purified BabA and immobilized Le(b) structures on self-assembled monolayers. Dynamic force spectroscopy revealed two similar but statistically different bond populations. These findings suggest that the BabA may form different adhesive attachments to the gastric mucosa in ways that enhance the efficiency and stability of bacterial adhesion.

  18. The Histone Deacetylase Complex 1 Protein of Arabidopsis Has the Capacity to Interact with Multiple Proteins Including Histone 3-Binding Proteins and Histone 1 Variants.

    Science.gov (United States)

    Perrella, Giorgio; Carr, Craig; Asensi-Fabado, Maria A; Donald, Naomi A; Páldi, Katalin; Hannah, Matthew A; Amtmann, Anna

    2016-05-01

    Intrinsically disordered proteins can adopt multiple conformations, thereby enabling interaction with a wide variety of partners. They often serve as hubs in protein interaction networks. We have previously shown that the Histone Deacetylase Complex 1 (HDC1) protein from Arabidopsis (Arabidopsis thaliana) interacts with histone deacetylases and quantitatively determines histone acetylation levels, transcriptional activity, and several phenotypes, including abscisic acid sensitivity during germination, vegetative growth rate, and flowering time. HDC1-type proteins are ubiquitous in plants, but they contain no known structural or functional domains. Here, we explored the protein interaction spectrum of HDC1 using a quantitative bimolecular fluorescence complementation assay in tobacco (Nicotiana benthamiana) epidermal cells. In addition to binding histone deacetylases, HDC1 directly interacted with histone H3-binding proteins and corepressor-associated proteins but not with H3 or the corepressors themselves. Surprisingly, HDC1 also was able to interact with variants of the linker histone H1. Truncation of HDC1 to the ancestral core sequence narrowed the spectrum of interactions and of phenotypic outputs but maintained binding to a H3-binding protein and to H1. Thus, HDC1 provides a potential link between H1 and histone-modifying complexes.

  19. Multiple transmembrane binding sites for p-trifluoromethyldiazirinyl-etomidate, a photoreactive Torpedo nicotinic acetylcholine receptor allosteric inhibitor.

    Science.gov (United States)

    Hamouda, Ayman K; Stewart, Deirdre S; Husain, S Shaukat; Cohen, Jonathan B

    2011-06-10

    Photoreactive derivatives of the general anesthetic etomidate have been developed to identify their binding sites in γ-aminobutyric acid, type A and nicotinic acetylcholine receptors. One such drug, [(3)H]TDBzl-etomidate (4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzyl-[(3)H]1-(1-phenylethyl)-1H-imidazole-5-carboxylate), acts as a positive allosteric potentiator of Torpedo nACh receptor (nAChR) and binds to a novel site in the transmembrane domain at the γ-α subunit interface. To extend our understanding of the locations of allosteric modulator binding sites in the nAChR, we now characterize the interactions of a second aryl diazirine etomidate derivative, TFD-etomidate (ethyl-1-(1-(4-(3-trifluoromethyl)-3H-diazirin-3-yl)phenylethyl)-1H-imidazole-5-carboxylate). TFD-etomidate inhibited acetylcholine-induced currents with an IC(50) = 4 μM, whereas it inhibited the binding of [(3)H]phencyclidine to the Torpedo nAChR ion channel in the resting and desensitized states with IC(50) values of 2.5 and 0.7 mm, respectively. Similar to [(3)H]TDBzl-etomidate, [(3)H]TFD-etomidate bound to a site at the γ-α subunit interface, photolabeling αM2-10 (αSer-252) and γMet-295 and γMet-299 within γM3, and to a site in the ion channel, photolabeling amino acids within each subunit M2 helix that line the lumen of the ion channel. In addition, [(3)H]TFD-etomidate photolabeled in an agonist-dependent manner amino acids within the δ subunit M2-M3 loop (δIle-288) and the δ subunit transmembrane helix bundle (δPhe-232 and δCys-236 within δM1). The fact that TFD-etomidate does not compete with ion channel blockers at concentrations that inhibit acetylcholine responses indicates that binding to sites at the γ-α subunit interface and/or within δ subunit helix bundle mediates the TFD-etomidate inhibitory effect. These results also suggest that the γ-α subunit interface is a binding site for Torpedo nAChR negative allosteric modulators (TFD-etomidate) and for positive

  20. The chondroitin sulfate A-binding site of the VAR2CSA protein involves multiple N-terminal domains

    DEFF Research Database (Denmark)

    Dahlbäck, Madeleine; Jørgensen, Lars M; Nielsen, Morten A;

    2011-01-01

    by a parasite expressed protein named VAR2CSA. A vaccine protecting pregnant women against placental malaria should induce antibodies inhibiting the interaction between VAR2CSA and CSA. Much effort has been put into defining the part of the 350 kDa VAR2CSA protein that is responsible for binding. It has been...... of truncated VAR2CSA proteins. The experiments indicate that the core of the CSA-binding site is situated in three domains, DBL2X-CIDR(PAM) and a flanking domain, located in the N-terminal part of VAR2CSA. Furthermore, recombinant VAR2CSA subfragments containing this region elicit antibodies with high parasite...

  1. Protein-DNA binding specificity: a grid-enabled computational approach applied to single and multiple protein assemblies.

    Science.gov (United States)

    Zakrzewska, Krystyna; Bouvier, Benjamin; Michon, Alexis; Blanchet, Christophe; Lavery, Richard

    2009-12-01

    We use a physics-based approach termed ADAPT to analyse the sequence-specific interactions of three proteins which bind to DNA on the side of the minor groove. The analysis is able to estimate the binding energy for all potential sequences, overcoming the combinatorial problem via a divide-and-conquer approach which breaks the protein-DNA interface down into a series of overlapping oligomeric fragments. All possible base sequences are studied for each fragment. Energy minimisation with an all-atom representation and a conventional force field allows for conformational adaptation of the DNA and of the protein side chains for each new sequence. As a result, the analysis depends linearly on the length of the binding site and complexes as large as the nucleosome can be treated, although this requires access to grid computing facilities. The results on the three complexes studied are in good agreement with experiment. Although they all involve significant DNA deformation, it is found that this does not necessarily imply that the recognition will be dominated by the sequence-dependent mechanical properties of DNA.

  2. Expression Analysis and Binding Assays in the Chemosensory Protein Gene Family Indicate Multiple Roles in Helicoverpa armigera.

    Science.gov (United States)

    Li, Zhao-Qun; Zhang, Shuai; Luo, Jun-Yu; Zhu, Jing; Cui, Jin-Jie; Dong, Shuang-Lin

    2015-05-01

    Chemosensory proteins (CSPs) have been proposed to capture and transport hydrophobic chemicals to receptors on sensory neurons. We identified and cloned 24 CSP genes to better understand the physiological function of CSPs in Helicoverpa armigera. Quantitative real-time polymerase chain reaction assays indicate that CSP genes are ubiquitously expressed in adult H. armigera tissues. Broad expression patterns in adult tissues suggest that CSPs are involved in a diverse range of cellular processes, including chemosensation as well as other functions not related to chemosensation. The H. armigera CSPs that were highly transcribed in sensory organs or pheromone glands (HarmCSPs 6, 9, 18, 19), were recombinantly expressed in bacteria to explore their function. Fluorescent competitive binding assays were used to measure the binding affinities of these CSPs against 85 plant volatiles and 4 pheromone components. HarmCSP6 displays high binding affinity for pheromone components, whereas the other three proteins do not show affinities for any of the compounds tested. HarmCSP6 is expressed in numerous cells located in or close to long sensilla trichodea on the antennae of both males and females. These results suggest that HarmCSP6 may be involved in transporting female sex pheromones in H. armigera. PMID:25893790

  3. The tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) binds multiple AHRs and induces multiple CYP1 genes via AHR2 in zebrafish

    DEFF Research Database (Denmark)

    Jönsson, Maria E.; Franks, Diana G.; Woodin, Bruce R.;

    2009-01-01

    to FICZ is evolutionarily conserved in vertebrates by measuring FICZ binding to two zebrafish AHRs (AHR1B and AHR2) and its ability to induce zebrafish CYP1 genes (CYP1A, CYP1B1, CYP1C1, CYP1C2, and CYP1D1) in vivo. Exposure of zebrafish embryos (48 h-post-fertilization; hpf) to 10 nM FICZ for 6 h caused...... strong induction of CYP1A mRNA and a statistically significant but modest induction of CYP1B1 and CYP1C1. Neither CYP1C2 nor CYP1D1 expression was induced by FICZ under the conditions of dose, time or developmental stage examined here. CYP1A induction was significantly greater after 6 h than after 12 h...... of exposure to FICZ, suggesting a rapid degradation of inducer. The 6-h EC50 values for induction of CYP1A and CYP1B1 by FICZ were 0.6 and 0.5 nM compared to 72-h EC50 values of 2.3 and 2.7 nM for PCB126, indicating that in zebrafish embryos FICZ is a more potent inducer than PCB126. FICZ at 10 nM was able...

  4. Differential binding of Nocardia asteroides in the murine lung and brain suggests multiple ligands on the nocardial surface.

    OpenAIRE

    Beaman, B L

    1996-01-01

    The adherence of Nocardia asteroides in the murine brain and lungs was determined. Virulent strains had increased adherence in the brain and lungs, whereas less virulent strains bound in either the brain or lungs. Nocardiae that attached apically penetrated host cells. Multiple receptors on the nocardial surface may be involved in this differential attachment and penetration.

  5. Identification of multiple SNT-binding sites on NPM-ALK oncoprotein and their involvement in cell transformation.

    Science.gov (United States)

    Chikamori, M; Fujimoto, J; Tokai-Nishizumi, N; Yamamoto, T

    2007-05-01

    The t(2;5) chromosomal translocation occurs in anaplastic large-cell lymphoma arising from activated T lymphocytes. This genomic rearrangement generates the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) oncoprotein that is a chimeric protein consisting of parts of the nuclear protein NPM and ALK receptor protein-tyrosine kinase. We used yeast two-hybrid screening to identify an adaptor protein Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target (SNT)-2 as a new partner that interacted with the cytoplasmic domain of ALK. Immunoprecipitation assay revealed that SNT-1 and SNT-2 interacted with NPM-ALK and kinase-negative NPM-ALK mutant. Y156, Y567 and a 19-amino-acid sequence (aa 631-649) of NPM-ALK were essential for this interaction. The interaction through Y156 and Y567 was dependent on phosphorylation of these tyrosines, whereas the interaction through the 19-amino-acid sequence was independent of phosphorylation. NPM-ALK mutant protein mutated at these three binding sites showed significantly reduced transforming activity. This transformation-defective NPM-ALK mutant still interacted with signal transducing proteins such as phospholipase C-gamma and phosphatidylinositol 3-kinase, which were previously reported to be relevant to NPM-ALK-dependent tumorigenesis. These observations indicate that the three SNT-binding sites of NPM-ALK are important for its transforming activity. This raises a possibility that SNT family proteins play significant roles in cellular transformation triggered by NPM-ALK, which though remains to be verified.

  6. Multiple Metal Binding Domains Enhance the Zn(II) Selectivity of the Divalent Metal Ion Transporter AztA

    Energy Technology Data Exchange (ETDEWEB)

    Liu, T.; Reyes-Caballero, H.; Li, C.; Scott, R.A.; Giedroc, D.P.

    2009-06-03

    Transition metal-transporting P{sub 1B}-type CPx ATPases play crucial roles in mediating metal homeostasis and resistance in all cells. The degree to which N-terminal metal binding domains (MBDs) confer metal specificity to the transporter is unclear. We show that the two MBDs of the Zn/Cd/Pb effluxing pump Anabaena AztA are functionally nonequivalent, but only with respect to zinc resistance. Inactivation of the a-MBD largely abrogates resistance to high intracellular Zn(II) levels, whereas inactivation of the b-MBD is not as deleterious. In contrast, inactivation of either the a- or b-MBD has little measurable impact on Cd(II) and Pb(II) resistance. The membrane proximal b-MBD binds Zn(II) with a higher affinity than the distal N-terminal a-MBD. Facile Zn(II)-specific intermolecular transfer from the a-MBD to the higher-affinity b-MBD is readily observed by {sup 1}H-{sup 15}N HSQC spectroscopy. Unlike Zn(II), Cd(II) and Pb(II) form saturated 1:1 S{sub 4} or S{sub 3}(O/N) complexes with AztA{sup aHbH}, where a single metal ion bridges the two MBDs. We propose that the tandem MBDs enhance Zn(II)-specific transport, while stabilizing a non-native inter-MBD Cd/Pb cross-linked structure that is a poor substrate and/or regulator for the transporter.

  7. Vaccination with conserved regions of erythrocyte-binding antigens induces neutralizing antibodies against multiple strains of Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Julie Healer

    Full Text Available BACKGROUND: A highly effective vaccine against Plasmodium falciparum malaria should induce potent, strain transcending immunity that broadly protects against the diverse population of parasites circulating globally. We aimed to identify vaccine candidates that fulfill the criteria. METHODS: We have measured growth inhibitory activity of antibodies raised to a range of antigens to identify those that can efficiently block merozoite invasion for geographically diverse strains of P. falciparum. RESULTS: This has shown that the conserved Region III-V, of the P. falciparum erythrocyte-binding antigen (EBA-175 was able to induce antibodies that potently inhibit merozoite invasion across diverse parasite strains, including those reliant on invasion pathways independent of EBA-175 function. Additionally, the conserved RIII-V domain of EBA-140 also induced antibodies with strong in vitro parasite growth inhibitory activity. CONCLUSION: We identify an alternative, highly conserved region (RIV-V of EBA-175, present in all EBA proteins, that is the target of potent, strain transcending neutralizing antibodies, that represents a strong candidate for development as a component in a malaria vaccine.

  8. Eomesodermin promotes interferon-γ expression and binds to multiple conserved noncoding sequences across the Ifng locus in mouse thymoma cell lines.

    Science.gov (United States)

    Fukuoka, Natsuki; Harada, Misuzu; Nishida, Ai; Ito, Yuko; Shiota, Hideki; Kataoka, Takao

    2016-02-01

    The T-box transcription factors T-bet and eomesodermin (Eomes) have been shown to regulate the lineage-specific expression of interferon-γ (IFN-γ). However, in contrast to T-bet, the role of Eomes in the expression of IFN-γ remains unclear. In this study, we investigated the Eomes-dependent expression of IFN-γ in the mouse thymoma BW5147 and EL4 cells, which do not express T-bet or Eomes. The ectopic expression of Eomes induced BW5147 and EL4 cells to produce IFN-γ in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM). In BW5147 cells, Eomes augmented luciferase activity driven by the Ifng promoter encoding from -2500 to +113 bp; however, it was not increased by a stimulation with PMA and IM. A chromatin immunoprecipitation assay showed that Eomes bound to the Ifng promoter and conserved noncoding sequence (CNS) -22 kb across the Ifng locus with high efficacy in BW5147 cells. Moreover, Eomes increased permissive histone modifications in the Ifng promoter and multiple CNSs. The stimulation with PMA and IM greatly augmented Eomes binding to CNS-54, CNS-34, CNS+19 and CNS+30, which was inhibited by FK506. These results indicated that Eomes bound to the Ifng promoter and multiple CNSs in stimulation-dependent and stimulation-independent manners. PMID:26749212

  9. Women with multiple chemical sensitivity have increased harm avoidance and reduced 5-HT(1A receptor binding potential in the anterior cingulate and amygdala.

    Directory of Open Access Journals (Sweden)

    Lena Hillert

    Full Text Available Multiple chemical sensitivity (MCS is a common condition, characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the underlying mechanisms are unknown. Contrary to the expectations it was recently found that persons with MCS activate the odor-processing brain regions less than controls, while their activation of the anterior cingulate cortex (ACC is increased. The present follow-up study was designed to test the hypotheses that MCS subjects have increased harm avoidance and deviations in the serotonin system, which could render them intolerant to environmental odors. Twelve MCS and 11 control subjects, age 22-44, all working or studying females, were included in a PET study where 5-HT(1A receptor binding potential (BP was assessed after bolus injection of [(11C]WAY100635. Psychological profiles were assessed by the Temperament and Character Inventory and the Swedish universities Scales of Personality. All MCS and 12 control subjects were also tested for emotional startle modulation in an acoustic startle test. MCS subjects exhibited significantly increased harm avoidance, and anxiety compared to controls. They also had a reduced 5-HT(1A receptor BP in amygdala (p = 0.029, ACC (p = 0.005 (planned comparisons, significance level 0.05, and insular cortex (p = 0.003; significance level p<0.005 with Bonferroni correction, and showed an inverse correlation between degree of anxiety and the BP in the amygdala (planned comparison. No group by emotional category difference was found in the startle test. Increased harm avoidance and the observed changes in the 5-HT(1A receptor BP in the regions processing harm avoidance provides a plausible pathophysiological ground for the symptoms described in MCS, and yields valuable information for our general understanding of idiopathic environmental intolerances.

  10. A Regulatory MDM4 Genetic Variant Locating in the Binding Sequence of Multiple MicroRNAs Contributes to Susceptibility of Small Cell Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Feng Gao

    Full Text Available A functional rs4245739 A>C single nucleotide polymorphism (SNP locating in the MDM43'-untranslated (3'-UTR region creates a miR-191-5p or miR-887-3p targeting sites. This change results in decreased expression of oncogene MDM4. Therefore, we examined the association between this SNP and small cell lung cancer (SCLC risk as well as its regulatory function in SCLC cells. Genotypes were determined in two independent case-control sets consisted of 520SCLC cases and 1040 controls from two regions of China. Odds ratios (ORs and 95% confidence intervals (CIs were estimated by logistic regression. The impact of the rs4245739 SNP on miR-191-5p/miR-887-3p mediated MDM4 expression regulation was investigated using luciferase reporter gene assays. We found that the MDM4 rs4245739AC and CC genotypes were significantly associated with decreased SCLC susceptibility compared with the AA genotype in both case-control sets (Shandong set: OR = 0.53, 95% CI = 0.32-0.89, P = 0.014; Jiangsu set: OR = 0.47, 95% CI = 0.26-0.879, P = 0.017. Stratified analyses indicated that there was a significantly multiplicative interaction between rs4245739 and smoking (Pinteractioin = 0.048. After co-tranfection of miRNAs and different allelic-MDM4 reporter constructs into SCLC cells, we found that the both miR-191-5p and miR-887-3p can lead to significantly decreased MDM4 expression activities in the construct with C-allelic 3'-UTR but not A-allelic 3'-UTR, suggesting a consistent genotype-phenotype correlation. Our data illuminate that the MDM4rs4245739SNP contributes to SCLC risk and support the notion that gene 3'-UTR genetic variants, impacting miRNA-binding, might modify SCLC susceptibility.

  11. Rhodopsin TM6 Can Interact with Two Separate and Distinct Sites on Arrestin: Evidence for Structural Plasticity and Multiple Docking Modes in Arrestin–Rhodopsin Binding

    OpenAIRE

    Sinha, Abhinav; Jones Brunette, Amber M.; Fay, Jonathan F.; Schafer, Christopher T.; Farrens, David L.

    2014-01-01

    Various studies have implicated the concave surface of arrestin in the binding of the cytosolic surface of rhodopsin. However, specific sites of contact between the two proteins have not previously been defined in detail. Here, we report that arrestin shares part of the same binding site on rhodopsin as does the transducin Gα subunit C-terminal tail, suggesting binding of both proteins to rhodopsin may share some similar underlying mechanisms. We also identify two areas of contact between the...

  12. NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets

    DEFF Research Database (Denmark)

    Nielsen, Morten; Andreatta, Massimo

    2016-01-01

    Background: Binding of peptides to MHC class I molecules (MHC-I) is essential for antigen presentation to cytotoxic T-cells.Results: Here, we demonstrate how a simple alignment step allowing insertions and deletions in a pan-specific MHC-I binding machine-learning model enables combining informat......Background: Binding of peptides to MHC class I molecules (MHC-I) is essential for antigen presentation to cytotoxic T-cells.Results: Here, we demonstrate how a simple alignment step allowing insertions and deletions in a pan-specific MHC-I binding machine-learning model enables combining...

  13. Synthesis and molecular recognition of novel oligo(ethylenediamino) bridged bis(beta-cyclodextrin)s and their copper(II) complexes: enhanced molecular binding ability and selectivity by multiple recognition.

    Science.gov (United States)

    Liu, Y; You, C C; Li, B

    2001-03-16

    Four bridged bis(beta-cyclodextrin)s tethered by different lengths of oligo(ethylenediamine)s have been synthesized and their inclusion complexation behavior with selected substrates elucidated by circular dichroism spectroscopy and fluorescence decay. In order to study their binding ability quantitatively, inclusion complexation stability constants with four dye guests, that is, brilliant green (BG), methyl orange (MO), ammonium 8-anilino-1-naphthalenesulfonic acid (ANS), and sodium 6-(p-toluidino)-2-naphthalenesulfonate (TNS), have been determined in aqueous solution at 25 degrees C with spectrophotometric, spectropolarimetric, or spectrofluorometric titrations. The results obtained indicate that the two tethered cyclodextrin units might cooperatively bind to a guest, and the molecular binding ability toward model substrates, especially linear guests such as TNS and MO, could be extended. The tether length plays a crucial role in the molecular recognition, the binding constants for ANS and TNS decrease linearly with an increase in the tether length of dimeric cyclodextrin. The Gibbs free energy changes (-deltaGo) for the unit increment per ethylene are 0.99 kJ mol(-1) for ANS and 0.44 kJmol(-1) for TNS, respectively. On the other hand, the presence of a copper(II) ion in metallobis(beta-cyclodextrin)s oligo(ethylenediamino) tethers enhances not only the original binding ability, but also the molecular selectivity through triple or multiple recognition, as compared with the parent bis(beta-cyclodextrin)s.

  14. The sea urchin stem–loop-binding protein: a maternally expressed protein that probably functions in expression of multiple classes of histone mRNA

    Science.gov (United States)

    Robertson, Anthony J.; Howard, Jason T.; Dominski, Zbigniew; Schnackenberg, Bradley J.; Sumerel, Jan L.; McCarthy, John J.; Coffman, James A.; Marzluff, William F.

    2004-01-01

    Following the completion of oogenesis and oocyte maturation, histone mRNAs are synthesized and stored in the sea urchin egg pronucleus. Histone mRNAs are the only mRNAs that are not polyadenylated but instead end in a stem–loop which has been conserved in evolution. The 3′ end binds the stem–loop-binding protein (SLBP), and SLBP is required for histone pre-mRNA processing as well as translation of the histone mRNAs. A cDNA encoding a 59 kDa sea urchin SLBP (suSLBP) has been cloned from an oocyte cDNA library. The suSLBP contains an RNA-binding domain that is similar to the RNA-binding domain found in SLBPs from other species, although there is no similarity between the rest of the suSLBP and other SLBPs. The suSLBP is present at constant levels in eggs and for the first 12 h of development. The levels of suSLBP then decline and remain at a low level for the rest of embryogenesis. The suSLBP is concentrated in the egg pronucleus and is released from the nucleus only when cells enter the first mitosis. SuSLBP expressed by in vitro translation does not bind the stem–loop RNA, suggesting that suSLBP is modified to activate RNA binding in sea urchin embryos. PMID:14762208

  15. In vivo binding of spiperone and N-methylspiperone to dopaminergic and serotonergic sites in the rat brain: Multiple modeling and implications for PET scanning

    International Nuclear Information System (INIS)

    Equilibrium models are derived and applied to in vivo binding of spiperone in the rat brain. The models express the concentration of the ligand in the striatum and frontal cortex as a function of the accumulation in the cerebellum. The models differ with respect to the description of specific binding. Nonlinear regression analysis shows that the in vivo specific binding of 3H-labeled spiperone in the frontal cortex (mainly serotonergic) can be described by a noninteracting sites model, whereas the specific binding in the striatum (mainly dopaminergic) can best be described by models that lead to sigmoid saturation curves. These results were tested and partly confirmed by determining the region-of-interest/cerebellar radioactivity ratio of 11C-labeled N-methylspiperone, with and without pretreatment with haloperidol. The estimated Bmax was 32 fmol/mg wet tissue in the frontal cortex and approximately 90 fmol/mg wet tissue in the striatum. The free plus nonspecific binding of spiperone was similar in the frontal cortex but lower in the striatum than in the cerebellum. The occurrence of sigmoidicity can be best explained by the existence of high-affinity/low-capacity sites in the cerebellum rather than mutual interactions of striatal sites. The consequence of the present analysis for positron emission tomography is that the striatal/cerebellar activity ratio is not an accurate parameter of specific binding features at tracer doses of spiperone or N-methylspiperone

  16. Targeted deletion of multiple CTCF-binding elements in the human C-MYC gene reveals a requirement for CTCF in C-MYC expression.

    Directory of Open Access Journals (Sweden)

    Wendy M Gombert

    Full Text Available BACKGROUND: Insulators and domain boundaries both shield genes from adjacent enhancers and inhibit intrusion of heterochromatin into transgenes. Previous studies examined the functional mechanism of the MYC insulator element MINE and its CTCF binding sites in the context of transgenes that were randomly inserted into the genome by transfection. However, the contribution of CTCF binding sites to both gene regulation and maintenance of chromatin has not been tested at the endogenous MYC gene. METHODOLOGY/PRINCIPAL FINDINGS: To determine the impact of CTCF binding on MYC expression, a series of mutant human chromosomal alleles was prepared in homologous recombination-efficient DT40 cells and individually transferred by microcell fusion into murine cells. Functional tests reported here reveal that deletion of CTCF binding elements within the MINE does not impact the capacity of this locus to correctly organize an 'accessible' open chromatin domain, suggesting that these sites are not essential for the formation of a competent, transcriptionally active locus. Moreover, deletion of the CTCF site at the MYC P2 promoter reduces transcription but does not affect promoter acetylation or serum-inducible transcription. Importantly, removal of either CTCF site leads to DNA methylation of flanking sequences, thereby contributing to progressive loss of transcriptional activity. CONCLUSIONS: These findings collectively demonstrate that CTCF-binding at the human MYC locus does not repress transcriptional activity but is required for protection from DNA methylation.

  17. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.

    Directory of Open Access Journals (Sweden)

    Andrea D Coviello

    Full Text Available Sex hormone-binding globulin (SHBG is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106, PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11, GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16, ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09, JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35, SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08, NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12, ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14, TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14, LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07, BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08, and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06. These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08, women p = 0.66, heterogeneity p = 0.003. Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion

  18. Multiple Plasmodium falciparum erythrocyte membrane protein 1 variants per genome can bind IgM via its Fc fragment Fcμ

    DEFF Research Database (Denmark)

    Jeppesen, Anine; Ditlev, Sisse Bolm; Soroka, Vladyslav;

    2015-01-01

    The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) adhesive proteins expressed on the surfaces of infected erythrocytes (IEs) are of key importance in the pathogenesis of P. falciparum malaria. Several structurally and functionally defined PfEMP1 types have been associated...... with severe clinical manifestations, such as cerebral malaria in children and placental malaria in pregnant women. PfEMP1 that can bind the Fc part of IgM (Fcμ) characterizes one such type, although the functional significance of this IgM binding to PfEMP1 remains unclear. In this study, we report...... the identification and functional analysis of five IgM-binding PfEMP1 proteins encoded by P. falciparum NF54. In addition to the VAR2CSA-type PFL0030c protein, already known to bind Fcμ and to mediate chondroitin sulfate A (CSA)-specific adhesion of IEs in the placenta, we found four PfEMP1 proteins not previously...

  19. Genome-Wide Mapping of Binding Sites Reveals Multiple Biological Functions of the Transcription Factor Cst6p in Saccharomyces cerevisiae

    Science.gov (United States)

    Bergenholm, David

    2016-01-01

    ABSTRACT In the model eukaryote Saccharomyces cerevisiae, the transcription factor Cst6p has been reported to play important roles in several biological processes. However, the genome-wide targets of Cst6p and its physiological functions remain unknown. Here, we mapped the genome-wide binding sites of Cst6p at high resolution. Cst6p binds to the promoter regions of 59 genes with various biological functions when cells are grown on ethanol but hardly binds to the promoter at any gene when cells are grown on glucose. The retarded growth of the CST6 deletion mutant on ethanol is attributed to the markedly decreased expression of NCE103, encoding a carbonic anhydrase, which is a direct target of Cst6p. The target genes of Cst6p have a large overlap with those of stress-responsive transcription factors, such as Sko1p and Skn7p. In addition, a CST6 deletion mutant growing on ethanol shows hypersensitivity to oxidative stress and ethanol stress, assigning Cst6p as a new member of the stress-responsive transcriptional regulatory network. These results show that mapping of genome-wide binding sites can provide new insights into the function of transcription factors and highlight the highly connected and condition-dependent nature of the transcriptional regulatory network in S. cerevisiae. PMID:27143390

  20. Genome-Wide Mapping of Binding Sites Reveals Multiple Biological Functions of the Transcription Factor Cst6p in> Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Liu, Guodong; Bergenholm, David; Nielsen, Jens

    2016-01-01

    In the model eukaryote Saccharomyces cerevisiae, the transcription factor Cst6p has been reported to play important roles in several biological processes. However, the genome-wide targets of Cst6p and its physiological functions remain unknown. Here, we mapped the genome-wide binding sites of Cst...

  1. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

    NARCIS (Netherlands)

    A.D. Coviello (Andrea); R. Haring (Robin); M. Wellons (Melissa); D. Vaidya (Dhananjay); T. Lehtimäki (Terho); S. Keildson (Sarah); K.L. Lunetta (Kathryn); C. He (Chunyan); M. Fornage (Myriam); V. Lagou (Vasiliki); M. Mangino (Massimo); N.C. Onland-Moret (Charlotte); B. Chen (Benjamin); J. Eriksson (Joel); M. Garcia (Melissa); Y. Liu (Yongmei); A. Koster (Annemarie); K. Lohman (Kurt); L.-P. Lyytikäinen; A.K. Petersen; C.A.J. Prescott; L. Stolk (Lisette); L. Vandenput (Liesbeth); A.R. Wood (Andrew); W.V. Zhuang; A. Ruokonen (Aimo); A.L. Hartikainen; A. Pouta (Anneli); S. Bandinelli (Stefania); R. Biffar (Reiner); G. Brabant (Georg); D.G. Cox (David); S. Cummings; L. Ferrucci (Luigi); M.J. Gunter (Marc J.); S.E. Hankinson (Susan); H. Martikainen (Hannu); A. Hofman (Albert); G. Homuth (Georg); T. Illig (Thomas); J.O. Jansson; A.D. Johnson (Andrew); D. Karasik (David); M. Karlsson (Magnus); J. Kettunen (Johannes); D.P. Kiel (Douglas); P. Kraft (Peter); O.̈. Ljunggren; M. Lorentzon (Mattias); M. Maggio (Marcello); M.R.P. Markus (Marcello R. P.); D. Mellström (Dan); I. Miljkovic (Iva); D. Mirel (Daniel); S. Nelson (Sarah); L. Morin Papunen (Laure); P.H.M. Peeters; I. Prokopenko (Inga); L.J. Raffel (Leslie); M. Reincke (Martin); A.P. Reiner (Alex); K. Rexrode (Kathryn); F. Rivadeneira Ramirez (Fernando); S.M. Schwartz (Stephen); D.S. Siscovick (David); N. Soranzo (Nicole); D. Stöckl (Doris); S. Tworoger (Shelley); A.G. Uitterlinden (André); C.H. van Gils (Carla); R.S. Vasan (Ramachandran Srini); H.E. Wichmann (Erich); G. Zhai (Guangju); S. Bhasin (Shalender); M. Bidlingmaier; S.J. Chanock (Stephen); I. de Vivo (Immaculata); T.B. Harris (Tamara); D. Hunter (David); M. Kähönen (Mika); P. Ouyang (Pamela); T.D. Spector (Timothy); Y.T. van der Schouw (Yvonne); J. Viikari (Jorma); H. Wallaschofski (Henri); M.I. McCarthy (Mark); T.M. Frayling (Timothy); J.C. Murray (Jeffrey); S. Franks (Steve); M.R. Jarvelin; F.A. de Jong (Floris); O. Raitakari (Olli); A. Teumer (Alexander); C. Ohlsson (Claes); J. Murabito (Joanne); J.R.B. Perry (John)

    2012-01-01

    textabstractSex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers s

  2. Tyrosine 105 and threonine 212 at outermost substrate binding subsites -6 and +4 control substrate specificity, oligosaccharide cleavage patterns, and multiple binding modes of barley alpha-amylase 1

    DEFF Research Database (Denmark)

    Bak-Jensen, K.S.; André, G.; Gottschalk, T.E.;

    2004-01-01

    in plant alpha-amylases whereas Thr(212) varies in these and related enzymes. Compared with wild-type AMY1, the subsite -6 mutant Y105A has 140, 15, and activity (k(cat)/K-m) on starch, amylose DP17, and 2-chloro-4-nitrophenyl β-D-maltoheptaoside, whereas T212Y at subsite +4 has 32, 370, and 90......% activity, respectively. Thus engineering of aromatic stacking interactions at the ends of the 10-subsite long binding cleft affects activity very differently, dependent on the substrate. Y105A dominates in dual subsite -6/+4 [Y105A/T212(Y/W)] AMY1 mutants having almost retained and low activity on starch......The role in activity of outer regions in the substrate binding cleft in alpha-amylases is illustrated by mutational analysis of Tyr(105) and Thr(212) localized at subsites - 6 and +4 ( substrate cleavage occurs between subsites -1 and +1) in barley alpha-amylase 1 (AMY1). Tyr(105) is conserved...

  3. T-cell memory responses elicited by yellow fever vaccine are targeted to overlapping epitopes containing multiple HLA-I and -II binding motifs.

    Directory of Open Access Journals (Sweden)

    Andréa Barbosa de Melo

    Full Text Available The yellow fever vaccines (YF-17D-204 and 17DD are considered to be among the safest vaccines and the presence of neutralizing antibodies is correlated with protection, although other immune effector mechanisms are known to be involved. T-cell responses are known to play an important role modulating antibody production and the killing of infected cells. However, little is known about the repertoire of T-cell responses elicited by the YF-17DD vaccine in humans. In this report, a library of 653 partially overlapping 15-mer peptides covering the envelope (Env and nonstructural (NS proteins 1 to 5 of the vaccine was utilized to perform a comprehensive analysis of the virus-specific CD4(+ and CD8(+ T-cell responses. The T-cell responses were screened ex-vivo by IFN-γ ELISPOT assays using blood samples from 220 YF-17DD vaccinees collected two months to four years after immunization. Each peptide was tested in 75 to 208 separate individuals of the cohort. The screening identified sixteen immunodominant antigens that elicited activation of circulating memory T-cells in 10% to 33% of the individuals. Biochemical in-vitro binding assays and immunogenetic and immunogenicity studies indicated that each of the sixteen immunogenic 15-mer peptides contained two or more partially overlapping epitopes that could bind with high affinity to molecules of different HLAs. The prevalence of the immunogenicity of a peptide in the cohort was correlated with the diversity of HLA-II alleles that they could bind. These findings suggest that overlapping of HLA binding motifs within a peptide enhances its T-cell immunogenicity and the prevalence of the response in the population. In summary, the results suggests that in addition to factors of the innate immunity, "promiscuous" T-cell antigens might contribute to the high efficacy of the yellow fever vaccines.

  4. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Vowinckel, E; Reutens, D; Becher, B;

    1997-01-01

    Activated glial cells are implicated in regulating and effecting the immune response that occurs within the CNS as part of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The peripheral benzodiazepine receptor (PBR) is expressed in glial cells. We exa...

  5. The ETFDH c.158A>G Variation Disrupts the Balanced Binding of ESE and ESS Proteins Causing Missplicing and Multiple acyl-CoA Dehydrogenation Deficiency

    DEFF Research Database (Denmark)

    Olsen, Rikke K J; Brøner, Sabrina; Sabaratnam, Rugivan;

    2013-01-01

    Multiple acyl-CoA dehydrogenation deficiency is a disorder of fatty acid and amino acid oxidation caused by defects of electron transfer flavoprotein (ETF) or its dehydrogenase (ETFDH). A clear relationship between genotype and phenotype makes genotyping of patients important not only...

  6. From 2 + 2 to 8 + 8 Condensation Products of Diamine and Dialdehyde: Giant Container-Shaped Macrocycles for Multiple Anion Binding.

    Science.gov (United States)

    Gregoliński, Janusz; Ślepokura, Katarzyna; Paćkowski, Tomasz; Panek, Jarosław; Stefanowicz, Piotr; Lisowski, Jerzy

    2016-07-01

    The combination of 2,6-diformylpyridine and trans-1,2-diaminocyclopentane fragments results in 2 + 2, 3 + 3, 4 + 4, 6 + 6, and 8 + 8 macrocyclic imine condensation products. These imines can be reduced to the corresponding 2 + 2, 3 + 3, 4 + 4, 6 + 6, and 8 + 8 macrocyclic amines. The X-ray crystal structures of their protonated derivatives show a rich variety of macrocycle conformations ranging from a stepped 2 + 2 macrocycle to a multiply folded 8 + 8 macrocycle of globular shape. These compounds bind anions via hydrogen bonds: two chloride anions are bound above and below the macrocyclic ring of the 2 + 2 amine, one chloride anion is bound approximately in the center of the 3 + 3 macrocycle, and two chloride anions are deeply buried inside a folded container-shaped 4 + 4 macrocycle, while in the case of the previously reported 6 + 6 amine four chloride anions and two solvent molecules are buried inside a container-shaped macrocycle. Yet another situation was observed for a multiply folded protonated 8 + 8 macrocycle which binds six sulfate anions; two of them are deeply buried inside the container structure while four anions interact with the clefts at the surface of the container.

  7. From 2 + 2 to 8 + 8 Condensation Products of Diamine and Dialdehyde: Giant Container-Shaped Macrocycles for Multiple Anion Binding.

    Science.gov (United States)

    Gregoliński, Janusz; Ślepokura, Katarzyna; Paćkowski, Tomasz; Panek, Jarosław; Stefanowicz, Piotr; Lisowski, Jerzy

    2016-07-01

    The combination of 2,6-diformylpyridine and trans-1,2-diaminocyclopentane fragments results in 2 + 2, 3 + 3, 4 + 4, 6 + 6, and 8 + 8 macrocyclic imine condensation products. These imines can be reduced to the corresponding 2 + 2, 3 + 3, 4 + 4, 6 + 6, and 8 + 8 macrocyclic amines. The X-ray crystal structures of their protonated derivatives show a rich variety of macrocycle conformations ranging from a stepped 2 + 2 macrocycle to a multiply folded 8 + 8 macrocycle of globular shape. These compounds bind anions via hydrogen bonds: two chloride anions are bound above and below the macrocyclic ring of the 2 + 2 amine, one chloride anion is bound approximately in the center of the 3 + 3 macrocycle, and two chloride anions are deeply buried inside a folded container-shaped 4 + 4 macrocycle, while in the case of the previously reported 6 + 6 amine four chloride anions and two solvent molecules are buried inside a container-shaped macrocycle. Yet another situation was observed for a multiply folded protonated 8 + 8 macrocycle which binds six sulfate anions; two of them are deeply buried inside the container structure while four anions interact with the clefts at the surface of the container. PMID:27304017

  8. Crystal Structures of Apo and Metal-Bound Forms of the UreE Protein from Helicobacter pylori: Role of Multiple Metal Binding Sites

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Rong; Munger, Christine; Asinas, Abdalin; Benoit, Stephane L.; Miller, Erica; Matte, Allan; Maier, Robert J.; Cygler, Miroslaw (McGill); (Georgia); (Biotech Res.)

    2010-10-22

    The crystal structure of the urease maturation protein UreE from Helicobacter pylori has been determined in its apo form at 2.1 {angstrom} resolution, bound to Cu{sup 2+} at 2.7 {angstrom} resolution, and bound to Ni{sup 2+} at 3.1 {angstrom} resolution. Apo UreE forms dimers, while the metal-bound enzymes are arranged as tetramers that consist of a dimer of dimers associated around the metal ion through coordination by His102 residues from each subunit of the tetramer. Comparison of independent subunits from different crystal forms indicates changes in the relative arrangement of the N- and C-terminal domains in response to metal binding. The improved ability of engineered versions of UreE containing hexahistidine sequences at either the N-terminal or C-terminal end to provide Ni{sup 2+} for the final metal sink (urease) is eliminated in the H102A version. Therefore, the ability of the improved Ni{sup 2+}-binding versions to deliver more nickel is likely an effect of an increased local concentration of metal ions that can rapidly replenish transferred ions bound to His102.

  9. [(3) H]-L685,458 binding sites are abundant in multiple peripheral organs in rats: implications for safety assessment of putative γ-secretase targeting drugs.

    Science.gov (United States)

    Yang, Zhi-Ying; Li, Jian-Ming; Xiao, Ling; Mou, Lin; Cai, Yan; Huang, He; Luo, Xue-Gang; Yan, Xiao-Xin

    2014-12-01

    γ-Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism-based toxicity needs to be thoroughly evaluated for γ-secretase inhibitory and/or modulatory drugs. This study comparatively assessed putative γ-secretase catalytic sites in rat peripheral tissues relative to brain and explored an effort of its pharmacological inhibition on hair regeneration. Using [(3) H]-labelled L685,458, a potent γ-secretase inhibitor, as probe, we found more abundant presence of γ-secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that γ-secretase may execute important biological functions in many peripheral systems, as in the brain. The development of γ-secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions.

  10. [(3) H]-L685,458 binding sites are abundant in multiple peripheral organs in rats: implications for safety assessment of putative γ-secretase targeting drugs.

    Science.gov (United States)

    Yang, Zhi-Ying; Li, Jian-Ming; Xiao, Ling; Mou, Lin; Cai, Yan; Huang, He; Luo, Xue-Gang; Yan, Xiao-Xin

    2014-12-01

    γ-Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism-based toxicity needs to be thoroughly evaluated for γ-secretase inhibitory and/or modulatory drugs. This study comparatively assessed putative γ-secretase catalytic sites in rat peripheral tissues relative to brain and explored an effort of its pharmacological inhibition on hair regeneration. Using [(3) H]-labelled L685,458, a potent γ-secretase inhibitor, as probe, we found more abundant presence of γ-secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that γ-secretase may execute important biological functions in many peripheral systems, as in the brain. The development of γ-secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions. PMID:24861611

  11. Tumor-promoting function of single nucleotide polymorphism rs1836724 (C3388T) alters multiple potential legitimate microRNA binding sites at the 3'-untranslated region of ErbB4 in breast cancer.

    Science.gov (United States)

    Bagheri, Fatemeh; Mesrian Tanha, Hamzeh; Mojtabavi Naeini, Marjan; Ghaedi, Kamran; Azadeh, Mansoureh

    2016-05-01

    ErbB4 can act as either a tumor-suppressor gene or an oncogene in breast cancer. Multiple genetic factors including single nucleotide polymorphisms (SNPs) affect gene expression patterns. Multiple 3'-untranslated region (3'-UTR) SNPs reside within the target binding site of microRNAs, which can strengthen or weaken binding to target genes. The present study aimed to predict potential 3'‑UTR variants of ErbB4 that alter the target binding site of microRNAs (miRNAs) and to clarify the association of the potential variant with the risk of developing breast cancer. In silico prediction was performed to identify potential functional SNPs within miRNA target binding sites in the 3'‑UTR of ErbB4. Thus, 146 patients and controls were genotyped using restriction fragment length polymorphism-polymerase chain reaction. In addition to the Cochran-Armitage test for trend, allele and genotype frequency differences were determined to investigate the association between rs1836724 and the susceptibility to breast cancer. Bioinformatics analysis identified rs1836724 to be a polymorphism in the seed region of four miRNA binding sites (hsa-miR335-5p, hsa-miR-28-5p, has‑miR‑708‑5p and has‑miR‑665), which may participate in the development of breast cancer. Logistic regression data indicated that the T allele of the polymorphism [OR (95% CI)=1.72 (1.056‑2.808), P=0.029] is associated with the risk of breast cancer. Using bioinformatics tools, a correlation was indicated between the presence of the T allele and a reduction in ErbB4 RNA silencing based on miRNA interaction. Furthermore, case subgroup data analysis revealed an association between the C/T genotype and an ER positive phenotype [OR (95% CI)=6.00 (1.082‑33.274), P=0.028] compared with the T/T genotype. ErbB4 and estrogen receptor 1 (ESR1) are regulated by identical miRNAs thus there may be a competition for binding sites. Due to this pattern, if the interaction between miRNAs with one gene is reduced, it

  12. The Protamine-like DNA-binding Protein P6.9 Epigenetically Up-regulates Autographa californica Multiple Nucleopolyhedrovirus Gene Transcription in the Late Infection Phase

    Institute of Scientific and Technical Information of China (English)

    Ying Peng; Kun Li; Rong-juan Pei; Chun-chen Wu; Chang-yong Liang; Yun Wang; Xin-wen Chen

    2012-01-01

    Protamines are a group of highly basic proteins first discovered in spermatozoon that allow for denser packaging of DNA than histones and will result in down-regulation of gene transcription[1].It is well recognized that the Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) encodes P6.9,a protamine-like protein that forms the viral subnucleosome through binding to the viral genome[29].Previous research demonstrates that P6.9 is essential for viral nucleocapsid assembly,while it has no influence on viral genome replication[31].In the present study,the role of P6.9 in viral gene transcription regulation is characterized.In contrast to protamines or other protamine-like proteins that usually down-regulate gene transcription,P6.9 appears to up-regulate viral gene transcription at 12-24 hours post infection (hpi),whereas it is non-essential for the basal level of viral gene transcription.Fluorescence microscopy reveals the P6.9's co-localization with DNA is temporally and spatially synchronized with P6.9's impact on viral gene transcription,indicating the P6.9-DNA association contributes to transcription regulation.Chromatin fractionation assay further reveals an unexpected co-existence of P6.9 and host RNA polymerase Ⅱ in the same transcriptionally active chromatin fraction at 24 hpi,which may probably contribute to viral gene transcription up-regulation in the late infection phase.

  13. In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug-binding site and altered growth.

    Science.gov (United States)

    Ross, Leila S; Gamo, Francisco Javier; Lafuente-Monasterio, Maria José; Singh, Onkar M P; Rowland, Paul; Wiegand, Roger C; Wirth, Dyann F

    2014-06-27

    Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild-type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity.

  14. 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.

  15. The zinc binuclear cluster activator AlcR is able to bind to single sites but requires multiple repeated sites for synergistic activation of the alcA gene in Aspergillus nidulans.

    Science.gov (United States)

    Panozzo, C; Capuano, V; Fillinger, S; Felenbok, B

    1997-09-01

    The alcA gene which is part of the recently identified ethanol regulon, is one of the most strongly inducible genes in Aspergillus nidulans. Its transcriptional activation is mediated by the AlcR transactivator which contains a DNA-binding domain belonging to the C6 zinc binuclear cluster family. AlcR differs from the other members of this family by several features, the most striking characteristic being its binding to both symmetric and asymmetric DNA sites with the same apparent affinity. However, AlcR is also able to bind to a single site with high affinity, suggesting that unlike the other C6 proteins, AlcR binds as a monomer. In this report, we show that AlcR targets, to be functional in vivo, have to be organized as inverted or direct repeats. In addition, we show a strong synergistic activation of alcA transcription in which the number and the position of the AlcR-binding sites are crucial. The fact that the AlcR unit for in vitro binding is a single site whereas the in vivo functional unit is a repeat opens the question of the mechanism of the strong alcA transactivation. These results show that AlcR displays both in vitro and in vivo a new range of binding specificity and provides a novel example in the C6 zinc cluster protein family.

  16. Clone and analysis of human RNA binding protein with multiple splicing 2 gene%人类多重剪接RNA结合蛋白类基因的克隆和分析

    Institute of Scientific and Technical Information of China (English)

    张雅娟; 肖娟娟; 鲁德意; 王尉平

    2013-01-01

    Objective To assemble and clone human RNA binding protein with multiple splicing 2(RBPMS2) gene by homologous sequence aligning. Methods Human RBPMS2 gene was taken as an information probe for searching the coding sequece in GeneBank database by homologous sequence aligning. Then the highly homologous expressed sequence tag(EST) was assembled to the contig using VECTOR NTI software. The chromosome localization,domain and expression pattern of RBPMS2 were analyzed by UCSC Genome Blat Server, SMART and Unigene database, respectively. Results A novel cDNA sequence of human RBPMS2 gene was cloned, which contained complete open reading frame(ORF). RBPMS2 gene encoded a 209 amino acides protein with MW 22. 5 KDa and pi 8.63. SMART analysis showed that RBPMS2 protein included a RNA recognition motif (RRM) domain. RBPMS2 was mapping on the fifteenth chromosome, located at 15q22. 31, and consisted of seven exons and six introns. Unigene database presented that RBPMS2 was widely expressed in ovotid,zygote,blastula,embryo at different developmental stages, bladder and kidney. Conclusion A novel human RBPMS2 gene has been cloned and analyzed.%目的 通过同源筛选的方法拼接并克隆人类多重剪接RNA结合蛋白2(RBPMS2)基因.方法 采用同源筛选策略,以人RBPMS2基因作为信息探针,在GeneBank数据库中进行分析,将获得的高度同源的表达序列标签(EST)用VECTOR NTI软件拼接成重叠群.通过UCSCGenome Blat Server分析,确定RBPMS2基因的染色体定位,SMART网上分析工具进行结构域预测,Unigene数据库进行表达谱分析.结果 电子克隆到人类RBPMS2新基因cDNA序列,含完整的开放阅读框(ORF).RBPMS2基因编码的多肽由209个氨基酸组成,分子量22.5 KDa,等电点8.63.SMART分析显示RBPMS2蛋白包含1个RNA识别模体(RRM)结构域.RBPMS2基因位于第15号染色体,定位在15q22.31,由7个外显子和6个内含子组成.电子表达谱分析显示RBPMS2在卵细胞

  17. Multiple Perspectives / Multiple Readings

    Directory of Open Access Journals (Sweden)

    Simon Biggs

    2005-01-01

    Full Text Available People experience things from their own physical point of view. What they see is usually a function of where they are and what physical attitude they adopt relative to the subject. With augmented vision (periscopes, mirrors, remote cameras, etc we are able to see things from places where we are not present. With time-shifting technologies, such as the video recorder, we can also see things from the past; a time and a place we may never have visited.In recent artistic work I have been exploring the implications of digital technology, interactivity and internet connectivity that allow people to not so much space/time-shift their visual experience of things but rather see what happens when everybody is simultaneously able to see what everybody else can see. This is extrapolated through the remote networking of sites that are actual installation spaces; where the physical movements of viewers in the space generate multiple perspectives, linked to other similar sites at remote locations or to other viewers entering the shared data-space through a web based version of the work.This text explores the processes involved in such a practice and reflects on related questions regarding the non-singularity of being and the sense of self as linked to time and place.

  18. Analyzing binding data.

    Science.gov (United States)

    Motulsky, Harvey J; Neubig, Richard R

    2010-07-01

    Measuring the rate and extent of radioligand binding provides information on the number of binding sites, and their affinity and accessibility of these binding sites for various drugs. This unit explains how to design and analyze such experiments.

  19. Multiple Myeloma

    Science.gov (United States)

    Multiple myeloma is a cancer that begins in plasma cells, a type of white blood cell. These cells ... bones. No one knows the exact causes of multiple myeloma, but it is more common in older people ...

  20. Multiple Pregnancy

    Science.gov (United States)

    ... Can multiple pregnancy affect my risk of postpartum depression? Having multiples might increase your risk of postpartum ... Membership For Journalists For Junior Fellows For Medical Students For Patients Contact Us Copyright Information Privacy Statement ...

  1. Multiplicity Counting

    Energy Technology Data Exchange (ETDEWEB)

    Geist, William H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-12-01

    This set of slides begins by giving background and a review of neutron counting; three attributes of a verification item are discussed: 240Pueff mass; α, the ratio of (α,n) neutrons to spontaneous fission neutrons; and leakage multiplication. It then takes up neutron detector systems – theory & concepts (coincidence counting, moderation, die-away time); detector systems – some important details (deadtime, corrections); introduction to multiplicity counting; multiplicity electronics and example distributions; singles, doubles, and triples from measured multiplicity distributions; and the point model: multiplicity mathematics.

  2. Hardware device binding and mutual authentication

    Science.gov (United States)

    Hamlet, Jason R; Pierson, Lyndon G

    2014-03-04

    Detection and deterrence of device tampering and subversion by substitution may be achieved by including a cryptographic unit within a computing device for binding multiple hardware devices and mutually authenticating the devices. The cryptographic unit includes a physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a binding PUF value. The cryptographic unit uses the binding PUF value during an enrollment phase and subsequent authentication phases. During a subsequent authentication phase, the cryptographic unit uses the binding PUF values of the multiple hardware devices to generate a challenge to send to the other device, and to verify a challenge received from the other device to mutually authenticate the hardware devices.

  3. 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.

  4. 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

  5. Multiple Gliomas

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Multiple gliomas are well-recognized but uncommon tumors. The incidence of multiple gliomas according to some reports ranges from 0.5% to 20% of all gliomas diagnosed. Multiple gliomas can be divided into two categories. One is by location of the lesions (multifocal and multicentric). The second type is by the time of the lesions occur (synchronous and metachronous). The lesions generally show hypo, or isodensity on CT; a hypo- or isointense signal on T1-weighted images, and a hyperintense signal on T2-weighted images. Glioblastoma is the most frequent histotype. The prognosis of multiple gliomas remains unfavorable. The treatment of multiple gliomas includes surgery, radiotherapy and chemotherapy. Distinction between multicentric and multifocal gliomas is difficult. This report reviews in detail the aspects of multiple gliomas mentioned above.

  6. Multiple sclerosis

    International Nuclear Information System (INIS)

    Multiple sclerosis is the most common chronic inflammatory disease of myelin with interspersed lesions in the white matter of the central nervous system. Magnetic resonance imaging (MRI) plays a key role in the diagnosis and monitoring of white matter diseases. This article focuses on key findings in multiple sclerosis as detected by MRI. (orig.)

  7. Total iron binding capacity

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003489.htm Total iron binding capacity To use the sharing features on this page, please enable JavaScript. Total iron binding capacity (TIBC) is a blood test to ...

  8. Plant Hormone Binding Sites

    OpenAIRE

    Napier, Richard

    2004-01-01

    • Aims Receptors for plant hormones are becoming identified with increasing rapidity, although a frustrating number remain unknown. There have also been many more hormone‐binding proteins described than receptors. This Botanical Briefing summarizes what has been discovered about hormone binding sites, their discovery and descriptions, and will not dwell on receptor functions or activities except where these are relevant to understand binding.

  9. Analysis of binding heterogeneity.

    NARCIS (Netherlands)

    Nederlof, M.M.

    1992-01-01

    Binding heterogeneity, due to different functional groups on a reactive surface, plays an important role in the binding of small molecules or ions to many adsorbents, both in industrial processes and in natural environments. The binding heterogeneity is described by a distribution of affinity consta

  10. Multiple homicides.

    Science.gov (United States)

    Copeland, A R

    1989-09-01

    A study of multiple homicides or multiple deaths involving a solitary incident of violence by another individual was performed on the case files of the Office of the Medical Examiner of Metropolitan Dade County in Miami, Florida, during 1983-1987. A total of 107 multiple homicides were studied: 88 double, 17 triple, one quadruple, and one quintuple. The 236 victims were analyzed regarding age, race, sex, cause of death, toxicologic data, perpetrator, locale of the incident, and reason for the incident. This article compares this type of slaying with other types of homicide including those perpetrated by serial killers. Suggestions for future research in this field are offered.

  11. Analyzing radioligand binding data.

    Science.gov (United States)

    Motulsky, Harvey; Neubig, Richard

    2002-08-01

    Radioligand binding experiments are easy to perform, and provide useful data in many fields. They can be used to study receptor regulation, discover new drugs by screening for compounds that compete with high affinity for radioligand binding to a particular receptor, investigate receptor localization in different organs or regions using autoradiography, categorize receptor subtypes, and probe mechanisms of receptor signaling, via measurements of agonist binding and its regulation by ions, nucleotides, and other allosteric modulators. This unit reviews the theory of receptor binding and explains how to analyze experimental data. Since binding data are usually best analyzed using nonlinear regression, this unit also explains the principles of curve fitting with nonlinear regression.

  12. Multiple sclerosis

    Science.gov (United States)

    Houtchens MK, Lublin FD, Miller AE, Khoury SJ. Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. In: Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, ...

  13. Multiple myeloma.

    LENUS (Irish Health Repository)

    Collins, Conor D

    2012-02-01

    Advances in the imaging and treatment of multiple myeloma have occurred over the past decade. This article summarises the current status and highlights how an understanding of both is necessary for optimum management.

  14. Simultaneous optimal experimental design for in vitro binding parameter estimation.

    Science.gov (United States)

    Ernest, C Steven; Karlsson, Mats O; Hooker, Andrew C

    2013-10-01

    Simultaneous optimization of in vitro ligand binding studies using an optimal design software package that can incorporate multiple design variables through non-linear mixed effect models and provide a general optimized design regardless of the binding site capacity and relative binding rates for a two binding system. Experimental design optimization was employed with D- and ED-optimality using PopED 2.8 including commonly encountered factors during experimentation (residual error, between experiment variability and non-specific binding) for in vitro ligand binding experiments: association, dissociation, equilibrium and non-specific binding experiments. Moreover, a method for optimizing several design parameters (ligand concentrations, measurement times and total number of samples) was examined. With changes in relative binding site density and relative binding rates, different measurement times and ligand concentrations were needed to provide precise estimation of binding parameters. However, using optimized design variables, significant reductions in number of samples provided as good or better precision of the parameter estimates compared to the original extensive sampling design. Employing ED-optimality led to a general experimental design regardless of the relative binding site density and relative binding rates. Precision of the parameter estimates were as good as the extensive sampling design for most parameters and better for the poorly estimated parameters. Optimized designs for in vitro ligand binding studies provided robust parameter estimation while allowing more efficient and cost effective experimentation by reducing the measurement times and separate ligand concentrations required and in some cases, the total number of samples. PMID:23943088

  15. STRUCTURAL FEATURES OF PLANT CHITINASES AND CHITIN-BINDING PROTEINS

    NARCIS (Netherlands)

    BEINTEMA, JJ

    1994-01-01

    Structural features of plant chitinases and chitin-binding proteins are discussed. Many of these proteins consist of multiple domains,of which the chitin-binding hevein domain is a predominant one. X-ray and NMR structures of representatives of the major classes of these proteins are available now,

  16. Studies of the silencing of Baculovirus DNA binding protein

    NARCIS (Netherlands)

    Quadt, I.; Lent, van J.W.M.; Knebel-Morsdorf, D.

    2007-01-01

    Baculovirus DNA binding protein (DBP) binds preferentially single-stranded DNA in vitro and colocalizes with viral DNA replication sites. Here, its putative role as viral replication factor has been addressed by RNA interference. Silencing of DBP in Autographa californica multiple nucleopolyhedrovir

  17. Multiple myeloma

    International Nuclear Information System (INIS)

    Conventional radiography is the means generally used in the assessment of skeletal involvement in multiple myeloma. Many findings such as osteolytic lesions, fractures, and osteoporosis are characteristic of myeloma. However, it seems likely that the extent of bone destruction is sometimes underestimated by radiography. Bone scintigraphy is considered a sensitive technique for the detection of skeletal metastatic lesions, but contradictory results have been reported in multiple myeloma, and many reports indicate that bone scintigraphy is less effective than conventional radiography. This phenomenon could depend on the fact that myeloma is a bone-marrow disease; bone structure is only indirectly involved; furthermore, studies have demonstrated that myelomatous lesions induce, by osteclast activation, larger bone resorption than new bone formation. On this basis the authors proposed the evaluation of bone marrow scanning plus bone scanning in comparison to conventional diagnostic radiology for the detection of skeletal involvement in multiple myeloma

  18. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, Egon; Stenager, E N; Knudsen, Lone;

    1994-01-01

    In a cross-sectional study of 117 randomly selected patients (52 men, 65 women) with definite multiple sclerosis, it was found that 76 percent were married or cohabitant, 8 percent divorced. Social contacts remained unchanged for 70 percent, but outgoing social contacts were reduced for 45 percent......, need for structural changes in home and need for pension became greater with increasing physical handicap. No significant differences between gender were found. It is concluded that patients and relatives are under increased social strain, when multiple sclerosis progresses to a moderate handicap...

  19. Python bindings for libcloudph++

    OpenAIRE

    Jarecka, Dorota; Arabas, Sylwester; Del Vento, Davide

    2015-01-01

    This technical note introduces the Python bindings for libcloudph++. The libcloudph++ is a C++ library of algorithms for representing atmospheric cloud microphysics in numerical models. The bindings expose the complete functionality of the library to the Python users. The bindings are implemented using the Boost.Python C++ library and use NumPy arrays. This note includes listings with Python scripts exemplifying the use of selected library components. An example solution for using the Python ...

  20. DNS & Bind Cookbook

    CERN Document Server

    Liu, Cricket

    2011-01-01

    The DNS & BIND Cookbook presents solutions to the many problems faced by network administrators responsible for a name server. Following O'Reilly's popular problem-and-solution cookbook format, this title is an indispensable companion to DNS & BIND, 4th Edition, the definitive guide to the critical task of name server administration. The cookbook contains dozens of code recipes showing solutions to everyday problems, ranging from simple questions, like, "How do I get BIND?" to more advanced topics like providing name service for IPv6 addresses. It's full of BIND configuration files that yo

  1. Python bindings for libcloudph++

    CERN Document Server

    Jarecka, Dorota; Del Vento, Davide

    2015-01-01

    This technical note introduces the Python bindings for libcloudph++. The libcloudph++ is a C++ library of algorithms for representing atmospheric cloud microphysics in numerical models. The bindings expose the complete functionality of the library to the Python users. The bindings are implemented using the Boost.Python C++ library and use NumPy arrays. This note includes listings with Python scripts exemplifying the use of selected library components. An example solution for using the Python bindings to access libcloudph++ from Fortran is presented.

  2. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Jensen, K

    1988-01-01

    Forty-two (12%) of a total of 366 patients with multiple sclerosis (MS) had psychiatric admissions. Of these, 34 (81%) had their first psychiatric admission in conjunction with or after the onset of MS. Classification by psychiatric diagnosis showed that there was a significant positive correlation...

  3. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Knudsen, L; Jensen, K

    1994-01-01

    In a cross-sectional study of 94 patients (42 males, 52 females) with definite multiple sclerosis (MS) in the age range 25-55 years, the correlation of neuropsychological tests with the ability to read TV-subtitles and with the use of sedatives is examined. A logistic regression analysis reveals...

  4. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Jensen, K

    1990-01-01

    An investigation on the correlation between ability to read TV subtitles and the duration of visual evoked potential (VEP) latency in 14 patients with definite multiple sclerosis (MS), indicated that VEP latency in patients unable to read the TV subtitles was significantly delayed in comparison...

  5. Multiple Sclerosis.

    Science.gov (United States)

    Plummer, Nancy; Michael, Nancy, Ed.

    This module on multiple sclerosis is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  6. Multiple myeloma

    International Nuclear Information System (INIS)

    Multiple myeloma is a malignant plasma cell tumor that is thought to originate proliferation of a single clone of abnormal plasma cell resulting production of a whole monoclonal paraprotein. The authors experienced a case of multiple myeloma with severe mandibular osteolytic lesions in 46-year-old female. As a result of careful analysis of clinical, radiological, histopathological features, and laboratory findings, we diagnosed it as multiple myeloma, and the following results were obtained. 1. Main clinical symptoms were intermittent dull pain on the mandibular body area, abnormal sensation of lip and pain due to the fracture on the right clavicle. 2. Laboratory findings revealed M-spike, reversed serum albumin-globulin ratio, markedly elevated ESR and hypercalcemia. 3. Radiographically, multiple osteolytic punched-out radiolucencies were evident on the skull, zygoma, jaw bones, ribs, clavicle and upper extremities. Enlarged liver and increased uptakes on the lesional sites in RN scan were also observed. 4. Histopathologically, markedly hypercellular marrow with sheets of plasmoblasts and megakaryocytes were also observed.

  7. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Knudsen, L; Jensen, K

    1991-01-01

    In a cross-sectional investigation of 116 patients with multiple sclerosis, the social and sparetime activities of the patient were assessed by both patient and his/her family. The assessments were correlated to physical disability which showed that particularly those who were moderately disabled...

  8. Melanin-binding radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Packer, S; Fairchild, R G; Watts, K P; Greenberg, D; Hannon, S J

    1980-01-01

    The scope of this paper is limited to an analysis of the factors that are important to the relationship of radiopharmaceuticals to melanin. While the authors do not attempt to deal with differences between melanin-binding vs. melanoma-binding, a notable variance is assumed. (PSB)

  9. DNS BIND Server Configuration

    Directory of Open Access Journals (Sweden)

    Radu MARSANU

    2011-01-01

    Full Text Available After a brief presentation of the DNS and BIND standard for Unix platforms, the paper presents an application which has a principal objective, the configuring of the DNS BIND 9 server. The general objectives of the application are presented, follow by the description of the details of designing the program.

  10. Multiple Sklerose

    OpenAIRE

    Hoffmann, Sarah

    2010-01-01

    Background: Multiple Sclerosis (MS) is the most common disabling neurological disease affecting young adults and the number of chronically sick MS patients to be found in the world of employment is on the increase. Research activities in the field of MS are numerous and wide-ranging. However, precise bibliometric analyses of research on the subject of MS do not exist so far. Methods: The present dissertation employs classical bibliometric tools with novel scientometric and visualizing tec...

  11. Multiple myeloma

    International Nuclear Information System (INIS)

    This chapter overviews the outcome of the previous studies on multiple myeloma and its related diseases. The incidence of multiple myeloma has become frequent 20 years after A-bombing. As of 1976, it is found to be increased, depending upon bone marrow doses of 50 rad or more (based on T65DR). This is noticeable in A-bomb survivors aged 20-59 years at the time of exposure. The number of autopsy cases has been increased since 1975, and has been significantly high since 1981. Mass screening for A-bomb survivors has revealed the existence of M proteinemia characterized by findings similar to those of multiple myeloma and benign monoclonal gammopathy. There is no significant difference in the incidence of subtype of M proteinemia by distance from the hypocenter. These findings suggest that M proteinemia may be one of the delayed effects of A-bomb radiation. Otherwise, an increased incidence of M proteinemia may be attributable to the cancer-prone age in A-bomb survivors aged 30 years or less at the time of exposure. (N.K.)

  12. Multiple sclerosis

    International Nuclear Information System (INIS)

    Eleven patients with a definite diagnosis of multiple sclerosis were examined in terms of correlations between the clinical features and the results of cranial computed tomography (CT), and magnetic resonance imaging (MRI). Results: In 5 of the 11 patients, both CT and MRI demonstrated lesions consistent with a finding of multiple sclerosis. In 3 patients, only MRI demonstrated lesions. In the remaining 3 patients, neither CT nor MRI revealed any lesion in the brain. All 5 patients who showed abnormal findings on both CT and MRI had clinical signs either of cerebral or brainstem - cerebellar lesions. On the other hand, two of the 3 patients with normal CT and MRI findings had optic-nerve and spinal-cord signs. Therefore, our results suggested relatively good correlations between the clinical features, CT, and MRI. MRI revealed cerebral lesions in two of the four patients with clinical signs of only optic-nerve and spinal-cord lesions. MRI demonstrated sclerotic lesions in 3 of the 6 patients whose plaques were not detected by CT. In conclusion, MRI proved to be more helpful in the demonstration of lesions attributable to chronic multiple sclerosis. (author)

  13. Palmitate and stearate binding to human serum albumin. Determination of relative binding constants

    DEFF Research Database (Denmark)

    Vorum, H; Fisker, K; Honoré, B

    1997-01-01

    Multiple binding equilibria of two apparently insoluble ligands, palmitate and stearate, to defatted human serum albumin were studied in a 66 mM sodium phosphate buffer (pH 7.4) at 37 degrees C, by determination of dialytic exchange rates of ligands among identical equilibrium solutions. The expe...

  14. A new zinc binding fold underlines the versatility of zinc binding modules in protein evolution.

    Science.gov (United States)

    Sharpe, Belinda K; Matthews, Jacqueline M; Kwan, Ann H Y; Newton, Anthea; Gell, David A; Crossley, Merlin; Mackay, Joel P

    2002-05-01

    Many different zinc binding modules have been identified. Their abundance and variety suggests that the formation of zinc binding folds might be relatively common. We have determined the structure of CH1(1), a 27-residue peptide derived from the first cysteine/histidine-rich region (CH1) of CREB binding protein (CBP). This peptide forms a highly ordered zinc-dependent fold that is distinct from known folds. The structure differs from a subsequently determined structure of a larger region from the CH3 region of CBP, and the CH1(1) fold probably represents a nonphysiologically active form. Despite this, the fold is thermostable and tolerant to both multiple alanine mutations and changes in the zinc-ligand spacing. Our data support the idea that zinc binding domains may arise frequently. Additionally, such structures may prove useful as scaffolds for protein design, given their stability and robustness.

  15. SHBG (Sex Hormone Binding Globulin)

    Science.gov (United States)

    ... as: Testosterone-estrogen Binding Globulin; TeBG Formal name: Sex Hormone Binding Globulin Related tests: Testosterone , Free Testosterone, ... I should know? How is it used? The sex hormone binding globulin (SHBG) test may be used ...

  16. Multiple Myeloma Overview

    Science.gov (United States)

    ... Web version Multiple Myeloma Overview What is multiple myeloma? Multiple myeloma (say: my-a-low-ma) is a ... Do I need to be screened for multiple myeloma? Source Multiple Myeloma: Recognition and Management by ED George, R ...

  17. Albumin and multiple sclerosis.

    Science.gov (United States)

    LeVine, Steven M

    2016-01-01

    Leakage of the blood-brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth. PMID:27067000

  18. Multiple sclerosis.

    Science.gov (United States)

    Filippi, Massimo; Preziosa, Paolo; Rocca, Maria A

    2016-01-01

    Due to its sensitivity to the different multiple sclerosis (MS)-related abnormalities, magnetic resonance imaging (MRI) has become an established tool to diagnose MS and to monitor its evolution. MRI has been included in the diagnostic workup of patients with clinically isolated syndromes suggestive of MS, and ad hoc criteria have been proposed and are regularly updated. In patients with definite MS, the ability of conventional MRI techniques to explain patients' clinical status and progression of disability is still suboptimal. Several advanced MRI-based technologies have been applied to estimate overall MS burden in the different phases of the disease. Their use has allowed the heterogeneity of MS pathology in focal lesions, normal-appearing white matter and gray matter to be graded in vivo. Recently, additional features of MS pathology, including macrophage infiltration and abnormal iron deposition, have become quantifiable. All of this, combined with functional imaging techniques, is improving our understanding of the mechanisms associated with MS evolution. In the near future, the use of ultrahigh-field systems is likely to provide additional insight into disease pathophysiology. However, the utility of advanced MRI techniques in clinical trial monitoring and in assessing individual patients' response to treatment still needs to be assessed. PMID:27432676

  19. Integrating multiple calendars using tau ZAMAN

    DEFF Research Database (Denmark)

    Jensen, Christian Søndergaard; Urgun, B; Dyreson, C. E.;

    2007-01-01

    , for instance between the Gregorian and Islamic calendars. tZAMAN is a system that provides a natural language and calendarindependent framework for integrating multiple calendars. tZAMAN performs "runtime-binding" of calendars and language support. A running tZAMAN system dynamically loads calendars...

  20. Cellulose binding domain proteins

    Energy Technology Data Exchange (ETDEWEB)

    Shoseyov, Oded (Karmey Yosef, IL); Shpiegl, Itai (Rehovot, IL); Goldstein, Marc (Davis, CA); Doi, Roy (Davis, CA)

    1998-01-01

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production thereof. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques.

  1. Sequential memory: Binding dynamics

    Science.gov (United States)

    Afraimovich, Valentin; Gong, Xue; Rabinovich, Mikhail

    2015-10-01

    Temporal order memories are critical for everyday animal and human functioning. Experiments and our own experience show that the binding or association of various features of an event together and the maintaining of multimodality events in sequential order are the key components of any sequential memories—episodic, semantic, working, etc. We study a robustness of binding sequential dynamics based on our previously introduced model in the form of generalized Lotka-Volterra equations. In the phase space of the model, there exists a multi-dimensional binding heteroclinic network consisting of saddle equilibrium points and heteroclinic trajectories joining them. We prove here the robustness of the binding sequential dynamics, i.e., the feasibility phenomenon for coupled heteroclinic networks: for each collection of successive heteroclinic trajectories inside the unified networks, there is an open set of initial points such that the trajectory going through each of them follows the prescribed collection staying in a small neighborhood of it. We show also that the symbolic complexity function of the system restricted to this neighborhood is a polynomial of degree L - 1, where L is the number of modalities.

  2. Lectin binding in meningiomas.

    Science.gov (United States)

    Kleinert, R; Radner, H

    1987-01-01

    Forty-two meningiomas of different morphological sub-type were examined to determine their pattern of binding to 11 different lectins which characterize cell surface components such as carbohydrate residues. Histiocytic and xanthoma cells within meningiomas could be demonstrated with six different lectins: wheat germ agglutinin (WGA), peanut agglutinin (PNA) Bauhinia purpurea agglutinin (BPA), Helix pomatia agglutinin (HPA), Vicia fava agglutinin (VFA) and Soyabean agglutinin (SBA). Vascular elements including endothelial cells and intimal cells, bound Ulex europaeus agglutinin type 1 (UEA 1), WGA and HPA. The fibrous stroma in fibrous and fibroblastic meningiomas bound PNA, Laburnum alpinum agglutinin (LAA) and SBA. Tumour cells in meningotheliomatous meningiomas and some areas of anaplastic meningiomas bound Concanavalin A, PNA, LAA and VFA whereas tumour cells in fibrous and fibroblastic meningiomas bound BPA, LAA and VFA. Lectin binding has proved to be of value in detecting histiocytic and xanthoma cells together with vascular elements within meningiomas. In addition, the different lectin binding patterns allow different histological sub-types of meningioma to be distinguished although the biological significance of the binding patterns is unclear. PMID:3658105

  3. Multiple Myeloma Symptoms

    Science.gov (United States)

    ... Center Finder Home » About Multiple Myeloma » Symptoms Multiple Myeloma Symptoms Multiple myeloma symptoms may vary by patient, with the ... to be managed or prevented. The most common multiple myeloma symptoms may include: Bone pain or bone fractures ...

  4. Multiple System Atrophy

    Science.gov (United States)

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy Information Page Condensed from Multiple System Atrophy ... Trials Organizations Publicaciones en Español What is Multiple System Atrophy? Multiple system atrophy (MSA) is a progressive ...

  5. Complement Component C3 Binds to Activated Normal Platelets without Preceding Proteolytic Activation and Promotes Binding to Complement Receptor 1

    OpenAIRE

    Osama A Hamad; Nilsson, Per H.; Wouters, Diana; Lambris, John D.; Ekdahl, Kristina N.; Nilsson, Bo

    2010-01-01

    It has been reported that complement is activated on the surface of activated platelets, despite the presence of multiple regulators of complement activation. To reinvestigate the mechanisms by which activated platelets bind to complement components, the presence of complement proteins on the surfaces of nonactivated and thrombin receptor-activating peptide-activated platelets was analyzed by flow cytometry and Western blot analyses. C1q, C4, C3, and C9 were found to bind to thrombin receptor...

  6. Binding-energy distribution and dephasing of localized biexcitons

    DEFF Research Database (Denmark)

    Langbein, Wolfgang Werner; Hvam, Jørn Märcher; Umlauff, M.;

    1997-01-01

    We report on the binding energy and dephasing of localized biexciton states in narrow ZnSe multiple quantum wells. The measured binding-energy distribution of the localized biexcitons shows a width of 2.2 meV centered at 8.5 meV, and is fairly independent of the exciton localization energy. In four......-wave mixing, the biexciton photon echo decays fast and nonexponentially. This behavior results from the inhomogeneous broadening of the biexciton binding energy, as we show by a comparison with an analytical model calculation. The fast decay is thus not related to a fast microscopic biexciton dephasing....

  7. Mycobacterial PE_PGRS Proteins Contain Calcium-Binding Motifs with Parallel β-roll Folds

    Institute of Scientific and Technical Information of China (English)

    Nandita; Bachhawat; Balvinder; Singh

    2007-01-01

    The PE_PGRS family of proteins unique to mycobacteria is demonstrated to con- rain multiple calcium-binding and glycine-rich sequence motifs GGXGXD/NXUX. This sequence repeat constitutes a calcium-binding parallel/3-roll or parallel β-helix structure and is found in RTX toxins secreted by many Gram-negative bacteria. It is predicted that the highly homologous PE_PGRS proteins containing multiple copies of the nona-peptide motif could fold into similar calcium-binding structures. The implication of the predicted calcium-binding property of PE_PGRS proteins in the Ught of macrophage-pathogen interaction and pathogenesis is presented.

  8. Improved assay for measuring heparin binding to bull sperm

    International Nuclear Information System (INIS)

    The binding of heparin to sperm has been used to study capacitation and to rank relative fertility of bulls. Previous binding assays were laborious, used 107 sperm per assay point, and required large amounts of radiolabeled heparin. A modified heparin-binding assay is described that used only 5 x 104 cells per incubation well and required reduced amounts of [3H] heparin. The assay was performed in 96-well Millititer plates, enabling easy incubation and filtering. Dissociation constants and concentrations of binding sites did not differ if analyzed by Scatchard plots, Woolf plots, or by log-logit transformed weighted nonlinear least squares regression, except in the case of outliers. In such cases, Scatchard analysis was more sensitive to outliers. Nonspecific binding was insignificant using nonlinear logistic fit regression and a proportion graph. The effects were tested of multiple free-thawing of sperm in either a commercial egg yolk extender, 40 mM Tris buffer with 8% glycerol, or 40 mM Tris buffer without glycerol. Freeze-thawing in extender did not affect the dissociation constant or the concentration of binding sites. However, freeze-thawing three times in 40 mM Tris reduced the concentration of binding sites and lowered the dissociation constant (raised the affinity). The inclusion of glycerol in the 40 mM Tris did not significantly affect the estimated dissociation constant or the concentration of binding sites as compared to 40 mM Tris without glycerol

  9. Human DC-SIGN Binds Specific Human Milk Glycans

    Science.gov (United States)

    Noll, Alexander J.; Yu, Ying; Lasanajak, Yi; Duska-McEwen, Geralyn; Buck, Rachael H.; Smith, David F.; Cummings, Richard D.

    2016-01-01

    Human milk glycans (HMGs) are prebiotics, pathogen receptor decoys, and regulators of host physiology and immune responses. Mechanistically, human lectins (glycan-binding proteins, hGBPs) expressed by dendritic cells (DC) are of major interest, as these cells directly contact HMGs. To explore such interactions, we screened many C-type lectins and Siglecs expressed by DC for glycan binding on microarrays presenting over 200 HMGs. Unexpectedly, DC-SIGN showed robust binding to many HMGs, whereas other C-type lectins failed to bind, and Siglecs-5 and -9 showed weak binding to a few glycans. By contrast, most hGBPs bound to multiple glycans on other microarrays lacking HMGs. An α-linked fucose residue was characteristic of HMGs bound by DC-SIGN. Binding of DC-SIGN to the simple HMGs 2′-fucosyllactose (2′-FL) and 3-fucosyllactose (3-FL) was confirmed by flow cytometry to beads conjugated with 2′-FL or 3-FL, as well as the ability of the free glycans to inhibit DC-SIGN binding. 2′-FL had an IC50 of ~1 mM for DC-SIGN, which is within the physiological concentration of 2′-FL in human milk. These results demonstrate that DC-SIGN among the many hGBPs expressed by DC binds to α-fucosylated HMGs, and suggest that such interactions may be important in influencing immune responses in the developing infant. PMID:26976925

  10. Structural modeling for DNA binding to antioxidants resveratrol, genistein and curcumin.

    Science.gov (United States)

    N'soukpoé-Kossi, C N; Bourassa, P; Mandeville, J S; Bekale, L; Tajmir-Riahi, H A

    2015-10-01

    Several models are presented here for the bindings of the antioxidant polyphenols resveratrol, genistein and curcumin with DNA in aqueous solution at physiological conditions. Multiple spectroscopic methods and molecular modeling were used to locate the binding sites of these polyphenols with DNA duplex. Structural models showed that intercalation is more stable for resveratrol and genistein than groove bindings, while curcumin interaction is via DNA grooves. Docking showed more stable complexes formed with resveratrol and genistein than curcumin with the free binding energies of -4.62 for resveratrol-DNA (intercalation), -4.28 for resveratrol-DNA (groove binding), -4.54 for genistein-DNA (intercalation), -4.38 for genistein-DNA (groove binding) and -3.84 kcal/mol for curcumin-DNA (groove binding). The free binding energies show polyphenol-DNA complexation is spontaneous at room temperature. At high polyphenol concentration a major DNA aggregation occurred, while biopolymer remained in B-family structure. PMID:26188387

  11. Megalin binds and mediates cellular internalization of folate binding protein

    DEFF Research Database (Denmark)

    Birn, Henrik; Zhai, Xiaoyue; Holm, Jan;

    2005-01-01

    Folate is an essential vitamin involved in a number of biological processes. High affinity folate binding proteins (FBPs) exist both as glycosylphosphatidylinositol-linked, membrane associated folate binding proteins and as soluble FBPs in plasma and some secretory fluids such as milk, saliva...... to bind and mediate cellular uptake of FBP. Surface plasmon resonance analysis shows binding of bovine and human milk FBP to immobilized megalin, but not to low density lipoprotein receptor related protein. Binding of (125)I-labeled folate binding protein (FBP) to sections of kidney proximal tubule, known...... to express high levels of megalin, is inhibitable by excess unlabeled FBP and by receptor associated protein, a known inhibitor of binding to megalin. Immortalized rat yolk sac cells, representing an established model for studying megalin-mediated uptake, reveal (125)I-labeled FBP uptake which is inhibited...

  12. Carboplatin binding to histidine

    Energy Technology Data Exchange (ETDEWEB)

    Tanley, Simon W. M. [University of Manchester, Brunswick Street, Manchester M13 9PL (United Kingdom); Diederichs, Kay [University of Konstanz, D-78457 Konstanz (Germany); Kroon-Batenburg, Loes M. J. [Utrecht University, Padualaan 8, 3584 CH Utrecht (Netherlands); Levy, Colin [University of Manchester, 131 Princess Street, Manchester M1 7DN (United Kingdom); Schreurs, Antoine M. M. [Utrecht University, Padualaan 8, 3584 CH Utrecht (Netherlands); Helliwell, John R., E-mail: john.helliwell@manchester.ac.uk [University of Manchester, Brunswick Street, Manchester M13 9PL (United Kingdom)

    2014-08-29

    An X-ray crystal structure showing the binding of purely carboplatin to histidine in a model protein has finally been obtained. This required extensive crystallization trials and various novel crystal structure analyses. Carboplatin is a second-generation platinum anticancer agent used for the treatment of a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine (in hen egg-white lysozyme; HEWL) showed the partial conversion of carboplatin to cisplatin owing to the high NaCl concentration used in the crystallization conditions. HEWL co-crystallizations with carboplatin in NaBr conditions have now been carried out to confirm whether carboplatin converts to the bromine form and whether this takes place in a similar way to the partial conversion of carboplatin to cisplatin observed previously in NaCl conditions. Here, it is reported that a partial chemical transformation takes place but to a transplatin form. Thus, to attempt to resolve purely carboplatin binding at histidine, this study utilized co-crystallization of HEWL with carboplatin without NaCl to eliminate the partial chemical conversion of carboplatin. Tetragonal HEWL crystals co-crystallized with carboplatin were successfully obtained in four different conditions, each at a different pH value. The structural results obtained show carboplatin bound to either one or both of the N atoms of His15 of HEWL, and this particular variation was dependent on the concentration of anions in the crystallization mixture and the elapsed time, as well as the pH used. The structural details of the bound carboplatin molecule also differed between them. Overall, the most detailed crystal structure showed the majority of the carboplatin atoms bound to the platinum centre; however, the four-carbon ring structure of the cyclobutanedicarboxylate moiety (CBDC) remained elusive. The potential impact of the results for the administration of carboplatin as an anticancer agent are described.

  13. Iron Mineralogy and Uranium-Binding Environment in the Rhizosphere of a Wetland Soil

    Science.gov (United States)

    Wetlands mitigate the migration of groundwater contaminants through a series of biogeochemical gradients that enhance multiple contaminant-binding processes. The hypothesis of this study was that wetland plant roots contribute organic carbon and release O2 within the ...

  14. Complement Component C3 Binds to Activated Normal Platelets without Preceding Proteolytic Activation and Promotes Binding to Complement Receptor 1

    NARCIS (Netherlands)

    O.A. Hamad; P.H. Nilsson; D. Wouters; J.D. Lambris; K.N. Ekdahl; B. Nilsson

    2010-01-01

    It has been reported that complement is activated on the surface of activated platelets, despite the presence of multiple regulators of complement activation. To reinvestigate the mechanisms by which activated platelets bind to complement components, the presence of complement proteins on the surfac

  15. Visually Relating Gene Expression and in vivo DNA Binding Data

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Min-Yu; Mackey, Lester; Ker?,; nen, Soile V. E.; Weber, Gunther H.; Jordan, Michael I.; Knowles, David W.; Biggin, Mark D.; Hamann, Bernd

    2011-09-20

    Gene expression and in vivo DNA binding data provide important information for understanding gene regulatory networks: in vivo DNA binding data indicate genomic regions where transcription factors are bound, and expression data show the output resulting from this binding. Thus, there must be functional relationships between these two types of data. While visualization and data analysis tools exist for each data type alone, there is a lack of tools that can easily explore the relationship between them. We propose an approach that uses the average expression driven by multiple of ciscontrol regions to visually relate gene expression and in vivo DNA binding data. We demonstrate the utility of this tool with examples from the network controlling early Drosophila development. The results obtained support the idea that the level of occupancy of a transcription factor on DNA strongly determines the degree to which the factor regulates a target gene, and in some cases also controls whether the regulation is positive or negative.

  16. Interference of peptides and specific antibodies with the function of the Actinobacillus pleuropneumoniae transferrin-binding protein.

    OpenAIRE

    Strutzberg, K; Franz, B.; Gerlach, G F

    1997-01-01

    Multiple-antigenic peptides (MAPs) containing transferrin-binding domains of the Actinobacillus pleuropneumoniae serotype 7-derived transferrin-binding protein (TfbA) (K. Strutzberg, L. von Olleschik, B. Franz, C. Pyne, M. A. Schmidt, and G.-F. Gerlach, Infect. Immun. 63:3846-3850, 1995) were constructed. It was found that the MAPs inhibited transferrin binding of the recombinant TfbA protein, whereas antibodies directed against transferrin-binding domains failed to do so.

  17. Human pentraxin 3 binds to the complement regulator c4b-binding protein.

    Directory of Open Access Journals (Sweden)

    Anne Braunschweig

    Full Text Available The long pentraxin 3 (PTX3 is a soluble recognition molecule with multiple functions including innate immune defense against certain microbes and the clearance of apoptotic cells. PTX3 interacts with recognition molecules of the classical and lectin complement pathways and thus initiates complement activation. In addition, binding of PTX3 to the alternative complement pathway regulator factor H was shown. Here, we show that PTX3 binds to the classical and lectin pathway regulator C4b-binding protein (C4BP. A PTX3-binding site was identified within short consensus repeats 1-3 of the C4BP α-chain. PTX3 did not interfere with the cofactor activity of C4BP in the fluid phase and C4BP maintained its complement regulatory activity when bound to PTX3 on surfaces. While C4BP and factor H did not compete for PTX3 binding, the interaction of C4BP with PTX3 was inhibited by C1q and by L-ficolin. PTX3 bound to human fibroblast- and endothelial cell-derived extracellular matrices and recruited functionally active C4BP to these surfaces. Whereas PTX3 enhanced the activation of the classical/lectin pathway and caused enhanced C3 deposition on extracellular matrix, deposition of terminal pathway components and the generation of the inflammatory mediator C5a were not increased. Furthermore, PTX3 enhanced the binding of C4BP to late apoptotic cells, which resulted in an increased rate of inactivation of cell surface bound C4b and a reduction in the deposition of C5b-9. Thus, in addition to complement activators, PTX3 interacts with complement inhibitors including C4BP. This balanced interaction on extracellular matrix and on apoptotic cells may prevent excessive local complement activation that would otherwise lead to inflammation and host tissue damage.

  18. Analytic QCD Binding Potentials

    CERN Document Server

    Fried, H M; Grandou, T; Sheu, Y -M

    2011-01-01

    This paper applies the analytic forms of a recent non-perturbative, manifestly gauge- and Lorentz-invariant description (of the exchange of all possible virtual gluons between quarks ($Q$) and/or anti-quarks ($\\bar{Q}$) in a quenched, eikonal approximation) to extract analytic forms for the binding potentials generating a model $Q$-$\\bar{Q}$ "pion", and a model $QQQ$ "nucleon". Other, more complicated $Q$, $\\bar{Q}$ contributions to such color-singlet states may also be identified analytically. An elementary minimization technique, relevant to the ground states of such bound systems, is adopted to approximate the solutions to a more proper, but far more complicated Schroedinger/Dirac equation; the existence of possible contributions to the pion and nucleon masses due to spin, angular momentum, and "deformation" degrees of freedom is noted but not pursued. Neglecting electromagnetic and weak interactions, this analysis illustrates how the one new parameter making its appearance in this exact, realistic formali...

  19. On Multiplicative Fractional Calculus

    OpenAIRE

    Abdeljawad, Thabet

    2015-01-01

    We set the main concepts for multiplicative fractional calculus. We define Caputo, Riemann and Letnikov multiplicative fractional derivatives and multiplicative fractional integrals and study some of their properties. Finally, the multiplicative analogue of the local conformable fractional derivative and integral is studied.

  20. Binding modes of thrombin binding aptamers investigated by simulations and experiments

    Science.gov (United States)

    Trapaidze, A.; Bancaud, A.; Brut, M.

    2015-01-01

    Thrombin binding aptamers HD1 and HD22 are the most studied aptamers, both for therapeutic and sensing purposes. Yet, there is still no commercialized aptamer-based sensor device for thrombin detection, suggesting that the binding modes of these aptamers remain to be precisely described. Here, we investigate thrombin-aptamer interactions with molecular dynamics simulations, and show that the different solved structures of HD1-thrombin complex are energetically similar and consequently possibly co-existing. Conversely, HD22 folding is much more stable, and its binding energy with thrombin is significantly larger than that of HD1 complexes. These results are confronted to experiments, which consist in monitoring aggregation of aptamer-functionalized gold nanoparticles triggered by thrombin. HD1 alone, but not HD22, can trigger aggregation, meaning that this aptamer has multiple sites of interactions with thrombin. Furthermore, pre-incubation of HD22 with thrombin impedes HD1 aggregation, suggesting that HD1 and HD22 have competing affinities for the same binding site. Altogether, this study shows that the characterization of aptamer-thrombin interactions by structural and kinetic experiments joined to simulations is necessary for the development of biosensors.

  1. Quarkonium Binding and Entropic Force

    CERN Document Server

    Satz, Helmut

    2015-01-01

    A Q-Qbar bound state represents a balance between repulsive kinetic and attractive potential energy. In a hot quark-gluon plasma, the interaction potential experiences medium effects. Color screening modifies the attractive binding force between the quarks, while the increase of entropy with Q-Qbar separation gives rise to a growing repulsion. We study the role of these phenomena for in-medium Q-Qbar binding and dissociation. It is found that the relevant potential for Q-Qbar binding is the free energy F; with increasing Q-Qbar separation, further binding through the internal energy U is compensated by repulsive entropic effects.

  2. HTLV-1 Tax Protein Stimulation of DNA Binding of bZIP Proteins by Enhancing Dimerization

    Science.gov (United States)

    Wagner, Susanne; Green, Michael R.

    1993-10-01

    The Tax protein of human T cell leukemia virus type-1 (HTLV-I) transcriptionally activates the HTLV-I promoter. This activation requires binding sites for activating transcription factor (ATF) proteins, a family of cellular proteins that contain basic region-leucine zipper (bZIP) DNA binding domains. Data are presented showing that Tax increases the in vitro DNA binding activity of multiple ATF proteins. Tax also stimulated DNA binding by other bZIP proteins, but did not affect DNA binding proteins that lack a bZIP domain. The increase in DNA binding occurred because Tax promotes dimerization of the bZIP domain in the absence of DNA, and the elevated concentration of the bZIP homodimer then facilitates the DNA binding reaction. These results help explain how Tax activates viral transcription and transforms cells.

  3. Inhibition of RNA Polymerase II Transcription in Human Cells by Synthetic DNA-Binding Ligands

    Science.gov (United States)

    Dickinson, Liliane A.; Gulizia, Richard J.; Trauger, John W.; Baird, Eldon E.; Mosier, Donald E.; Gottesfeld, Joel M.; Dervan, Peter B.

    1998-10-01

    Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole--imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-1, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity. The ability of small molecules to target predetermined DNA sequences located with RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication.

  4. Human DC-SIGN binds specific human milk glycans.

    Science.gov (United States)

    Noll, Alexander J; Yu, Ying; Lasanajak, Yi; Duska-McEwen, Geralyn; Buck, Rachael H; Smith, David F; Cummings, Richard D

    2016-05-15

    Human milk glycans (HMGs) are prebiotics, pathogen receptor decoys and regulators of host physiology and immune responses. Mechanistically, human lectins (glycan-binding proteins, hGBP) expressed by dendritic cells (DCs) are of major interest, as these cells directly contact HMGs. To explore such interactions, we screened many C-type lectins and sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed by DCs for glycan binding on microarrays presenting over 200 HMGs. Unexpectedly, DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) showed robust binding to many HMGs, whereas other C-type lectins failed to bind, and Siglec-5 and Siglec-9 showed weak binding to a few glycans. By contrast, most hGBP bound to multiple glycans on other microarrays lacking HMGs. An α-linked fucose residue was characteristic of HMGs bound by DC-SIGN. Binding of DC-SIGN to the simple HMGs 2'-fucosyl-lactose (2'-FL) and 3-fucosyl-lactose (3-FL) was confirmed by flow cytometry to beads conjugated with 2'-FL or 3-FL, as well as the ability of the free glycans to inhibit DC-SIGN binding. 2'-FL had an IC50 of ∼1 mM for DC-SIGN, which is within the physiological concentration of 2'-FL in human milk. These results demonstrate that DC-SIGN among the many hGBP expressed by DCs binds to α-fucosylated HMGs, and suggest that such interactions may be important in influencing immune responses in the developing infant. PMID:26976925

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

    Directory of Open Access Journals (Sweden)

    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

  6. Binding Energy and Enzymatic Catalysis.

    Science.gov (United States)

    Hansen, David E.; Raines, Ronald T.

    1990-01-01

    Discussed is the fundamental role that the favorable free energy of binding of the rate-determining transition state plays in catalysis. The principle that all of the catalytic factors discussed are realized by the use of this binding energy is reviewed. (CW)

  7. Evolution of the acyl-CoA binding protein (ACBP)

    DEFF Research Database (Denmark)

    Burton, Mark; Rose, Timothy M; Faergeman, Nils J;

    2005-01-01

    Acyl-CoA-binding protein (ACBP) is a 10 kDa protein that binds C12-C22 acyl-CoA esters with high affinity. In vitro and in vivo experiments suggest that it is involved in multiple cellular tasks including modulation of fatty acid biosynthesis, enzyme regulation, regulation of the intracellular ac......-specific paralogues have evolved altered functions. The appearance of ACBP very early on in evolution points towards a fundamental role of ACBP in acyl-CoA metabolism, including ceramide synthesis and in signalling....

  8. Multiple-Ring Digital Communication Network

    Science.gov (United States)

    Kirkham, Harold

    1992-01-01

    Optical-fiber digital communication network to support data-acquisition and control functions of electric-power-distribution networks. Optical-fiber links of communication network follow power-distribution routes. Since fiber crosses open power switches, communication network includes multiple interconnected loops with occasional spurs. At each intersection node is needed. Nodes of communication network include power-distribution substations and power-controlling units. In addition to serving data acquisition and control functions, each node acts as repeater, passing on messages to next node(s). Multiple-ring communication network operates on new AbNET protocol and features fiber-optic communication.

  9. Binding of [125I] Concanavalin A to isolated Langerhans islets of rats

    International Nuclear Information System (INIS)

    Langerhans islets of rats were isolated using Lacy's collagenase technique and were incubated in vitro. The binding of iodine-labelled Concanavalin A to isolated Langerhans islets was investigated. We were unable to decide whether multiple Concanavalin A binding sites are located on the cell membrane, or whether the Concanavalin A binding sites are negatively influenced via a allosteric protein. Although the secretion mechanism induced by sulfony urea is not influenced by Concanavalin A, enhanced binding of Concanavalin A indicates that the region of identification cannot be identical for glucose and sulfonyl urea. (orig./MG)

  10. Generalized internal multiple imaging

    KAUST Repository

    Zuberi, Mohammad Akbar Hosain

    2014-12-04

    Various examples are provided for generalized internal multiple imaging (GIMI). In one example, among others, a method includes generating a higher order internal multiple image using a background Green\\'s function and rendering the higher order internal multiple image for presentation. In another example, a system includes a computing device and a generalized internal multiple imaging (GIMI) application executable in the computing device. The GIMI application includes logic that generates a higher order internal multiple image using a background Green\\'s function and logic that renders the higher order internal multiple image for display on a display device. In another example, a non-transitory computer readable medium has a program executable by processing circuitry that generates a higher order internal multiple image using a background Green\\'s function and renders the higher order internal multiple image for display on a display device.

  11. National Multiple Sclerosis Society

    Science.gov (United States)

    ... Join the Community Stay Informed Corporate Support National Multiple Sclerosis Society Our Mission: People affected by MS can ... 10.5 Million in New Research to Stop Multiple Sclerosis, Restore Function and End MS Forever October 11, ...

  12. Challenges of Parenting Multiples

    Science.gov (United States)

    ... the American Society for Reproductive Medicine Challenges of Parenting Multiples There are many psychological, social, and economic ... the unique challenges and rewards that come from parenting multiples. For more information on the medical aspects ...

  13. Caring for Multiples

    Science.gov (United States)

    ... labor & premature birth The newborn intensive care unit (NICU) Birth defects & other health conditions Loss & grief Tools & ... Home > Complications & Loss > The newborn intensive care unit (NICU) > Caring for multiples Caring for multiples E-mail ...

  14. Depression and Multiple Sclerosis

    Science.gov (United States)

    Depression - National Multiple Sclerosis Society Skip to navigation Skip to content Menu Navigation National Multiple Sclerosis Society ... Twitter Email Home Symptoms & Diagnosis MS Symptoms Depression Depression Share Smaller Text Larger Text Print In this ...

  15. Multiple Mucosal Neuroma Syndrome

    Directory of Open Access Journals (Sweden)

    Thami Gurvinder P

    1997-01-01

    Full Text Available A case of multiple mucosal neuroma syndrome recently classified as Multiple Endocrinal Neoplasia (MEN, type 2b, is reported for its rarity and importance of diagnosis at an early age.

  16. ALICE Forward Multiplicity Detector

    CERN Multimedia

    Christensen, C

    2013-01-01

    The Forward Multiplicity Detector (FMD) extends the coverage for multiplicity of charge particles into the forward regions - giving ALICE the widest coverage of the 4 LHC experiments for these measurements.

  17. Fatigue and Multiple Sclerosis

    Science.gov (United States)

    Fatigue - National Multiple Sclerosis Society Skip to navigation Skip to content Menu Navigation National Multiple Sclerosis Society ... Twitter Email Home Symptoms & Diagnosis MS Symptoms Fatigue Fatigue Share Smaller Text Larger Text Print In this ...

  18. Drosophila Stathmins Bind Tubulin Heterodimers with High and Variable Stoichiometries*

    Science.gov (United States)

    Lachkar, Sylvie; Lebois, Marion; Steinmetz, Michel O.; Guichet, Antoine; Lal, Neha; Curmi, Patrick A.; Sobel, André; Ozon, Sylvie

    2010-01-01

    In vertebrates, stathmins form a family of proteins possessing two tubulin binding repeats (TBRs), which each binds one soluble tubulin heterodimer. The stathmins thus sequester two tubulins in a phosphorylation-dependent manner, providing a link between signal transduction and microtubule dynamics. In Drosophila, we show here that a single stathmin gene (stai) encodes a family of D-stathmin proteins. Two of the D-stathmins are maternally deposited and then restricted to germ cells, and the other two are detected in the nervous system during embryo development. Like in vertebrates, the nervous system-enriched stathmins contain an N-terminal domain involved in subcellular targeting. All the D-stathmins possess a domain containing three or four predicted TBRs, and we demonstrate here, using complementary biochemical and biophysical methods, that all four predicted TBR domains actually bind tubulin. D-stathmins can indeed bind up to four tubulins, the resulting complex being directly visualized by electron microscopy. Phylogenetic analysis shows that the presence of regulated multiple tubulin sites is a conserved characteristic of stathmins in invertebrates and allows us to predict key residues in stathmin for the binding of tubulin. Altogether, our results reveal that the single Drosophila stathmin gene codes for a stathmin family similar to the multigene vertebrate one, but with particular tubulin binding properties. PMID:20145240

  19. Drosophila stathmins bind tubulin heterodimers with high and variable stoichiometries.

    Science.gov (United States)

    Lachkar, Sylvie; Lebois, Marion; Steinmetz, Michel O; Guichet, Antoine; Lal, Neha; Curmi, Patrick A; Sobel, André; Ozon, Sylvie

    2010-04-01

    In vertebrates, stathmins form a family of proteins possessing two tubulin binding repeats (TBRs), which each binds one soluble tubulin heterodimer. The stathmins thus sequester two tubulins in a phosphorylation-dependent manner, providing a link between signal transduction and microtubule dynamics. In Drosophila, we show here that a single stathmin gene (stai) encodes a family of D-stathmin proteins. Two of the D-stathmins are maternally deposited and then restricted to germ cells, and the other two are detected in the nervous system during embryo development. Like in vertebrates, the nervous system-enriched stathmins contain an N-terminal domain involved in subcellular targeting. All the D-stathmins possess a domain containing three or four predicted TBRs, and we demonstrate here, using complementary biochemical and biophysical methods, that all four predicted TBR domains actually bind tubulin. D-stathmins can indeed bind up to four tubulins, the resulting complex being directly visualized by electron microscopy. Phylogenetic analysis shows that the presence of regulated multiple tubulin sites is a conserved characteristic of stathmins in invertebrates and allows us to predict key residues in stathmin for the binding of tubulin. Altogether, our results reveal that the single Drosophila stathmin gene codes for a stathmin family similar to the multigene vertebrate one, but with particular tubulin binding properties. PMID:20145240

  20. Multiple Indicators, Multiple Causes Measurement Error Models

    OpenAIRE

    Tekwe, Carmen D.; Carter, Randy L.; Cullings, Harry M.; Carroll, Raymond J.

    2014-01-01

    Multiple Indicators, Multiple Causes Models (MIMIC) are often employed by researchers studying the effects of an unobservable latent variable on a set of outcomes, when causes of the latent variable are observed. There are times however when the causes of the latent variable are not observed because measurements of the causal variable are contaminated by measurement error. The objectives of this paper are: (1) to develop a novel model by extending the classical linear MIMIC model to allow bot...

  1. MUPEMURE - Multiple Perspectives on Multiple Representations

    OpenAIRE

    Weinberger, Armin; Bodemer, Daniel; Kapur, Manu; Molinari, Gaëlle; Rummel, Nikol

    2011-01-01

    A large body of research has been concerned with learners' difficulties to detect and avoid misconceptions and to construct relations between multiple representations for building coherent mental representations of STEM topics. Moreover, much research has been invested in the questions of how to choose the optimal representation of knowledge to optimize cognitive load and how to design multiple representations for learning purposes. MUPEMURE builds on this work and takes it further by asking ...

  2. [3]tetrahydrotrazodone binding. Association with serotonin binding sites

    International Nuclear Information System (INIS)

    High (17 nM) and low (603 nM) affinity binding sites for [3]tetrahydrotrazodone ([3] THT), a biologically active analogue of trazodone, have been identified in rat brain membranes. The substrate specificity, concentration, and subcellular and regional distributions of these sites suggest that they may represent a component of the serotonin transmitter system. Pharmacological analysis of [3]THT binding, coupled with brain lesion and drug treatment experiments, revealed that, unlike other antidepressants, [3] THT does not attach to either a biogenic amine transporter or serotonin binding sites. Rather, it would appear that [3]THT may be an antagonist ligand for the serotonin binding site. This probe may prove of value in defining the mechanism of action of trazodone and in further characterizing serotonin receptors

  3. Influence of multiple ionization in laser filamentation

    International Nuclear Information System (INIS)

    Laser filaments in gases result from the nonlinear balance between optical Kerr self-focusing and plasma generation in the single ionization limit, i.e., the pulse intensity is supposed to remain moderate enough (∼1014 W cm−2) to apply photo-ionization theories valid for an averaged ion charge less than unity. However, no theory has attempted so far to consider how an ionization model allowing a priori multiple-charged states could impact the standard filamentation scenario. Here, we discuss a multiple photo-ionization scheme that relies on probabilities assuming successive single-electron ionizations. We numerically show that a multiple ionization scheme can increase the clamping intensity, the peak electron density and supercontinuum generation in gases with high binding energy, e.g., helium. (paper)

  4. The PUF binding landscape in metazoan germ cells

    Science.gov (United States)

    Prasad, Aman; Porter, Douglas F.; Kroll-Conner, Peggy L.; Mohanty, Ipsita; Ryan, Anne R.; Crittenden, Sarah L.; Wickens, Marvin; Kimble, Judith

    2016-01-01

    PUF (Pumilio/FBF) proteins are RNA-binding proteins and conserved stem cell regulators. The Caenorhabditis elegans PUF proteins FBF-1 and FBF-2 (collectively FBF) regulate mRNAs in germ cells. Without FBF, adult germlines lose all stem cells. A major gap in our understanding of PUF proteins, including FBF, is a global view of their binding sites in their native context (i.e., their “binding landscape”). To understand the interactions underlying FBF function, we used iCLIP (individual-nucleotide resolution UV crosslinking and immunoprecipitation) to determine binding landscapes of C. elegans FBF-1 and FBF-2 in the germline tissue of intact animals. Multiple iCLIP peak-calling methods were compared to maximize identification of both established FBF binding sites and positive control target mRNAs in our iCLIP data. We discovered that FBF-1 and FBF-2 bind to RNAs through canonical as well as alternate motifs. We also analyzed crosslinking-induced mutations to map binding sites precisely and to identify key nucleotides that may be critical for FBF–RNA interactions. FBF-1 and FBF-2 can bind sites in the 5′UTR, coding region, or 3′UTR, but have a strong bias for the 3′ end of transcripts. FBF-1 and FBF-2 have strongly overlapping target profiles, including mRNAs and noncoding RNAs. From a statistically robust list of 1404 common FBF targets, 847 were previously unknown, 154 were related to cell cycle regulation, three were lincRNAs, and 335 were shared with the human PUF protein PUM2. PMID:27165521

  5. Membrane binding of Neuronal Calcium Sensor-1 (NCS1).

    Science.gov (United States)

    Lemire, Samuel; Jeromin, Andreas; Boisselier, Élodie

    2016-03-01

    Neuronal Calcium Sensor-1 (NCS1) belongs to the family of Neuronal Calcium Sensor (NCS) proteins. NCS1 is composed of four EF-hand motifs and an N-terminal myristoylation. However, the presence of a calcium-myristoyl switch in NCS1 and its role in the membrane binding are controversial. The model of Langmuir lipid monolayers is thus used to mimic the cell membrane in order to characterize the membrane interactions of NCS1. Two binding parameters are calculated from monolayer measurements: the maximum insertion pressure, up to which protein binding is energetically favorable, and the synergy, reporting attractive or repulsive interactions with the lipid monolayers. Binding membrane measurements performed in the presence of myristoylated NCS1 reveal better binding interactions for phospholipids composed of phosphoethanolamine polar head groups and unsaturated fatty acyl chains. In the absence of calcium, the membrane binding measurements are drastically modified and suggest that the protein is more strongly bound to the membrane. Indeed, the binding of calcium by three EF-hand motifs of NCS1 leads to a conformation change. NCS1 arrangement at the membrane could thus be reshuffled for better interactions with its substrates. The N-terminal peptide of NCS1 is composed of two amphiphilic helices involved in the membrane interactions of NCS1. Moreover, the presence of the myristoyl group has a weak influence on the membrane binding of NCS1 suggesting the absence of a calcium-myristoyl switch mechanism in this protein. The myristoylation could thus have a structural role required in the folding/unfolding of NCS1 which is essential to its multiple biological functions.

  6. 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

  7. Characterization of the target DNA sequence for the DNA-binding domain of zinc finger protein 191

    Institute of Scientific and Technical Information of China (English)

    Haoyue Wang; Ruilin Sun; Guoxiang Liu; Minghui Yao; Jian Fei; Hebai Shen

    2008-01-01

    Studies on the DNA-binding properties of transcription factors are important in searching for the downstream genes regulated by these factors. In the present study, we report on the DNA-binding property of a Cys2His2-type transcription factor, zinc finger protein 191 (Zfp191), which has been newly found to play a significant role in mice.By constructing a fusion protein containing the DNA-binding domain of Zfp191,we characterized target DNA by determining the protein's binding specificity and dependence on zinc.The data showed that the DNA-binding domain of Zfp191can specifically bind to the TCAT repeat motif and that there is a cooperative effect among the target DNA's multiple binding sites.Furthermore,the binding reaction is dependent on zinc.This work provides a foundation for further studies on the role of Zfp191 in gene regulation and development.

  8. Structural studies of sugar binding proteins

    OpenAIRE

    Sooriyaarachchi, Sanjeewani

    2010-01-01

    Binding proteins, which are themselves non-enzymatic, play an important role in enzymatic reactions as well as non-enzymatic processes by providing a binding platform for the specific recognition of particular molecules. For example, periplasmic binding proteins play a vital role in nutrient uptake in Gram-negative bacteria. In the present study, three sugar binding proteins, including two periplasmic binding proteins and a β-glucan binding protein, are described. The glucose/galactose bindin...

  9. Stability and Sugar Recognition Ability of Ricin-Like Carbohydrate Binding Domains

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Jianzhuang [ORNL; Nellas, Ricky B [ORNL; Glover, Mary M [ORNL; Shen, Tongye [ORNL

    2011-01-01

    Lectins are a class of proteins known for their novel binding to saccharides. Understanding this sugar recognition process can be crucial in creating structure-based designs of proteins with various biological roles. We focus on the sugar binding of a particular lectin, ricin, which has two -trefoil carbohydrate-binding domains (CRDs) found in several plant protein toxins. The binding ability of possible sites of ricin-like CRD has been puzzling. The apo and various (multiple) ligand-bound forms of the sugar-binding domains of ricin were studied by molecular dynamics simulations. By evaluating structural stability, hydrogen bond dynamics, flexibility, and binding energy, we obtained a detailed picture of the sugar recognition of the ricin-like CRD. Unlike what was previously believed, we found that the binding abilities of the two known sites are not independent of each other. The binding ability of one site is positively affected by the other site. While the mean positions of different binding scenarios are not altered significantly, the flexibility of the binding pockets visibly decreases upon multiple ligand binding. This change in flexibility seems to be the origin of the binding cooperativity. All the hydrogen bonds that are strong in the monoligand state are also strong in the double-ligand complex, although the stability is much higher in the latter form due to cooperativity. These strong hydrogen bonds in a monoligand state are deemed to be the essential hydrogen bonds. Furthermore, by examining the structural correlation matrix, the two domains are structurally one entity. Galactose hydroxyl groups, OH4 and OH3, are the most critical parts in both site 1 and site 2 recognition.

  10. Multiple Myeloma and Diabetes

    OpenAIRE

    Azar, Sami T.; Mira S. Zantout; Zeinab A. Issa

    2011-01-01

    Multiple myeloma is a malignant plasma cell disorder that accounts for approximately 10% of all hematologic cancers. It is characterized by accumulation of clonal plasma cells, predominantly in the bone marrow. The prevalence of type 2 diabetes is increasing; therefore, it is expected that there will be an increase in the diagnosis of multiple myeloma with concomitant diabetes mellitus. The treatment of multiple myeloma and diabetes mellitus is multifaceted. The coexistence of the two conditi...

  11. Complex Multiplicative Calculus

    OpenAIRE

    Bashirov, Agamirza; Riza, Mustafa

    2011-01-01

    In the present paper we extend the concepts of multiplicative de- rivative and integral to complex-valued functions of complex variable. Some drawbacks, arising with these concepts in the real case, are explained satis- factorily. Properties of complex multiplicative derivatives and integrals are studied. In particular, the fundamental theorem of complex multiplicative calculus, relating these concepts, is proved. It is shown that complex multi- plicative calculus is not just another realizat...

  12. Analysis of xylosyltransferase II binding to the anticoagulant heparin

    Energy Technology Data Exchange (ETDEWEB)

    Casanova, Javier Carrera; Ambrosius, Michael; Kuhn, Joachim; Kleesiek, Knut [Institut fuer Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitaetsklinik der Ruhr-Universitaet Bochum, Georgstrasse 11, 32545 Bad Oeynhausen (Germany); Goetting, Christian, E-mail: cgoetting@hdz-nrw.de [Institut fuer Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitaetsklinik der Ruhr-Universitaet Bochum, Georgstrasse 11, 32545 Bad Oeynhausen (Germany)

    2009-05-22

    The key enzymes in the biosynthetic pathway of glycosaminoglycan production are represented by the human xylosyltransferase I and its isoform II (XylT-I and XylT-II). The glycosaminoglycan heparin interacts with a variety of proteins, thereby regulating their activities, also those of xylosyltransferases. The identification of unknown amino acids responsible for heparin-binding of XylT-II was addressed in this study. Thus, six XylT-II fragments were designed as fusion proteins with MBP and we received soluble and purified MBP/XylT-II from Escherichia coli. Heparin-binding studies showed that all fragments bound with low affinity to heparin. Prolonging of XylT-II fragments did not account for a cooperative effect of multiple heparin-binding motifs and in turn for a stronger heparin-binding. Sequence alignment and surface polarity plot led to the identification of two highly positively charged Cardin-Weintraub motifs with surface accessibility, resulting in combination with short clusters of basic amino acids for strong heparin-binding of native xylosyltransferases.

  13. Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin.

    Science.gov (United States)

    Sviripa, Vitaliy M; Burikhanov, Ravshan; Obiero, Josiah M; Yuan, Yaxia; Nickell, Justin R; Dwoskin, Linda P; Zhan, Chang-Guo; Liu, Chunming; Tsodikov, Oleg V; Rangnekar, Vivek M; Watt, David S

    2016-01-01

    Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or "arylquins" induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner. A structure-activity study identified arylquins that promote Par-4 secretion, and an evaluation of arylquin binding to the hERG potassium ion channel using a [(3)H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par-4 secretory activity. A binding study that relied on the natural fluorescence of arylquins and that used the purified rod domain of vimentin (residues 99-411) suggested that the mechanism behind Par-4 release involved arylquin binding to multiple sites in the rod domain.

  14. Statistical mechanical model of coupled transcription from multiple promoters due to transcription factor titration

    OpenAIRE

    Rydenfelt, Mattias; Cox, Robert Sidney; Garcia, Hernan; Phillips, Rob

    2014-01-01

    Transcription factors (TFs) with regulatory action at multiple promoter targets is the rule rather than the exception, with examples ranging from the cAMP receptor protein (CRP) in E. coli that regulates hundreds of different genes simultaneously to situations involving multiple copies of the same gene, such as plasmids, retrotransposons, or highly replicated viral DNA. When the number of TFs heavily exceeds the number of binding sites, TF binding to each promoter can be regarded as independe...

  15. Measuring and evaluating interferon beta-induced antibodies in patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Ross, C; Clemmesen, K M; Sørensen, P S;

    2006-01-01

    Administration of interferons (IFNs) may induce antibodies that interfere with therapeutic efficacy. We have optimized and validated methods for large-scale economic screening. Sera from patients with relapsing-remitting multiple sclerosis (MS) were investigated for binding antibody (BAb) by prot......Administration of interferons (IFNs) may induce antibodies that interfere with therapeutic efficacy. We have optimized and validated methods for large-scale economic screening. Sera from patients with relapsing-remitting multiple sclerosis (MS) were investigated for binding antibody (BAb...

  16. Identification of High Affinity Fatty Acid Binding Sites on Human Serum Albumin by MM-PBSA Method

    OpenAIRE

    Fujiwara, Shin-ichi; Amisaki, Takashi

    2007-01-01

    Human serum albumin (HSA) has seven common fatty acid (FA) binding sites. In this study, we used the molecular mechanics Poisson-Boltzmann surface area method to identify high affinity FA binding sites on HSA in terms of binding free energy. Using multiple HSA-FA (myristate, palmitate) complex models constructed by molecular dynamics simulations, two methods were performed in molecular mechanics Poisson-Boltzmann surface area, the “three-trajectory method” and the “single-trajectory method”. ...

  17. JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles

    DEFF Research Database (Denmark)

    Mathelier, Anthony; Fornes, Oriol; Arenillas, David J;

    2016-01-01

    JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we...

  18. The Accuracy of Multiples

    Directory of Open Access Journals (Sweden)

    Stauropoulos Antonios

    2011-01-01

    Full Text Available Problem statement: Equity valuation with the use of multiples is widely used by academics and practitioners concerning its functionality. This study aims to explore the sensitivity of three multiples in terms of accuracy. Approach: Price-to-Sales (P/S multiple, the price-to-book value of equity (P/B multiple and the Price-to-Earnings (P/E multiple are three multiples under consideration, using both current and one-year-ahead earnings forecasts. Results: Evidence of empirical results show that, the multiples P/mdfy1 and P/mnfy1 are effective in terms of accuracy, with their means being negatively biased and their medians being positively biased. Finally, current earnings are identified as more appropriate value driver for the calculation of the P/E ratio by terms of accuracy. The results can be considered as reliable owing to the large sample and the procedure followed for its selection. Conclusion: This study offers a better understanding of the valuation approach through the use of multiples, in order analysts assumption to be more carefully and properly chosen and their results to be more accurately produced.

  19. Suicide and multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E N; Stenager, Egon; Koch-Henriksen, N;

    1992-01-01

    In a nationwide investigation the risk of death by suicide for patients with multiple sclerosis (MS) was assessed using records kept at the Danish Multiple Sclerosis Registry (DMSR) and the Danish National Register of Cause of Death. The investigation covers all MS patients registered with DSMR...

  20. Orchestrating Multiple Intelligences

    Science.gov (United States)

    Moran, Seana; Kornhaber, Mindy; Gardner, Howard

    2006-01-01

    Education policymakers often go astray when they attempt to integrate multiple intelligences theory into schools, according to the originator of the theory, Howard Gardner, and his colleagues. The greatest potential of a multiple intelligences approach to education grows from the concept of a profile of intelligences. Each learner's intelligence…

  1. Applying Multiple Intelligences

    Science.gov (United States)

    Christodoulou, Joanna A.

    2009-01-01

    The ideas of multiple intelligences introduced by Howard Gardner of Harvard University more than 25 years ago have taken form in many ways, both in schools and in other sometimes-surprising settings. The silver anniversary of Gardner's learning theory provides an opportunity to reflect on the ways multiple intelligences theory has taken form and…

  2. Constraining Multiple Grammars

    Science.gov (United States)

    Hopp, Holger

    2014-01-01

    This article offers the author's commentary on the Multiple Grammars (MG) language acquisition theory proposed by Luiz Amaral and Tom Roeper in the present issue. Multiple Grammars advances the claim that optionality is a constitutive characteristic of any one grammar, with interlanguage grammars being perhaps the clearest examples of a…

  3. [Multiple pulmonary hyalinizing granuloma].

    Science.gov (United States)

    Haro, M; Ruiz, J; Vila, X; Avellanet, M; Izquierdo, J

    1994-01-01

    The causes of multiple pulmonary nodules are many, with metastasis being the most feared. A rare but possible etiology, however, is hyalinizing multiple granuloma. We present a case that allows us to review this condition and its course, as well as a variety of associated immunological changes and possible complications. PMID:8087395

  4. Multiple Stages 2

    DEFF Research Database (Denmark)

    Andreasen, John

    Multiple stages 2: theatrical futures, set design, community plays, cultural capitals, democracy & drama, WWII dramas, performance on adoption, promenade about emigration, qualities in political theatre, performance analysis, dramaturgical education, Toulmin Variations......Multiple stages 2: theatrical futures, set design, community plays, cultural capitals, democracy & drama, WWII dramas, performance on adoption, promenade about emigration, qualities in political theatre, performance analysis, dramaturgical education, Toulmin Variations...

  5. Imaging of multiple reflections

    NARCIS (Netherlands)

    Berkhout, A.J.; Verschuur, D.J.

    2006-01-01

    Current multiple-removal algorithms in seismic processing use either differential moveout or predictability. If the differential moveout between primaries and multiples is small, prediction is the only option available. In the last decade, multidimensional prediction-error filtering by weighted conv

  6. ALICE Photon Multiplicity Detector

    CERN Multimedia

    Nayak, T

    2013-01-01

    Photon Multiplicity Detector (PMD) measures the multiplicity and spatial distribution of photons in the forward region of ALICE on a event-by-event basis. PMD is a pre-shower detector having fine granularity and full azimuthal coverage in the pseudo-rapidity region 2.3 < η < 3.9.

  7. Hadron Multiplicities at HERMES

    OpenAIRE

    Hillenbrand, A.; Hartig, M.

    2005-01-01

    Hadron multiplicities of $\\pim$, $\\pip$, $\\km$ and $\\kp$ have been measured in the deep-inelastic scattering of 27.5 GeV positrons off a hydrogen target. The data used in this analysis have been collected during the 2000 HERA running period. The multiplicities were obtained for 0.15$< z

  8. Probing protein phosphatase substrate binding

    DEFF Research Database (Denmark)

    Højlys-Larsen, Kim B.; Sørensen, Kasper Kildegaard; Jensen, Knud Jørgen;

    2012-01-01

    profile of the integrin-linked kinase associated phosphatase (ILKAP), a member of the protein phosphatase 2C (PP2C) family. Phosphatases can potentially dephosphorylate these phosphopeptide substrates but, interestingly, performing the binding studies at 4 °C allowed efficient binding to phosphopeptides...... around the phosphorylated residue are important for the binding affinity of ILKAP. We conclude that solid-phase affinity pull-down of proteins from complex mixtures can be applied in phosphoproteomics and systems biology.......Proteomics and high throughput analysis for systems biology can benefit significantly from solid-phase chemical tools for affinity pull-down of proteins from complex mixtures. Here we report the application of solid-phase synthesis of phosphopeptides for pull-down and analysis of the affinity...

  9. Water binding in legume seeds

    Science.gov (United States)

    Vertucci, C. W.; Leopold, A. C.

    1987-01-01

    The physical status of water in seeds has a pivotal role in determining the physiological reactions that can take place in the dry state. Using water sorption isotherms from cotyledon and axis tissue of five leguminous seeds, the strength of water binding and the numbers of binding sites have been estimated using van't Hoff analyses and the D'Arcy/Watt equation. These parameters of water sorption are calculated for each of the three regions of water binding and for a range of temperatures. Water sorption characteristics are reflective of the chemical composition of the biological materials as well as the temperature at which hydration takes place. Changes in the sorption characteristics with temperature and hydration level may suggest hydration-induced structural changes in cellular components.

  10. Nonlinearity arising from noncooperative transcription factor binding enhances negative feedback and promotes genetic oscillations

    CERN Document Server

    Lengyel, Iván M; Oates, Andrew C; Morelli, Luis G

    2015-01-01

    We study the effects of multiple binding sites in the promoter of a genetic oscillator. We evaluate the regulatory function of a promoter with multiple binding sites in the absence of cooperative binding, and consider different hypotheses for how the number of bound repressors affects transcription rate. Effective Hill exponents of the resulting regulatory functions reveal an increase in the nonlinearity of the feedback with the number of binding sites. We identify optimal configurations that maximize the nonlinearity of the feedback. We use a generic model of a biochemical oscillator to show that this increased nonlinearity is reflected in enhanced oscillations, with larger amplitudes over wider oscillatory ranges. Although the study is motivated by genetic oscillations in the zebrafish segmentation clock, our findings may reveal a general principle for gene regulation.

  11. Computational Prediction of RNA-Binding Proteins and Binding Sites.

    Science.gov (United States)

    Si, Jingna; Cui, Jing; Cheng, Jin; Wu, Rongling

    2015-01-01

    Proteins and RNA interaction have vital roles in many cellular processes such as protein synthesis, sequence encoding, RNA transfer, and gene regulation at the transcriptional and post-transcriptional levels. Approximately 6%-8% of all proteins are RNA-binding proteins (RBPs). Distinguishing these RBPs or their binding residues is a major aim of structural biology. Previously, a number of experimental methods were developed for the determination of protein-RNA interactions. However, these experimental methods are expensive, time-consuming, and labor-intensive. Alternatively, researchers have developed many computational approaches to predict RBPs and protein-RNA binding sites, by combining various machine learning methods and abundant sequence and/or structural features. There are three kinds of computational approaches, which are prediction from protein sequence, prediction from protein structure, and protein-RNA docking. In this paper, we review all existing studies of predictions of RNA-binding sites and RBPs and complexes, including data sets used in different approaches, sequence and structural features used in several predictors, prediction method classifications, performance comparisons, evaluation methods, and future directions.

  12. Computational Prediction of RNA-Binding Proteins and Binding Sites

    Directory of Open Access Journals (Sweden)

    Jingna Si

    2015-11-01

    Full Text Available Proteins and RNA interaction have vital roles in many cellular processes such as protein synthesis, sequence encoding, RNA transfer, and gene regulation at the transcriptional and post-transcriptional levels. Approximately 6%–8% of all proteins are RNA-binding proteins (RBPs. Distinguishing these RBPs or their binding residues is a major aim of structural biology. Previously, a number of experimental methods were developed for the determination of protein–RNA interactions. However, these experimental methods are expensive, time-consuming, and labor-intensive. Alternatively, researchers have developed many computational approaches to predict RBPs and protein–RNA binding sites, by combining various machine learning methods and abundant sequence and/or structural features. There are three kinds of computational approaches, which are prediction from protein sequence, prediction from protein structure, and protein-RNA docking. In this paper, we review all existing studies of predictions of RNA-binding sites and RBPs and complexes, including data sets used in different approaches, sequence and structural features used in several predictors, prediction method classifications, performance comparisons, evaluation methods, and future directions.

  13. A peek into tropomyosin binding and unfolding on the actin filament.

    Directory of Open Access Journals (Sweden)

    Abhishek Singh

    that local disorder is a property typical of coiled coil binding sites and proteins that have multiple binding partners, of which tropomyosin is one type.

  14. Skyrmions with low binding energies

    Directory of Open Access Journals (Sweden)

    Mike Gillard

    2015-06-01

    Full Text Available Nuclear binding energies are investigated in two variants of the Skyrme model: the first replaces the usual Skyrme term with a term that is sixth order in derivatives, and the second includes a potential that is quartic in the pion fields. Solitons in the first model are shown to deviate significantly from ansätze previously assumed in the literature. The binding energies obtained in both models are lower than those obtained from the standard Skyrme model, and those obtained in the second model are close to the experimental values.

  15. Skyrmions with low binding energies

    Energy Technology Data Exchange (ETDEWEB)

    Gillard, Mike, E-mail: m.n.gillard@leeds.ac.uk; Harland, Derek, E-mail: d.g.harland@leeds.ac.uk; Speight, Martin, E-mail: speight@maths.leeds.ac.uk

    2015-06-15

    Nuclear binding energies are investigated in two variants of the Skyrme model: the first replaces the usual Skyrme term with a term that is sixth order in derivatives, and the second includes a potential that is quartic in the pion fields. Solitons in the first model are shown to deviate significantly from ansätze previously assumed in the literature. The binding energies obtained in both models are lower than those obtained from the standard Skyrme model, and those obtained in the second model are close to the experimental values.

  16. Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site.

    Science.gov (United States)

    Chen, Hongming; Tucker, Julie; Wang, Xiaotao; Gavine, Paul R; Phillips, Chris; Augustin, Martin A; Schreiner, Patrick; Steinbacher, Stefan; Preston, Marian; Ogg, Derek

    2016-05-01

    MAP kinases act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, regulation of transcription and development. As a member of the MAP kinase family, ERK5 (MAPK7) is involved in the downstream signalling pathways of various cell-surface receptors, including receptor tyrosine kinases and G protein-coupled receptors. In the current study, five structures of the ERK5 kinase domain co-crystallized with ERK5 inhibitors are reported. Interestingly, three of the compounds bind at a novel allosteric binding site in ERK5, while the other two bind at the typical ATP-binding site. Binding of inhibitors at the allosteric site is accompanied by displacement of the P-loop into the ATP-binding site and is shown to be ATP-competitive in an enzymatic assay of ERK5 kinase activity. Kinase selectivity data show that the most potent allosteric inhibitor exhibits superior kinase selectivity compared with the two inhibitors that bind at the canonical ATP-binding site. An analysis of these structures and comparison with both a previously published ERK5-inhibitor complex structure (PDB entry 4b99) and the structures of three other kinases (CDK2, ITK and MEK) in complex with allosteric inhibitors are presented.

  17. Synthetic heparin-binding growth factor analogs

    Science.gov (United States)

    Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.

    2007-01-23

    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

  18. Calcium binding protein-mediated regulation of voltage-gated calcium channels linked to human diseases

    Institute of Scientific and Technical Information of China (English)

    Nasrin NFJATBAKHSH; Zhong-ping FENG

    2011-01-01

    Calcium ion entry through voltage-gated calcium channels is essential for cellular signalling in a wide variety of cells and multiple physiological processes. Perturbations of voltage-gated calcium channel function can lead to pathophysiological consequences. Calcium binding proteins serve as calcium sensors and regulate the calcium channel properties via feedback mechanisms. This review highlights the current evidences of calcium binding protein-mediated channel regulation in human diseases.

  19. DETERMINANTS OF LIGAND BINDING AFFINITY AND COOPERATIVITY AT THE GLUT1 ENDOFACIAL SITE

    OpenAIRE

    Robichaud, Trista; Appleyard, Antony N.; Herbert, Richard B.; Henderson, Peter J. F.; Carruthers, Anthony

    2011-01-01

    Cytochalasin B (CB) and forskolin (FSK) inhibit GLUT1-mediated sugar transport in red cells by binding at or close to the GLUT1 endofacial sugar binding site. Paradoxically, very low concentrations of each of these inhibitors produce a modest stimulation of sugar transport (Cloherty, E. K., Levine, K. B., & Carruthers, A. (2001). The red blood cell glucose transporter presents multiple, nucleotide-sensitive sugar exit sites. Biochemistry, 40(51), 15549–15561). This result is consistent with t...

  20. Prediction of SAMPL3 Host-Guest Affinities with the Binding Energy Distribution Analysis Method (BEDAM)

    OpenAIRE

    Gallicchio, Emilio; Ronald M Levy

    2012-01-01

    BEDAM calculations are described to predict the free energies of binding of a series of anaesthetic drugs to a recently characterized acyclic cucurbituril host. The modeling predictions, conducted as part of the SAMPL3 host-guest affinity blind challenge, are generally in good quantitative agreement with the experimental measurements. The correlation coefficient between computed and measured binding free energies is 70% with high statistical significance. Multiple conformational stereoisomers...

  1. Multiple scattering tomography.

    Science.gov (United States)

    Modregger, Peter; Kagias, Matias; Peter, Silvia; Abis, Matteo; Guzenko, Vitaliy A; David, Christian; Stampanoni, Marco

    2014-07-11

    Multiple scattering represents a challenge for numerous modern tomographic imaging techniques. In this Letter, we derive an appropriate line integral that allows for the tomographic reconstruction of angular resolved scattering distributions, even in the presence of multiple scattering. The line integral is applicable to a wide range of imaging techniques utilizing various kinds of probes. Here, we use x-ray grating interferometry to experimentally validate the framework and to demonstrate additional structural sensitivity, which exemplifies the impact of multiple scattering tomography. PMID:25062159

  2. Bayesian multiple target tracking

    CERN Document Server

    Streit, Roy L

    2013-01-01

    This second edition has undergone substantial revision from the 1999 first edition, recognizing that a lot has changed in the multiple target tracking field. One of the most dramatic changes is in the widespread use of particle filters to implement nonlinear, non-Gaussian Bayesian trackers. This book views multiple target tracking as a Bayesian inference problem. Within this framework it develops the theory of single target tracking, multiple target tracking, and likelihood ratio detection and tracking. In addition to providing a detailed description of a basic particle filter that implements

  3. Sex hormone binding globulin phenotypes

    DEFF Research Database (Denmark)

    Cornelisse, M M; Bennett, Patrick; Christiansen, M;

    1994-01-01

    Human sex hormone binding globulin (SHBG) is encoded by a normal and a variant allele. The resulting SHBG phenotypes (the homozygous normal SHBG, the heterozygous SHBG and the homozygous variant SHBG phenotype) can be distinguished by their electrophoretic patterns. We developed a novel detection...

  4. 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, ...

  5. Cellulose binding domain fusion proteins

    Energy Technology Data Exchange (ETDEWEB)

    Shoseyov, Oded (Karmey Yosef, IL); Shpiegl, Itai (Rehovot, IL); Goldstein, Marc A. (Davis, CA); Doi, Roy H. (Davis, CA)

    1998-01-01

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production thereof. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques.

  6. Effect of four-alpha-helix bundle cavity size on volatile anesthetic binding energetics.

    Science.gov (United States)

    Manderson, Gavin A; Michalsky, Stuart J; Johansson, Jonas S

    2003-09-30

    Currently, it is thought that inhalational anesthetics cause anesthesia by binding to ligand-gated ion channels. This is being investigated using four-alpha-helix bundles, small water-soluble analogues of the transmembrane domains of the "natural" receptor proteins. The study presented here specifically investigates how multiple alanine-to-valine substitutions (which each decrease the volume of the internal binding cavity by 38 A(3)) affect structure, stability, and anesthetic binding affinity of the four-alpha-helix bundles. Structure remains essentially unchanged when up to four alanine residues are changed to valine. However, stability increases as the number of these substitutions is increased. Anesthetic binding affinities are also affected. Halothane binds to the four-alpha-helix bundle variants with 0, 1, and 2 substitutions with equivalent affinities but binds to the variants with 3 and 4 more tightly. The same order of binding affinities was observed for chloroform, although for a particular variant, chloroform was bound less tightly. The observed differences in binding affinities may be explained in terms of a modulation of van der Waals and hydrophobic interactions between ligand and receptor. These, in turn, could result from increased four-alpha-helix bundle binding cavity hydrophobicity, a decrease in cavity size, or improved ligand/receptor shape complementarity.

  7. Comparison of crystal and solution hemoglobin binding of selected antigelling agents and allosteric modifiers

    Energy Technology Data Exchange (ETDEWEB)

    Mehanna, A.S.; Abraham, D.J. (Virginia Commonwealth Univ., Richmond (USA))

    1990-04-24

    This paper details comprehensive binding studies (solution and X-ray) of human hemoglobin A with a group of halogenated carboxylic acids that were investigated as potential antisickling agents. It is, to our knowledge, the first study to compare solution and crystal binding for a series of compounds under similar high-salt conditions used for cocrystallization. The compounds include ((3,4-dichlorobenzyl)oxy)acetic acid, ((p-bromobenzyl)oxy)acetic acid, clofibric acid, and bezafibrate. The location and stereochemistry of binding sites have been established by X-ray crystallography, while the number of binding sites and affinity constants were measured by using equilibrium dialysis. The observed crystal structures are consistent with the binding observed in solution and that the number of binding sites is independent of salt concentration, while the binding constant increases with increasing salt concentration. The studies also reveal that relatively small changes in the chemical structure of a drug molecule can result in entirely different binding sites on the protein. Moreover, the X-ray studies provide a possible explanation for the multiplicity in function exhibited by these compounds as allosteric modulators and/or antisickling agents. Finally, the studies indicate that these compounds bind differently to the R and T states of hemoglobin, and observation of special significance to the original design of these agents.

  8. BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology.

    Science.gov (United States)

    Gilson, Michael K; Liu, Tiqing; Baitaluk, Michael; Nicola, George; Hwang, Linda; Chong, Jenny

    2016-01-01

    BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel discrimination, and support vector machine methods. Specialized data sets are also available, such as binding data for hundreds of congeneric series of ligands, drawn from BindingDB and organized for use in validating drug design methods. BindingDB offers several forms of programmatic access, and comes with extensive background material and documentation. Here, we provide the first update of BindingDB since 2007, focusing on new and unique features and highlighting directions of importance to the field as a whole.

  9. Genome-wide prediction, display and refinement of binding sites with information theory-based models

    Directory of Open Access Journals (Sweden)

    Leeder J Steven

    2003-09-01

    Full Text Available Abstract Background We present Delila-genome, a software system for identification, visualization and analysis of protein binding sites in complete genome sequences. Binding sites are predicted by scanning genomic sequences with information theory-based (or user-defined weight matrices. Matrices are refined by adding experimentally-defined binding sites to published binding sites. Delila-Genome was used to examine the accuracy of individual information contents of binding sites detected with refined matrices as a measure of the strengths of the corresponding protein-nucleic acid interactions. The software can then be used to predict novel sites by rescanning the genome with the refined matrices. Results Parameters for genome scans are entered using a Java-based GUI interface and backend scripts in Perl. Multi-processor CPU load-sharing minimized the average response time for scans of different chromosomes. Scans of human genome assemblies required 4–6 hours for transcription factor binding sites and 10–19 hours for splice sites, respectively, on 24- and 3-node Mosix and Beowulf clusters. Individual binding sites are displayed either as high-resolution sequence walkers or in low-resolution custom tracks in the UCSC genome browser. For large datasets, we applied a data reduction strategy that limited displays of binding sites exceeding a threshold information content to specific chromosomal regions within or adjacent to genes. An HTML document is produced listing binding sites ranked by binding site strength or chromosomal location hyperlinked to the UCSC custom track, other annotation databases and binding site sequences. Post-genome scan tools parse binding site annotations of selected chromosome intervals and compare the results of genome scans using different weight matrices. Comparisons of multiple genome scans can display binding sites that are unique to each scan and identify sites with significantly altered binding strengths

  10. Tenascin C promiscuously binds growth factors via its fifth fibronectin type III-like domain.

    Directory of Open Access Journals (Sweden)

    Laura De Laporte

    Full Text Available Tenascin C (TNC is an extracellular matrix protein that is upregulated during development as well as tissue remodeling. TNC is comprised of multiple independent folding domains, including 15 fibronectin type III-like (TNCIII domains. The fifth TNCIII domain (TNCIII5 has previously been shown to bind heparin. Our group has shown that the heparin-binding fibronectin type III domains of fibronectin (FNIII, specifically FNIII12-14, possess affinity towards a large number of growth factors. Here, we show that TNCIII5 binds growth factors promiscuously and with high affinity. We produced recombinant fragments of TNC representing the first five TNCIII repeats (TNCIII1-5, as well as subdomains, including TNCIII5, to study interactions with various growth factors. Multiple growth factors of the platelet-derived growth factor (PDGF family, the fibroblast growth factor (FGF family, the transforming growth factor beta (TGF-β superfamily, the insulin-like growth factor binding proteins (IGF-BPs, and neurotrophins were found to bind with high affinity to this region of TNC, specifically to TNCIII5. Surface plasmon resonance was performed to analyze the kinetics of binding of TNCIII1-5 with TGF-β1, PDGF-BB, NT-3, and FGF-2. The promiscuous yet high affinity of TNC for a wide array of growth factors, mediated mainly by TNCIII5, may play a role in multiple physiological and pathological processes involving TNC.

  11. Binding equilibrium of I- to serum albumin with resonance Rayleigh scattering

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The binding equilibrium between I- and human serum albumin (HSA) or bovine serum albumin (BSA) has been studied by means of the resonance Rayleigh scattering (RRS) and equilibrium dialysis. It has been found for the first time that RRS and multiple frequency scattering (MFS) are enhanced as the I- binding to the HSA and BSA, but fluorescence quenches. The equilibrium dialysis results suggest that the binding of I- to HSA and BSA fits a phase-distribution model other than Scatchard model, and that the order of magnitude of its phase-distribution constant was found to be 104. It is most probable that Cl- or other anion ions influence the binding of I- by changing the ionic strength in the solution. The dialysis at different pH indicates that the binding mechanism is due to the electrostatic forces between the I- and protonated basic amino-acid residues.

  12. Binding equilibrium of I~- to serum albumin with resonance Rayleigh scattering

    Institute of Scientific and Technical Information of China (English)

    梁宏; 沈星灿; 蒋治良; 何锡文; 申泮文

    2000-01-01

    The binding equilibrium between l- and human serum albumin (HSA) or bovine serum albumin (BSA) has been studied by means of the resonance Rayleigh scattering (RRS) and equilibrium dialysis. It has been found for the first time that RRS and multiple frequency scattering (MFS) are enhanced as the l- binding to the HSA and BSA, but fluorescence quenches. The equilibrium dialysis results suggest that the binding of l- to HSA and BSA fits a phase-distribution model other than Scsitchard model, and that the order of magnitude of its phase-distribution constant was found to be 104. It is most probable that Cl~ or other anion ions influence the binding of P by changing the ionic strength in the solution. The dialysis at different pH indicates that the binding mechanism is due to the electrostatic forces between the T-and protonated basic amino-acid residues.

  13. The complexity of condensed tannin binding to bovine serum albumin--An isothermal titration calorimetry study.

    Science.gov (United States)

    Kilmister, Rachel L; Faulkner, Peta; Downey, Mark O; Darby, Samuel J; Falconer, Robert J

    2016-01-01

    Isothermal titration calorimetry was applied to study the binding of purified proanthocyanidin oligomers to bovine serum albumin (BSA). The molecular weight of the proanthocyanidin oligomer had a major impact on its binding to BSA. The calculated change in enthalpy (ΔH) and association constant (Ka) became greater as the oligomer size increased then plateaued at the heptameric oligomer. These results support a model for precipitation of proteins by proanthocyanidin where increased oligomer size enhanced the opportunity for cross linkages between proteins ultimately forming sediment-able complexes. The authors suggest tannin binding to proteins is opportunistic and involves multiple sites, each with a different Ka and ΔH of binding. The ΔH of binding comprises both an endothermic hydrophobic interaction and exothermic hydrogen bond component. This suggests the calculated entropy value (ΔS) for tannin-protein interactions is subject to a systematic error and should be interpreted with caution.

  14. Functionalization of exposed core fibers with multiligand binding molecules for fluorescence based ion sensing

    Science.gov (United States)

    Kostecki, Roman; Heng, Sabrina; Ebendorff-Heidepriem, Heike; Abell, Andrew D.; Monro, Tanya M.

    2014-05-01

    The results of functionalizing exposed-core optical fiber with multiligand binding sensor molecules for ion detection is presented. We show that the capacity of the sensor molecules to bind multiple ligands is negated when the sensor molecules are covalently bound, making the method ineffective where multiligand binding fluoroionophores are needed. An alternate functionalization method using thin film polymer doped with multiligand binding fluoroionophores is shown, demonstrating the ability for ion detection in a case where multiligand binding is needed. This one step functionalizing process for optical fiber sensing applications does not require surface attachment functional groups and has the potential to be inline with fiber drawing so that long lengths of functionalized fiber can be fabricated.

  15. Rehabilitation and multiple sclerosis

    DEFF Research Database (Denmark)

    Dalgas, Ulrik

    2011-01-01

    In a chronic and disabling disease like multiple sclerosis, rehabilitation becomes of major importance in the preservation of physical, psychological and social functioning. Approximately 80% of patients have multiple sclerosis for more than 35 years and most will develop disability at some point...... of their lives, emphasising the importance of rehabilitation in order to maintain quality of life. An important aspect of multiple sclerosis rehabilitation is the preservation of physical functioning. Hot topics in the rehabilitation of physical function include (1) exercise therapy, (2) robot-assisted training...... and (3) pharmacological interventions. Exercise therapy has for many years been a controversial issue in multiple sclerosis rehabilitation and the advice generally given to patients was not to participate in physical exercise, since it was thought to lead to a worsening of symptoms or fatigue. However...

  16. Multiple sclerosis - discharge

    Science.gov (United States)

    Houtchens MK, Lublin FD, Miller AE, Khoury SJ. Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. In: Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, ...

  17. Pomalidomide for Multiple Myeloma

    Science.gov (United States)

    A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

  18. Multiple sclerosis research

    International Nuclear Information System (INIS)

    This volume proceedings contains four contributions which are in INIS scope, dealing with MRI and SPECT in the diagnosis of multiple sclerosis and assessment of disease activity. (H.W.). refs.; figs.; tabs

  19. Connecting the Production Multiple

    DEFF Research Database (Denmark)

    Lichen, Alex Yu; Mouritsen, Jan

    was implementing sales and operations planning (S&OP) process to foster integration on its demand chain. Although actors wanted to see what it is to produce, that is to say, the object Production, as a singular object that could be diffused across time and space, Production became more multiple because the S......&OP process itself is a fluid object, but there is still possibility to organise the messy Production. There are connections between the Production multiple and the managerial technology fluid. The fluid enacted the multiplicity of Production thus making it more difficult to be organised because there were...... always Other representations that enact new relations between presences, manifest absences and others. The multiple was organised in the sense that its mutually exclusive realities were managed by different constituents of the fluid located in these diverse realities. Accounting incompleteness...

  20. [Psychoneuroimmunology and multiple sclerosis].

    Science.gov (United States)

    Mel'nikov, M V; Pashchenkov, M V; Boĭko, A N

    2015-01-01

    In this review, the authors discuss interactions between mental, nervous and immune systems in multiple sclerosis, an impact of psycho-emotional stress on disease development and progression as well as possible mechanisms of these interactions.

  1. Protein binding assay for hyaluronate

    Energy Technology Data Exchange (ETDEWEB)

    Lacy, B.E.; Underhill, C.B.

    1986-11-01

    A relatively quick and simple assay for hyaluronate was developed using the specific binding protein, hyaluronectin. The hyaluronectin was obtained by homogenizing the brains of Sprague-Dawley rats, and then centrifuging the homogenate. The resulting supernatant was used as a source of crude hyaluronectin. In the binding assay, the hyaluronectin was mixed with (/sup 3/H)hyaluronate, followed by an equal volume of saturated (NH/sub 4/)/sub 2/SO/sub 4/, which precipitated the hyaluronectin and any (/sup 3/H)hyaluronate associated with it, but left free (/sup 3/H)hyaluronate in solution. The mixture was then centrifuged, and the amount of bound (/sup 3/H)hyaluronate in the precipitate was determined. Using this assay, the authors found that hyaluronectin specifically bound hyaluronate, since other glycosaminoglycans failed to compete for the binding protein. In addition, the interaction between hyaluronectin and hyaluronate was of relatively high affinity, and the size of the hyaluronate did not appear to substantially alter the amount of binding. To determine the amount of hyaluronate in an unknown sample, they used a competition assay in which the binding of a set amount of (/sup 3/H)hyaluronate was blocked by the addition of unlabeled hyaluronate. By comparing the degree of competition of the unknown samples with that of known amounts of hyaluronate, it was possible to determine the amount of hyaluronate in the unknowns. They have found that this method is sensitive to 1 ..mu..g or less of hyaluronate, and is unaffected by the presence of proteins.

  2. Improvement of a streptavidin-binding aptamer by LNA- and α-l-LNA-substitutions

    DEFF Research Database (Denmark)

    Jørgensen, Anna S; Hansen, Lykke H; Vester, Birte;

    2014-01-01

    Forty modified versions of a streptavidin-binding aptamer each containing single or multiple LNA or α-l-LNA-substitutions were synthesized and their dissociation constants determined by surface plasmon resonance experiments. Both full-length and truncated versions of the aptamer were studied and...... compared with the unmodified DNA aptamers. A ∼two-fold improvement in binding affinity was achieved by incorporation of LNA nucleotides in the 3'-part of the stems of the streptavidin-binding aptamer whereas LNA- and α-l-LNA-substitutions in the terminal stem increased the serum stability....

  3. Choice and multiple reinforcers

    OpenAIRE

    Moore, Jay

    1982-01-01

    Pigeons chose between equivalent two-component mixed and multiple terminal-link schedules of reinforcement in the concurrent-chains procedure. The pigeons preferred the multiple schedule over the mixed when the components of the compound schedules were differentiated in terms of density of reinforcement, but the pigeons were indifferent when the components were differentiated in terms of number of reinforcers per cycle. Taken together, these results indicate that a local variable, the interva...

  4. Multiple Sclerosis And Psoriasis

    OpenAIRE

    Özışık, Handan Işın; Kızkın, Sibel; Hazneci, Ersoy; Özcan, Cemal

    2005-01-01

    Natural and recombinant interferons are increasingly being used to treat patients with multiple sclerosis and various inflammatory, infectious, and neoplastic processes. Adverse reactions are usually limited to headache, fever, and myalgia, but occasional unexpected problems can be severe enough to limit use of the drug. One such problem is the exacerbation of psoriasis. In our clinic, two patients with multiple sclerosis who were receiving injections of interferon had a psoriasis...

  5. Angiogenesis and Multiple Myeloma

    OpenAIRE

    Giuliani, Nicola; Storti, Paola; Bolzoni, Marina; Palma, Benedetta Dalla; Bonomini, Sabrina

    2011-01-01

    The bone marrow microenvironment in multiple myeloma is characterized by an increased microvessel density. The production of pro-angiogenic molecules is increased and the production of angiogenic inhibitors is suppressed, leading to an “angiogenic switch”. Here we present an overview of the role of angiogenesis in multiple myeloma, the pro-angiogenic factors produced by myeloma cells and the microenvironment, and the mechanisms involved in the myeloma-induced angiogenic switch. Current data s...

  6. Generalized internal multiple imaging

    KAUST Repository

    Zuberi, M. A. H.

    2014-08-05

    Internal multiples deteriorate the image when the imaging procedure assumes only single scattering, especially if the velocity model does not have sharp contrasts to reproduce such scattering in the Green’s function through forward modeling. If properly imaged, internal multiples (internally scattered energy) can enhance the seismic image. Conventionally, to image internal multiples, accurate, sharp contrasts in the velocity model are required to construct a Green’s function with all the scattered energy. As an alternative, we have developed a generalized internal multiple imaging procedure that images any order internal scattering using the background Green’s function (from the surface to each image point), constructed from a smooth velocity model, usually used for conventional imaging. For the first-order internal multiples, the approach consisted of three steps, in which we first back propagated the recorded surface seismic data using the background Green’s function, then crosscorrelated the back-propagated data with the recorded data, and finally crosscorrelated the result with the original background Green’s function. This procedure images the contribution of the recorded first-order internal multiples, and it is almost free of the single-scattering recorded energy. The cost includes one additional crosscorrelation over the conventional single-scattering imaging application. We generalized this method to image internal multiples of any order separately. The resulting images can be added to the conventional single-scattering image, obtained, e.g., from Kirchhoff or reverse-time migration, to enhance the image. Application to synthetic data with reflectors illuminated by multiple scattering (double scattering) demonstrated the effectiveness of the approach.

  7. The interaction of versican with its binding partners

    Institute of Scientific and Technical Information of China (English)

    Yao Jiong WU; David P.LA PIERRE; Jin WU; Albert J.YEE; Burton B.YANG

    2005-01-01

    Versican belongs to the family of the large aggregating chondroitin sulfate proteoglycans located primarily within the extracellular matrix (ECM).Versican,like other members of its family,has unique N- and C-terminal globular regions,each with multiple motifs.A large glycosaminoglycan-binding region lies between them.This review will begin by outlining these structures,in the context of ECM proteoglycans.The diverse binding partners afforded to versican by virtue of its modular design will then be examined.These include ECM components,such as hyaluronan,type Ⅰ collagen,tenascin-R,fibulin-1,and -2,fibrillin-1,fibronectin,P- and L-selectins,and chemokines.Versican also binds to the cell surface proteins CD44,integrin β1,epidermal growth factor receptor,and P-selectin glycoprotein ligand-1.These multiple interactors play important roles in cell behaviour,and the roles of versican in modulating such processes are discussed.

  8. The conserved Tarp actin binding domain is important for chlamydial invasion.

    Directory of Open Access Journals (Sweden)

    Travis J Jewett

    Full Text Available The translocated actin recruiting phosphoprotein (Tarp is conserved among all pathogenic chlamydial species. Previous reports identified single C. trachomatis Tarp actin binding and proline rich domains required for Tarp mediated actin nucleation. A peptide antiserum specific for the Tarp actin binding domain was generated and inhibited actin polymerization in vitro and C. trachomatis entry in vivo, indicating an essential role for Tarp in chlamydial pathogenesis. Sequence analysis of Tarp orthologs from additional chlamydial species and C. trachomatis serovars indicated multiple putative actin binding sites. In order to determine whether the identified actin binding domains are functionally conserved, GST-Tarp fusions from multiple chlamydial species were examined for their ability to bind and nucleate actin. Chlamydial Tarps harbored variable numbers of actin binding sites and promoted actin nucleation as determined by in vitro polymerization assays. Our findings indicate that Tarp mediated actin binding and nucleation is a conserved feature among diverse chlamydial species and this function plays a critical role in bacterial invasion of host cells.

  9. STN1 OB Fold Mutation Alters DNA Binding and Affects Selective Aspects of CST Function

    Science.gov (United States)

    Bhattacharjee, Anukana; Stewart, Jason; Chaiken, Mary; Price, Carolyn M.

    2016-01-01

    Mammalian CST (CTC1-STN1-TEN1) participates in multiple aspects of telomere replication and genome-wide recovery from replication stress. CST resembles Replication Protein A (RPA) in that it binds ssDNA and STN1 and TEN1 are structurally similar to RPA2 and RPA3. Conservation between CTC1 and RPA1 is less apparent. Currently the mechanism underlying CST action is largely unknown. Here we address CST mechanism by using a DNA-binding mutant, (STN1 OB-fold mutant, STN1-OBM) to examine the relationship between DNA binding and CST function. In vivo, STN1-OBM affects resolution of endogenous replication stress and telomere duplex replication but telomeric C-strand fill-in and new origin firing after exogenous replication stress are unaffected. These selective effects indicate mechanistic differences in CST action during resolution of different replication problems. In vitro binding studies show that STN1 directly engages both short and long ssDNA oligonucleotides, however STN1-OBM preferentially destabilizes binding to short substrates. The finding that STN1-OBM affects binding to only certain substrates starts to explain the in vivo separation of function observed in STN1-OBM expressing cells. CST is expected to engage DNA substrates of varied length and structure as it acts to resolve different replication problems. Since STN1-OBM will alter CST binding to only some of these substrates, the mutant should affect resolution of only a subset of replication problems, as was observed in the STN1-OBM cells. The in vitro studies also provide insight into CST binding mechanism. Like RPA, CST likely contacts DNA via multiple OB folds. However, the importance of STN1 for binding short substrates indicates differences in the architecture of CST and RPA DNA-protein complexes. Based on our results, we propose a dynamic DNA binding model that provides a general mechanism for CST action at diverse forms of replication stress. PMID:27690379

  10. Antimicrobial Peptide-Lipid Binding Interactions and Binding Selectivity

    OpenAIRE

    Lad, Mitaben D.; Birembaut, Fabrice; Clifton, Luke A.; Frazier, Richard A.; Webster, John R. P.; Green, Rebecca J.

    2007-01-01

    Surface pressure measurements, external reflection-Fourier transform infrared spectroscopy, and neutron reflectivity have been used to investigate the lipid-binding behavior of three antimicrobial peptides: melittin, magainin II, and cecropin P1. As expected, all three cationic peptides were shown to interact more strongly with the anionic lipid, 1,2 dihexadecanoyl-sn-glycerol-3-(phosphor-rac-(1-glycerol)) (DPPG), compared to the zwitterionic lipid, 1,2 dihexadecanoyl-sn-glycerol-3-phosphocho...

  11. Characteristics of human erythrocyte insulin binding sites.

    OpenAIRE

    Okada, Yoshio

    1981-01-01

    Insulin and human erythrocyte cell membrane interactions were studied with respect to binding and dissociation. The per cent of specific binding of 125I-labeled insulin to erythrocytes was directly proportional to the cell concentration. The optimum pH for binding was 8.1. The initial binding rate was directly proportional to, and the steady state insulin binding was reversely proportional to, the incubation temperature. The per cent of specific binding of 125I-labeled insulin was 12.10 +/- 1...

  12. MutS recognition: Multiple mismatches and sequence context effects

    Indian Academy of Sciences (India)

    Amita Joshi; Basuthkar J Rao

    2001-12-01

    Escherichia coli MutS is a versatile repair protein that specifically recognizes not only various types of mismatches but also single stranded loops of up to 4 nucleotides in length. Specific binding, followed by the next step of tracking the DNA helix that locates hemi-methylated sites, is regulated by the conformational state of the protein as a function of ATP binding/hydrolysis. Here, we study how various molecular determinants of a heteroduplex regulate mismatch recognition by MutS, the critical first step of mismatch repair. Using classical DNase I footprinting assays, we demonstrate that the hierarchy of MutS binding to various types of mismatches is identical whether the mismatches are present singly or in multiples. Moreover, this unique hierarchy is indifferent both to the differential level of DNA helical flexibility and to the unpaired status of the mismatched bases in a heteroduplex. Surprisingly, multiple mismatches exhibit reduced affinity of binding to MutS, compared to that of a similar single mismatch. Such a reduction in the affinity might be due to sequence context effects, which we established more directly by studying two identical single mismatches in an altered sequence background. A mismatch, upon simply being flipped at the same location, elicits changes in MutS specific contacts, thereby underscoring the importance of sequence context in modulating MutS binding to mismatches.

  13. RNA-protein binding kinetics in an automated microfluidic reactor.

    Science.gov (United States)

    Ridgeway, William K; Seitaridou, Effrosyni; Phillips, Rob; Williamson, James R

    2009-11-01

    Microfluidic chips can automate biochemical assays on the nanoliter scale, which is of considerable utility for RNA-protein binding reactions that would otherwise require large quantities of proteins. Unfortunately, complex reactions involving multiple reactants cannot be prepared in current microfluidic mixer designs, nor is investigation of long-time scale reactions possible. Here, a microfluidic 'Riboreactor' has been designed and constructed to facilitate the study of kinetics of RNA-protein complex formation over long time scales. With computer automation, the reactor can prepare binding reactions from any combination of eight reagents, and is optimized to monitor long reaction times. By integrating a two-photon microscope into the microfluidic platform, 5-nl reactions can be observed for longer than 1000 s with single-molecule sensitivity and negligible photobleaching. Using the Riboreactor, RNA-protein binding reactions with a fragment of the bacterial 30S ribosome were prepared in a fully automated fashion and binding rates were consistent with rates obtained from conventional assays. The microfluidic chip successfully combines automation, low sample consumption, ultra-sensitive fluorescence detection and a high degree of reproducibility. The chip should be able to probe complex reaction networks describing the assembly of large multicomponent RNPs such as the ribosome.

  14. Strongly Multiplicative and 3-Multiplicative Linear Secret Sharing Schemes

    CERN Document Server

    Zhang, Zhifang; Chee, Yeow Meng; Ling, San; Wang, Huaxiong; 10.1007/978-3-540-89255-7

    2008-01-01

    Strongly multiplicative linear secret sharing schemes (LSSS) have been a powerful tool for constructing secure multiparty computation protocols. However, it remains open whether or not there exist efficient constructions of strongly multiplicative LSSS from general LSSS. In this paper, we propose the new concept of a 3-multiplicative LSSS, and establish its relationship with strongly multiplicative LSSS. More precisely, we show that any 3-multiplicative LSSS is a strongly multiplicative LSSS, but the converse is not true; and that any strongly multiplicative LSSS can be efficiently converted into a 3-multiplicative LSSS. Furthermore, we apply 3-multiplicative LSSS to the computation of unbounded fan-in multiplication, which reduces its round complexity to four (from five of the previous protocol based on strongly multiplicative LSSS). We also give two constructions of 3-multiplicative LSSS from Reed-Muller codes and algebraic geometric codes. We believe that the construction and verification of 3-multiplicati...

  15. Dissection of the Critical Binding Determinants of Cellular Retinoic Acid Binding Protein II by Mutagenesis and Fluorescence Binding Assay

    OpenAIRE

    Vasileiou, Chrysoula; Lee, Kin Sing Stephen; Crist, Rachael M.; Vaezeslami, Soheila; Goins, Sarah M.; Geiger, James H.; Borhan, Babak

    2009-01-01

    The binding of retinoic acid to mutants of Cellular Retinoic Acid Binding Protein II (CRABPII) was evaluated to better understand the importance of the direct protein/ligand interactions. The important role of Arg111 for the correct structure and function of the protein was verified and other residues that directly affect retinoic acid binding have been identified. Furthermore, retinoic acid binding to CRABPII mutants that lack all previously identified interacting amino acids was rescued by ...

  16. Human plasminogen binding protein tetranectin

    DEFF Research Database (Denmark)

    Kastrup, J S; Rasmussen, H; Nielsen, B B;

    1997-01-01

    The recombinant human plasminogen binding protein tetranectin (TN) and the C-type lectin CRD of this protein (TN3) have been crystallized. TN3 crystallizes in the tetragonal space group P4(2)2(1)2 with cell dimensions a = b = 64.0, c = 75.7 A and with one molecule per asymmetric unit. The crystals...... to at least 2.5 A. A full data set has been collected to 3.0 A. The asymmetric unit contains one monomer of TN. Molecular replacement solutions for TN3 and TN have been obtained using the structure of the C-type lectin CRD of rat mannose-binding protein as search model. The rhombohedral space group indicates...

  17. Binding effects and nuclear shadowing

    OpenAIRE

    Indumathi, D.; Wei ZHU

    1996-01-01

    The effects of nuclear binding on nuclear structure functions have so far been studied mainly at fixed target experiments, and there is currently much interest in obtaining a clearer understanding of this phenomenon. We use an existing dynamical model of nuclear structure functions, that gives good agreement with current data, to study this effect in a kinematical regime (low $x$, high $Q^2$) that can possibly be probed by an upgrade of {\\sc hera} at {\\sc desy} into a nuclear accelerator.

  18. Calcium binding by dietary fibre

    International Nuclear Information System (INIS)

    Dietary fibre from plants low in phytate bound calcium in proportion to its uronic-acid content. This binding by the non-cellulosic fraction of fibre reduces the availability of calcium for small-intestinal absorption, but the colonic microbial digestion of uronic acids liberates the calcium. Thus the ability to maintain calcium balance on high-fibre diets may depend on the adaptive capacity on the colon for calcium. (author)

  19. RNA-binding IMPs promote cell adhesion and invadopodia formation

    DEFF Research Database (Denmark)

    Vikesaa, Jonas; Hansen, Thomas V O; Jønson, Lars;

    2006-01-01

    Oncofetal RNA-binding IMPs have been implicated in mRNA localization, nuclear export, turnover and translational control. To depict the cellular actions of IMPs, we performed a loss-of-function analysis, which showed that IMPs are necessary for proper cell adhesion, cytoplasmic spreading...... and invadopodia formation. Loss of IMPs was associated with a coordinate downregulation of mRNAs encoding extracellular matrix and adhesion proteins. The transcripts were present in IMP RNP granules, implying that IMPs were directly involved in the post-transcriptional control of the transcripts. In particular......, we show that a 5.0 kb CD44 mRNA contained multiple IMP-binding sites in its 3'UTR, and following IMP depletion this species became unstable. Direct knockdown of the CD44 transcript mimicked the effect of IMPs on invadopodia, and we infer that CD44 mRNA stabilization may be involved in IMP...

  20. General Bindings and Alpha-Equivalence in Nominal Isabelle

    CERN Document Server

    Urban, Christian

    2012-01-01

    Nominal Isabelle is a definitional extension of the Isabelle/HOL theorem prover. It provides a proving infrastructure for reasoning about programming language calculi involving named bound variables (as opposed to de-Bruijn indices). In this paper we present an extension of Nominal Isabelle for dealing with general bindings, that means term constructors where multiple variables are bound at once. Such general bindings are ubiquitous in programming language research and only very poorly supported with single binders, such as lambda-abstractions. Our extension includes new definitions of alpha-equivalence and establishes automatically the reasoning infrastructure for alpha-equated terms. We also prove strong induction principles that have the usual variable convention already built in.

  1. [Larval stages of Ascaris lumbricoides: hyaluronan-binding capacity].

    Science.gov (United States)

    Ponce-León, Patricia; Foresto, Patricia; Valverde, Juana

    2009-03-01

    Hyaluronic acid has important functions in inflammatory and tissue reparation processes. Owing to the varied strategies of the parasites to evade the host's immune response, as well as the multiple functions and physiological importance of hyaluronic acid, the aim was to study the hyaluronan binding capacity by Ascaris lumbricoides larval stages. Larval concentrates were prepared by hatching A. lumbricoides eggs. The larvae were collected by the Baermann method. The test of serum soluble CD44 detection by Agregation Inhibition was modified. All the larval concentrates presented hyaluronan binding capacity. The obtained results allow to suppose the existence of an hyaluronic acid specific receptor in A. lumbricoides. This receptor eventually might compete with the usual receptors of the host. The parasite might use this mechanism to evade the immune response.

  2. Detection of site-specific binding and co-binding of ligands to macromolecules using sup 19 F NMR

    Energy Technology Data Exchange (ETDEWEB)

    Jenkins, B.G. (Massachusetts General Hospital and Harvard Medical School, Charlestown (USA))

    1991-01-01

    Study of ligand-macromolecular interactions by {sup 19}F nuclear magnetic resonance (NMR) spectroscopy affords many opportunities for obtaining molecular biochemical and pharmaceutical information. This is due to the absence of a background fluorine signal, as well as the relatively high sensitivity of {sup 19}F NMR. Use of fluorine-labeled ligands enables one to probe not only binding and co-binding phenomena to macromolecules, but also can provide data on binding constants, stoichiometries, kinetics, and conformational properties of these complexes. Under conditions of slow exchange and macromolecule-induced chemical shifts, multiple {sup 19}F NMR resonances can be observed for free and bound ligands. These shifted resonances are a direct correlate of the concentration of ligand bound in a specific state rather than the global concentrations of bound or free ligand which are usually determined using other techniques such as absorption spectroscopy or equilibrium dialysis. Examples of these interactions are demonstrated both from the literature and from interactions of 5-fluorotryptophan, 5-fluorosalicylic acid, flurbiprofen, and sulindac sulfide with human serum albumin. Other applications of {sup 19}F NMR to study of these interactions in vivo, as well for receptor binding and metabolic tracing of fluorinated drugs and proteins are discussed.

  3. Material Binding Peptides for Nanotechnology

    Directory of Open Access Journals (Sweden)

    Urartu Ozgur Safak Seker

    2011-02-01

    Full Text Available Remarkable progress has been made to date in the discovery of material binding peptides and their utilization in nanotechnology, which has brought new challenges and opportunities. Nowadays phage display is a versatile tool, important for the selection of ligands for proteins and peptides. This combinatorial approach has also been adapted over the past decade to select material-specific peptides. Screening and selection of such phage displayed material binding peptides has attracted great interest, in particular because of their use in nanotechnology. Phage display selected peptides are either synthesized independently or expressed on phage coat protein. Selected phage particles are subsequently utilized in the synthesis of nanoparticles, in the assembly of nanostructures on inorganic surfaces, and oriented protein immobilization as fusion partners of proteins. In this paper, we present an overview on the research conducted on this area. In this review we not only focus on the selection process, but also on molecular binding characterization and utilization of peptides as molecular linkers, molecular assemblers and material synthesizers.

  4. Anion binding in biological systems

    Science.gov (United States)

    Feiters, Martin C.; Meyer-Klaucke, Wolfram; Kostenko, Alexander V.; Soldatov, Alexander V.; Leblanc, Catherine; Michel, Gurvan; Potin, Philippe; Küpper, Frithjof C.; Hollenstein, Kaspar; Locher, Kaspar P.; Bevers, Loes E.; Hagedoorn, Peter-Leon; Hagen, Wilfred R.

    2009-11-01

    We compare aspects of biological X-ray absorption spectroscopy (XAS) studies of cations and anions, and report on some examples of anion binding in biological systems. Brown algae such as Laminaria digitata (oarweed) are effective accumulators of I from seawater, with tissue concentrations exceeding 50 mM, and the vanadate-containing enzyme haloperoxidase is implicated in halide accumulation. We have studied the chemical state of iodine and its biological role in Laminaria at the I K edge, and bromoperoxidase from Ascophyllum nodosum (knotted wrack) at the Br K edge. Mo is essential for many forms of life; W only for certain archaea, such as Archaeoglobus fulgidus and the hyperthermophilic archaeon Pyrococcus furiosus, and some bacteria. The metals are bound and transported as their oxo-anions, molybdate and tungstate, which are similar in size. The transport protein WtpA from P. furiosus binds tungstate more strongly than molybdate, and is related in sequence to Archaeoglobus fulgidus ModA, of which a crystal structure is known. We have measured A. fulgidus ModA with tungstate at the W L3 (2p3/2) edge, and compared the results with the refined crystal structure. XAS studies of anion binding are feasible even if only weak interactions are present, are biologically relevant, and give new insights in the spectroscopy.

  5. Anion binding in biological systems

    Energy Technology Data Exchange (ETDEWEB)

    Feiters, Martin C [Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen (Netherlands); Meyer-Klaucke, Wolfram [EMBL Hamburg Outstation at DESY, Notkestrasse 85, D-22607 Hamburg (Germany); Kostenko, Alexander V; Soldatov, Alexander V [Faculty of Physics, Southern Federal University, Sorge 5, Rostov-na-Donu, 344090 (Russian Federation); Leblanc, Catherine; Michel, Gurvan; Potin, Philippe [Centre National de la Recherche Scientifique and Universite Pierre et Marie Curie Paris-VI, Station Biologique de Roscoff, Place Georges Teissier, BP 74, F-29682 Roscoff cedex, Bretagne (France); Kuepper, Frithjof C [Scottish Association for Marine Science, Dunstaffnage Marine Laboratory, Oban, Argyll PA37 1QA, Scotland (United Kingdom); Hollenstein, Kaspar; Locher, Kaspar P [Institute of Molecular Biology and Biophysics, ETH Zuerich, Schafmattstrasse 20, Zuerich, 8093 (Switzerland); Bevers, Loes E; Hagedoorn, Peter-Leon; Hagen, Wilfred R, E-mail: m.feiters@science.ru.n [Department of Biotechnology, Delft University of Technology, Julianalaan 67, 2628 BC Delft (Netherlands)

    2009-11-15

    We compare aspects of biological X-ray absorption spectroscopy (XAS) studies of cations and anions, and report on some examples of anion binding in biological systems. Brown algae such as Laminaria digitata (oarweed) are effective accumulators of I from seawater, with tissue concentrations exceeding 50 mM, and the vanadate-containing enzyme haloperoxidase is implicated in halide accumulation. We have studied the chemical state of iodine and its biological role in Laminaria at the I K edge, and bromoperoxidase from Ascophyllum nodosum (knotted wrack) at the Br K edge. Mo is essential for many forms of life; W only for certain archaea, such as Archaeoglobus fulgidus and the hyperthermophilic archaeon Pyrococcus furiosus, and some bacteria. The metals are bound and transported as their oxo-anions, molybdate and tungstate, which are similar in size. The transport protein WtpA from P. furiosus binds tungstate more strongly than molybdate, and is related in sequence to Archaeoglobus fulgidus ModA, of which a crystal structure is known. We have measured A. fulgidus ModA with tungstate at the W L{sub 3} (2p{sub 3/2}) edge, and compared the results with the refined crystal structure. XAS studies of anion binding are feasible even if only weak interactions are present, are biologically relevant, and give new insights in the spectroscopy.

  6. Multiplicities of dihedral discriminants

    Science.gov (United States)

    Mayer, Daniel C.

    1992-04-01

    Given the discriminant {d_k} of a quadratic field k, the number of cyclic relative extensions N\\vert k of fixed odd prime degree p with dihedral absolute Galois group of order 2p, which share a common conductor f, is called the multiplicity of the dihedral discriminant {d_N} = {f^{2(p - 1)}}d_k^p . In this paper, general formulas for multiplicities of dihedral discriminants are derived by analyzing the p-rank of the ring class group mod f of k. For the special case p = 3,{d_k} = - 3 , an elementary proof is given additionally. The theory is illustrated by a discussion of all known discriminants of multiplicity ≥ 5 of totally real and complex cubic fields.

  7. The Future Multiple

    DEFF Research Database (Denmark)

    Spaniol, Matthew Jon; Rowland, Nicholas James

    2015-01-01

    , if “the future” were so preposterous an idea, then “futures” would cease to be a critical alternative to it. Futures needs the future; they are relationally bound together in a multiplicity. This paper considers what such a logical reality implies for a field that distances itself from the future and self......Purpose – This paper asks “Why is the future in futures studies plural?” The attitude toward inquiry, based on post-actor-network theory (ANT) literature, positions philosophical questions about the ontological character of the future within the context of “planning” for it (i.e. in practice......). Multiplicity, as a post-ANT sensibility, helps one make sense of the empirical materials. This paper examines the possibility that rather than being alternatives to one another, plural futures and the singular future might co-exist in practice, and, thus, constitute a multiplicity. Design...

  8. Multiple origins of life

    Science.gov (United States)

    Raup, D. M.; Valentine, J. W.

    1983-01-01

    There is some indication that life may have originated readily under primitive earth conditions. If there were multiple origins of life, the result could have been a polyphyletic biota today. Using simple stochastic models for diversification and extinction, we conclude: (1) the probability of survival of life is low unless there are multiple origins, and (2) given survival of life and given as many as 10 independent origins of life, the odds are that all but one would have gone extinct, yielding the monophyletic biota we have now. The fact of the survival of our particular form of life does not imply that it was unique or superior.

  9. Neutron multiplicity analysis tool

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, Scott L [Los Alamos National Laboratory

    2010-01-01

    I describe the capabilities of the EXCOM (EXcel based COincidence and Multiplicity) calculation tool which is used to analyze experimental data or simulated neutron multiplicity data. The input to the program is the count-rate data (including the multiplicity distribution) for a measurement, the isotopic composition of the sample and relevant dates. The program carries out deadtime correction and background subtraction and then performs a number of analyses. These are: passive calibration curve, known alpha and multiplicity analysis. The latter is done with both the point model and with the weighted point model. In the current application EXCOM carries out the rapid analysis of Monte Carlo calculated quantities and allows the user to determine the magnitude of sample perturbations that lead to systematic errors. Neutron multiplicity counting is an assay method used in the analysis of plutonium for safeguards applications. It is widely used in nuclear material accountancy by international (IAEA) and national inspectors. The method uses the measurement of the correlations in a pulse train to extract information on the spontaneous fission rate in the presence of neutrons from ({alpha},n) reactions and induced fission. The measurement is relatively simple to perform and gives results very quickly ({le} 1 hour). By contrast, destructive analysis techniques are extremely costly and time consuming (several days). By improving the achievable accuracy of neutron multiplicity counting, a nondestructive analysis technique, it could be possible to reduce the use of destructive analysis measurements required in safeguards applications. The accuracy of a neutron multiplicity measurement can be affected by a number of variables such as density, isotopic composition, chemical composition and moisture in the material. In order to determine the magnitude of these effects on the measured plutonium mass a calculational tool, EXCOM, has been produced using VBA within Excel. This

  10. Problems of multiple transfusions.

    Science.gov (United States)

    GARDNER, F H

    1958-02-01

    The use of blood infusion in large amounts is increasing sharply. Increased knowledge of blood group antigens has alerted physicians to the possible hazards of hemolytic reactions to subgroups that must be eliminated by proper cross-matching techniques. Multiple transfusions of preserved blood often defeat their purpose in control of bleeding, for thrombocytopenia is enhanced. Careful selection of blood or preparations of plasma concentrates offer increased protection to the recipient.Plastic bag equipment increases the yield of viable platelets and keeps blood in usable condition for longer periods of storage. The use of multiple transfusions has complicated the selection of preserved blood to control pigment metabolism. PMID:13500210

  11. Multiple Sclerosis in Children

    Directory of Open Access Journals (Sweden)

    Soroor INALOO

    2013-06-01

    Full Text Available How to Cite This Article: Inaloo S, Haghbin S. Multiple Sclerosis in Children. Iran J Child Neurol. 2013 Spring;7(2:1-10. Multiple sclerosis (MS is the most important immune-mediated demyelinated disease of human which is typically the disease of young adults. A total of 4% to 5% of MS population are pediatric. Pediatric MS is defined as the appearance of MS before the age of sixteen. About 80% of the pediatric cases and nearly all adolescent onset patients present with attacks typical to adult MS. Approximately 97% to 99% of the affected children have relapsing-remitting MS, while 85% to 95% of the adults experience such condition. MS in children is associated with more frequent and severe relapses. Treatment is the same as adults. We aimed to review the epidemiology, etiology, clinical manifestations, and treatment of MS in children. References1. Lublin F. History of modern multiple sclerosis therapy. J Neurol 2005 Sep;252(Suppl 3:iii3-iii9. Review.2. Murray TJ. Robert Carswell: the first illustrator of MS. Int MS J 2009 Sep;16(3:98-101.3. Kabat EA, Glusman M, Knaub V. Quantitative estimation of the albumin and gamma globulin in normal and pathologic cerebrospinal fluid by immunochemical methods. Am J Med 1948 May;4(5:653-62.4. Kumar DR, Aslinia F, Yale SH, Mazza JJ. Jean-Martin Charcot: the father of neurology. Clin Med Res 2011 Mar;9(1:46-9.5. Dawson JD. The histology of disseminated sclerosis.Trans of the Roy Soc Edinb. 1916;50:517-740.6. Gadoth N. Multiple sclerosis in children. Brain Dev 2003 Jun;25(4:229-32. Review.7. Banwell BL. Pediatric multiple sclerosis. Curr Neurol Neurosci Rep 2004 May;4(3:245-52.8. Renoux C, Vukusic S, Mikaeloff Y, Edan G, Clanet M, Dubois B, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007 Jun 21;356(25:2603-13.9. Boiko A, Vorobeychicle G, Paty D, Devonshire V, Sondovnick D. Early onset multiple sclerosis: a long longitudinal study. Neurology 2002 Oct 8

  12. Multiple Roles of Secretaries

    Institute of Scientific and Technical Information of China (English)

    刘倩; 王姝濒; 赵柳

    2015-01-01

    The work of secretaries is very comprehensive and secretaries are key members of a company team.The study on the multiple roles of secretaries is not only about the theory but also about the practice.To understand and study the multiple roles of secretaries can strengthen secretaries’ ability of adaption and secretaries’ strain capacity.The purpose of this paper is to present a way of looking at the complexities of secretaries’ roles,and let secretaries have a better understanding of their roles to act out perfectly.

  13. Multiple Roles of Secretaries

    Institute of Scientific and Technical Information of China (English)

    刘倩; 王姝濒; 赵柳

    2015-01-01

    The work of secretaries is very comprehensive and secretaries are key members of a company team.The study on the multiple roles of secretaries is not only about the theory but also about the practice.To understand and study the multiple roles of secretaries can strengthen secretaries’ ability of adaption and secretaries’ strain capacity.The purpose of this paper is to present a way oflooking at the complexities of secretaries’ roles,and let secretaries have a better understanding of their roles to act out perfectly.

  14. Computational Design of DNA-Binding Proteins.

    Science.gov (United States)

    Thyme, Summer; Song, Yifan

    2016-01-01

    Predicting the outcome of engineered and naturally occurring sequence perturbations to protein-DNA interfaces requires accurate computational modeling technologies. It has been well established that computational design to accommodate small numbers of DNA target site substitutions is possible. This chapter details the basic method of design used in the Rosetta macromolecular modeling program that has been successfully used to modulate the specificity of DNA-binding proteins. More recently, combining computational design and directed evolution has become a common approach for increasing the success rate of protein engineering projects. The power of such high-throughput screening depends on computational methods producing multiple potential solutions. Therefore, this chapter describes several protocols for increasing the diversity of designed output. Lastly, we describe an approach for building comparative models of protein-DNA complexes in order to utilize information from homologous sequences. These models can be used to explore how nature modulates specificity of protein-DNA interfaces and potentially can even be used as starting templates for further engineering. PMID:27094297

  15. Spatial distribution of predicted transcription factor binding sites in Drosophila ChIP peaks.

    Science.gov (United States)

    Pettie, Kade P; Dresch, Jacqueline M; Drewell, Robert A

    2016-08-01

    In the development of the Drosophila embryo, gene expression is directed by the sequence-specific interactions of a large network of protein transcription factors (TFs) and DNA cis-regulatory binding sites. Once the identity of the typically 8-10bp binding sites for any given TF has been determined by one of several experimental procedures, the sequences can be represented in a position weight matrix (PWM) and used to predict the location of additional TF binding sites elsewhere in the genome. Often, alignments of large (>200bp) genomic fragments that have been experimentally determined to bind the TF of interest in Chromatin Immunoprecipitation (ChIP) studies are trimmed under the assumption that the majority of the binding sites are located near the center of all the aligned fragments. In this study, ChIP/chip datasets are analyzed using the corresponding PWMs for the well-studied TFs; CAUDAL, HUNCHBACK, KNIRPS and KRUPPEL, to determine the distribution of predicted binding sites. All four TFs are critical regulators of gene expression along the anterio-posterior axis in early Drosophila development. For all four TFs, the ChIP peaks contain multiple binding sites that are broadly distributed across the genomic region represented by the peak, regardless of the prediction stringency criteria used. This result suggests that ChIP peak trimming may exclude functional binding sites from subsequent analyses.

  16. 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

  17. Erythropoietin binding protein from mammalian serum

    Energy Technology Data Exchange (ETDEWEB)

    Clemons, G.K.

    1997-04-29

    Purified mammalian erythropoietin binding-protein is disclosed, and its isolation, identification, characterization, purification, and immunoassay are described. The erythropoietin binding protein can be used for regulation of erythropoiesis by regulating levels and half-life of erythropoietin. A diagnostic kit for determination of level of erythropoietin binding protein is also described. 11 figs.

  18. Erythropoietin binding protein from mammalian serum

    Energy Technology Data Exchange (ETDEWEB)

    Clemons, Gisela K. (Berkeley, CA)

    1997-01-01

    Purified mammalian erythropoietin binding-protein is disclosed, and its isolation, identification, characterization, purification, and immunoassay are described. The erythropoietin binding protein can be used for regulation of erythropoiesis by regulating levels and half-life of erythropoietin. A diagnostic kit for determination of level of erythropoietin binding protein is also described.

  19. Cell-type specificity of ChIP-predicted transcription factor binding sites

    Directory of Open Access Journals (Sweden)

    Håndstad Tony

    2012-08-01

    Full Text Available Abstract Background Context-dependent transcription factor (TF binding is one reason for differences in gene expression patterns between different cellular states. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq identifies genome-wide TF binding sites for one particular context—the cells used in the experiment. But can such ChIP-seq data predict TF binding in other cellular contexts and is it possible to distinguish context-dependent from ubiquitous TF binding? Results We compared ChIP-seq data on TF binding for multiple TFs in two different cell types and found that on average only a third of ChIP-seq peak regions are common to both cell types. Expectedly, common peaks occur more frequently in certain genomic contexts, such as CpG-rich promoters, whereas chromatin differences characterize cell-type specific TF binding. We also find, however, that genotype differences between the cell types can explain differences in binding. Moreover, ChIP-seq signal intensity and peak clustering are the strongest predictors of common peaks. Compared with strong peaks located in regions containing peaks for multiple transcription factors, weak and isolated peaks are less common between the cell types and are less associated with data that indicate regulatory activity. Conclusions Together, the results suggest that experimental noise is prevalent among weak peaks, whereas strong and clustered peaks represent high-confidence binding events that often occur in other cellular contexts. Nevertheless, 30-40% of the strongest and most clustered peaks show context-dependent regulation. We show that by combining signal intensity with additional data—ranging from context independent information such as binding site conservation and position weight matrix scores to context dependent chromatin structure—we can predict whether a ChIP-seq peak is likely to be present in other cellular contexts.

  20. Multiple primary bronchogenic carcinomas.

    Science.gov (United States)

    Yang, X; Ji, H; Paljarvi, L; Soimakallio, S

    1996-07-01

    Multiple primary bronchogenic carcinomas (MPBCa) are extremely rare. The differentiation of a MPBCa from a pulmonary metastasis due to an extrathoracic neoplasm is sometimes difficult. We reviewed 324 pathologically proved primary pulmonary carcinomas and found six cases of MPBCa (1.9%). We herewith present the series and discuss the diagnosis of MPBCa. PMID:21594435

  1. Multiple snapshot compressive beamforming

    DEFF Research Database (Denmark)

    Gerstoft, Peter; Xenaki, Angeliki; Mecklenbrauker, Christoph F.;

    2015-01-01

    For sound fields observed on an array, compressive sensing (CS) reconstructs the multiple source signals at unknown directions-of-arrival (DOAs) using a sparsity constraint. The DOA estimation is posed as an underdetermined problem expressing the field at each sensor as a phase-lagged superposition...

  2. Ordering, materiality and multiplicity

    DEFF Research Database (Denmark)

    van der Duim, René; Ren, Carina Bregnholm; Jóhannesson, Gunnar Thór

    2013-01-01

    In this article we discuss how ANT has been translated into tourism research and show how it has impacted the field by presenting three concepts integral to the ANT approach: ordering, materiality and multiplicity. We first introduce ANT and draw attention to current ANT studies in tourism...

  3. Multiple Grammars and MOGUL

    Science.gov (United States)

    Truscott, John

    2014-01-01

    Optionality is a central phenomenon in second language acquisition (SLA), for which any adequate theory must account. Amaral and Roeper (this issue; henceforth A&R) offer an appealing approach to it, using Roeper's Multiple Grammars Theory, which was created with first language in mind but which extends very naturally to SLA. They include…

  4. Multiple Choriangiomas of Placenta

    Directory of Open Access Journals (Sweden)

    Vijay Shankar S,

    2011-01-01

    Full Text Available Placental chorangiomas, not an uncommon condition is often small and hence usually goes unnoticed . However the incidence of complications is high when the chorangioma is large. We hereby present an unusual case of large and multiple choriangiomas with secondary changes and associated congenital anomalies with hydrops fetalis.

  5. Multiple Chemical Sensitivity

    DEFF Research Database (Denmark)

    Junge, Anne Gram

    Et voksende antal mennesker i Danmark oplever at være overfølsomme over for dufte og kemikalier. Imidlertid er den tilskrevne diagnose Multiple Chemical Sensitivity (MCS) ikke medicinsk anerkendt i Danmark pga. mangel på organiske og patofysiologisk basis for symptomerne. Dette speciale bygger på...

  6. Multiple chemical sensitivity

    DEFF Research Database (Denmark)

    Tran, Marie Thi Dao; Arendt-Nielsen, Lars; Kupers, Ron;

    2013-01-01

    BACKGROUND: Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by recurrent, non-specific symptoms in response to chemically unrelated exposures in non-toxic concentrations. Although the pathophysiology of MCS remains unknown, central sensitization may be an important factor...

  7. Multiple Endocrine Neoplasia Syndromes

    Science.gov (United States)

    ... type 2A disease. Almost everyone with type 2A disease develops medullary thyroid cancer (see Medullary cancer ). About 40 to ... stones in about 25% of people. Type 2B disease Multiple endocrine neoplasia type 2B can consist of Medullary thyroid cancer Pheochromocytomas Growths around nerves (neuromas) Many ...

  8. Multiple Cutaneous Reticulohistiocytoma

    Science.gov (United States)

    Hemmady, Karishma D; Someshwar, Shylaja S; Jerajani, Hemangi R

    2016-01-01

    Multicentric reticulohistiocytosis is a rare non-Langerhans cell histiocytosis characterized in its full form by severe destructive arthritis, cutaneous nodules, and systemic manifestations. Cutaneous lesions may precede, accompany, or more commonly develop later than other features in this disease. We describe a case of multiple cutaneous reticulohistiocytoma without any systemic associations after thorough investigations. PMID:26955136

  9. Multiple Primary Cancer Monograph

    Science.gov (United States)

    To identify groups of cancer survivors that are at increased risk for multiple primary cancers, investigators led an effort to provide the first comprehensive population-based analysis of the risk of subsequent cancer in the U.S., resulting in a monograph.

  10. Multiple cystic swelling: Initial presentation of multiple myeloma

    OpenAIRE

    Kumar Sunil; Jain A; Waghmare Swati

    2010-01-01

    Multiple myeloma, a disease allied to malignancy of reticuloendothelial cells, is not an uncommon condition. However, the diagnosis is often made quite late because the disease has multiple modes of presentation. We are reporting a case of multiple myeloma in a 55-year-old male who presented with multiple cystic swellings on the chest.

  11. The multiple Dirichlet product and the multiple Dirichlet series

    OpenAIRE

    Onozuka, Tomokazu

    2016-01-01

    First, we define the multiple Dirichlet product and study the properties of it. From those properties, we obtain a zero-free region of a multiple Dirichlet series and a multiple Dirichlet series expression of the reciprocal of a multiple Dirichlet series.

  12. Stable optical trapping based on optical binding forces.

    Science.gov (United States)

    Grzegorczyk, Tomasz M; Kemp, Brandon A; Kong, Jin Au

    2006-03-24

    Various trapping configurations have been realized so far, either based on the scattering force or the gradient force. In this Letter, we propose a new trapping regime based on the equilibrium between a scattering force and optical binding forces only. The trap is realized from the interaction between a single plane wave and a series of fixed small particles, and is efficient at trapping multiple free particles. The effects are demonstrated analytically upon computing the exact scattering from a collection of cylindrical particles and calculating the Lorentz force on each free particle via the Maxwell stress tensor. PMID:16605823

  13. Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators.

    Science.gov (United States)

    Karapetyan, Sargis; Buchler, Nicolas E

    2015-12-01

    Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ultrasensitivity that is specific for repression. We then use stochastic simulation to show that multiple binding sites increase the coherence of oscillations by mitigating the binary noise. Slow values of DNA unbinding rate are also effective in alleviating molecular noise due to the increased distance from the bifurcation point. Our work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, can have a significant impact on the temporal and stochastic dynamics of genetic oscillators.

  14. Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators

    Science.gov (United States)

    Karapetyan, Sargis; Buchler, Nicolas E.

    2015-12-01

    Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ultrasensitivity that is specific for repression. We then use stochastic simulation to show that multiple binding sites increase the coherence of oscillations by mitigating the binary noise. Slow values of DNA unbinding rate are also effective in alleviating molecular noise due to the increased distance from the bifurcation point. Our work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, can have a significant impact on the temporal and stochastic dynamics of genetic oscillators.

  15. The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis

    OpenAIRE

    Ding, Di; Enriquez-Algeciras, Mabel; Dave, Kunjan R; Perez-Pinzon, Miguel; Bhattacharya, Sanjoy K.

    2012-01-01

    Bhattacharya and collaborators find that a mouse model for multiple sclerosis develops mitochondrial dysfunction through deimination of REF, an RNA-binding protein involved in mRNA transport into mitochondria.

  16. Synthetic heparin-binding factor analogs

    Science.gov (United States)

    Pena, Louis A.; Zamora, Paul O.; Lin, Xinhua; Glass, John D.

    2010-04-20

    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain, and preferably two peptide chains branched from a dipeptide branch moiety composed of two trifunctional amino acid residues, which peptide chain or chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a linker, which may be a hydrophobic linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

  17. The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition.

    Science.gov (United States)

    Wienk, Hans; Slootweg, Jack C; Speerstra, Sietske; Kaptein, Robert; Boelens, Rolf; Folkers, Gert E

    2013-07-01

    To maintain the integrity of the genome, multiple DNA repair systems exist to repair damaged DNA. Recognition of altered DNA, including bulky adducts, pyrimidine dimers and interstrand crosslinks (ICL), partially depends on proteins containing helix-hairpin-helix (HhH) domains. To understand how ICL is specifically recognized by the Fanconi anemia proteins FANCM and FAAP24, we determined the structure of the HhH domain of FAAP24. Although it resembles other HhH domains, the FAAP24 domain contains a canonical hairpin motif followed by distorted motif. The HhH domain can bind various DNA substrates; using nuclear magnetic resonance titration experiments, we demonstrate that the canonical HhH motif is required for double-stranded DNA (dsDNA) binding, whereas the unstructured N-terminus can interact with single-stranded DNA. Both DNA binding surfaces are used for binding to ICL-like single/double-strand junction-containing DNA substrates. A structural model for FAAP24 bound to dsDNA has been made based on homology with the translesion polymerase iota. Site-directed mutagenesis, sequence conservation and charge distribution support the dsDNA-binding model. Analogous to other HhH domain-containing proteins, we suggest that multiple FAAP24 regions together contribute to binding to single/double-strand junction, which could contribute to specificity in ICL DNA recognition.

  18. Solution NMR characterization of chemokine CXCL8/IL-8 monomer and dimer binding to glycosaminoglycans: structural plasticity mediates differential binding interactions.

    Science.gov (United States)

    Joseph, Prem Raj B; Mosier, Philip D; Desai, Umesh R; Rajarathnam, Krishna

    2015-11-15

    Chemokine CXCL8/interleukin-8 (IL-8) plays a crucial role in directing neutrophils and oligodendrocytes to combat infection/injury and tumour cells in metastasis development. CXCL8 exists as monomers and dimers and interaction of both forms with glycosaminoglycans (GAGs) mediate these diverse cellular processes. However, very little is known regarding the structural basis underlying CXCL8-GAG interactions. There are conflicting reports on the affinities, geometry and whether the monomer or dimer is the high-affinity GAG ligand. To resolve these issues, we characterized the binding of a series of heparin-derived oligosaccharides [heparin disaccharide (dp2), heparin tetrasaccharide (dp4), heparin octasaccharide (dp8) and heparin 14-mer (dp14)] to the wild-type (WT) dimer and a designed monomer using solution NMR spectroscopy. The pattern and extent of binding-induced chemical shift perturbation (CSP) varied between dimer and monomer and between longer and shorter oligosaccharides. NMR-based structural models show that different interaction modes coexist and that the nature of interactions varied between monomer and dimer and oligosaccharide length. MD simulations indicate that the binding interface is structurally plastic and provided residue-specific details of the dynamic nature of the binding interface. Binding studies carried out under conditions at which WT CXCL8 exists as monomers and dimers provide unambiguous evidence that the dimer is the high-affinity GAG ligand. Together, our data indicate that a set of core residues function as the major recognition/binding site, a set of peripheral residues define the various binding geometries and that the structural plasticity of the binding interface allows multiplicity of binding interactions. We conclude that structural plasticity most probably regulates in vivo CXCL8 monomer/dimer-GAG interactions and function.

  19. Conceptualizing Mind and Consciousness: Using Constructivist Ideas to Transcend the Physical Bind

    Science.gov (United States)

    Becker, Joe

    2008-01-01

    Philosophers and scientists seeking to conceptualize consciousness, and subjective experience in particular, have focused on sensation and perception, and have emphasized binding--how a percept holds together. Building on a constructivist approach to conception centered on separistic-holistic complexes incorporating multiple levels of abstraction,…

  20. Pyelolithotomy by the use of a hydrophilous macromolecular binding material ("pyeloform" pyelotomy).

    Science.gov (United States)

    Nagy, Z; Frang, D; Jávor, A; Götz, F; Szatmári, J; Vizi, L; Kovács, G

    1984-01-01

    The use of a synthetic macromolecular hydrophilous binding material for the extraction of multiple renal calculi (" Pyeloform " pyelotomy) is reported. An account of the results of animal studies in vitro is given and the possibilities of the method in are pointed out. PMID:6724825

  1. The Role of Attention in the Maintenance of Feature Bindings in Visual Short-term Memory

    Science.gov (United States)

    Johnson, Jeffrey S.; Hollingworth, Andrew; Luck, Steven J.

    2008-01-01

    This study examined the role of attention in maintaining feature bindings in visual short-term memory. In a change-detection paradigm, participants attempted to detect changes in the colors and orientations of multiple objects; the changes consisted of new feature values in a feature-memory condition and changes in how existing feature values were…

  2. 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...

  3. The role of DNA binding sites and slow unbinding kinetics in titration-based oscillators

    CERN Document Server

    Karapetyan, Sargis

    2015-01-01

    Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ul...

  4. Positive Control Mutations in the MyoD Basic Region Fail to Show Cooperative DNA Binding and Transcriptional Activation in vitro

    Science.gov (United States)

    Bengal, Eyal; Flores, Osvaldo; Rangarajan, Pundi N.; Chen, Amy; Weintraub, Harold; Verma, Inder M.

    1994-06-01

    An in vitro transcription system from HeLa cells has been established in which MyoD and E47 proteins activate transcription both as homodimers and heterodimers. However, heterodimers activate transcription more efficiently than homodimers, and function synergistically from multiple binding sites. Positive control mutants in the basic region of MyoD that have previously been shown to be defective in initiating the myogenic program, can bind DNA but have lost their ability to function as transcriptional activators in vitro. Additionally, positive control mutants, unlike wild-type MyoD, fail to bind cooperatively to DNA. We propose that binding of MyoD complexes to high affinity MyoD binding sites induces conformational changes that facilitate cooperative binding to multiple sites and promote transcriptional activation.

  5. Evolution of Binary Stars in Multiple-Population Globular Clusters

    CERN Document Server

    Hong, Jongsuk; Sollima, Antonio; McMillan, Stephen L W; D'Antona, Franca; D'Ercole, Annibale

    2015-01-01

    The discovery of multiple stellar populations in globular clusters has implications for all the aspects of the study of these stellar systems. In this paper, by means of N-body simulations, we study the evolution of binary stars in multiple-population clusters and explore the implications of the initial differences in the spatial distribution of different stellar populations for the evolution and survival of their binary stars. Our simulations show that initial differences between the spatial distribution of first-generation (FG) and second-generation (SG) stars can leave a fingerprint in the current properties of the binary population. SG binaries are disrupted more efficiently than those of the FG population resulting in a global SG binary fraction smaller than that of the FG. As for surviving binaries, dynamical evolution produces a difference between the SG and the FG binary binding energy distribution with the SG population characterized by a larger fraction of high binding energy (more bound) binaries. ...

  6. Custom-designed MLPA using multiple short synthetic probes

    DEFF Research Database (Denmark)

    Serizawa, R.R.; Ralfkiaer, U.; Dahl, C.;

    2010-01-01

    Ligation of two oligonucleotide probes hybridized adjacently to a DNA template has been widely used for detection of genome alterations. The multiplex ligation-dependent probe amplification (MLPA) technique allows simultaneous screening of multiple target sequences in a single reaction by using......-stranded bacteriophage vector to introduce a sequence of defined length between the primer binding site and the specific target sequence. Here we demonstrate that differences in amplicon length can be achieved by using multiple short synthetic probes for each target sequence. When joined by a DNA ligase, these probes...

  7. Infinite sets and double binds.

    Science.gov (United States)

    Arden, M

    1984-01-01

    There have been many attempts to bring psychoanalytical theory up to date. This paper approaches the problem by discussing the work of Gregory Bateson and Ignacio Matte-Blanco, with particular reference to the use made by these authors of Russell's theory of logical types. Bateson's theory of the double bind and Matte-Blanco's bilogic are both based on concepts of logical typing. It is argued that the two theories can be linked by the idea that neurotic symptoms are based on category errors in thinking. Clinical material is presented from the analysis of a middle-aged woman. The intention is to demonstrate that the process of making interpretations can be thought of as revealing errors in thinking. Changes in the patient's inner world are then seen to be the result of clarifying childhood experiences based on category errors. Matte-Blanco's theory of bilogic and infinite experiences is a re-evaluation of the place of the primary process in mental life. It is suggested that a combination of bilogic and double bind theory provides a possibility of reformulating psychoanalytical theory.

  8. Curability of Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Raymond Alexanian

    2012-01-01

    Full Text Available Among 792 patients with multiple myeloma treated from 1987 to 2010 and assessed after 18 months, there were 167 patients with complete remission. For those 60 patients treated between 1987–1998 and with long followup, the latest relapse occurred after 11.8 years, so that 13 patients have remained in sustained complete remission for longer than 12 years (range 12–22 years. These results suggest that 3% of all patients treated during that period may be cured of multiple myeloma. In addition to immunofixation, more sensitive techniques for the detection of residual disease should be applied more consistently in patients with apparent complete remission in order to identify those with potential cure.

  9. Chronic progressive multiple sclerosis

    International Nuclear Information System (INIS)

    A long-lasting immunological suppression action seems to be produced by total lymphoid irradiation; some authors emphasize the favorable effect of this treatment on chronic progressive multiple sclerosis. In order to evaluate the actual role of TLI, 6 patients affected with chronic progressive multiple sclerosis were submitted to TLI with shaped and personalized fields at the Istituto del Radio, University of Brescia, Italy. The total dose delivered was 19.8 Gy in 4 weeks, 1.8 Gy/day, 5d/w; a week elapsed between the first and the second irradiation course. Disability according to Kurtzke scale was evaluated, together with blood lymphocyte count and irradiation side-effects, over a mean follow-up period of 20.8 months (range: 13-24). Our findings indicate that: a) disease progression was not markedly reduced by TLI; b) steroid hormones responsivity was restored after irradiation, and c) side-effects were mild and tolerable

  10. Suicide and multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E N; Stenager, Egon; Koch-Henriksen, Nils;

    1992-01-01

    In a nationwide investigation the risk of death by suicide for patients with multiple sclerosis (MS) was assessed using records kept at the Danish Multiple Sclerosis Registry (DMSR) and the Danish National Register of Cause of Death. The investigation covers all MS patients registered with DSMR...... with an onset of the disease within the period 1953-85, or for whom MS was diagnosed in the same period. Fifty three of the 5525 cases in the onset cohort group committed suicide. Using the figures from the population death statistics by adjustment to number of subjects, duration of observation, sex, age......, and calendar year at the start of observation, the expected number of suicides was calculated to be nearly 29. The cumulative lifetime risk of suicide from onset of MS, using an actuarial method of calculation, was 1.95%. The standard mortality ratio (SMR) of suicide in MS was 1.83. It was highest for males...

  11. Multiple part feeding

    DEFF Research Database (Denmark)

    Hvilshøj, Mads; Bøgh, Simon; Nielsen, Oluf Skov;

    2012-01-01

    Purpose - The purpose of this paper is to present experience from a real-world demonstration of autonomous industrial mobile manipulation (AIMM) based on the mobile manipulator "Little Helper" performing multiple part feeding at the pump manufacturer Grundfos A/S. Design/methodology/approach - Th......Purpose - The purpose of this paper is to present experience from a real-world demonstration of autonomous industrial mobile manipulation (AIMM) based on the mobile manipulator "Little Helper" performing multiple part feeding at the pump manufacturer Grundfos A/S. Design......" is capable of successfully servicing four part feeders in three production cells using command signals from an Open Process Control (OPC) server. Furthermore, the paper presents future research and development suggestions for AIMM, which contributes to near-term industrial maturation and implementation...

  12. Formation of multiple networks

    DEFF Research Database (Denmark)

    Magnani, Matteo; Rossi, Luca

    2013-01-01

    While most research in Social Network Analysis has focused on single networks, the availability of complex on-line data about individuals and their mutual heterogenous connections has recently determined a renewed interest in multi-layer network analysis. To the best of our knowledge, in this paper...... we introduce the first network formation model for multiple networks. Network formation models are among the most popular tools in traditional network studies, because of both their practical and theoretical impact. However, existing models are not sufficient to describe the generation of multiple...... networks. Our model, motivated by an empirical analysis of real multi-layered network data, is a conservative extension of single-network models and emphasizes the additional level of complexity that we experience when we move from a single- to a more complete and realistic multi-network context....

  13. Albumin and multiple sclerosis

    OpenAIRE

    LeVine, Steven M

    2016-01-01

    Leakage of the blood–brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furth...

  14. Multiple cystic lung disease

    OpenAIRE

    Flavia Angélica Ferreira Francisco; Arthur Soares Souza; Gláucia Zanetti; Edson Marchiori

    2015-01-01

    Multiple cystic lung disease represents a diverse group of uncommon disorders that can present a diagnostic challenge due to the increasing number of diseases associated with this presentation. High-resolution computed tomography of the chest helps to define the morphological aspects and distribution of lung cysts, as well as associated findings. The combination of appearance upon imaging and clinical features, together with extrapulmonary manifestations, when present, permits confident and a...

  15. Multiple Peril Crop Insurance

    OpenAIRE

    Edwards, William M.; Hofstrand, Donald

    2003-01-01

    Multiple Peril Crop Insurance (MPCI) is a broad-based crop insurance program regulated by the U.S. Department of Agriculture and subsidized by the Federal Crop Insurance Corporation(FCIC). Crops eligible for MPCI coverage in Iowa include corn, sobyeans, oats, wheat, seed corn, popcorn, barley, potatoes, sweet corn, canning beans, dry beans, forages, grain sorghum, green peas, tomatoes, and nursery stocks. Not all of these crops can be insured in all counties.

  16. Strategizing in multiple ways

    DEFF Research Database (Denmark)

    Larsen, Mette Vinther; Madsen, Charlotte Øland; Rasmussen, Jørgen Gulddahl

    2013-01-01

    Strategy processes are kinds of wayfaring where different actors interpret a formally defined strat-egy differently. In the everyday practice of organizations strategizing takes place in multiple ways through narratives and sensible actions. This forms a meshwork of polyphonic ways to enact one a...... based on this development paper is whether one can understand these diver-gent strategic wayfaring processes as constructive for organizations....

  17. Metamemory in multiple sclerosis

    OpenAIRE

    Claffey, Austin M

    2010-01-01

    This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University. The concept of metamemory proposes that supplementary to typically measured memory abilities, memory monitoring and control processes are used to optimise learning. Accurate memory monitoring appears to be underpinned by a range of cognitive, and possibly affective, contributions. In populations with these deficits, metamemory has been shown to be impaired. In Multiple Sclerosis (MS), only...

  18. Multiple plots in R

    DEFF Research Database (Denmark)

    Edwards, Stefan McKinnon

    2012-01-01

    In this chapter I will investigate how to combine multiple plots into a single. The scenario is a dataset of a series of measurements, on three samples in three situations. There are many ways we can display this, e.g. 3d graphs or faceting. 3d graphs are not good for displaying static data so we...... will not go there. Faceting is strictly speaking for plotting all variable / classes against each other....

  19. Deep Multiple Kernel Learning

    OpenAIRE

    Strobl, Eric; Visweswaran, Shyam

    2013-01-01

    Deep learning methods have predominantly been applied to large artificial neural networks. Despite their state-of-the-art performance, these large networks typically do not generalize well to datasets with limited sample sizes. In this paper, we take a different approach by learning multiple layers of kernels. We combine kernels at each layer and then optimize over an estimate of the support vector machine leave-one-out error rather than the dual objective function. Our experiments on a varie...

  20. Multiple muons in MACRO

    Science.gov (United States)

    Heinz, R.

    1985-01-01

    An analysis of the multiple muon events in the Monopole Astrophysics and Cosmic Ray Observatory detector was conducted to determine the cosmic ray composition. Particular emphasis is placed on the interesting primary cosmic ray energy region above 2000 TeV/nucleus. An extensive study of muon production in cosmic ray showers has been done. Results were used to parameterize the characteristics of muon penetration into the Earth to the location of a detector.

  1. Multiple carpometacarpal dislocations.

    OpenAIRE

    Kumar, A.; Olney, D B

    1994-01-01

    We present a case of dislocations of the carpometacarpal joints without associated fractures. Although carpometacarpal injuries are relatively uncommon, it is rare for multiple carpometacarpal dislocations to occur without associated fractures. The injury is difficult to diagnose because of swelling of the hand. A lateral radiograph of the wrist has been found to be mandatory to its precise diagnosis if suspected. In the case presented here early diagnosis and closed manipulation in the accid...

  2. Multiple myeloma: 45 cases

    International Nuclear Information System (INIS)

    We evaluated 45 cases of multiple myelomas retrospectively confirmed in Severance Hospital from the period of 1983-1989. In order to assess the radiologic features of the multiple myeloma and to assist in possible early diagnosis and treatment. The result were as follows: 1. IgG(41%) was the most common immunoglobulin type secreted followed by light chain(36%). IgA(19%) and IgD(2%). Two percent of the patients had non-secretory type. 89% of patients were in their stage III of the disease. 2. Among the 45 patients, 96% had abnormal plain radiographic findings with average number of 4.5 lesions. Common sites were the spine, rib, skull, pelvis, and humerus in descending orders. The findings were localized or diffuse osteolytic bone destruction(85%). osteoporosis(49%), pathologic fracture and endosteal scalloping(55%). Osteoporosis was more prominent in stage III than stage II. 3. Both plain X-ray and radioisotope study was available for comparison in 28 patients. Concordance between the two studies were 44%, lesions detected only on plain X-ray film were 51%, and lesions detected only on the radioisotope were 5%. The plain radiography was able to detect only 54% of bone lesions confirmed by bone marrow biopsy. With the above results, accurate evaluation of bone lesions in multiple myeloma may be difficult with radiologic studies only. But familiarity with these radiologic findings of the this disease entity is necessary for early suspicion of the disease, thus for early diagnosis and treatment

  3. Multiple myeloma: 45 cases

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Hee Chul; Suh, Jin Suck; Park, Chang Yun [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1990-10-15

    We evaluated 45 cases of multiple myelomas retrospectively confirmed in Severance Hospital from the period of 1983-1989. In order to assess the radiologic features of the multiple myeloma and to assist in possible early diagnosis and treatment. The result were as follows: 1. IgG(41%) was the most common immunoglobulin type secreted followed by light chain(36%). IgA(19%) and IgD(2%). Two percent of the patients had non-secretory type. 89% of patients were in their stage III of the disease. 2. Among the 45 patients, 96% had abnormal plain radiographic findings with average number of 4.5 lesions. Common sites were the spine, rib, skull, pelvis, and humerus in descending orders. The findings were localized or diffuse osteolytic bone destruction(85%). osteoporosis(49%), pathologic fracture and endosteal scalloping(55%). Osteoporosis was more prominent in stage III than stage II. 3. Both plain X-ray and radioisotope study was available for comparison in 28 patients. Concordance between the two studies were 44%, lesions detected only on plain X-ray film were 51%, and lesions detected only on the radioisotope were 5%. The plain radiography was able to detect only 54% of bone lesions confirmed by bone marrow biopsy. With the above results, accurate evaluation of bone lesions in multiple myeloma may be difficult with radiologic studies only. But familiarity with these radiologic findings of the this disease entity is necessary for early suspicion of the disease, thus for early diagnosis and treatment.

  4. Multiples waveform inversion

    KAUST Repository

    Zhang, D. L.

    2013-01-01

    To increase the illumination of the subsurface and to eliminate the dependency of FWI on the source wavelet, we propose multiples waveform inversion (MWI) that transforms each hydrophone into a virtual point source with a time history equal to that of the recorded data. These virtual sources are used to numerically generate downgoing wavefields that are correlated with the backprojected surface-related multiples to give the migration image. Since the recorded data are treated as the virtual sources, knowledge of the source wavelet is not required, and the subsurface illumination is greatly enhanced because the entire free surface acts as an extended source compared to the radiation pattern of a traditional point source. Numerical tests on the Marmousi2 model show that the convergence rate and the spatial resolution of MWI is, respectively, faster and more accurate then FWI. The potential pitfall with this method is that the multiples undergo more than one roundtrip to the surface, which increases attenuation and reduces spatial resolution. This can lead to less resolved tomograms compared to conventional FWI. The possible solution is to combine both FWI and MWI in inverting for the subsurface velocity distribution.

  5. Multiple organ procurement

    Directory of Open Access Journals (Sweden)

    Vuković Milivoje

    2007-01-01

    Full Text Available Introduction. Liver transplantation is the most demanding of all solid organ transplantations. It requires perfect organization and motivation of health care professionals, patients and their families. This article deals with the procedure for multiple organ procurement, reviews criteria for organ donation and describes the surgical technique for multiple organ procurement. Discussion. Adequate selection and evaluation of cadaveric donors and of organs for transplantation should include early identification of potential donors, and early diagnosis of brain death. The procurement of the highest number of viable organs for transplantation requires excellence in each of the phases. Early and aggressive physiologic support in the maintenance of potential donors can reduce organ donor loss due to irreversible asystole or multiorgan failure (it is almost always possible to maintain organ perfusion pressure and increase the number of organs without increasing post-transplant morbidity or mortality. The ideal donor is a young, previously healthy, brain dead, victim of an accident. Conclusion. The surgical procedure for multiple organ procurement from brain death donors must be performed without intraopertive organ damage. .

  6. Experimental and theoretical study on the binding of 2-mercaptothiazoline to bovine serum albumin

    International Nuclear Information System (INIS)

    2-Mercaptothiazoline (MTZ) is widely utilized as a brightening and stabilization agent, corrosion inhibitor and antifungal reagent. The residue of MTZ in the environment is potentially hazardous to human health. In this study, the binding mode of MTZ with bovine serum albumin (BSA) was investigated using spectroscopic and molecular docking methods under physiological conditions. MTZ could spontaneously bind with BSA through hydrogen bond and van der Waals interactions with one binding site. The site marker displacement experiments and the molecular docking revealed that MTZ bound into site II (subdomain IIIA) of BSA, which further resulted in some backbone structures and microenvironmental changes of BSA. This work is helpful for understanding the transportation, distribution and toxicity effects of MTZ in blood. - Highlights: • The mechanism was explored by multiple spectroscopic and molecular docking methods. • MTZ can spontaneously bind with BSA at subdomain IIIA (site II). • MTZ can lead to some conformational changes of BSA

  7. Experimental and theoretical study on the binding of 2-mercaptothiazoline to bovine serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Teng, Yue, E-mail: tengyue@jiangnan.edu.cn; Wang, Xiang; Zou, Luyi; Huang, Ming; Du, Xianzheng

    2015-05-15

    2-Mercaptothiazoline (MTZ) is widely utilized as a brightening and stabilization agent, corrosion inhibitor and antifungal reagent. The residue of MTZ in the environment is potentially hazardous to human health. In this study, the binding mode of MTZ with bovine serum albumin (BSA) was investigated using spectroscopic and molecular docking methods under physiological conditions. MTZ could spontaneously bind with BSA through hydrogen bond and van der Waals interactions with one binding site. The site marker displacement experiments and the molecular docking revealed that MTZ bound into site II (subdomain IIIA) of BSA, which further resulted in some backbone structures and microenvironmental changes of BSA. This work is helpful for understanding the transportation, distribution and toxicity effects of MTZ in blood. - Highlights: • The mechanism was explored by multiple spectroscopic and molecular docking methods. • MTZ can spontaneously bind with BSA at subdomain IIIA (site II). • MTZ can lead to some conformational changes of BSA.

  8. Ligand-receptor binding kinetics in surface plasmon resonance cells: A Monte Carlo analysis

    CERN Document Server

    Carroll, Jacob; Forsten-Williams, Kimberly; Täuber, Uwe C

    2016-01-01

    Surface plasmon resonance (SPR) chips are widely used to measure association and dissociation rates for the binding kinetics between two species of chemicals, e.g., cell receptors and ligands. It is commonly assumed that ligands are spatially well mixed in the SPR region, and hence a mean-field rate equation description is appropriate. This approximation however ignores the spatial fluctuations as well as temporal correlations induced by multiple local rebinding events, which become prominent for slow diffusion rates and high binding affinities. We report detailed Monte Carlo simulations of ligand binding kinetics in an SPR cell subject to laminar flow. We extract the binding and dissociation rates by means of the techniques frequently employed in experimental analysis that are motivated by the mean-field approximation. We find major discrepancies in a wide parameter regime between the thus extracted rates and the known input simulation values. These results underscore the crucial quantitative importance of s...

  9. Cooperativity between calmodulin-binding sites in Kv7.2 channels.

    Science.gov (United States)

    Alaimo, Alessandro; Alberdi, Araitz; Gomis-Perez, Carolina; Fernández-Orth, Juncal; Gómez-Posada, Juan Camilo; Areso, Pilar; Villarroel, Alvaro

    2013-01-01

    Among the multiple roles assigned to calmodulin (CaM), controlling the surface expression of Kv7.2 channels by binding to two discontinuous sites is a unique property of this Ca(2+) binding protein. Mutations that interfere with CaM binding or the sequestering of CaM prevent this M-channel component from exiting the endoplasmic reticulum (ER), which reduces M-current density in hippocampal neurons, enhancing excitability and offering a rational mechanism to explain some forms of benign familial neonatal convulsions (BFNC). Previously, we identified a mutation (S511D) that impedes CaM binding while allowing the channel to exit the ER, hinting that CaM binding may not be strictly required for Kv7.2 channel trafficking to the plasma membrane. Alternatively, this interaction with CaM might escape detection and, indeed, we now show that the S511D mutant contains functional CaM-binding sites that are not detected by classical biochemical techniques. Surface expression and function is rescued by CaM, suggesting that free CaM in HEK293 cells is limiting and reinforcing the hypothesis that CaM binding is required for ER exit. Within the CaM-binding domain formed by two sites (helix A and helix B), we show that CaM binds to helix B with higher apparent affinity than helix A, both in the presence and absence of Ca(2+), and that the two sites cooperate. Hence, CaM can bridge two binding domains, anchoring helix A of one subunit to helix B of another subunit, in this way influencing the function of Kv7.2 channels.

  10. Erythropoietin binding sites in human foetal tissues

    Energy Technology Data Exchange (ETDEWEB)

    Pekonen, F.; Rosenloef, K.; Rutanen, E.-M.

    1987-01-01

    Using /sup 125/I labelled recombinant DNA human erythropoietin (EP), we have explored the presence and properties of EP binding sites in foetal human tissues. The EP binding site is present in the foetal liver already during the first trimester of pregnancy. The binding site has a equilibrium association constant of 4.1-6.2 x 10/sup 9/l/mol and is specific for EP. The cross-reactivities of FSH, TSH, hCG, insulin and renin substrate were less than 0.01%. The EP binding capacity of foetal liver was 5.4-16 fmol/mg membrane protein. In foetal lung tissue, a slight EP binding activity was observed, whereas foetal spleen, muscle, brain, thyroid and placental tissues were virtually devoid of EP binding capacity. The same level of binding was reached at 37 deg. C in 1 h and at 4 deg. C in 24 h. The binding was pH-dependent with maximal specific binding at pH 7.7. SDS-PAGE gel electrophoresis analysis of covalently cross-linked /sup 125/I-EP to foetal liver membranes suggested that the EP binding site was composed of two subunits with an apparent mol wt of 41000 and 86000 dalton, respectively.

  11. Binding characteristics of swine erythrocyte insulin receptors

    International Nuclear Information System (INIS)

    Crossbred gilts had 8.8 +/- 1.1% maximum binding of [125I]insulin to insulin receptors on erythrocytes. The number of insulin-binding sites per cell was 137 +/- 19, with a binding affinity ranging from 7.4 X 10(7)M-1 to 11.2 X 10(7)M-1 and mean of 8.8 X 10(7)M-1. Pregnant sows had a significant increase in maximum binding due to an increase in number of receptor sites per cell. Lactating sows fed a high-fiber diet and a low-fiber diet did not develop a significant difference in maximum binding of insulin. Sows fed the low-fiber diet had a significantly higher number of binding sites and a significantly lower binding affinity than did sows fed a high-fiber diet. Receptor-binding affinity was lower in the low-fiber diet group than in cycling gilts, whereas data from sows fed the high-fiber diet did not differ from data for cycling gilts. Data from this study indicated that insulin receptors of swine erythrocytes have binding characteristics similar to those in other species. Pregnancy and diet will alter insulin receptor binding in swine

  12. Erythropoietin binding sites in human foetal tissues

    International Nuclear Information System (INIS)

    Using 125I labelled recombinant DNA human erythropoietin (EP), we have explored the presence and properties of EP binding sites in foetal human tissues. The EP binding site is present in the foetal liver already during the first trimester of pregnancy. The binding site has a equilibrium association constant of 4.1-6.2 x 109l/mol and is specific for EP. The cross-reactivities of FSH, TSH, hCG, insulin and renin substrate were less than 0.01%. The EP binding capacity of foetal liver was 5.4-16 fmol/mg membrane protein. In foetal lung tissue, a slight EP binding activity was observed, whereas foetal spleen, muscle, brain, thyroid and placental tissues were virtually devoid of EP binding capacity. The same level of binding was reached at 37 deg. C in 1 h and at 4 deg. C in 24 h. The binding was pH-dependent with maximal specific binding at pH 7.7. SDS-PAGE gel electrophoresis analysis of covalently cross-linked 125I-EP to foetal liver membranes suggested that the EP binding site was composed of two subunits with an apparent mol wt of 41000 and 86000 dalton, respectively. (author)

  13. Adaptive evolution of transcription factor binding sites

    Directory of Open Access Journals (Sweden)

    Berg Johannes

    2004-10-01

    Full Text Available Abstract Background The regulation of a gene depends on the binding of transcription factors to specific sites located in the regulatory region of the gene. The generation of these binding sites and of cooperativity between them are essential building blocks in the evolution of complex regulatory networks. We study a theoretical model for the sequence evolution of binding sites by point mutations. The approach is based on biophysical models for the binding of transcription factors to DNA. Hence we derive empirically grounded fitness landscapes, which enter a population genetics model including mutations, genetic drift, and selection. Results We show that the selection for factor binding generically leads to specific correlations between nucleotide frequencies at different positions of a binding site. We demonstrate the possibility of rapid adaptive evolution generating a new binding site for a given transcription factor by point mutations. The evolutionary time required is estimated in terms of the neutral (background mutation rate, the selection coefficient, and the effective population size. Conclusions The efficiency of binding site formation is seen to depend on two joint conditions: the binding site motif must be short enough and the promoter region must be long enough. These constraints on promoter architecture are indeed seen in eukaryotic systems. Furthermore, we analyse the adaptive evolution of genetic switches and of signal integration through binding cooperativity between different sites. Experimental tests of this picture involving the statistics of polymorphisms and phylogenies of sites are discussed.

  14. Determining the ice-binding planes of antifreeze proteins by fluorescence-based ice plane affinity.

    Science.gov (United States)

    Basu, Koli; Garnham, Christopher P; Nishimiya, Yoshiyuki; Tsuda, Sakae; Braslavsky, Ido; Davies, Peter

    2014-01-15

    Antifreeze proteins (AFPs) are expressed in a variety of cold-hardy organisms to prevent or slow internal ice growth. AFPs bind to specific planes of ice through their ice-binding surfaces. Fluorescence-based ice plane affinity (FIPA) analysis is a modified technique used to determine the ice planes to which the AFPs bind. FIPA is based on the original ice-etching method for determining AFP-bound ice-planes. It produces clearer images in a shortened experimental time. In FIPA analysis, AFPs are fluorescently labeled with a chimeric tag or a covalent dye then slowly incorporated into a macroscopic single ice crystal, which has been preformed into a hemisphere and oriented to determine the a- and c-axes. The AFP-bound ice hemisphere is imaged under UV light to visualize AFP-bound planes using filters to block out nonspecific light. Fluorescent labeling of the AFPs allows real-time monitoring of AFP adsorption into ice. The labels have been found not to influence the planes to which AFPs bind. FIPA analysis also introduces the option to bind more than one differently tagged AFP on the same single ice crystal to help differentiate their binding planes. These applications of FIPA are helping to advance our understanding of how AFPs bind to ice to halt its growth and why many AFP-producing organisms express multiple AFP isoforms.

  15. Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?

    KAUST Repository

    Fornander, Louise H.

    2013-05-16

    Hoechst 33258 binds with high affinity into the minor groove of AT-rich sequences of double-helical DNA. Despite extensive studies of this and analogous DNA binding molecules, there still remains uncertainty concerning the interactions when multiple ligand molecules are accommodated within close distance. Albeit not of direct concern for most biomedical applications, which are at low drug concentrations, interaction studies for higher drug binding are important as they can give fundamental insight into binding mechanisms and specificity, including drug self-stacking interactions that can provide base-sequence specificity. Using circular dichroism (CD), isothermal titration calorimetry (ITC), and proton nuclear magnetic resonance (1H NMR), we examine the binding of Hoechst 33258 to three oligonucleotide duplexes containing AT regions of different lengths: [d(CGCGAATTCGCG)]2 (A2T2), [d(CGCAAATTTGCG)]2 (A3T 3), and [d(CGAAAATTTTCG)]2 (A4T4). We find similar binding geometries in the minor groove for all oligonucleotides when the ligand-to-duplex ratio is less than 1:1. At higher ratios, a second ligand can be accommodated in the minor groove of A4T4 but not A2T2 or A3T3. We conclude that the binding of the second Hoechst to A4T4 is not cooperative and that the molecules are sitting with a small separation apart, one after the other, and not in a sandwich structure as previously proposed. © 2013 American Chemical Society.

  16. Synthetic LPS-Binding Polymer Nanoparticles

    Science.gov (United States)

    Jiang, Tian

    Lipopolysaccharide (LPS), one of the principal components of most gram-negative bacteria's outer membrane, is a type of contaminant that can be frequently found in recombinant DNA products. Because of its strong and even lethal biological effects, selective LPS removal from bioproducts solution is of particular importance in the pharmaceutical and health care industries. In this thesis, for the first time, a proof-of-concept study on preparing LPS-binding hydrogel-like NPs through facile one-step free-radical polymerization was presented. With the incorporation of various hydrophobic (TBAm), cationic (APM, GUA) monomers and cross-linkers (BIS, PEG), a small library of NPs was constructed. Their FITC-LPS binding behaviors were investigated and compared with those of commercially available LPS-binding products. Moreover, the LPS binding selectivity of the NPs was also explored by studying the NPs-BSA interactions. The results showed that all NPs obtained generally presented higher FITC-LPS binding capacity in lower ionic strength buffer than higher ionic strength. However, unlike commercial poly-lysine cellulose and polymyxin B agarose beads' nearly linear increase of FITC-LPS binding with particle concentration, NPs exhibited serious aggregation and the binding quickly saturated or even decreased at high particle concentration. Among various types of NPs, higher FITC-LPS binding capacity was observed for those containing more hydrophobic monomers (TBAm). However, surprisingly, more cationic NPs with higher content of APM exhibited decreased FITC-LPS binding in high ionic strength conditions. Additionally, when new cationic monomer and cross-linker, GUA and PEG, were applied to replace APM and BIS, the obtained NPs showed improved FITC-LPS binding capacity at low NP concentration. But compared with APM- and BIS-containing NPs, the FITC-LPS binding capacity of GUA- and PEG-containing NPs saturated earlier. To investigate the NPs' binding to proteins, we tested the NPs

  17. Why tight-binding theory?

    Science.gov (United States)

    Harrison, Walter A.

    2002-12-01

    In the context of computational physics other methods are more accurate, but tight-binding theory allows very direct physical interpretation and is simple enough to allow much more realistic treatments beyond the local density approximation. We address several important questions of this last category: How does the gap enhancement from Coulomb correlations vary from material to material? Should the enhanced gap be used for calculating the dielectric constant? For calculating the effective mass in k-dot-p theory? How valid is the scissors approximation? How does one line up bands at an interface? How should we match the envelope function at interfaces in effective-mass theory? Why can the resulting quantum-well states seem to violate the uncertainty principle? How should f-shell electrons be treated when they are intermediate between band-like and core-like? The answers to all of these questions are given and discussed.

  18. DNA binding hydroxyl radical probes

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Vicky J.; Konigsfeld, Katie M.; Aguilera, Joe A. [Department of Radiology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0610 (United States); Milligan, Jamie R., E-mail: jmilligan@ucsd.edu [Department of Radiology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0610 (United States)

    2012-01-15

    The hydroxyl radical is the primary mediator of DNA damage by the indirect effect of ionizing radiation. It is a powerful oxidizing agent produced by the radiolysis of water and is responsible for a significant fraction of the DNA damage associated with ionizing radiation. There is therefore an interest in the development of sensitive assays for its detection. The hydroxylation of aromatic groups to produce fluorescent products has been used for this purpose. We have examined four different chromophores, which produce fluorescent products when hydroxylated. Of these, the coumarin system suffers from the fewest disadvantages. We have therefore examined its behavior when linked to a cationic peptide ligand designed to bind strongly to DNA. - Highlights: > Examined four aromatic groups as a means to detect hydroxyl radicals by fluorescence. > Coumarin system suffers from the fewest disadvantages. > Characterized its reactivity when linked to a hexa-arginine peptide.

  19. Gamma Oscillations and Visual Binding

    Science.gov (United States)

    Robinson, Peter A.; Kim, Jong Won

    2006-03-01

    At the root of visual perception is the mechanism the brain uses to analyze features in a scene and bind related ones together. Experiments show this process is linked to oscillations of brain activity in the 30-100 Hz gamma band. Oscillations at different sites have correlation functions (CFs) that often peak at zero lag, implying simultaneous firing, even when conduction delays are large. CFs are strongest between cells stimulated by related features. Gamma oscillations are studied here by modeling mm-scale patchy interconnections in the visual cortex. Resulting predictions for gamma responses to stimuli account for numerous experimental findings, including why oscillations and zero-lag synchrony are associated, observed connections with feature preferences, the shape of the zero-lag peak, and variations of CFs with attention. Gamma waves are found to obey the Schroedinger equation, opening the possibility of cortical analogs of quantum phenomena. Gamma instabilities are tied to observations of gamma activity linked to seizures and hallucinations.

  20. The helical structure of DNA facilitates binding

    Science.gov (United States)

    Berg, Otto G.; Mahmutovic, Anel; Marklund, Emil; Elf, Johan

    2016-09-01

    The helical structure of DNA imposes constraints on the rate of diffusion-limited protein binding. Here we solve the reaction-diffusion equations for DNA-like geometries and extend with simulations when necessary. We find that the helical structure can make binding to the DNA more than twice as fast compared to a case where DNA would be reactive only along one side. We also find that this rate advantage remains when the contributions from steric constraints and rotational diffusion of the DNA-binding protein are included. Furthermore, we find that the association rate is insensitive to changes in the steric constraints on the DNA in the helix geometry, while it is much more dependent on the steric constraints on the DNA-binding protein. We conclude that the helical structure of DNA facilitates the nonspecific binding of transcription factors and structural DNA-binding proteins in general.

  1. Multiple constant multiplication optimizations for field programmable gate arrays

    CERN Document Server

    Kumm, Martin

    2016-01-01

    This work covers field programmable gate array (FPGA)-specific optimizations of circuits computing the multiplication of a variable by several constants, commonly denoted as multiple constant multiplication (MCM). These optimizations focus on low resource usage but high performance. They comprise the use of fast carry-chains in adder-based constant multiplications including ternary (3-input) adders as well as the integration of look-up table-based constant multipliers and embedded multipliers to get the optimal mapping to modern FPGAs. The proposed methods can be used for the efficient implementation of digital filters, discrete transforms and many other circuits in the domain of digital signal processing, communication and image processing. Contents Heuristic and ILP-Based Optimal Solutions for the Pipelined Multiple Constant Multiplication Problem Methods to Integrate Embedded Multipliers, LUT-Based Constant Multipliers and Ternary (3-Input) Adders An Optimized Multiple Constant Multiplication Architecture ...

  2. Multiple Ca2+ sensors in secretion

    DEFF Research Database (Denmark)

    Walter, Alexander M; Groffen, Alexander J; Sørensen, Jakob Balslev;

    2011-01-01

    Regulated neurotransmitter secretion depends on Ca(2+) sensors, C2 domain proteins that associate with phospholipids and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complexes to trigger release upon Ca(2+) binding. Ca(2+) sensors are thought to prevent spontaneous...... fusion at rest (clamping) and to promote fusion upon Ca(2+) activation. At least eight, often coexpressed, Ca(2+) sensors have been identified in mammals. Accumulating evidence suggests that multiple Ca(2+) sensors interact, rather than work autonomously, to produce the complex secretory response...... observed in neurons and secretory cells. In this review, we present several working models to describe how different sensors might be arranged to mediate synchronous, asynchronous and spontaneous neurotransmitter release. We discuss the scenario that different Ca(2+) sensors typically act on one shared...

  3. Nature of multiple-nucleus cluster galaxies

    Energy Technology Data Exchange (ETDEWEB)

    Merritt, D.

    1984-05-01

    In models for the evolution of galaxy clusters which include dynamical friction with the dark binding matter, the distribution of galaxies becomes more concentrated to the cluster center with time. In a cluster like Coma, this evolution could increase by a factor of approximately 3 the probability of finding a galaxy very close to the cluster center, without decreasing the typical velocity of such a galaxy significantly below the cluster mean. Such an enhancement is roughly what is needed to explain the large number of first-ranked cluster galaxies which are observed to have extra ''nuclei''; it is also consistent with the high velocities typically measured for these ''nuclei.'' Unlike the cannibalism model, this model predicts that the majority of multiple-nucleus systems are transient phenomena, and not galaxies in the process of merging.

  4. The Border Multiple

    DEFF Research Database (Denmark)

    of European borders by looking at border practices in the light of the mobility turn, and thus as dynamic, multiple, diverse and best expressed in everyday experiences of people living at and with borders, rather than focusing on static territorial divisions between states and regions at geopolitical...... level. It provides border scholars and researchers as well as policymakers with new empirical and theoretical evidence on the de- and re-bordering processes going on in diverse border regions in Europe, both within and outside of the EU....

  5. Relighting multiple color textures

    Institute of Scientific and Technical Information of China (English)

    DIAO Chang-yu; LU Dong-ming; LIU Gang

    2005-01-01

    With the development of digital library technology, library books made of paper can be digital released and read, and Endangered Cultural Heritages can be preserved. Traditional library's contents and functions can be greatly enhanced by digital technologies. For these new library objects, the primary key problem is precisely reconstructing their 3D models. When constructing complete 3D models, multiple color texture maps are often necessary. A commonly encountered problem uncounted during fusing of textures from multiple color images is color distortion. Each texture of a single 3D model may be obtained under possibly different lighting conditions and color response of the camera. To remove any visible seam and improve color consistency between the textures while avoiding color distortion, we propose a new efficient algorithm to relight all the texture images globally,spread residual light difference, and recolor each image by homogeneous transformation. A relative illumination model was adopted to obtain the relighting function. We choose lαβ color space with minimal correlation between channels for many natural scenes, for calculating the relighting result. Looking into two overlapped images A and B, we can pairwise relight B into A's luminosity condition in two steps. We first scale B's l channel by the lA/lB ratio of the overlapped region. We can assume A and B are in a same color plane now. Then a homogeneous transformation is applied to B's α and β channels which moves B into A's hue and saturation condition. For multiple overlapped color textures, a patch based weighted global relighting method was proposed to minimize the total color difference. The pairwise relighting method was used between each two overlapped images, and the difference in every overlapped region after relighting was weighted and summed up to construct an energy value. We used Nelder-Mead method to find a minimal energy value and the relighting parameters for every image. After

  6. Multiple granular cell tumor.

    Science.gov (United States)

    Jones, J K; Kuo, T T; Griffiths, C M; Itharat, S

    1980-10-01

    Eleven cases of granular cell tumor were reviewed. In two of the cases multiple sites of involvement were seen. The tumor occurred in the oral cavity in both of these cases and each was initially wrongly diagnosed as squamous cell carcinoma. The most common site was the subcutaneous tissue (nine patients) and the tongue was involved in three cases. In one patient the parotid gland was involved. Eight of the patients were females and three were males; seven were black and four were white. The importance of differentiating between squamous cell carcinoma and granular cell tumor is stressed, as is the need for a simple wide surgical excision. PMID:7421377

  7. Distributed multiple description coding

    CERN Document Server

    Bai, Huihui; Zhao, Yao

    2011-01-01

    This book examines distributed video coding (DVC) and multiple description coding (MDC), two novel techniques designed to address the problems of conventional image and video compression coding. Covering all fundamental concepts and core technologies, the chapters can also be read as independent and self-sufficient, describing each methodology in sufficient detail to enable readers to repeat the corresponding experiments easily. Topics and features: provides a broad overview of DVC and MDC, from the basic principles to the latest research; covers sub-sampling based MDC, quantization based MDC,

  8. Multiple pulmonary rheumatoid nodules.

    Science.gov (United States)

    Sargin, Gokhan; Senturk, Taskin

    2015-01-01

    We present a case of 45-year-old female patient with the diagnosis of seropositive rheumatoid arthritis, who was admitted to our rheumatology department with exacerbation of the disease. The patient's disease activity score (DAS 28) was 6.9. Physical examination revealed changes in the lung auscultation as a rough breathing sound at the middle and lower lobe of the right lung. Chest X-ray revealed multiple nodular densities in both lungs. Lung biopsy was performed for the diagnosis and revealed necrotizing granulomas with central fibrinoid necrosis surrounded by epithelioid cells. Such a histopathological picture is typical for rheumatoid nodules. Finally the patient was treated with rituximab, with significant improvement.

  9. Quantum Interference of Multiple Beams Induced by Multiple Scattering

    DEFF Research Database (Denmark)

    Ott, Johan Raunkjær; Mortensen, N. Asger; Lodahl, Peter

    2011-01-01

    We report on quantum interference induced by the transmission of quantized light through a multiple-scattering medium. We show that entangled states can be created by multiple-scattering and that quantum interference survives disorder averaging.......We report on quantum interference induced by the transmission of quantized light through a multiple-scattering medium. We show that entangled states can be created by multiple-scattering and that quantum interference survives disorder averaging....

  10. Methods for Improving Aptamer Binding Affinity

    OpenAIRE

    Hijiri Hasegawa; Nasa Savory; Koichi Abe; Kazunori Ikebukuro

    2016-01-01

    Aptamers are single stranded oligonucleotides that bind a wide range of biological targets. Although aptamers can be isolated from pools of random sequence oligonucleotides using affinity-based selection, aptamers with high affinities are not always obtained. Therefore, further refinement of aptamers is required to achieve desired binding affinities. The optimization of primary sequences and stabilization of aptamer conformations are the main approaches to refining the binding properties of a...

  11. Collective bargaining under non-binding contracts

    OpenAIRE

    Dobbelaere, S.; Luttens, R.I.

    2011-01-01

    We introduce collective bargaining in a static framework where the firm and its risk-neutral employees negotiate over wages in a non-binding contract setting. Our main result is the equivalence between the non-binding collective equilibrium wage-employment contract and the equilibrium contract under binding risk-neutral efficient bargaining. We also demonstrate that our non-cooperative equilibrium wages and profits coincide with the Owen values of the corresponding cooperative game with the c...

  12. A computational model for feature binding

    Institute of Scientific and Technical Information of China (English)

    SHI ZhiWei; SHI ZhongZhi; LIU Xi; SHI ZhiPing

    2008-01-01

    The "Binding Problem" is an important problem across many disciplines, including psychology, neuroscience, computational modeling, and even philosophy. In this work, we proposed a novel computational model, Bayesian Linking Field Model, for feature binding in visual perception, by combining the idea of noisy neuron model, Bayesian method, Linking Field Network and competitive mechanism.Simulation Experiments demonstrated that our model perfectly fulfilled the task of feature binding in visual perception and provided us some enlightening idea for future research.

  13. A computational model for feature binding

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The "Binding Problem" is an important problem across many disciplines, including psychology, neuroscience, computational modeling, and even philosophy. In this work, we proposed a novel computational model, Bayesian Linking Field Model, for feature binding in visual perception, by combining the idea of noisy neuron model, Bayesian method, Linking Field Network and competitive mechanism. Simulation Experiments demonstrated that our model perfectly fulfilled the task of feature binding in visual perception and provided us some enlightening idea for future research.

  14. RNA Binding Specificity of Drosophila Muscleblind†

    OpenAIRE

    Goers, Emily S.; Voelker, Rodger B.; Gates, Devika P.; Berglund, J. Andrew

    2008-01-01

    Members of the muscleblind family of RNA binding proteins found in Drosophila and mammals are key players in both the human disease myotonic dystrophy and the regulation of alternative splicing. Recently, the mammalian muscleblind-like protein, MBNL1, has been shown to have interesting RNA binding properties with both endogenous and disease-related RNA targets. Here we report the characterization of RNA binding properties of the Drosophila muscleblind protein Mbl. Mutagenesis of double-strand...

  15. Copper(II) binding properties of hepcidin

    OpenAIRE

    Kulprachakarn, Kanokwan; Chen, Yu-Lin; Kong, Xiaole; Arno, Maria Chiara; Hider, Robert Charles; Srichairatanakool, Somdet; Bansal, Sukhvinder

    2016-01-01

    Hepcidin is a peptide hormone that regulates the homeostasis of iron metabolism. The N-terminal domain of hepcidin is conserved amongst a range of species and is capable of binding CuII and NiII through the amino terminal copper–nickel binding motif (ATCUN). It has been suggested that the binding of copper to hepcidin may have biological relevance. In this study we have investigated the binding of CuII with model peptides containing the ATCUN motif, fluorescently labelled hepcidin and hepcidi...

  16. Advances on Plant Pathogenic Mycotoxin Binding Proteins

    Institute of Scientific and Technical Information of China (English)

    WANG Chao-hua; DONG Jin-gao

    2002-01-01

    Toxin-binding protein is one of the key subjects in plant pathogenic mycotoxin research. In this paper, new advances in toxin-binding proteins of 10 kinds of plant pathogenic mycotoxins belonging to Helminthosporium ,Alternaria ,Fusicoccum ,Verticillium were reviewed, especially the techniques and methods of toxin-binding proteins of HS-toxin, HV-toxin, HMT-toxin, HC-toxin. It was proposed that the isotope-labeling technique and immunological chemistry technique should be combined together in research of toxin-binding protein, which will be significant to study the molecular recognition mechanism between host and pathogenic fungus.

  17. Classification of a Haemophilus influenzae ABC transporter HI1470/71 through its cognate molybdate periplasmic binding protein, MolA.

    Science.gov (United States)

    Tirado-Lee, Leidamarie; Lee, Allen; Rees, Douglas C; Pinkett, Heather W

    2011-11-01

    molA (HI1472) from H. influenzae encodes a periplasmic binding protein (PBP) that delivers substrate to the ABC transporter MolB(2)C(2) (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 for tungstate and molybdate is significantly lower than observed for the class II ModA molybdate-binding proteins that have nanomolar to low micromolar affinity for molybdate. The presence of two molybdate loci in H. influenzae suggests multiple transport systems for one substrate, with molABC constituting a low-affinity molybdate locus. PMID:22078568

  18. Classification of a Haemophilus influenzae ABC Transporter HI1470/71 through Its Cognate Molybdate Periplasmic Binding Protein, MolA

    Energy Technology Data Exchange (ETDEWEB)

    Tirado-Lee, Leidamarie; Lee, Allen; Rees, Douglas C.; Pinkett, Heather W. (CIT); (NWU)

    2014-10-02

    molA (HI1472) from H. influenzae encodes a periplasmic binding protein (PBP) that delivers substrate to the ABC transporter MolB{sub 2}C{sub 2} (formerly HI1470/71). The structures of MolA with molybdate and tungstate in the binding pocket were solved to 1.6 and 1.7 {angstrom} 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 {approx}100 {mu}M binding affinity for tungstate and molybdate is significantly lower than observed for the class II ModA molybdate-binding proteins that have nanomolar to low micromolar affinity for molybdate. The presence of two molybdate loci in H. influenzae suggests multiple transport systems for one substrate, with molABC constituting a low-affinity molybdate locus.

  19. MULTIPRED2: A computational system for large-scale identification of peptides predicted to bind to HLA supertypes and alleles

    DEFF Research Database (Denmark)

    Zhang, Guang Lan; DeLuca, David S.; Keskin, Derin B.;

    2011-01-01

    MULTIPRED2 is a computational system for facile prediction of peptide binding to multiple alleles belonging to human leukocyte antigen (HLA) class I and class II DR molecules. It enables prediction of peptide binding to products of individual HLA alleles, combination of alleles, or HLA supertypes...... groups in North America. MULTIPRED2 is an important tool to complement wet-lab experimental methods for identification of T-cell epitopes. It is available at http://cvc.dfci.harvard.edu/multipred2/....

  20. Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

    OpenAIRE

    Safa, Ahmad R.

    2004-01-01

    A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-sp...

  1. Diet-induced alterations in intestinal and extrahepatic lipid metabolism in liver fatty acid binding protein knockout mice

    OpenAIRE

    Newberry, Elizabeth P.; Kennedy, Susan M; Xie, Yan; Luo, Jianyang; Davidson, Nicholas O.

    2008-01-01

    Liver fatty acid binding protein (L-FABP) is highly expressed in both enterocytes and hepatocytes and binds multiple ligands, including saturated (SFA), unsaturated fatty acids (PUFA), and cholesterol. L-fabp−/− mice were protected against obesity and hepatic steatosis on a high saturated fat (SF), high cholesterol “Western” diet and manifested a similar phenotype when fed with a high SF, low cholesterol diet. There were no significant differences in fecal fat content or food consumption betw...

  2. Tuberous Sclerosis: Multiple Presentations

    Directory of Open Access Journals (Sweden)

    M. Sanei Taheri

    2008-01-01

    Full Text Available Introduction: Tuberous sclerosis is an autosomal do-minant genetic disorder that involves multiple or-gans. The predominant lesions are the hamartomas. Classically tuberous sclerosis has been characterized by a classic clinical triad of facial angiofibromas in 90%,retardation in 50-80%,seizure 80-90% and all three in 30%."nThe disease occurs in 1:100,000 persons in all races with nearly equal distribution between the sexes. "nCase Presentation: We had six patients who admitted with different presentations of tuberous sclerosis with a past history of convulsion from childhood, skin le-sions and mental retardation, also with new onset headache and changed pattern of convulsion. In physical examination facial angiofibromas and sub-ungual fibromas apparently detected. Brain CT scan study with contrast showed multiple calcified nod-ules associated with tubers and ventriculomegaly, also an enhancing enlarged nodule at foramen of mo-nro, which was suggestive of subependymal giant cell astrocytoma (SGCA. In abdominal and pelvic CT scan and ultrasonography, massive bilateral angio-myolipomatosis diagnosed. Also Focal hypodense le-sions in liver which were hyperechoic in ultrasono-graphy were diagnosed. With MRI study tubers, white matter lesions and subependymal nodules asso-ciated with SGCA were detected better. After surgery SGCA was proved."nDiscussion: Our patients had different presentations and various findings of this spectrum discussed in this lecture.

  3. Anthropology and Multiple Modernities

    DEFF Research Database (Denmark)

    Thomassen, Bjørn

    Anthropology never had an easy relationship with the concept of modernity. The “reflexive turn” which developed during the 1980s and 1990s tackled the concept of modernity as a culturally constructed narrative underlying Western self-assumptions of self and other– assumptions that needed to be un......Anthropology never had an easy relationship with the concept of modernity. The “reflexive turn” which developed during the 1980s and 1990s tackled the concept of modernity as a culturally constructed narrative underlying Western self-assumptions of self and other– assumptions that needed...... to be unpacked and left behind. The debate was an essential part of a disciplininary reflexivity reconsidering anthropology’s epistemological and political roots in that very modernity. From the mid 1990s modernity was, somewhat surprisingly, reintroduced as a useful if not necessary conceptual tool...... better. This paper will tentatively argue that if anthropology wishes to embrace the concept of multiple modernities, it could profitably do so by taking more seriously the intellectual trajectory that paved the way for the idea of “multiple modernities”. This trajectory moves outside anthropology...

  4. Smoldering Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Minjie Gao

    2015-01-01

    Full Text Available Smoldering multiple myeloma (SMM is an asymptomatic precursor stage of multiple myeloma (MM characterized by clonal bone marrow plasma cells (BMPC ≥ 10% and/or M protein level ≥ 30 g/L in the absence of end organ damage. It represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS and symptomatic MM. The risk of progression to symptomatic MM is not uniform, and several parameters have been reported to predict the risk of progression. These include the level of M protein and the percentage of BMPC, the proportion of immunophenotypically aberrant plasma cells, and the presence of immunoparesis, free light-chain (FLC ratio, peripheral blood plasma cells (PBPC, pattern of serum M protein evolution, abnormal magnetic resonance imaging (MRI, cytogenetic abnormalities, IgA isotype, and Bence Jones proteinuria. So far treatment is still not recommended for SMM, because several trials suggested that patients with SMM do not benefit from early treatment. However, the Mateos et al. trial showed a survival benefit after early treatment with lenalidomide plus dexamethasone in patients with high-risk SMM. This trial has prompted a reevaluation of early treatment in an asymptomatic patient population.

  5. 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.

  6. Structural analysis of site-directed mutants of cellular retinoic acid-binding protein II addresses the relationship between structural integrity and ligand binding

    Energy Technology Data Exchange (ETDEWEB)

    Vaezeslami, Soheila [Rigaku Americas Corporation, 9009 New Trails Drive, The Woodlands, TX 77381 (United States); Jia, Xiaofei; Vasileiou, Chrysoula; Borhan, Babak; Geiger, James H., E-mail: geiger@chemistry.msu.edu [Chemistry Department, Michigan State University, East Lansing, MI 48824-1322 (United States); Rigaku Americas Corporation, 9009 New Trails Drive, The Woodlands, TX 77381 (United States)

    2008-12-01

    A water network stabilizes the structure of cellular retionic acid binding protein II. The structural integrity of cellular retinoic acid-binding protein II (CRABPII) has been investigated using the crystal structures of CRABPII mutants. The overall fold was well maintained by these CRABPII mutants, each of which carried multiple different mutations. A water-mediated network is found to be present across the large binding cavity, extending from Arg111 deep inside the cavity to the α2 helix at its entrance. This chain of interactions acts as a ‘pillar’ that maintains the integrity of the protein. The disruption of the water network upon loss of Arg111 leads to decreased structural integrity of the protein. A water-mediated network can be re-established by introducing the hydrophilic Glu121 inside the cavity, which results in a rigid protein with the α2 helix adopting an altered conformation compared with wild-type CRABPII.

  7. Global workspace dynamics: Cortical "binding and propagation enables conscious contents.

    Directory of Open Access Journals (Sweden)

    Bernard J Baars

    2013-05-01

    Full Text Available A global workspace is a hub of binding and propagation in a population of loosely coupled signaling elements. Global workspace (GW architectures recruit many distributed, specialized agents to help resolve focal ambiguities. In the brain, conscious experiences may reflect a global workspace function. For animals the natural world is full of fitness-related ambiguities, suggesting a general adaptive pressure for brains to resolve focal ambiguities quickly and accurately. In humans and related species the cortico-thalamic (C-T core is believed to underlie conscious aspects of perception, thinking, learning, feelings of knowing, emotions, imagery, working memory and executive control. The C-T core has many anatomical hubs, but conscious percepts are unitary and internally consistent at any given moment. The repertoire of conscious contents is a large, open set. These points suggest that a brain-based GW capacity cannot be localized in a single anatomical hub. Rather, it should be sought in a dynamic capacity for adaptive binding and propagation of neural signals over multi-hub networks. We refer to this as dynamic global workspace theory (dGW. In this view, conscious contents can arise in any region of the C-T core when multiple signal streams settle on a winner-take-all equilibrium. The resulting bound gestalt may ignite an any-to-many broadcast, lasting ~100-200 ms, and trigger widespread adaptation in established networks. Binding and broadcasting may involve theta/gamma or alpha/gamma phase coupling. Conscious contents (qualia may reflect their sources in cortex. Sensory percepts may bind and broadcast from posterior regions, while non-sensory feelings of knowing (FOKs may be frontotemporal. The small focal capacity of conscious contents may be the biological price to pay for global access. We propose that in the intact brain the hippocampal/rhinal complex may support conscious event organization as well as episodic memory coding.

  8. Generation of multiple excitons in Ag2S quantum dots: Single high-energy versus multiple-photon excitation

    KAUST Repository

    Sun, Jingya

    2014-02-20

    We explored biexciton generation via carrier multiplication (or multiple-exciton generation) by high-energy photons and by multiple-photon absorption in Ag2S quantum dots (QDs) using femtosecond broad-band transient absorption spectroscopy. Irrespective of the size of the QDs and how the multiple excitons are generated in the Ag2S QDs, two distinct characteristic time constants of 9.6-10.2 and 135-175 ps are obtained for the nonradiative Auger recombination of the multiple excitons, indicating the existence of two binding excitons, namely, tightly bound and weakly bound excitons. More importantly, the lifetimes of multiple excitons in Ag 2S QDs were about 1 and 2 orders of magnitude longer than those of comparable size PbS QDs and single-walled carbon nanotubes, respectively. This result is significant because it suggests that by utilizing an appropriate electron acceptor, there is a higher possibility to extract multiple electron-hole pairs in Ag2S QDs, which should improve the performance of QD-based solar cell devices. © 2014 American Chemical Society.

  9. Evolutionary Stability Against Multiple Mutations

    CERN Document Server

    Ghatak, Anirban; Shaiju, A J

    2012-01-01

    It is known (see e.g. Weibull (1995)) that ESS is not robust against multiple mutations. In this article, we introduce robustness against multiple mutations and study some equivalent formulations and consequences.

  10. Computational structural analysis: multiple proteins bound to DNA.

    Directory of Open Access Journals (Sweden)

    Andrija Tomovic

    Full Text Available BACKGROUND: With increasing numbers of crystal structures of proteinratioDNA and proteinratioproteinratioDNA complexes publically available, it is now possible to extract sufficient structural, physical-chemical and thermodynamic parameters to make general observations and predictions about their interactions. In particular, the properties of macromolecular assemblies of multiple proteins bound to DNA have not previously been investigated in detail. METHODOLOGY/PRINCIPAL FINDINGS: We have performed computational structural analyses on macromolecular assemblies of multiple proteins bound to DNA using a variety of different computational tools: PISA; PROMOTIF; X3DNA; ReadOut; DDNA and DCOMPLEX. Additionally, we have developed and employed an algorithm for approximate collision detection and overlapping volume estimation of two macromolecules. An implementation of this algorithm is available at http://promoterplot.fmi.ch/Collision1/. The results obtained are compared with structural, physical-chemical and thermodynamic parameters from proteinratioprotein and single proteinratioDNA complexes. Many of interface properties of multiple proteinratioDNA complexes were found to be very similar to those observed in binary proteinratioDNA and proteinratioprotein complexes. However, the conformational change of the DNA upon protein binding is significantly higher when multiple proteins bind to it than is observed when single proteins bind. The water mediated contacts are less important (found in less quantity between the interfaces of components in ternary (proteinratioproteinratioDNA complexes than in those of binary complexes (proteinratioprotein and proteinratioDNA.The thermodynamic stability of ternary complexes is also higher than in the binary interactions. Greater specificity and affinity of multiple proteins binding to DNA in comparison with binary protein-DNA interactions were observed. However, protein-protein binding affinities are stronger in

  11. Multiple Intelligences and quotient spaces

    OpenAIRE

    Malatesta, Mike; Quintana, Yamilet

    2006-01-01

    The Multiple Intelligence Theory (MI) is one of the models that study and describe the cognitive abilities of an individual. In [7] is presented a referential system which allows to identify the Multiple Intelligences of the students of a course and to classify the level of development of such Intelligences. Following this tendency, the purpose of this paper is to describe the model of Multiple Intelligences as a quotient space, and also to study the Multiple Intelligences of an individual in...

  12. Multiplicative Runge-Kutta Methods

    OpenAIRE

    Aktöre, Hatice

    2011-01-01

    ABSTRACT: In this thesis the multiplicative Runge-Kutta Method is developed employing the idea of the ordinary Runge-Kutta Method to multiplicative calculus. The multiplicative Runge-Kutta Methods for the orders 2,3, and 4 are developed and discussed. The developed algorithms are applied to examples where the solutions of the Ordinary Differential Equations are known. This gives the opportunity to check the relative error of the calculation reliably. The results in the multiplicative case are...

  13. Predicting the Impact of Missense Mutations on Protein-Protein Binding Affinity.

    Science.gov (United States)

    Li, Minghui; Petukh, Marharyta; Alexov, Emil; Panchenko, Anna R

    2014-04-01

    The crucial prerequisite for proper biological function is the protein's ability to establish highly selective interactions with macromolecular partners. A missense mutation that alters the protein binding affinity may cause significant perturbations or complete abolishment of the function, potentially leading to diseases. The availability of computational methods to evaluate the impact of mutations on protein-protein binding is critical for a wide range of biomedical applications. Here, we report an efficient computational approach for predicting the effect of single and multiple missense mutations on protein-protein binding affinity. It is based on a well-tested simulation protocol for structure minimization, modified MM-PBSA and statistical scoring energy functions with parameters optimized on experimental sets of several thousands of mutations. Our simulation protocol yields very good agreement between predicted and experimental values with Pearson correlation coefficients of 0.69 and 0.63 and root-mean-square errors of 1.20 and 1.90 kcal mol(-1) for single and multiple mutations, respectively. Compared with other available methods, our approach achieves high speed and prediction accuracy and can be applied to large datasets generated by modern genomics initiatives. In addition, we report a crucial role of water model and the polar solvation energy in estimating the changes in binding affinity. Our analysis also reveals that prediction accuracy and effect of mutations on binding strongly depends on the type of mutation and its location in a protein complex. PMID:24803870

  14. Multiple myeloma with lung plasmacytoma

    OpenAIRE

    Rajendra Prasad; Sanjay Kumar Verma; Rakhi Sodhi

    2011-01-01

    Malignant myeloma (MM) is a clonal proliferation of plasma cells with multiple osteolytic lesions. Extramedullary dissemination of multiple myeloma in lung is relatively uncommon. Hereby, we present a case of multiple myeloma with lung plasmacytoma of lung in a 45-years-old, non-smoker, female.

  15. Dihedral symmetries of multiple logarithms

    OpenAIRE

    Agarwala, Susama

    2011-01-01

    This paper finds relationships between multiple logarithms with a dihedral group action on the arguments. I generalize the combinatorics developed in Gangl, Goncharov and Levin's R-deco polygon representation of multiple logarithms to find these relations. By writing multiple logarithms as iterated integrals, my arguments are valid for iterated integrals as over an arbitrary field.

  16. The Verrucomicrobia LexA-binding Motif: Insights into the Evolutionary Dynamics of the SOS Response

    Directory of Open Access Journals (Sweden)

    Ivan Erill

    2016-07-01

    Full Text Available The SOS response is the primary bacterial mechanism to address DNA damage, coordinating multiple cellular processes that include DNA repair, cell division and translesion synthesis. In contrast to other regulatory systems, the composition of the SOS genetic network and the binding motif of its transcriptional repressor, LexA, have been shown to vary greatly across bacterial clades, making it an ideal system to study the co-evolution of transcription factors and their regulons. Leveraging comparative genomics approaches and prior knowledge on the core SOS regulon, here we define the binding motif of the Verrucomicrobia, a recently described phylum of emerging interest due to its association with eukaryotic hosts. Site directed mutagenesis of the Verrucomicrobium spinosum recA promoter confirms that LexA binds a 14 bp palindromic motif with consensus sequence TGTTC-N4-GAACA. Computational analyses suggest that recognition of this novel motif is determined primarily by changes in base-contacting residues of the third alpha helix of the LexA helix-turn-helix DNA binding motif. In conjunction with comparative genomics analysis of the LexA regulon in the Verrucomicrobia phylum, electrophoretic shift assays reveal that LexA binds to operators in the promoter region of DNA repair genes and a mutagenesis cassette in this organism, and identify previously unreported components of the SOS response. The identification of tandem LexA-binding sites generating instances of other LexA-binding motifs in the lexA gene promoter of Verrucomicrobia species leads us to postulate a novel mechanism for LexA-binding motif evolution. This model, based on gene duplication, successfully addresses outstanding questions in the intricate co-evolution of the LexA protein, its binding motif and the regulatory network it controls.

  17. The Verrucomicrobia LexA-Binding Motif: Insights into the Evolutionary Dynamics of the SOS Response.

    Science.gov (United States)

    Erill, Ivan; Campoy, Susana; Kılıç, Sefa; Barbé, Jordi

    2016-01-01

    The SOS response is the primary bacterial mechanism to address DNA damage, coordinating multiple cellular processes that include DNA repair, cell division, and translesion synthesis. In contrast to other regulatory systems, the composition of the SOS genetic network and the binding motif of its transcriptional repressor, LexA, have been shown to vary greatly across bacterial clades, making it an ideal system to study the co-evolution of transcription factors and their regulons. Leveraging comparative genomics approaches and prior knowledge on the core SOS regulon, here we define the binding motif of the Verrucomicrobia, a recently described phylum of emerging interest due to its association with eukaryotic hosts. Site directed mutagenesis of the Verrucomicrobium spinosum recA promoter confirms that LexA binds a 14 bp palindromic motif with consensus sequence TGTTC-N4-GAACA. Computational analyses suggest that recognition of this novel motif is determined primarily by changes in base-contacting residues of the third alpha helix of the LexA helix-turn-helix DNA binding motif. In conjunction with comparative genomics analysis of the LexA regulon in the Verrucomicrobia phylum, electrophoretic shift assays reveal that LexA binds to operators in the promoter region of DNA repair genes and a mutagenesis cassette in this organism, and identify previously unreported components of the SOS response. The identification of tandem LexA-binding sites generating instances of other LexA-binding motifs in the lexA gene promoter of Verrucomicrobia species leads us to postulate a novel mechanism for LexA-binding motif evolution. This model, based on gene duplication, successfully addresses outstanding questions in the intricate co-evolution of the LexA protein, its binding motif and the regulatory network it controls.

  18. The Verrucomicrobia LexA-Binding Motif: Insights into the Evolutionary Dynamics of the SOS Response.

    Science.gov (United States)

    Erill, Ivan; Campoy, Susana; Kılıç, Sefa; Barbé, Jordi

    2016-01-01

    The SOS response is the primary bacterial mechanism to address DNA damage, coordinating multiple cellular processes that include DNA repair, cell division, and translesion synthesis. In contrast to other regulatory systems, the composition of the SOS genetic network and the binding motif of its transcriptional repressor, LexA, have been shown to vary greatly across bacterial clades, making it an ideal system to study the co-evolution of transcription factors and their regulons. Leveraging comparative genomics approaches and prior knowledge on the core SOS regulon, here we define the binding motif of the Verrucomicrobia, a recently described phylum of emerging interest due to its association with eukaryotic hosts. Site directed mutagenesis of the Verrucomicrobium spinosum recA promoter confirms that LexA binds a 14 bp palindromic motif with consensus sequence TGTTC-N4-GAACA. Computational analyses suggest that recognition of this novel motif is determined primarily by changes in base-contacting residues of the third alpha helix of the LexA helix-turn-helix DNA binding motif. In conjunction with comparative genomics analysis of the LexA regulon in the Verrucomicrobia phylum, electrophoretic shift assays reveal that LexA binds to operators in the promoter region of DNA repair genes and a mutagenesis cassette in this organism, and identify previously unreported components of the SOS response. The identification of tandem LexA-binding sites generating instances of other LexA-binding motifs in the lexA gene promoter of Verrucomicrobia species leads us to postulate a novel mechanism for LexA-binding motif evolution. This model, based on gene duplication, successfully addresses outstanding questions in the intricate co-evolution of the LexA protein, its binding motif and the regulatory network it controls. PMID:27489856

  19. Combined fluorescence and electrochemical investigation on the binding interaction between organic acid and human serum albumin

    Institute of Scientific and Technical Information of China (English)

    CHEN Yan-Min; GUO Liang-Hong

    2009-01-01

    Human serum albumin (HSA) is a plasma protein responsible for the binding and transport of fatty acids and a variety of exogenous chemicals such as drugs and environmental pollutants. Such binding plays a crucial role in determining the ADME (absorption, distribution, metabolism, and excretion) and bioavailability of the pollutants. We report investigation on the binding interaction between HSA and acetic acid (C2), octanoic acid (C8) and dodecanoic acid (C12) by the combination of site-specific fluorescent probe, tryptophan intrinsic fluorescence and tyrosine electrochemistry. Two fluorescent probes, dansylamide and dansyl-L-proline, were employed in the displacement measurement to study fatty acid interaction with the two drug-binding sites on HSA. Intrinsic fluorescence of tryptophan in HSA was monitored upon addition of the fatty acids into HSA. Electrocatalyzed response of the tyrosine residues in HSA by a redox mediator was used to investigate the binding interaction. Qualitatively, observations made by the three approaches are very similar. HSA did not show any change in either fluorescence or electrochemistry after mixing with C2, suggesting there is no significant interaction with the short-chain fatty acid. For C8, the measured signal dropped in a single-exponential fashion, indicative of independent and non-cooperative binding. The calculated association constant and binding ratio is 3.1×106 L/mol and 1 with drug binding Site I, 1.1×107 L/mol and 1 with Site II, and 7.0×104 L/mol and 4 with the tryptophan site. The measurement with C12 displayed multiple phases of fluorescence change, suggesting cooperativity and allosteric effect of C12 binding. These results correlate well with those obtained by the established methods, and validate the new approach as a viable tool to study the interactions of environmental pollutants with biological molecules.

  20. Bayes multiple decision functions.

    Science.gov (United States)

    Wu, Wensong; Peña, Edsel A

    2013-01-01

    This paper deals with the problem of simultaneously making many (M) binary decisions based on one realization of a random data matrix X. M is typically large and X will usually have M rows associated with each of the M decisions to make, but for each row the data may be low dimensional. Such problems arise in many practical areas such as the biological and medical sciences, where the available dataset is from microarrays or other high-throughput technology and with the goal being to decide which among of many genes are relevant with respect to some phenotype of interest; in the engineering and reliability sciences; in astronomy; in education; and in business. A Bayesian decision-theoretic approach to this problem is implemented with the overall loss function being a cost-weighted linear combination of Type I and Type II loss functions. The class of loss functions considered allows for use of the false discovery rate (FDR), false nondiscovery rate (FNR), and missed discovery rate (MDR) in assessing the quality of decision. Through this Bayesian paradigm, the Bayes multiple decision function (BMDF) is derived and an efficient algorithm to obtain the optimal Bayes action is described. In contrast to many works in the literature where the rows of the matrix X are assumed to be stochastically independent, we allow a dependent data structure with the associations obtained through a class of frailty-induced Archimedean copulas. In particular, non-Gaussian dependent data structure, which is typical with failure-time data, can be entertained. The numerical implementation of the determination of the Bayes optimal action is facilitated through sequential Monte Carlo techniques. The theory developed could also be extended to the problem of multiple hypotheses testing, multiple classification and prediction, and high-dimensional variable selection. The proposed procedure is illustrated for the simple versus simple hypotheses setting and for the composite hypotheses setting

  1. Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

    OpenAIRE

    Kimura Shioko; Paiz Jorge; Yoneda Mitsuhiro; Kido Taketomo; Vinson Charles; Ward Jerrold M

    2012-01-01

    Abstract Background The CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. Methods A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP) gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino)-1-(3-pyri...

  2. Predicting the binding patterns of hub proteins: a study using yeast protein interaction networks.

    Directory of Open Access Journals (Sweden)

    Carson M Andorf

    Full Text Available BACKGROUND: Protein-protein interactions are critical to elucidating the role played by individual proteins in important biological pathways. Of particular interest are hub proteins that can interact with large numbers of partners and often play essential roles in cellular control. Depending on the number of binding sites, protein hubs can be classified at a structural level as singlish-interface hubs (SIH with one or two binding sites, or multiple-interface hubs (MIH with three or more binding sites. In terms of kinetics, hub proteins can be classified as date hubs (i.e., interact with different partners at different times or locations or party hubs (i.e., simultaneously interact with multiple partners. METHODOLOGY: Our approach works in 3 phases: Phase I classifies if a protein is likely to bind with another protein. Phase II determines if a protein-binding (PB protein is a hub. Phase III classifies PB proteins as singlish-interface versus multiple-interface hubs and date versus party hubs. At each stage, we use sequence-based predictors trained using several standard machine learning techniques. CONCLUSIONS: Our method is able to predict whether a protein is a protein-binding protein with an accuracy of 94% and a correlation coefficient of 0.87; identify hubs from non-hubs with 100% accuracy for 30% of the data; distinguish date hubs/party hubs with 69% accuracy and area under ROC curve of 0.68; and SIH/MIH with 89% accuracy and area under ROC curve of 0.84. Because our method is based on sequence information alone, it can be used even in settings where reliable protein-protein interaction data or structures of protein-protein complexes are unavailable to obtain useful insights into the functional and evolutionary characteristics of proteins and their interactions. AVAILABILITY: We provide a web server for our three-phase approach: http://hybsvm.gdcb.iastate.edu.

  3. Networks amid multiple logics

    DEFF Research Database (Denmark)

    Bergenholtz, Carsten; Bjerregaard, Toke

    The present study investigates how a high-tech-small-firm (HTSF) can carry out an inter-organizational search of actors located at universities. Responding to calls to study how firms navigate multiple institutional norms, this research examines the different strategies used by a HTSF to balance...... adopted academic norm-sets, commercial imperatives and formal regulations to support formation of networks and collaborations with universities. The findings show how the significance of weak and strong ties for the formation of collaborations and networks with universities is relative to the...... institutional embeddedness in different industries. The research thus illuminates how a HTSF effectively can combine different search and collaboration strategies depending on institutional contexts and logics governing R&D work. The concluding section outlines implications for future research and the...

  4. On Multiple Appearances

    DEFF Research Database (Denmark)

    Bork Petersen, Franziska

    2012-01-01

    reduction and epoché to focus on how dancing bodies appear in a stage context. To test these tools’ ability to explore dancing bodies from a third-person perspective, I analyse the Danish choreographer Kitt Johnson’s solo performance Drift (2011) - focussing on her shifting physical appearance. While...... phenomenology helps me to describe the multiple and radically different guises that Johnson assumes in her piece, my analysis, ultimately, does not aim to distil a truer, more real being from her appearances as is often the case in phenomenological philosophy. I complement my analytical approach...... with the Deleuzian notion of becoming animal and suggest that Johnson stages what could, in Judith Butler’s terms, be called a critical contingency of bodily appearance....

  5. MULTIPLE GALAXY COLLISIONS

    Science.gov (United States)

    2002-01-01

    Here is a sampling of 15 ultraluminous infrared galaxies viewed by NASA's Hubble Space Telescope. Hubble's sharp vision reveals more complexity within these galaxies, which astronomers are interpreting as evidence of a multiple-galaxy pileup. These images, taken by the Wide Field and Planetary Camera 2, are part of a three-year study of 123 galaxies within 3 billion light-years of Earth. The study was conducted in 1996, 1997, and 1999. False colors were assigned to these photos to enhance fine details within these coalescing galaxies. Credits: NASA, Kirk Borne (Raytheon and NASA Goddard Space Flight Center, Greenbelt, Md.), Luis Colina (Instituto de Fisica de Cantabria, Spain), and Howard Bushouse and Ray Lucas (Space Telescope Science Institute, Baltimore, Md.)

  6. Multiple detectors "Influence Method".

    Science.gov (United States)

    Rios, I J; Mayer, R E

    2016-05-01

    The "Influence Method" is conceived for the absolute determination of a nuclear particle flux in the absence of known detector efficiency and without the need to register coincidences of any kind. This method exploits the influence of the presence of one detector in the count rate of another detector, when they are placed one behind the other and define statistical estimators for the absolute number of incident particles and for the efficiency (Rios and Mayer, 2015a). Its detailed mathematical description was recently published (Rios and Mayer, 2015b) and its practical implementation in the measurement of a moderated neutron flux arising from an isotopic neutron source was exemplified in (Rios and Mayer, 2016). With the objective of further reducing the measurement uncertainties, in this article we extend the method for the case of multiple detectors placed one behind the other. The new estimators for the number of particles and the detection efficiency are herein derived. PMID:26943904

  7. Multiple stage railgun

    International Nuclear Information System (INIS)

    A multiple stage magnetic railgun accelerator for accelerating a projectile by movement of a plasma arc along the rails. The railgun is divided into a plurality of successive rail stages which are sequentially energized by separate energy sources as the projectile moves through the bore of the railgun. Propagation of energy from an energized rail stage back towards the breech end of the railgun can be prevented by connection of the energy sources to the rails through isolation diodes. Propagation of energy from an energized rail stage back towards the breech end of the railgun can also be prevented by dividing the rails into electrically isolated rail sections. In such case means are used to extinguish the arc at the end of each energized stage and a fuse or laser device is used to initiate a new plasma arc in the next energized rail stage

  8. Quantum Optical Multiple Scattering

    DEFF Research Database (Denmark)

    Ott, Johan Raunkjær

    . In the first part we use a scattering-matrix formalism combined with results from random-matrix theory to investigate the interference of quantum optical states on a multiple scattering medium. We investigate a single realization of a scattering medium thereby showing that it is possible to create entangled...... interference survives even after disorder averaging. The quantum interference manifests itself through increased photon correlations. Furthermore, the theoretical description of a measurement procedure is presented. In this work we relate the noise power spectrum of the total transmitted or reflected light...... to the photon correlations after ensemble averaging. This analysis enables us to describe an experimental observation of the quantum nature of light that survives the averaging over disorder. In the second part we investigate inelastic scattering. This we do by first treating the scattering of light on dipoles...

  9. Multiple Commutator Formulas

    OpenAIRE

    Hazrat, R.; Zhang, Z.

    2011-01-01

    Let A be a quasi-finite R-algebra (i.e., a direct limit of module finite algebras) with identity. Let I_i, i=0,...,m, be two-sided ideals of A, \\GL_n(A,I_i) the principal congruence subgroup of level I_i in GL_n(A) and E_n(A,I_i) be the relative elementary subgroup of level I_i. We prove a multiple commutator formula [E_n(A,I_0),\\GL_n(A,I_1),& \\GL_n(A, I_2),..., \\GL_n(A, I_m)] = [E_n(A,I_0),E_n(A,I_1),E_n(A, I_2),..., E_n(A, I_m)], which is a broad generalization of the standard commutator fo...

  10. Multiple gas reduction strategy

    Energy Technology Data Exchange (ETDEWEB)

    A. Kurosawa [Institute of Applied Energy, Tokyo (Japan)

    2003-07-01

    Future global warming has a close relationship with the abatement potential of six greenhouse gases (GHGs), including carbon dioxide (CO{sub 2}), methane (CH{sub 4}), nitrous oxide (N{sub 2}O), hydrofluorocarbons (HFCs), perfluorocarbons (PFCs), and sulfur hexafluoride (SF6). Therefore, multiple gas reduction flexibility should be assessed. The emission of each non-CO{sub 2} GHG is calculated endogenously by the sum of the product of the emission factor and the endogenous activity index using an integrated assessment model, GRAPE (Global Relationship Assessment to Protect the Environment). The model consists of five modules dealing with issues on energy, climate, land use, macroeconomics and environmental impacts. The uncertainty in the non-CO{sub 2} GHG emission inventory and emission factors is discussed. 5 refs., 3 figs., 1 tab.

  11. Swamp Works- Multiple Projects

    Science.gov (United States)

    Carelli, Jonathan M.; Schuler, Jason M.; Chandler, Meredith L.

    2013-01-01

    My Surface Systems internship over the summer 2013 session covered a broad range of projects that utilized multiple fields of engineering and technology. This internship included a project to create a command center for a 120 ton regolith bin, for the design and assembly of a blast shield to add further protection for the Surface Systems engineers, for the design and assembly of a portable four monitor hyper wall strip that could extend as large as needed, research and programming a nano drill that could be utilized on a next generation robot or rover, and social media tasks including the making of videos, posting to social networking websites and creation of a new outreach program to help spread the word about the Swamp Works laboratory.

  12. Reduced Multiplication Modules

    Indian Academy of Sciences (India)

    Karim Samei

    2011-05-01

    An -module is called a multiplication module if for each submodule of , = for some ideal of . As defined for a commutative ring , an -module is said to be reduced if the intersection of prime submodules of is zero. The prime spectrum and minimal prime submodules of the reduced module are studied. Essential submodules of are characterized via a topological property. It is shown that the Goldie dimension of is equal to the Souslin number of Spec (). Also a finitely generated module is a Baer module if and only if Spec () is an extremally disconnected space; if and only if it is a -module. It is proved that a prime submodule is minimal in if and only if for each $x\\in N,\\mathrm{Ann}(x)\

  13. Complement factor H binding by different Lyme disease and relapsing fever Borrelia in animals and human

    OpenAIRE

    Gil Horacio; Camafeita Emilio; Escudero Raquel; Bhide Mangesh R; Jado Isabel; Anda Pedro

    2009-01-01

    Abstract Background Borreliae employ multiple immune evasive strategies such as binding to complement regulatory proteins [factor H (fH) and factor H like-1 (FHL1)], differential regulation of surface membrane proteins, antigenic variation, and binding of plasminogen/plasmin and matrix metalloproteinases. As a complement regulatory subunit, fH serves as a cofactor for the factor I-mediated cleavage of C3b. fH binding by Borrelia has been correlated with pathogenesis as well as with host diver...

  14. Thermodynamics of ligand binding to acyl-coenzyme A binding protein studied by titration calorimetry

    DEFF Research Database (Denmark)

    Færgeman, Nils J.; Sigurskjold, B W; Kragelund, B B;

    1996-01-01

    Ligand binding to recombinant bovine acyl-CoA binding protein (ACBP) was examined using isothermal microcalorimetry. Microcalorimetric measurements confirm that the binding affinity of acyl-CoA esters for ACBP is strongly dependent on the length of the acyl chain with a clear preference for acyl-...

  15. Biodiscovery of aluminum binding peptides

    Science.gov (United States)

    Adams, Bryn L.; Sarkes, Deborah A.; Finch, Amethist S.; Hurley, Margaret M.; Stratis-Cullum, Dimitra

    2013-05-01

    Cell surface peptide display systems are large and diverse libraries of peptides (7-15 amino acids) which are presented by a display scaffold hosted by a phage (virus), bacteria, or yeast cell. This allows the selfsustaining peptide libraries to be rapidly screened for high affinity binders to a given target of interest, and those binders quickly identified. Peptide display systems have traditionally been utilized in conjunction with organic-based targets, such as protein toxins or carbon nanotubes. However, this technology has been expanded for use with inorganic targets, such as metals, for biofabrication, hybrid material assembly and corrosion prevention. While most current peptide display systems employ viruses to host the display scaffold, we have recently shown that a bacterial host, Escherichia coli, displaying peptides in the ubiquitous, membrane protein scaffold eCPX can also provide specific peptide binders to an organic target. We have, for the first time, extended the use of this bacterial peptide display system for the biodiscovery of aluminum binding 15mer peptides. We will present the process of biopanning with macroscopic inorganic targets, binder enrichment, and binder isolation and discovery.

  16. CTCF Binding Polarity Determines Chromatin Looping

    NARCIS (Netherlands)

    de Wit, Elzo; Vos, Erica S M; Holwerda, Sjoerd J B; Valdes-Quezada, Christian; Verstegen, Marjon J A M; Teunissen, Hans; Splinter, Erik; Wijchers, Patrick J; Krijger, Peter H L; de Laat, Wouter

    2015-01-01

    CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional (3D) organization of chromatin. In this study, we assayed the 3D genomic contact profiles of a large number of CTCF binding sites with high-resolution 4C-seq. As recently reported, our data also suggest that ch

  17. Localization-enhanced biexciton binding in semiconductors

    DEFF Research Database (Denmark)

    Langbein, Wolfgang Werner; Hvam, Jørn Märcher

    1999-01-01

    The influence of excitonic localization on the binding energy of biexcitons is investigated for quasi-three-dimensional and quasi-two-dimensional AlxGa1-xAs structures. An increase of the biexciton binding energy is observed for localization energies comparable to or larger than the free biexcito...

  18. Gravitational Binding Energy in Charged Cylindrical Symmetry

    CERN Document Server

    Sharif, M

    2014-01-01

    We consider static cylindrically symmetric charged gravitating object with perfect fluid and investigate the gravitational binding energy. It is found that only the localized part of the mass function provides the gravitational binding energy, whereas the non-localized part generated by the electric coupling does not contribute for such energy.

  19. Triazatriangulene as binding group for molecular electronics

    DEFF Research Database (Denmark)

    Wei, Zhongming; Wang, Xintai; Borges, Anders;

    2014-01-01

    The triazatriangulene (TATA) ring system was investigated as a binding group for tunnel junctions of molecular wires on gold surfaces. Self-assembled monolayers (SAMs) of TATA platforms with three different lengths of phenylene wires were fabricated, and their electrical conductance was recorded ...... with its high stability and directionality make this binding group very attractive for molecular electronic measurements and devices. (Figure Presented)....

  20. Binding of Quasi-Two-Dimensional Biexcitons

    DEFF Research Database (Denmark)

    Birkedal, Dan; Singh, Jai; Vadim, Lyssenko;

    1996-01-01

    Biexciton binding in GaAs quantum wells has been investigated for a range of well thicknesses (80-160 Angstrom) with spectrally resolved photoluminescence and transient degenerate four-wave mixing. Both light and heavy hole biexcitons are observed. The ratio of the binding energy of the heavy hole...

  1. DNA-binding activity in the excretory-secretory products of Trichinella pseudospiralis (Nematoda: Trichinelloidea)

    OpenAIRE

    Mak, CH; Ko, RCC

    2001-01-01

    A novel DNA-binding peptide of Mr approximately 30 kDa was documented for the first time in the excretory-secretory (E-S) products of the infective-stage larvae of Trichinella pseudospiralis. Larvae recovered from muscles of infected mice were maintained for 48 h in DMEM medium. E-S products of worms extracted from the medium were analysed for DNA-binding activity by the electrophoretic mobility shift assay (EMSA). Multiple DNA-protein complexes were detected. A comparison of the Mr of protei...

  2. Deregulated microRNAs in multiple myeloma.

    Science.gov (United States)

    Benetatos, Leonidas; Vartholomatos, George

    2012-02-15

    MicroRNAs are short noncoding RNAS involved in gene expression regulation under physiological and pathological situations. They bind to mRNA of target genes and are potential regulators of gene expression at a post-transcription level through the RNA interference pathway. They are estimated to represent 1% to 2% of the known eukaryotic genome, and it has been demonstrated that they are involved in the pathogenesis of neurodegenerative diseases, cancer, metabolism disorders, and heart disease. MicroRNAs are known to act as tumor suppressors or oncogenes in cancer biology. The authors describe the current knowledge on microRNA involvement in regulatory pathways that characterize multiple myeloma pathogenesis gained from in vitro and in vivo studies. These small molecules interact with important factors such as p53, SOCS1, IGF-1, IGF-1R, vascular endothelial growth factor, NF-κB, and others. As such, microRNAs represent an attractive therapeutic target in the context of multiple myeloma interfering with the myeloma regulatory networks. Further studies are needed to better understand their role in myelomagenesis and their therapeutic potential.

  3. (TH) diazepam binding to human granulocytes

    Energy Technology Data Exchange (ETDEWEB)

    Bond, P.A.; Cundall, R.L.; Rolfe, B.

    1985-07-08

    (TH)-diazepam binds to sites on human granulocyte membranes, with little or no binding to platelets or lymphocytes. These (TH)-diazepam binding sites are of the peripheral type, being strongly inhibited by R05-4864 (Ki=6.23nM) but only weakly by clonazepam (Ki=14 M). Binding of (TH) diazepam at 0 is saturable, specific and stereoselective. Scatchard analysis indicates a single class of sites with Bmax of 109 +/- 17f moles per mg of protein and K/sub D/ of 3.07 +/- 0.53nM. Hill plots of saturation experiments gave straight lines with a mean Hill coefficient of 1.03 +/- 0.014. Binding is time dependent and reversible and it varies linearly with granulocyte protein concentration over the range 0.025-0.300 mg of protein. 11 references, 3 figures, 1 table.

  4. [3H] diazepam binding to human granulocytes

    International Nuclear Information System (INIS)

    [3H]-diazepam binds to sites on human granulocyte membranes, with little or no binding to platelets or lymphocytes. These [3H]-diazepam binding sites are of the peripheral type, being strongly inhibited by R05-4864 (Ki=6.23nM) but only weakly by clonazepam (Ki=14μM). Binding of [3H] diazepam at 00 is saturable, specific and stereoselective. Scatchard analysis indicates a single class of sites with Bmax of 109 +/- 17f moles per mg of protein and K/sub D/ of 3.07 +/- 0.53nM. Hill plots of saturation experiments gave straight lines with a mean Hill coefficient of 1.03 +/- 0.014. Binding is time dependent and reversible and it varies linearly with granulocyte protein concentration over the range 0.025-0.300 mg of protein. 11 references, 3 figures, 1 table

  5. Multiple forms of complement C3 in trout that differ in binding to complement activators.

    OpenAIRE

    Sunyer, J O; Zarkadis, I K; Sahu, A.; LAMBRIS, J. D.

    1996-01-01

    In all other species analyzed to date, the functionally active form of complement component C3 exists as the product of a single gene. We have now identified and characterized three functional C3 proteins (C3-1, C3-3, and C3-4) in trout that are the products of at least two distinct C3 genes. All three proteins are composed of an alpha-and a beta-chain and contain a thioester bond in the alpha-chain. However, they differ in their electrophoretic mobility, glycosylation, reactivity with monosp...

  6. Drosophila SNAP-29 is an essential SNARE that binds multiple proteins involved in membrane traffic.

    Directory of Open Access Journals (Sweden)

    Hao Xu

    Full Text Available Each membrane fusion event along the secretory and endocytic pathways requires a specific set of SNAREs to assemble into a 4-helical coiled-coil, the so-called trans-SNARE complex. Although most SNAREs contribute one helix to the trans-SNARE complex, members of the SNAP-25 family contribute two helixes. We report the characterization of the Drosophila homologue of SNAP-29 (dSNAP-29, which is expressed throughout development. Unlike the other SNAP-25 like proteins in fruit fly (i.e., dSNAP-25 and dSNAP-24, which form SDS-resistant SNARE complexes with their cognate SNAREs, dSNAP-29 does not participate in any SDS-resistant complexes, despite its interaction with dsyntaxin1 and dsyntaxin16 in vitro. Immunofluorescence studies indicated that dSNAP-29 is distributed in various tissues, locating in small intracellular puncta and on the plasma membrane, where it associates with EH domain-containing proteins implicated in the endocytic pathway. Overexpression and RNAi studies suggested that dSNAP-29 mediates an essential process in Drosophila development.

  7. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients

    DEFF Research Database (Denmark)

    Bieghs, Liesbeth; Brohus, Malene; Kristensen, Ida B;

    2016-01-01

    and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM.......6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the...... profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration....

  8. Binding of the 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs to tRNA(phe..

    Directory of Open Access Journals (Sweden)

    Anirban Basu

    Full Text Available BACKGROUND: Three new analogs of berberine with aryl/ arylalkyl amino carbonyl methyl substituent at the 9-position of the isoquinoline chromophore along with berberrubine were studied for their binding to tRNA(phe by wide variety of biophysical techniques like spectrophotometry, spectrofluorimetry, circular dichroism, thermal melting, viscosity and isothermal titration calorimetry. METHODOLOGY/ PRINCIPAL FINDINGS: Scatchard binding isotherms revealed that the cooperative binding mode of berberine was propagated in the analogs also. Thermal melting studies showed that all the 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs stabilized the tRNA(phe more in comparison to berberine. Circular dichroism studies showed that these analogs perturbed the structure of tRNA(phe more in comparison to berberine. Ferrocyanide quenching studies and viscosity results proved the intercalative binding mode of these analogs into the helical organization of tRNA(phe. The binding was entropy driven for the analogs in sharp contrast to the enthalpy driven binding of berberine. The introduction of the aryl/arylalkyl amino carbonyl methyl substituent at the 9-position thus switched the enthalpy driven binding of berberine to entropy dominated binding. Salt and temperature dependent calorimetric studies established the involvement of multiple weak noncovalent interactions in the binding process. CONCLUSIONS/ SIGNIFICANCE: The results showed that 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs exhibited almost ten folds higher binding affinity to tRNA(phe compared to berberine whereas the binding of berberrubine was dramatically reduced by about twenty fold in comparison to berberine. The spacer length of the substitution at the 9-position of the isoquinoline chromophore appears to be critical in modulating the binding affinities towards tRNA(phe.

  9. Probing ligand-binding modes and binding mechanisms of benzoxazole-based amide inhibitors with soluble epoxide hydrolase by molecular docking and molecular dynamics simulation.

    Science.gov (United States)

    Chen, Hang; Zhang, Ying; Li, Liang; Han, Ju-Guang

    2012-08-30

    Soluble epoxide hydrolase (sEH) has become a new therapeutic target for treating a variety of human diseases. The inhibition of human sEH hydrolase activity was studied by molecular docking and molecular dynamics (MD) simulation techniques. A set of six benzoxazole-based amide inhibitors binding to sEH has been studied through molecular docking, MD simulation, free energy calculations, and energy decomposition analysis. On the basis of molecular mechanics-generalized Born/surface area (MM-GB/SA) computation and normal-mode analysis (NMA), the obtained results indicate that the rank of calculated binding free energies (ΔΔGTOT) of these inhibitors is in excellent agreement with that of experimental bioactivity data (IC50). The correlation coefficient (r(2)) between the predicted ΔΔGTOT and IC50 is 0.88. van der Waals energies are the largest component of the total energies, and the entropy changes play an indispensable role in determining the ΔΔGTOT. Rational binding modes were discussed and determined by the docking results and binding free energies. The free energy decomposition of each residue reveals that the residue Trp334 dominates the most binding free energies among all residues and that the activities for these molecules to the sEH are not decided by hydrogen bonds or a certain residue but by the common effect of multiple side chains in the active site.

  10. Phosphorylation-dependent changes in nucleotide binding, conformation, and dynamics of the first nucleotide binding domain (NBD1) of the sulfonylurea receptor 2B (SUR2B).

    Science.gov (United States)

    de Araujo, Elvin D; Alvarez, Claudia P; López-Alonso, Jorge P; Sooklal, Clarissa R; Stagljar, Marijana; Kanelis, Voula

    2015-09-11

    The sulfonylurea receptor 2B (SUR2B) forms the regulatory subunit of ATP-sensitive potassium (KATP) channels in vascular smooth muscle. Phosphorylation of the SUR2B nucleotide binding domains (NBD1 and NBD2) by protein kinase A results in increased channel open probability. Here, we investigate the effects of phosphorylation on the structure and nucleotide binding properties of NBD1. Phosphorylation sites in SUR2B NBD1 are located in an N-terminal tail that is disordered. Nuclear magnetic resonance (NMR) data indicate that phosphorylation of the N-terminal tail affects multiple residues in NBD1, including residues in the NBD2-binding site, and results in altered conformation and dynamics of NBD1. NMR spectra of NBD1 lacking the N-terminal tail, NBD1-ΔN, suggest that phosphorylation disrupts interactions of the N-terminal tail with the core of NBD1, a model supported by dynamic light scattering. Increased nucleotide binding of phosphorylated NBD1 and NBD1-ΔN, compared with non-phosphorylated NBD1, suggests that by disrupting the interaction of the NBD core with the N-terminal tail, phosphorylation also exposes the MgATP-binding site on NBD1. These data provide insights into the molecular basis by which phosphorylation of SUR2B NBD1 activates KATP channels. PMID:26198630

  11. Prediction of MHC binding peptides and epitopes from alfalfa mosaic virus.

    Science.gov (United States)

    Gomase, Virendra S; Kale, Karbhari V; Chikhale, Nandkishor J; Changbhale, Smruti S

    2007-08-01

    Peptide fragments from alfalfa mosaic virus involved multiple antigenic components directing and empowering the immune system to protect the host from infection. MHC molecules are cell surface proteins, which take active part in host immune reactions and involvement of MHC class-I & II in response to almost all antigens. Coat protein of alfalfa mosaic virus contains 221 aa residues. Analysis found five MHC ligands in coat protein as 64-LSSFNGLGV-72; 86- RILEEDLIY-94; 96-MVFSITPSY-104; 100- ITPSYAGTF-108; 110- LTDDVTTED-118; having rescaled binding affinity and c-terminal cleavage affinity more than 0.5. The predicted binding affinity is normalized by the 1% fractil. The MHC peptide binding is predicted using neural networks trained on c-terminals of known epitopes. In analysis predicted MHC/peptide binding is a log transformed value related to the IC50 values in nM units. Total numbers of peptides found are 213. Predicted MHC binding regions act like red flags for antigen specific and generate immune response against the parent antigen. So a small fragment of antigen can induce immune response against whole antigen. This theme is implemented in designing subunit and synthetic peptide vaccines. The sequence analysis method allows potential drug targets to identify active sites against plant diseases. The method integrates prediction of peptide MHC class I binding; proteosomal c-terminal cleavage and TAP transport efficiency. PMID:17691913

  12. Computational study of the binding modes of caffeine to the adenosine A2A receptor.

    Science.gov (United States)

    Liu, Yuli; Burger, Steven K; Ayers, Paul W; Vöhringer-Martinez, Esteban

    2011-12-01

    Using the recently solved crystal structure of the human adenosine A(2A) receptor, we applied MM/PBSA to compare the binding modes of caffeine with those of the high-affinity selective antagonist ZM241385. MD simulations were performed in the environment of the lipid membrane bilayer. Four low-energy binding modes of caffeine-A(2A) were found, all of which had similar energies. Assuming an equal contribution of each binding mode of caffeine, the computed binding free energy difference between caffeine and ZM241385 is -2.4 kcal/mol, which compares favorably with the experimental value, -3.6 kcal/mol. The configurational entropy contribution of -0.9 kcal/mol from multiple binding modes of caffeine helps explain how a small molecule like caffeine can compete with a significantly larger molecule, ZM241385, which can form many more interactions with the receptor. We also performed residue-wise energy decomposition and found that Phe168, Leu249, and Ile274 contribute most significantly to the binding modes of caffeine and ZM241385. PMID:21970461

  13. Computational investigation of stoichiometric effects, binding site heterogeneities, and selectivities of molecularly imprinted polymers.

    Science.gov (United States)

    Terracina, Jacob J; Bergkvist, Magnus; Sharfstein, Susan T

    2016-06-01

    A series of quantum mechanical (QM) computational optimizations of molecularly imprinted polymer (MIP) systems were used to determine optimal monomer-to-target ratios. Imidazole- and xanthine-derived target molecules were studied. The investigation included both small-scale models (3-7 molecules) and larger-scale models (15-35 molecules). The optimal ratios differed between the small and larger scales. For the larger models containing multiple targets, binding-site surface area analysis was used to quantify the heterogeneity of these sites. The more fully surrounded sites had greater binding energies. No discretization of binding modes was seen, furthering arguments for continuous affinity distribution models. Molecular mechanical (MM) docking was then used to measure the selectivities of the QM-optimized binding sites. Selectivity was also shown to improve as binding sites become more fully encased by the monomers. For internal sites, docking consistently showed selectivity favoring the molecules that had been imprinted via QM geometry optimizations. The computationally imprinted sites were shown to exhibit size-, shape-, and polarity-based selectivity. Here we present a novel approach to investigate the selectivity and heterogeneity of imprinted polymer binding sites, by applying the rapid orientation screening of MM docking to the highly accurate QM-optimized geometries. Modeling schemes were designed such that no computing clusters or other specialized modeling equipment would be required. Improving the in silico analysis of MIP system properties will ultimately allow for the production of more sensitive and selective polymers. PMID:27207254

  14. Binding of Bacillus thuringiensis proteins to a laboratory-selected line of Heliothis virescens.

    Science.gov (United States)

    MacIntosh, S C; Stone, T B; Jokerst, R S; Fuchs, R L

    1991-10-15

    A laboratory-selected colony of Heliothis virescens displaying a 20- to 70-fold level of resistance to Bacillus thuringiensis proteins was evaluated to identify mechanism(s) of resistance. Brush-border membrane vesicles were isolated from larval midgut epithelium from the susceptible and resistant strains of H. virescens. Two B. thuringiensis proteins, CryIA(b) and CryIA(c), were iodinated and shown to specifically bind to brush-border membrane vesicles of both insect strains. Multiple changes in the receptor-binding parameters were seen in the resistant strain as compared with the susceptible strain. A 2- to 4-fold reduction in binding affinity was accompanied by a 4- to 6-fold increase in binding-site concentration for both proteins. Although these two B. thuringiensis proteins competed for the same high-affinity binding site, competition experiments revealed different receptor specificity toward these proteins in the resistant H. virescens line. The H. virescens strains were not sensitive to a coleopteran-active protein, CryIIIA, nor did these proteins compete with the CryIA proteins for binding. Complexity of the mechanism of resistance is consistent with the complex mode of action of B. thuringiensis proteins. PMID:1924353

  15. Assembly of custom TALE-type DNA binding domains by modular cloning.

    Science.gov (United States)

    Morbitzer, Robert; Elsaesser, Janett; Hausner, Jens; Lahaye, Thomas

    2011-07-01

    Transcription activator-like effector (TALE) DNA binding proteins show tremendous potential as molecular tools for targeted binding to any desired DNA sequence. Their DNA binding domain consists of tandem arranged repeats, and due to this repetitive structure it is challenging to generate designer TALEs (dTALEs) with user-defined specificity. We present a cloning approach that facilitates the assembly of multiple repeat-encoding DNA fragments that translate into dTALEs with pre-defined DNA binding specificity. This method makes use of type IIS restriction enzymes in two sequential cut-ligase reactions to build dTALE repeat arrays. We employed this modular approach for generation of a dTALE that differentiates between two highly similar DNA sequences that are both targeted by the Xanthomonas TALE, AvrBs3. These data show that this modular assembly system allows rapid generation of highly specific TALE-type DNA binding domains that target binding sites of predefined length and sequence. This approach enables the rapid and flexible production of dTALEs for gene regulation and genome editing in routine and high-throughput applications.

  16. Histidine-rich glycoprotein binds fibrin(ogen) with high affinity and competes with thrombin for binding to the gamma'-chain.

    Science.gov (United States)

    Vu, Trang T; Stafford, Alan R; Leslie, Beverly A; Kim, Paul Y; Fredenburgh, James C; Weitz, Jeffrey I

    2011-09-01

    Histidine-rich glycoprotein (HRG) is an abundant protein that binds fibrinogen and other plasma proteins in a Zn(2+)-dependent fashion but whose function is unclear. HRG has antimicrobial activity, and its incorporation into fibrin clots facilitates bacterial entrapment and killing and promotes inflammation. Although these findings suggest that HRG contributes to innate immunity and inflammation, little is known about the HRG-fibrin(ogen) interaction. By immunoassay, HRG-fibrinogen complexes were detected in Zn(2+)-supplemented human plasma, a finding consistent with a high affinity interaction. Surface plasmon resonance determinations support this concept and show that in the presence of Zn(2+), HRG binds the predominant γ(A)/γ(A)-fibrinogen and the γ-chain elongated isoform, γ(A)/γ'-fibrinogen, with K(d) values of 9 nm. Likewise, (125)I-labeled HRG binds γ(A)/γ(A)- or γ(A)/γ'-fibrin clots with similar K(d) values when Zn(2+) is present. There are multiple HRG binding sites on fibrin(ogen) because HRG binds immobilized fibrinogen fragment D or E and γ'-peptide, an analog of the COOH terminus of the γ'-chain that mediates the high affinity interaction of thrombin with γ(A)/γ'-fibrin. Thrombin competes with HRG for γ'-peptide binding and displaces (125)I-HRG from γ(A)/γ'-fibrin clots and vice versa. Taken together, these data suggest that (a) HRG circulates in complex with fibrinogen and that the complex persists upon fibrin formation, and (b) by competing with thrombin for γ(A)/γ'-fibrin binding, HRG may modulate coagulation. Therefore, the HRG-fibrin interaction may provide a novel link between coagulation, innate immunity, and inflammation.

  17. Protein search for multiple targets on DNA

    Energy Technology Data Exchange (ETDEWEB)

    Lange, Martin [Johannes Gutenberg University, Mainz 55122 (Germany); Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Kochugaeva, Maria [Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Kolomeisky, Anatoly B., E-mail: tolya@rice.edu [Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005 (United States)

    2015-09-14

    Protein-DNA interactions are crucial for all biological processes. One of the most important fundamental aspects of these interactions is the process of protein searching and recognizing specific binding sites on DNA. A large number of experimental and theoretical investigations have been devoted to uncovering the molecular description of these phenomena, but many aspects of the mechanisms of protein search for the targets on DNA remain not well understood. One of the most intriguing problems is the role of multiple targets in protein search dynamics. Using a recently developed theoretical framework we analyze this question in detail. Our method is based on a discrete-state stochastic approach that takes into account most relevant physical-chemical processes and leads to fully analytical description of all dynamic properties. Specifically, systems with two and three targets have been explicitly investigated. It is found that multiple targets in most cases accelerate the search in comparison with a single target situation. However, the acceleration is not always proportional to the number of targets. Surprisingly, there are even situations when it takes longer to find one of the multiple targets in comparison with the single target. It depends on the spatial position of the targets, distances between them, average scanning lengths of protein molecules on DNA, and the total DNA lengths. Physical-chemical explanations of observed results are presented. Our predictions are compared with experimental observations as well as with results from a continuum theory for the protein search. Extensive Monte Carlo computer simulations fully support our theoretical calculations.

  18. Protein search for multiple targets on DNA

    International Nuclear Information System (INIS)

    Protein-DNA interactions are crucial for all biological processes. One of the most important fundamental aspects of these interactions is the process of protein searching and recognizing specific binding sites on DNA. A large number of experimental and theoretical investigations have been devoted to uncovering the molecular description of these phenomena, but many aspects of the mechanisms of protein search for the targets on DNA remain not well understood. One of the most intriguing problems is the role of multiple targets in protein search dynamics. Using a recently developed theoretical framework we analyze this question in detail. Our method is based on a discrete-state stochastic approach that takes into account most relevant physical-chemical processes and leads to fully analytical description of all dynamic properties. Specifically, systems with two and three targets have been explicitly investigated. It is found that multiple targets in most cases accelerate the search in comparison with a single target situation. However, the acceleration is not always proportional to the number of targets. Surprisingly, there are even situations when it takes longer to find one of the multiple targets in comparison with the single target. It depends on the spatial position of the targets, distances between them, average scanning lengths of protein molecules on DNA, and the total DNA lengths. Physical-chemical explanations of observed results are presented. Our predictions are compared with experimental observations as well as with results from a continuum theory for the protein search. Extensive Monte Carlo computer simulations fully support our theoretical calculations

  19. Improving Binding Affinity and Selectivity of Computationally Designed Ligand-Binding Proteins Using Experiments.

    Science.gov (United States)

    Tinberg, Christine E; Khare, Sagar D

    2016-01-01

    The ability to de novo design proteins that can bind small molecules has wide implications for synthetic biology and medicine. Combining computational protein design with the high-throughput screening of mutagenic libraries of computationally designed proteins is emerging as a general approach for creating binding proteins with programmable binding modes, affinities, and selectivities. The computational step enables the creation of a binding site in a protein that otherwise does not (measurably) bind the intended ligand, and targeted mutagenic screening allows for validation and refinement of the computational model as well as provides orders-of-magnitude increases in the binding affinity. Deep sequencing of mutagenic libraries can provide insights into the mutagenic binding landscape and enable further affinity improvements. Moreover, in such a combined computational-experimental approach where the binding mode is preprogrammed and iteratively refined, selectivity can be achieved (and modulated) by the placement of specified amino acid side chain groups around the ligand in defined orientations. Here, we describe the experimental aspects of a combined computational-experimental approach for designing-using the software suite Rosetta-proteins that bind a small molecule of choice and engineering, using fluorescence-activated cell sorting and high-throughput yeast surface display, high affinity and ligand selectivity. We illustrated the utility of this approach by performing the design of a selective digoxigenin (DIG)-binding protein that, after affinity maturation, binds DIG with picomolar affinity and high selectivity over structurally related steroids. PMID:27094290

  20. Continuous Multiple Vertebral Compression Fractures in Multiple Myeloma Patient

    OpenAIRE

    Hong, Sang Moon; Kim, Tae Wan; Park, Kwan Ho

    2012-01-01

    Multiple myeloma is a B-cell origin tumor characterized by hypercalcemia, osteolytic bony lesions, and pathologic fractures. Back pain is one of the most common presenting symptoms of multiple myeloma and about 60% of patients have vertebral involvement at the time of diagnosis7). Minimally invasive surgeries such as vertebroplasty and kyphoplasty are effective to relieve pain and improve the quality of life when a compression fracture occurs in multiple myeloma patients. We report a case of ...

  1. Specific insulin binding in bovine chromaffin cells; demonstration of preferential binding to adrenalin-storing cells

    Energy Technology Data Exchange (ETDEWEB)

    Serck-Hanssen, G.; Soevik, O.

    1987-12-28

    Insulin binding was studied in subpopulations of bovine chromaffin cells enriched in adrenalin-producing cells (A-cells) or noradrenalin-producing cells (NA-cells). Binding of /sup 125/I-insulin was carried out at 15/sup 0/C for 3 hrs in the absence or presence of excess unlabeled hormone. Four fractions of cells were obtained by centrifugation on a stepwise bovine serum albumin gradient. The four fractions were all shown to bind insulin in a specific manner and the highest binding was measured in the cell layers of higher densities, containing mainly A-cells. The difference in binding of insulin to the four subpopulations of chromaffin cells seemed to be related to differences in numbers of receptors as opposed to receptor affinities. The authors conclude that bovine chromaffin cells possess high affinity binding sites for insulin and that these binding sites are mainly confined to A-cells. 24 references, 2 figures, 1 table.

  2. Writing on Multiple Journeys

    Directory of Open Access Journals (Sweden)

    Sarah Robbins

    2012-06-01

    Full Text Available In their beautifully researched study and critical edition, Nellie Arnott’s Writings on Angola, 1905–1913: Missionary Narratives Linking Africa and America (Parlor Press, authors Sarah Robbins and Ann Ellis Pullen examine in fine detail the historical record of the transnational network of literary work produced by Arnott. Tracing her legacy in the study’s third chapter, “Writing on Multiple Journeys,” the authors argue on behalf of Arnott’s capacity to create authority and celebrity as well as a sense of community among her distant readers, underscoring the powerful and influential role that missionary women’s writing (mimicking to some extent the popular genre of travel writing played in shaping attitudes at home, not only with regard to race, but also in relation to women’s roles, place, and purpose. Robbins and Pullen display a conscientious resolve not to obscure the inherent contradictions in Arnott’s changing perspectives as they offer a historical narrative based on Arnott’s public and private texts, which also reveal the “consistent inconsistency” in her attitudes and beliefs. Details of and insights into educational practices in missionary schools, including the observation that mothers in the US appreciated the fact that their middle-class Christian children were sharing curriculum with Umbundu children in Angola, invite interesting conclusions about the transnational, transgenerational, and gendered effects of women’s work in the missionary world.

  3. Media and Multiplicity

    DEFF Research Database (Denmark)

    Blaagaard, Bolette

    2010-01-01

    In the past few years continental Europe has experienced a resurgence of right-wing party politics, nationalism and xenophobia. In this nationalist revival the media and advanced communications technologies have played a significant role, as evidenced by the debates following cases such as the Da......In the past few years continental Europe has experienced a resurgence of right-wing party politics, nationalism and xenophobia. In this nationalist revival the media and advanced communications technologies have played a significant role, as evidenced by the debates following cases...... such as the Danish cartoon controversy, and Dutch politician Geert Wilders’s film, Fitna. Simultaneously, however, the media is more diverse and rhizomatic than ever and offers potential for cosmopolitanism, transnational ethical relations as well as radical anti-racist and anti-fascist interventions. This article...... explores the tensions within the relation between journalistic practice and the construction of the idea of the nation and the multiplicity of media and cultures which inhabit the spheres of journalism and nation....

  4. Bayes Multiple Decision Functions

    CERN Document Server

    Wu, Wensong

    2011-01-01

    This paper deals with the problem of simultaneously making many (M) binary decisions based on one realization of a random data matrix X. M is typically large and X will usually have M rows associated with each of the M decisions to make, but for each row the data may be low dimensional. A Bayesian decision-theoretic approach for this problem is implemented with the overall loss function being a cost-weighted linear combination of Type I and Type II loss functions. The class of loss functions considered allows for the use of the false discovery rate (FDR), false nondiscovery rate (FNR), and missed discovery rate (MDR) in assessing the decision. Through this Bayesian paradigm, the Bayes multiple decision function (BMDF) is derived and an efficient algorithm to obtain the optimal Bayes action is described. In contrast to many works in the literature where the rows of the matrix X are assumed to be stochastically independent, we allow in this paper a dependent data structure with the associations obtained through...

  5. [Smoking and multiple sclerosis].

    Science.gov (United States)

    Arruti, Maialen; Castillo-Triviño, Tamara; Egüés, Nerea; Olascoaga, Javier

    2015-02-16

    Introduccion. La esclerosis multiple (EM) es una enfermedad autoinmune de etiologia compleja, hoy por hoy desconocida, en la que factores geneticos y ambientales determinan la susceptibilidad. En los ultimos años, el efecto del tabaco ha sido uno de los factores ambientales que ha emergido en la EM, y se ha asociado tanto a un aumento de la susceptibilidad como a un aumento de la progresion. Objetivo. Revisar la evidencia actual sobre el papel del tabaco en la EM. Desarrollo. Se incluye una actualizacion de los estudios publicados que han analizado distintos aspectos del tabaco en la EM: vias patogenicas implicadas, asociacion del tabaco y riesgo de EM, interaccion con otros factores de riesgo y efecto del tabaco en el curso de la enfermedad. Conclusiones. Los estudios observacionales demuestran que el tabaquismo incrementa de forma significativa el riesgo de EM (odds ratio ~ 1,5) y es un factor de riesgo independiente. Sin embargo, la EM es una enfermedad compleja y el aumento de riesgo por el tabaco puede diferir en funcion de la interaccion con otros factores geneticos y ambientales. El papel del tabaco como factor de progresion es mas controvertido, con resultados contradictorios y estudios de gran variabilidad, lo que dificulta establecer una conclusion firme. Los mecanismos por los que el tabaquismo modifica el riesgo y posiblemente la progresion de la enfermedad no son aun conocidos.

  6. Astrocytes in multiple sclerosis.

    Science.gov (United States)

    Ludwin, Samuel K; Rao, Vijayaraghava Ts; Moore, Craig S; Antel, Jack P

    2016-08-01

    Recent experimental and clinical studies on astrocytes are unraveling the capabilities of these multi-functional cells in normal homeostasis, and in central nervous system (CNS) disease. This review focuses on understanding their behavior in all aspects of the initiation, evolution, and resolution of the multiple sclerosis (MS) lesion. Astrocytes display remarkable flexibility and variability of their physical structure and biochemical output, each aspect finely tuned to the specific stage and location of the disease, participating in both pathogenic and beneficial changes seen in acute and progressive forms. As examples, chemo-attractive or repulsive molecules may facilitate the entry of destructive immune cells but may also aid in the recruitment of oligodendrocyte precursors, essential for repair. Pro-inflammatory cytokines may attack pathogenic cells and also destroy normal oligodendrocytes, myelin, and axons. Protective trophic factors may also open the blood-brain barrier and modulate the extracellular matrix to favor recruitment and persistence of CNS-specific immune cells. A chronic glial scar may confer structural support following tissue loss and inhibit ingress of further noxious insults and also inhibit migration of reparative cells and molecules into the damaged tissue. Continual study into these processes offers the therapeutic opportunities to enhance the beneficial capabilities of these cells while limiting their destructive effects. PMID:27207458

  7. Multiple cystic lung disease

    Directory of Open Access Journals (Sweden)

    Flavia Angélica Ferreira Francisco

    2015-12-01

    Full Text Available Multiple cystic lung disease represents a diverse group of uncommon disorders that can present a diagnostic challenge due to the increasing number of diseases associated with this presentation. High-resolution computed tomography of the chest helps to define the morphological aspects and distribution of lung cysts, as well as associated findings. The combination of appearance upon imaging and clinical features, together with extrapulmonary manifestations, when present, permits confident and accurate diagnosis of the majority of these diseases without recourse to open-lung biopsy. The main diseases in this group that are discussed in this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and folliculin gene-associated syndrome (Birt–Hogg–Dubé; other rare causes of cystic lung disease, including cystic metastasis of sarcoma, are also discussed. Disease progression is unpredictable, and understanding of the complications of cystic lung disease and their appearance during evolution of the disease are essential for management. Correlation of disease evolution and clinical context with chest imaging findings provides important clues for defining the underlying nature of cystic lung disease, and guides diagnostic evaluation and management.

  8. Multiple cystic lung disease.

    Science.gov (United States)

    Ferreira Francisco, Flavia Angélica; Soares Souza, Arthur; Zanetti, Gláucia; Marchiori, Edson

    2015-12-01

    Multiple cystic lung disease represents a diverse group of uncommon disorders that can present a diagnostic challenge due to the increasing number of diseases associated with this presentation. High-resolution computed tomography of the chest helps to define the morphological aspects and distribution of lung cysts, as well as associated findings. The combination of appearance upon imaging and clinical features, together with extrapulmonary manifestations, when present, permits confident and accurate diagnosis of the majority of these diseases without recourse to open-lung biopsy. The main diseases in this group that are discussed in this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and folliculin gene-associated syndrome (Birt-Hogg-Dubé); other rare causes of cystic lung disease, including cystic metastasis of sarcoma, are also discussed. Disease progression is unpredictable, and understanding of the complications of cystic lung disease and their appearance during evolution of the disease are essential for management. Correlation of disease evolution and clinical context with chest imaging findings provides important clues for defining the underlying nature of cystic lung disease, and guides diagnostic evaluation and management. PMID:26621970

  9. Multiple system atrophy.

    Science.gov (United States)

    Peeraully, Tasneem

    2014-04-01

    Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsive parkinsonism and/or cerebellar ataxia. Other clinical symptoms that can be associated with MSA include hyperreflexia, stridor, sleep apnea, and rapid eye movement sleep behavior disorder (RBD). Mean survival from time of diagnosis ranges between 6 to 10 years, and definitive diagnosis is made on autopsy with demonstration of oligodendroglial cytoplasmic inclusions consisting of fibrillar α-synuclein. Magnetic resonance imaging (MRI) may be positive for cruciform T2 hyperintensity within the pons (the "hot cross bun sign"), volume loss in the pons and cerebellum, and T2 signal loss in the dorsolateral putamen with hyperintense rim on fluid attenuated inversion recovery (FLAIR) sequencing. Although most cases are sporadic, genetic polymorphisms have been identified both in familial and sporadic cases of MSA, and influence observed phenotypes. Treatment is symptomatic, with both pharmacological and nonpharmacological strategies. There are currently no consensus guidelines on management. Current and future research is aimed at identifying biomarkers and developing disease-modifying therapies.

  10. Multiple Sklerose und Schwangerschaft

    Directory of Open Access Journals (Sweden)

    Berger T

    2009-01-01

    Full Text Available Da Multiple Sklerose (MS eine der häufigsten neurologischen Erkrankungen im jungen Erwachsenenalter ist und Frauen zwei- bis dreimal häufiger als Männer betrifft, sind Fragen nach Fertilität, Schwangerschaft und Geburt ein bedeutsames Gesprächsthema zwischen Patientinnen und behandelndem Arzt. Eine Schwangerschaft geht einher mit multiplen physiologischen Veränderungen, die auch zu einer Änderung des Immunstatus führen und so den Verlauf der MS (günstig beeinflussen können. Für die Dauer der Schwangerschaft ist eine Stabilisierung der MS mit einer Abnahme der Schubfrequenz festzustellen. Obwohl es dann in den ersten 6 Monaten postpartal zu einer Zunahme der Krankheitsaktivität kommen kann, lässt sich grundsätzlich sagen, dass eine Schwangerschaft keine längerfristigen negativen Effekte auf den weiteren Krankheitsverlauf ausübt. Auch hat MS keinen nachteiligen Einfluss auf die fetale Entwicklung und den positiven Geburtsausgang. Prinzipiell sind alle immunmodulatorischen und immunsuppressiven Medikamente in der Schwangerschaft kontraindiziert und sollten daher bei geplanter oder eingetretener Schwangerschaft unverzüglich abgesetzt werden. Eine Schubtherapie mit Kortikosteroiden kann hingegen durchaus auch während einer bestehenden Schwangerschaft durchgeführt werden.

  11. Erasure Multiple Descriptions

    CERN Document Server

    Ahmed, Ebad

    2010-01-01

    We consider a binary erasure version of the n-channel multiple descriptions problem with symmetric descriptions, i.e., the rates of the n descriptions are the same and the distortion constraint depends only on the number of messages received. We consider the case where there is no excess rate for every k out of n descriptions. Our goal is to characterize the achievable distortions D_1, D_2,...,D_n. We measure the fidelity of reconstruction using two distortion criteria: an average-case distortion criterion, under which distortion is measured by taking the average of the per-letter distortion over all source sequences, and a worst-case distortion criterion, under which distortion is measured by taking the maximum of the per-letter distortion over all source sequences. We present achievability schemes, based on random binning for average-case distortion and systematic MDS (maximum distance separable) codes for worst-case distortion, and prove optimality results for the corresponding achievable distortion region...

  12. [Diet and multiple sclerosis].

    Science.gov (United States)

    Pozuelo-Moyano, Beatriz; Benito-León, Julián

    2014-05-16

    Introduccion. El tipo de dieta se ha relacionado con el proceso inflamatorio que forma parte de la esclerosis multiple (EM). En los ultimos años, distintas lineas de investigacion han generado una gran cantidad de conocimiento sobre la participacion de la dieta en la patogenesis de la EM. Objetivo. Elucidar de modo critico las evidencias que relacionan distintos tipos de dietas y alimentos con la EM. Desarrollo. Se incluye una actualizacion de los estudios publicados mas significativos que han analizado el papel de la dieta en la patogenesis y en el tratamiento de la EM. Para explorar la asociacion entre la dieta y el riesgo de EM se ha revisado la evidencia disponible hasta el momento, pasando por estudios observacionales hasta terminar con estudios de intervencion. Conclusiones. Se necesita mas investigacion sobre la nutricion como factor de riesgo, ya que podria tener relacion con la enfermedad, y el control de esta podria llevar a una disminucion significativa de la incidencia o progresion de la patologia.

  13. Promoter binding factors regulating cyclin B transcription in the sea urchin embryo.

    Science.gov (United States)

    Thatcher, J D; McBride, B; Katula, K S

    1995-10-01

    Cyclin B is a key regulatory protein of the cell cycle, central to the control of the G2/M transition. In the developing sea urchin embryo, the cyclin B gene is transcriptionally regulated in concert with changing patterns of cell division. In an effort to understand the mechanism controlling cyclin B expression during development, we have conducted an analysis of the Strongylocentrotus purpuratus cyclin B gene promoter. DNase I foot-printing of the cyclin B upstream region revealed eight binding regions within 435 bp of the start of transcription; seven of these sites were within 215 bp. Found within these regions were consensus sequences for two CCAAT boxes, TATA, and E-boxes and sequences with some similarity to E2F and octamer binding motifs. Upstream sequences were functionally defined by generating cyclin B-CAT fusion genes, containing deletions and base specific mutations, and testing for relative levels of expression by gene transfer. Both CCAAT boxes were found to be essential for maximal levels of expression. A third binding site (PR7) with no recognizable consensus sequence was also found to act as a positive element. Our results suggest that protein binding to the E2F-like sequences may act to reduce expression. Protein binding was further characterized by gel mobility-shift and methylation interference. The CCAAT boxes were found to bind similar, if not identical, proteins. Sequence comparisons and methylation interference data indicate that the likely protein binding these CCAAT sequences is the characterized CCAAT-binding protein CP1. A probe containing site PR7 formed multiple gel shift complexes that, by methylation interference, appeared to be interrelated. One major complex was formed with an oligonucleotide containing the two E2F-like sequences. Protein binding to this probe was specific and required bases within the E2F-like sequences. Our results indicate that cyclin B is subject to positive and negative regulation, involving multiple factors

  14. 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

  15. Calmodulin Binding Proteins and Alzheimer's Disease.

    Science.gov (United States)

    O'Day, Danton H; Eshak, Kristeen; Myre, Michael A

    2015-01-01

    The small, calcium-sensor protein, calmodulin, is ubiquitously expressed and central to cell function in all cell types. Here the literature linking calmodulin to Alzheimer's disease is reviewed. Several experimentally-verified calmodulin-binding proteins are involved in the formation of amyloid-β plaques including amyloid-β protein precursor, β-secretase, presenilin-1, and ADAM10. Many others possess potential calmodulin-binding domains that remain to be verified. Three calmodulin binding proteins are associated with the formation of neurofibrillary tangles: two kinases (CaMKII, CDK5) and one protein phosphatase (PP2B or calcineurin). Many of the genes recently identified by genome wide association studies and other studies encode proteins that contain putative calmodulin-binding domains but only a couple (e.g., APOE, BIN1) have been experimentally confirmed as calmodulin binding proteins. At least two receptors involved in calcium metabolism and linked to Alzheimer's disease (mAchR; NMDAR) have also been identified as calmodulin-binding proteins. In addition to this, many proteins that are involved in other cellular events intimately associated with Alzheimer's disease including calcium channel function, cholesterol metabolism, neuroinflammation, endocytosis, cell cycle events, and apoptosis have been tentatively or experimentally verified as calmodulin binding proteins. The use of calmodulin as a potential biomarker and as a therapeutic target is discussed. PMID:25812852

  16. DNA Triplexes That Bind Several Cofactor Molecules.

    Science.gov (United States)

    Vollmer, Sven; Richert, Clemens

    2015-12-14

    Cofactors are critical for energy-consuming processes in the cell. Harnessing such processes for practical applications requires control over the concentration of cofactors. We have recently shown that DNA triplex motifs with a designed binding site can be used to capture and release nucleotides with low micromolar dissociation constants. In order to increase the storage capacity of such triplex motifs, we have explored the limits of ligand binding through designed cavities in the oligopurine tract. Oligonucleotides with up to six non-nucleotide bridges between purines were synthesized and their ability to bind ATP, cAMP or FAD was measured. Triplex motifs with several single-nucleotide binding sites were found to bind purines more tightly than triplexes with one large binding site. The optimized triplex consists of 59 residues and four C3-bridges. It can bind up to four equivalents of ligand with apparent Kd values of 52 µM for ATP, 9 µM for FAD, and 2 µM for cAMP. An immobilized version fuels bioluminescence via release of ATP at body temperature. These results show that motifs for high-density capture, storage and release of energy-rich biomolecules can be constructed from synthetic DNA. PMID:26561335

  17. Copper(II) binding properties of hepcidin.

    Science.gov (United States)

    Kulprachakarn, Kanokwan; Chen, Yu-Lin; Kong, Xiaole; Arno, Maria C; Hider, Robert C; Srichairatanakool, Somdet; Bansal, Sukhvinder S

    2016-06-01

    Hepcidin is a peptide hormone that regulates the homeostasis of iron metabolism. The N-terminal domain of hepcidin is conserved amongst a range of species and is capable of binding Cu(II) and Ni(II) through the amino terminal copper-nickel binding motif (ATCUN). It has been suggested that the binding of copper to hepcidin may have biological relevance. In this study we have investigated the binding of Cu(II) with model peptides containing the ATCUN motif, fluorescently labelled hepcidin and hepcidin using MALDI-TOF mass spectrometry. As with albumin, it was found that tetrapeptide models of hepcidin possessed a higher affinity for Cu(II) than that of native hepcidin. The log K 1 value of hepcidin for Cu(II) was determined as 7.7. Cu(II) binds to albumin more tightly than hepcidin (log K 1 = 12) and in view of the serum concentration difference of albumin and hepcidin, the bulk of kinetically labile Cu(II) present in blood will be bound to albumin. It is estimated that the concentration of Cu(II)-hepcidin will be less than one femtomolar in normal serum and thus the binding of copper to hepcidin is unlikely to play a role in iron homeostasis. As with albumin, small tri and tetra peptides are poor models for the metal binding properties of hepcidin. PMID:26883683

  18. [Binding to chicken liver lactatedehydrogenase (author's transl)].

    Science.gov (United States)

    Lluís, C; Bozal, J

    1976-06-01

    Some information about the lactate dehydrogenase NAD binding site has been obtained by working with coenzymes analogs of incomplete molecules. 5'AMP, 5'-ADP, ATP, 5'-c-AMP and 3'(2)-AMP inhibit chicken liver LDH activity competitively with NADH. 5"-AMP and 5'-ADP show a stronger inhibition power than ATP, suggesting that the presence of one or two phosphate groups at the 5' position of adenosine, is essential for the binding of the coenzyme analogs at the enzyme binding site. Ribose and ribose-5'-P do not appear to inhibit the LDH activity, proving that purine base lacking mononucleotides do not bind to the enzyme. 5"-ADPG inhibits LDH activity in the exactly as 5'-ADP, showing that ribose moiety may be replaced by glucose, without considerable effects on the coenzyme analog binding. 2'-desoxidenosin-5'-phosphate proves to be a poorer inhibitor of the LDH activity than 5'-AMP, indicating that an interaction between the--OH groups and the amino-acids of the LDH active center takes place. Nicotinamide does not produce any inhibition effect, while NMN and CMP induce a much weaker inhibition than the adenine analogues, thus indicating a lesser binding capacity to the enzyme. Therefore, the LDH binding site seems to show some definite specificity towards the adenina groups of the coenzyme.

  19. Glycolipid binding preferences of Shiga toxin variants.

    Directory of Open Access Journals (Sweden)

    Sayali S Karve

    Full Text Available The major virulence factor of Shiga toxin producing E. coli, is Shiga toxin (Stx, an AB5 toxin that consists of a ribosomal RNA-cleaving A-subunit surrounded by a pentamer of receptor-binding B subunits. The two major isoforms, Stx1 and Stx2, and Stx2 variants (Stx2a-h significantly differ in toxicity. The exact reason for this toxicity difference is unknown, however different receptor binding preferences are speculated to play a role. Previous studies used enzyme linked immunosorbent assay (ELISA to study binding of Stx1 and Stx2a toxoids to glycolipid receptors. Here, we studied binding of holotoxin and B-subunits of Stx1, Stx2a, Stx2b, Stx2c and Stx2d to glycolipid receptors globotriaosylceramide (Gb3 and globotetraosylceramide (Gb4 in the presence of cell membrane components such as phosphatidylcholine (PC, cholesterol (Ch and other neutral glycolipids. In the absence of PC and Ch, holotoxins of Stx2 variants bound to mixtures of Gb3 with other glycolipids but not to Gb3 or Gb4 alone. Binding of all Stx holotoxins significantly increased in the presence of PC and Ch. Previously, Stx2a has been shown to form a less stable B-pentamer compared to Stx1. However, its effect on glycolipid receptor binding is unknown. In this study, we showed that even in the absence of the A-subunit, the B-subunits of both Stx1 and Stx2a were able to bind to the glycolipids and the more stable B-pentamer formed by Stx1 bound better than the less stable pentamer of Stx2a. B-subunit mutant of Stx1 L41Q, which shows similar stability as Stx2a B-subunits, lacked glycolipid binding, suggesting that pentamerization is more critical for binding of Stx1 than Stx2a.

  20. Neutralization of influenza A viruses by insertion of a single antibody loop into the receptor binding site

    OpenAIRE

    Ekiert, Damian C.; Kashyap, Arun K.; Steel, John; Rubrum, Adam; Bhabha, Gira; Khayat, Reza; Lee, Jeong Hyun; Dillon, Michael A.; O’Neil, Ryann E.; Faynboym, Aleksandr M.; Horowitz, Michael; Horowitz, Lawrence; Ward, Andrew B.; Palese, Peter; Webby, Richard

    2012-01-01

    Immune recognition of protein antigens relies upon the combined interaction of multiple antibody loops, which provides a fairly large footprint and constrains the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of antibody C05 that neutralizes strains from multiple subtypes of influenza A viruses, in...

  1. Reciprocal allosteric modulation of carbon monoxide and warfarin binding to ferrous human serum heme-albumin.

    Directory of Open Access Journals (Sweden)

    Alessio Bocedi

    Full Text Available Human serum albumin (HSA, the most abundant protein in human plasma, could be considered as a prototypic monomeric allosteric protein, since the ligand-dependent conformational adaptability of HSA spreads beyond the immediate proximity of the binding site(s. As a matter of fact, HSA is a major transport protein in the bloodstream and the regulation of the functional allosteric interrelationships between the different binding sites represents a fundamental information for the knowledge of its transport function. Here, kinetics and thermodynamics of the allosteric modulation: (i of carbon monoxide (CO binding to ferrous human serum heme-albumin (HSA-heme-Fe(II by warfarin (WF, and (ii of WF binding to HSA-heme-Fe(II by CO are reported. All data were obtained at pH 7.0 and 25°C. Kinetics of CO and WF binding to the FA1 and FA7 sites of HSA-heme-Fe(II, respectively, follows a multi-exponential behavior (with the same relative percentage for the two ligands. This can be accounted for by the existence of multiple conformations and/or heme-protein axial coordination forms of HSA-heme-Fe(II. The HSA-heme-Fe(II populations have been characterized by resonance Raman spectroscopy, indicating the coexistence of different species characterized by four-, five- and six-coordination of the heme-Fe atom. As a whole, these results suggest that: (i upon CO binding a conformational change of HSA-heme-Fe(II takes place (likely reflecting the displacement of an endogenous ligand by CO, and (ii CO and/or WF binding brings about a ligand-dependent variation of the HSA-heme-Fe(II population distribution of the various coordinating species. The detailed thermodynamic and kinetic analysis here reported allows a quantitative description of the mutual allosteric effect of CO and WF binding to HSA-heme-Fe(II.

  2. Effect of positional dependence and alignment strategy on modeling transcription factor binding sites

    Directory of Open Access Journals (Sweden)

    Quader Saad

    2012-07-01

    Full Text Available Abstract Background Many consensus-based and Position Weight Matrix-based methods for recognizing transcription factor binding sites (TFBS are not well suited to the variability in the lengths of binding sites. Besides, many methods discard known binding sites while building the model. Moreover, the impact of Information Content (IC and the positional dependence of nucleotides within an aligned set of TFBS has not been well researched for modeling variable-length binding sites. In this paper, we propose ML-Consensus (Mixed-Length Consensus: a consensus model for variable-length TFBS which does not exclude any reported binding sites. Methods We consider Pairwise Score (PS as a measure of positional dependence of nucleotides within an alignment of TFBS. We investigate how the prediction accuracy of ML-Consensus is affected by the incorporation of IC and PS with a particular binding site alignment strategy. We perform cross-validations for datasets of six species from the TRANSFAC public database, and analyze the results using ROC curves and the Wilcoxon matched-pair signed-ranks test. Results We observe that the incorporation of IC and PS in ML-Consensus results in statistically significant improvement in the prediction accuracy of the model. Moreover, the existence of a core region among the known binding sites (of any length is witnessed by the pairwise coexistence of nucleotides within the core length. Conclusions These observations suggest the possibility of an efficient multiple sequence alignment algorithm for aligning TFBS, accommodating known binding sites of any length, for optimal (or near-optimal TFBS prediction. However, designing such an algorithm is a matter of further investigation.

  3. Steric and allosteric effects of fatty acids on the binding of warfarin to human serum albumin revealed by molecular dynamics and free energy calculations.

    Science.gov (United States)

    Fujiwara, Shin-Ichi; Amisaki, Takashi

    2011-01-01

    Human serum albumin (HSA) binds with drugs and fatty acids (FAs). This study was initiated to elucidate the relationship between the warfarin binding affinity of HSA and the positions of bound FA molecules. Molecular dynamics simulations of 11 HSA-warfarin-myristate complexes were performed. HSA-warfarin binding free energy was then calculated for each of the complexes by the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. The results indicated that the magnitude of the binding free energy was smaller in HSA-warfarin complexes that had 4 or more myristate molecules than in complexes with no myristate molecules. The unfavorable effect on the HSA-warfarin binding affinity was caused sterically by the binding of a myristate molecule to the FA binding site closest to the warfarin binding site. On the other hand, the magnitude of HSA-warfarin binding free energy was largest when 3 myristate molecules were bound to the high-affinity sites. The strongest HSA-warfarin binding was attributable to favorable entropic contribution related to larger atomic fluctuations of the amino acid residues at the warfarin binding site. In the binding of 2 myristate molecules to the sites with the highest and second-highest affinities, allosteric modulation that enhanced electrostatic interactions between warfarin and some of the amino acid residues around the warfarin binding site was observed. This study clarified the structural and energetic properties of steric/allosteric effects of FAs on the HSA-warfarin binding affinity and illustrated the approach to analyze protein-ligand interactions in situations such that multiple ligands bind to the other sites of the protein. PMID:21720037

  4. Measuring Binding Affinity of Protein-Ligand Interaction Using Spectrophotometry: Binding of Neutral Red to Riboflavin-Binding Protein

    Science.gov (United States)

    Chenprakhon, Pirom; Sucharitakul, Jeerus; Panijpan, Bhinyo; Chaiyen, Pimchai

    2010-01-01

    The dissociation constant, K[subscript d], of the binding of riboflavin-binding protein (RP) with neutral red (NR) can be determined by titrating RP to a fixed concentration of NR. Upon adding RP to the NR solution, the maximum absorption peak of NR shifts to 545 nm from 450 nm for the free NR. The change of the absorption can be used to determine…

  5. Multiple intelligences in school

    Directory of Open Access Journals (Sweden)

    Alejandro Castro Solano

    2016-02-01

    Full Text Available During many years has prevailed the idea of intelligence as a single problem solving ability (factor g considered the best predictor of student’s academic achievement. Recently, researches have begun to take an alternative view of the problem, understanding it is a multidimensional construct. Multiple intelligences (MI theory proposed by Gardner (1983 takes into account seven talents or skills individuals appear to have in certain amount. These latent bio-psychological potentials are stable and they are mantained through life. Theory of MI proposes that every person learns in relation to them. MI theory has many educational applications, however, very few efforts have been made to verify such statements. The main goal of this study is to analyze the IM differential individual profile of high school and university students studying the relation between IM, academic achievement and self efficacy competence on course performance. Two studies were carried out , the first was done with high school students (N=500 and the second with military students (N=362. Based on Armstrong’s proposals to assess IM, an inventory was designed. Main results point out that there is a correspondence between academic attainment, self interest and self perception of competence in different courses students take. MI are good predictors of academic achievement considering specific areas but they don’t provide a better estimation compared to traditional assessment instruments. Students who have failed in school were those with more spatial and corporal abilities, usually relegated by traditional instruction. High achievers were those with more logical and intrapersonal skills. Different relations were found for military students. For these latter students IM theory was not a valuable predictor of successful academic attainment. 

  6. Therapy of Multiple Myeloma

    Institute of Scientific and Technical Information of China (English)

    H.Goldschmidt; F.W.Cremer; 等

    2002-01-01

    Multiple Myeloma(MM)is characterised by the accumulation of malignanat plasma cells in the bone marrow producing a monocolonal immungoglobulin.The standard conventiona therapy in the combination of melphalan and prednisone resulting in a response rate of 40%-60% and in a median survival time of approximately 3 years.In order to improve the therapeutic efficacy va rious combination regimens have been tested.Most randomized trials have frailed to show a significant improvement in survival time when combination chemotherapy is used instead of melphalan with or without prednisone.The benefit of maintenance therapy with interferon-alpha has been demonstrated.The toxicity of interferon-alpha,which may reduce the quality of life,should be considered.Recently,myeloma-treatment has been modified.High-dose chemotherapy accompaniced by hematopoietic stem-cell support via autologous transplant is recommended up to the age of 65-70 years.First results from a French study comparing single versus double autologous transplantaiton have shown a benefit in terms of event-free survival for the sequential approach.Vaccinations as an adoptive immuntherapy to treat minimal residual dsease are umder way.The mortality rate of allogeneic transplantation of hemaatopoietic stem cells has been reduced in the last 5 years.The use of reduced conditioning regimens or the partial depletion of T cells in peripheral blood stem cell transplants in an effort to decrease transplant related mortality are promising approaches.Thalidomide and its derivates are a new class of agents with independent anti-tumour activity in MM.Encouraging results with this antiangiogenic therapy in phase Ⅱ trials have been reported.Supportive therapies,such as the treatment of anaemia with erythropoietin,the management of renal failure and the use of bisphosphonates,improve the life quality of MM patients.

  7. Multiple chronic benign pulmonary nodules.

    Science.gov (United States)

    Kalifa, L G; Schimmel, D H; Gamsu, G

    1976-11-01

    Four cases are discussed in which were found unusual multiple chronic pulmonary nodules: leiomyomatous hamartomas, rheumatoid nodules, multiple histoplasmomas, and possible multiple plasma cell granulomas (hyalinizing pulmonary nodules). In each case the initial impression of metastic malignancy was countered by more than 2 years' observation, during which time the lesions appeared to be benign. Histologic examination is necessary to exclude malignancy, although a definitive diagnosis may be difficult to establish. PMID:981596

  8. Global workspace dynamics: cortical "binding and propagation" enables conscious contents.

    Science.gov (United States)

    Baars, Bernard J; Franklin, Stan; Ramsoy, Thomas Zoega

    2013-01-01

    A global workspace (GW) is a functional hub of binding and propagation in a population of loosely coupled signaling elements. In computational applications, GW architectures recruit many distributed, specialized agents to cooperate in resolving focal ambiguities. In the brain, conscious experiences may reflect a GW function. For animals, the natural world is full of unpredictable dangers and opportunities, suggesting a general adaptive pressure for brains to resolve focal ambiguities quickly and accurately. GW theory aims to understand the differences between conscious and unconscious brain events. In humans and related species the cortico-thalamic (C-T) core is believed to underlie conscious aspects of perception, thinking, learning, feelings of knowing (FOK), felt emotions, visual imagery, working memory, and executive control. Alternative theoretical perspectives are also discussed. The C-T core has many anatomical hubs, but conscious percepts are unitary and internally consistent at any given moment. Over time, conscious contents constitute a very large, open set. This suggests that a brain-based GW capacity cannot be localized in a single anatomical hub. Rather, it should be sought in a functional hub - a dynamic capacity for binding and propagation of neural signals over multiple task-related networks, a kind of neuronal cloud computing. In this view, conscious contents can arise in any region of the C-T core when multiple input streams settle on a winner-take-all equilibrium. The resulting conscious gestalt may ignite an any-to-many broadcast, lasting ∼100-200 ms, and trigger widespread adaptation in previously established networks. To account for the great range of conscious contents over time, the theory suggests an open repertoire of binding coalitions that can broadcast via theta/gamma or alpha/gamma phase coupling, like radio channels competing for a narrow frequency band. Conscious moments are thought to hold only 1-4 unrelated items; this small

  9. Vascular comorbidities in multiple sclerosis

    DEFF Research Database (Denmark)

    Thormann, Anja; Magyari, Melinda; Koch-Henriksen, Nils;

    2016-01-01

    To investigate the occurrence of vascular comorbidities before and after the clinical onset of multiple sclerosis. In this combined case-control and cohort study, all Danish born citizens with onset of multiple sclerosis 1980-2005 were identified from the Danish Multiple Sclerosis Registry...... and randomly matched with controls regarding year of birth, gender, and municipality on January 1st in the year of multiple sclerosis (MS) onset (index date). Individual-level information on comorbidities was obtained from several independent nationwide registries and linked to the study population by unique...

  10. Multiplicative Thinking: Much More than Knowing Multiplication Facts and Procedures

    Science.gov (United States)

    Hurst, Chris; Hurrell, Derek

    2016-01-01

    Multiplicative thinking is accepted as a "big idea" of mathematics that underpins important mathematical concepts such as fraction understanding, proportional reasoning, and algebraic thinking. It is characterised by understandings such as the multiplicative relationship between places in the number system, basic and extended number…

  11. Multiple purpose electrical profit; Emprendimiento electrico de prestacion multiple

    Energy Technology Data Exchange (ETDEWEB)

    Assennato, H. [Electrica de Azul Ltda., Buenos Aires (Argentina)

    1986-12-31

    This paper shows the multiple purpose aspects of electrification projects in rural and isolated areas. The multiple aspects involved in the electrification process may include, over electric power supply: improvement of life quality, irrigation and rural mechanization. 4 figs., 6 tabs., 4 refs.

  12. Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro

    Directory of Open Access Journals (Sweden)

    Robert eRoot-Bernstein

    2014-07-01

    Full Text Available Rationale: Insulin resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome and obesity. The mechanism by which insulin and estrogen interact is unknown. We hypothesize that estrogen binds directly to insulin and the insulin receptor producing insulin resistance.Objectives: To determine the binding constants of steroid hormones to insulin, the insulin receptor, and insulin-like peptides derived from the insulin receptor; and to investigate the effect of estrogens on the binding of insulin to its receptor.Methods: Ultraviolet spectroscopy, capillary electrophoresis and NMR demonstrated estrogen binding to insulin and its receptor. Horse-radish peroxidase-linked insulin was used in an ELISA-like procedure to measure the effect of estradiol on binding of insulin to its receptor. Measurements: Binding constants for estrogens to insulin and the insulin receptor were determined by concentration-dependent spectral shifts. The effect of estradiol on insulin-HRP binding to its receptor was determined by shifts in the insulin binding curve. Main Results: Estradiol bound to insulin with a Kd of 12 x 10-9 M and to the insulin receptor with a Kd of 24 x 10-9 M, while other hormones had significantly less affinity. 200 nM estradiol shifted the binding curve of insulin to its receptor 0.8 log units to the right. Conclusions: Estradiol concentrations in many hyperestrogenemic syndromes are sufficient to interfere with insulin binding to its receptor producing significant insulin resistance.

  13. Tight-binding lattices with an oscillating imaginary gauge field

    Science.gov (United States)

    Longhi, Stefano

    2016-08-01

    We consider non-Hermitian dynamics of a quantum particle hopping on a one-dimensional tight-binding lattice made of N sites with asymmetric hopping rates induced by a time-periodic oscillating imaginary gauge field. A deeply different behavior is found depending on the lattice topology. While in a linear chain (open boundary conditions) an oscillating field can lead to a complex quasienergy spectrum via a multiple parametric resonance; in a ring topology (Born-von Karman periodic boundary conditions) an entirely real quasienergy spectrum can be found and the dynamics is pseudo-Hermitian. In the large-N limit, parametric instability and pseudo-Hermitian dynamics in the two different lattice topologies are physically explained on the basis of a simple picture of wave-packet propagation.

  14. Binding mode of dihydroquinazolinones with lysozyme and its antifungal activity against Aspergillus species.

    Science.gov (United States)

    Hemalatha, K; Madhumitha, G; Ravi, Lokesh; Khanna, V Gopiesh; Al-Dhabi, Naif Abdullah; Arasu, Mariadhas Valan

    2016-08-01

    Aspergillosis is one of the infectious fungal diseases affecting mainly the immunocompromised patients. The scarcity of the antifungal targets has identified the importance of N-myristoyl transferase (NMT) in the regulation of fungal pathway. The dihydroquinazolinone molecules were designed on the basis of fragments responsible for binding with the target enzyme. The aryl halide, 1(a-g), aryl boronic acid and potassium carbonate were heated together in water and dioxane mixture to yield new CC bond formation in dihydroquinazolinone. The bis(triphenylphosphine)palladium(II) dichloride was used as catalyst for the CC bond formation. The synthesized series were screened for their in vitro antifungal activity against Aspergillus niger and Aspergillus fumigatus. The binding interactions of the active compound with lysozyme were explored using multiple spectroscopic studies. Molecular docking study of dihydroquinazolinones with the enzyme revealed the information regarding various binding forces involved in the interaction. PMID:27214045

  15. A polyaromatic molecular tube that binds long hydrocarbons with high selectivity

    Science.gov (United States)

    Yazaki, Kohei; Sei, Yoshihisa; Akita, Munetaka; Yoshizawa, Michito

    2014-10-01

    Long hydrocarbon chains are essential components of biomolecules used for structure and function in living organisms. The selective recognition and effective binding of hydrocarbons within synthetic host compounds are problematic owing to their conformational flexibility and the lack of specific binding sites. Here we report a molecular tube with polyaromatic frameworks prepared by the Zincke cross-coupling reaction. The tube has a well-defined cylindrical cavity with a diameter and length of ~1 nm encircled by multiple anthracene panels and thereby binds long hydrocarbons containing branched methyl groups and/or unsaturated carbon-carbon double bonds (for example, heptamethylnonane, nervonic acid ester and squalene) with high selectivity in aqueous solutions.

  16. Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development.

    Directory of Open Access Journals (Sweden)

    Jonathan Göke

    2011-12-01

    Full Text Available Transcription factors are proteins that regulate gene expression by binding to cis-regulatory sequences such as promoters and enhancers. In embryonic stem (ES cells, binding of the transcription factors OCT4, SOX2 and NANOG is essential to maintain the capacity of the cells to differentiate into any cell type of the developing embryo. It is known that transcription factors interact to regulate gene expression. In this study we show that combinatorial binding is strongly associated with co-localization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an important role for embryogenesis by binding at conserved early developmental enhancers. Our data suggests that the fast evolutionary rewiring of regulatory networks mainly affects individual binding events, whereas "gene regulatory hotspots" which are bound by multiple factors and active in multiple tissues throughout early development are under stronger evolutionary constraints.

  17. Acyl-coenzyme A binding protein (ACBP)

    DEFF Research Database (Denmark)

    Kragelund, B B; Knudsen, J; Poulsen, F M

    1999-01-01

    Acyl-coenzyme A binding proteins are known from a large group of eukaryote species and to bind a long chain length acyl-CoA ester with very high affinity. Detailed biochemical mapping of ligand binding properties has been obtained as well as in-depth structural studies on the bovine apo-protein...... and of the complex with palmitoyl-CoA using NMR spectroscopy. In the four alpha-helix bundle structure, a set of 21 highly conserved residues present in more that 90% of all known sequences of acyl-coenzyme A binding proteins constitutes three separate mini-cores. These residues are predominantly located...... at the helix-helix interfaces. From studies of a large set of mutant proteins the role of the conserved residues has been related to structure, function, folding and stability....

  18. Acyl-coenzyme A binding protein, ACBP

    DEFF Research Database (Denmark)

    Kragelund, Birthe Brandt; Knudsen, J.; Poulsen, Flemming

    1999-01-01

    Acyl-coenzyme A binding proteins are known from a large group of eukaryote species and to bind a long chain length acyl-CoA ester with very high affinity. Detailed biochemical mapping of ligand binding properties has been obtained as well as in-depth structural studies on the bovine apo-protein...... and of the complex with palmitoyl-CoA using NMR spectroscopy. In the four a-helix bundle structure, a set of 21 highly conserved residues present in more that 90% of all known sequences of acyl-coenzyme A binding proteins constitutes three separate mini-cores. These residues are predominantly located at the helix......-helix interfaces. From studies of a large set of mutant proteins the role of the conserved residues has been related to structure, function, folding and stability....

  19. Tau Induces Cooperative Taxol Binding to Microtubules

    Science.gov (United States)

    Ross, Jennifer; Santangelo, Christian; Victoria, Makrides; Fygenson, Deborah

    2004-03-01

    Taxol and tau are two ligands which stabilize the microtubule (MT) lattice. Taxol is an anti-mitotic drug that binds β tubulin in the MT interior. Tau is a MT-associated protein that binds both α and β tubulin on the MT exterior. Both taxol and tau reduce MT dynamics and promote tubulin polymerization. Tau alone also acts as a buttress to bundle, stiffen, and space MTs. A structural study recently suggested that taxol and tau may interact by binding to the same site. Using fluorescence recovery after photobleaching, we find that tau induces taxol to bind MTs cooperatively depending on the tau concentration. We develop a model that correctly fits the data in the absence of tau and yields a measure of taxol cooperativity when tau is present.

  20. Adjustment of legally binding local plans

    DEFF Research Database (Denmark)

    Hvingel, Line Træholt; Aunsborg, Christian; Christensen, Finn Kjær;

    2012-01-01

    Traditionally, and by law, new urban areas in Denmark are regulated and planned through legally binding local plans. Recently a tendency has occurred: The municipalities make the legally binding local plans quite open for future adjustment, and they are using a substantial amount of ‘empowerment......, which seem to be beyond the scope of the Danish Planning Act. This paper deals with this problem through case studies and a legal analysis of present law. If the combination of the legally binding local plan and subsequent added requirements is misused, it will weaken the legal rights of the citizens...... the considerations of legal rights, the extend of the legal use of empowerment provisions and the combination of the use of legal binding local plans and other legal instruments such as easements and sales agreements....

  1. Peptide binding specificity of the chaperone calreticulin

    DEFF Research Database (Denmark)

    Sandhu, N.; Duus, K.; Jorgensen, C.S.;

    2007-01-01

    Calreticulin is a molecular chaperone with specificity for polypeptides and N-linked monoglucosylated glycans. In order to determine the specificity of polypeptide binding, the interaction of calreticulin with polypeptides was investigated using synthetic peptides of different length and composit...

  2. System Support for Managing Invalid Bindings

    CERN Document Server

    Das, Lachhman; Shah, Azhar; Khoumbati, Khalil; 10.5121/iju.2011.2303

    2011-01-01

    Context-aware adaptation is a central aspect of pervasive computing applications, enabling them to adapt and perform tasks based on contextual information. One of the aspects of context-aware adaptation is reconfiguration in which bindings are created between application component and remote services in order to realize new behaviour in response to contextual information. Various research efforts provide reconfiguration support and allow the development of adaptive context-aware applications from high-level specifications, but don't consider failure conditions that might arise during execution of such applications, making bindings between application and remote services invalid. To this end, we propose and implement our design approach to reconfiguration to manage invalid bindings. The development and modification of adaptive context-aware applications is a complex task, and an issue of an invalidity of bindings further complicates development efforts. To reduce the development efforts, our approach provides ...

  3. Genetics Home Reference: mannose-binding lectin deficiency

    Science.gov (United States)

    ... Health Conditions mannose-binding lectin deficiency mannose-binding lectin deficiency Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Mannose-binding lectin deficiency is a condition that affects the immune ...

  4. Convolutional neural network architectures for predicting DNA–protein binding

    Science.gov (United States)

    Zeng, Haoyang; Edwards, Matthew D.; Liu, Ge; Gifford, David K.

    2016-01-01

    Motivation: Convolutional neural networks (CNN) have outperformed conventional methods in modeling the sequence specificity of DNA–protein binding. Yet inappropriate CNN architectures can yield poorer performance than simpler models. Thus an in-depth understanding of how to match CNN architecture to a given task is needed to fully harness the power of CNNs for computational biology applications. Results: We present a systematic exploration of CNN architectures for predicting DNA sequence binding using a large compendium of transcription factor datasets. We identify the best-performing architectures by varying CNN width, depth and pooling designs. We find that adding convolutional kernels to a network is important for motif-based tasks. We show the benefits of CNNs in learning rich higher-order sequence features, such as secondary motifs and local sequence context, by comparing network performance on multiple modeling tasks ranging in difficulty. We also demonstrate how careful construction of sequence benchmark datasets, using approaches that control potentially confounding effects like positional or motif strength bias, is critical in making fair comparisons between competing methods. We explore how to establish the sufficiency of training data for these learning tasks, and we have created a flexible cloud-based framework that permits the rapid exploration of alternative neural network architectures for problems in computational biology. Availability and Implementation: All the models analyzed are available at http://cnn.csail.mit.edu. Contact: gifford@mit.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307608

  5. DNA-Aptamers Binding Aminoglycoside Antibiotics

    OpenAIRE

    Nadia Nikolaus; Beate Strehlitz

    2014-01-01

    Aptamers are short, single stranded DNA or RNA oligonucleotides that are able to bind specifically and with high affinity to their non-nucleic acid target molecules. This binding reaction enables their application as biorecognition elements in biosensors and assays. As antibiotic residues pose a problem contributing to the emergence of antibiotic-resistant pathogens and thereby reducing the effectiveness of the drug to fight human infections, we selected aptamers targeted against the aminog...

  6. Liver Fatty Acid Binding Protein and Obesity

    OpenAIRE

    Atshaves, B.P.; Martin, G G; Hostetler, H.A.; McIntosh, A.L.; Kier, A B; Schroeder, F.

    2010-01-01

    While low levels of unesterified long chain fatty acids (LCFAs) are normal metabolic intermediates of dietary and endogenous fat, LCFAs are also potent regulators of key receptors/enzymes, and at high levels become toxic detergents within the cell. Elevated levels of LCFAs are associated with diabetes, obesity, and metabolic syndrome. Consequently, mammals evolved fatty acid binding proteins (FABPs) that bind/sequester these potentially toxic free fatty acids in the cytosol and present them f...

  7. Binding capacity: cooperativity and buffering in biopolymers.

    Science.gov (United States)

    Di Cera, E; Gill, S J; Wyman, J

    1988-01-01

    The group of linkage potentials resulting from the energy of a physicochemical system expressed per mol of a reference component, say a polyfunctional macromolecule, leads to the concept of binding capacity. This concept applies equally to both chemical and physical ligands and opens the way to consideration of higher-order linkage relationships. It provides a means of exploring the consequences of thermodynamic stability on generalized binding phenomena in biopolymers. PMID:3422436

  8. Penicillin-Binding Protein Imaging Probes

    OpenAIRE

    Kocaoglu, Ozden; Carlson, Erin E.

    2013-01-01

    Penicillin-binding proteins (PBPs) are membrane-associated proteins involved in the biosynthesis of peptidoglycan (PG), the main component of bacterial cell walls. These proteins were discovered and named for their affinity to bind the β-lactam antibiotic penicillin. The importance of the PBPs has long been appreciated; however, the apparent functional redundancy of the ~5–15 proteins that most bacteria possess makes determination of their individual roles difficult. Existing techniques to st...

  9. Photonic Binding in Silicon-Colloid Microcavities

    OpenAIRE

    Xifré-Pérez, E.; García de Abajo, Francisco Javier; Fenollosa Esteve, Roberto; Meseguer, Francisco

    2009-01-01

    Photonic binding between two identical silicon-colloid-based microcavities is studied by using a generalized multipolar expansion. In contrast with previous works, we focus on low-order cavity modes that resemble low-energy electronic orbitals. For conservative light intensities, the interaction between cavity modes with moderate Q factors produces extremely large particle acceleration values. Optical forces dominate over vanderWaals, gravity, and Brownian motion, and they show a binding-anti...

  10. The readiness potential reflects intentional binding

    Directory of Open Access Journals (Sweden)

    Han-Gue eJo

    2014-06-01

    Full Text Available When a voluntary action is causally linked with a sensory outcome, the action and its consequent effect are perceived as being closer together in time. This effect is called intentional binding. Although many experiments were conducted on this phenomenon, the underlying neural mechanisms are not well understood. While intentional binding is specific to voluntary action, we presumed that preconscious brain activity (the readiness potential, RP, which occurs before an action is made, might play an important role in this binding effect. In this study, the brain dynamics were recorded with electroencephalography (EEG and analyzed in single-trials in order to estimate whether intentional binding is correlated with the early neural processes. Moreover, we were interested in different behavioral performance between meditators and non-meditators since meditators are expected to be able to keep attention more consistently on a task. Thus, we performed the intentional binding paradigm with twenty mindfulness meditators and compared them to matched controls. Although, we did not observe a group effect on either behavioral data or EEG recordings, we found that self-initiated movements following ongoing negative deflections of slow cortical potentials (SCPs result in a stronger binding effect compared to positive potentials, especially regarding the perceived time of the consequent effect. Our results provide the first direct evidence that the early neural activity within the range of SCPs affects perceived time of a sensory outcome that is caused by intentional action.

  11. The readiness potential reflects intentional binding.

    Science.gov (United States)

    Jo, Han-Gue; Wittmann, Marc; Hinterberger, Thilo; Schmidt, Stefan

    2014-01-01

    When a voluntary action is causally linked with a sensory outcome, the action and its consequent effect are perceived as being closer together in time. This effect is called intentional binding. Although many experiments were conducted on this phenomenon, the underlying neural mechanisms are not well understood. While intentional binding is specific to voluntary action, we presumed that preconscious brain activity (the readiness potential, RP), which occurs before an action is made, might play an important role in this binding effect. In this study, the brain dynamics were recorded with electroencephalography (EEG) and analyzed in single-trials in order to estimate whether intentional binding is correlated with the early neural processes. Moreover, we were interested in different behavioral performance between meditators and non-meditators since meditators are expected to be able to keep attention more consistently on a task. Thus, we performed the intentional binding paradigm with 20 mindfulness meditators and compared them to matched controls. Although, we did not observe a group effect on either behavioral data or EEG recordings, we found that self-initiated movements following ongoing negative deflections of slow cortical potentials (SCPs) result in a stronger binding effect compared to positive potentials, especially regarding the perceived time of the consequent effect. Our results provide the first direct evidence that the early neural activity within the range of SCPs affects perceived time of a sensory outcome that is caused by intentional action.

  12. DNA-Aptamers Binding Aminoglycoside Antibiotics

    Directory of Open Access Journals (Sweden)

    Nadia Nikolaus

    2014-02-01

    Full Text Available Aptamers are short, single stranded DNA or RNA oligonucleotides that are able to bind specifically and with high affinity to their non-nucleic acid target molecules. This binding reaction enables their application as biorecognition elements in biosensors and assays. As antibiotic residues pose a problem contributing to the emergence of antibiotic-resistant pathogens and thereby reducing the effectiveness of the drug to fight human infections, we selected aptamers targeted against the aminoglycoside antibiotic kanamycin A with the aim of constructing a robust and functional assay that can be used for water analysis. With this work we show that aptamers that were derived from a Capture-SELEX procedure targeting against kanamycin A also display binding to related aminoglycoside antibiotics. The binding patterns differ among all tested aptamers so that there are highly substance specific aptamers and more group specific aptamers binding to a different variety of aminoglycoside antibiotics. Also the region of the aminoglycoside antibiotics responsible for aptamer binding can be estimated. Affinities of the different aptamers for their target substance, kanamycin A, are measured with different approaches and are in the micromolar range. Finally, the proof of principle of an assay for detection of kanamycin A in a real water sample is given.

  13. Electrostatically biased binding of kinesin to microtubules.

    Directory of Open Access Journals (Sweden)

    Barry J Grant

    2011-11-01

    Full Text Available The minimum motor domain of kinesin-1 is a single head. Recent evidence suggests that such minimal motor domains generate force by a biased binding mechanism, in which they preferentially select binding sites on the microtubule that lie ahead in the progress direction of the motor. A specific molecular mechanism for biased binding has, however, so far been lacking. Here we use atomistic Brownian dynamics simulations combined with experimental mutagenesis to show that incoming kinesin heads undergo electrostatically guided diffusion-to-capture by microtubules, and that this produces directionally biased binding. Kinesin-1 heads are initially rotated by the electrostatic field so that their tubulin-binding sites face inwards, and then steered towards a plus-endwards binding site. In tethered kinesin dimers, this bias is amplified. A 3-residue sequence (RAK in kinesin helix alpha-6 is predicted to be important for electrostatic guidance. Real-world mutagenesis of this sequence powerfully influences kinesin-driven microtubule sliding, with one mutant producing a 5-fold acceleration over wild type. We conclude that electrostatic interactions play an important role in the kinesin stepping mechanism, by biasing the diffusional association of kinesin with microtubules.

  14. Transcriptional Activation of sclA by Mga Requires a Distal Binding Site in Streptococcus pyogenes

    OpenAIRE

    Almengor, Audry C.; McIver, Kevin S.

    2004-01-01

    Streptococcus pyogenes (the group A streptococcus [GAS]) is a medically significant pathogen of humans, causing a range of diseases from pharyngitis to necrotizing fasciitis. Several important GAS virulence genes are under the control of a pleiotropic regulator called Mga, or the multiple gene regulator of GAS, including the gene encoding the streptococcal collagen-like protein, or sclA. Analysis of the genome sequence upstream of sclA revealed two potential Mga-binding sites with homology to...

  15. Increased anticoagulant activity of thrombin-binding DNA aptamers by nanoscale organization on DNA nanostructures

    OpenAIRE

    Rangnekar, Abhijit; Zhang, Alex M.; Shiyuan Li, Susan; M. Bompiani, Kristin; Hansen, Majken Nørgaard; Gothelf, Kurt Vesterager; Sullenger, Bruce A; LaBean, Thomas H.

    2012-01-01

    Control over thrombin activity is much desired to regulate blood clotting in surgical and therapeutic situations. Thrombin-binding RNA and DNA aptamers have been used to inhibit thrombin activity and thus the coagulation cascade. Soluble DNA aptamers, as well as two different aptamers tethered by a flexible single-strand linker, have been shown to possess anticoagulant activity. Here, we link multiple aptamers at programmed positions on DNA nanostructures to optimize spacing and orientation o...

  16. Comparative study on ChIP-seq data: normalization and binding pattern characterization

    OpenAIRE

    Taslim, Cenny; Wu, Jiejun; Yan, Pearlly; Singer, Greg; Parvin, Jeffrey; Huang, Tim; Lin, Shili; Huang, Kun

    2009-01-01

    Motivation: Antibody-based Chromatin Immunoprecipitation assay followed by high-throughput sequencing technology (ChIP-seq) is a relatively new method to study the binding patterns of specific protein molecules over the entire genome. ChIP-seq technology allows scientist to get more comprehensive results in shorter time. Here, we present a non-linear normalization algorithm and a mixture modeling method for comparing ChIP-seq data from multiple samples and characterizing genes based on their ...

  17. Binding of Bacillus thuringiensis proteins to a laboratory-selected line of Heliothis virescens.

    OpenAIRE

    MacIntosh, S C; Stone, T B; Jokerst, R S; Fuchs, R L

    1991-01-01

    A laboratory-selected colony of Heliothis virescens displaying a 20- to 70-fold level of resistance to Bacillus thuringiensis proteins was evaluated to identify mechanism(s) of resistance. Brush-border membrane vesicles were isolated from larval midgut epithelium from the susceptible and resistant strains of H. virescens. Two B. thuringiensis proteins, CryIA(b) and CryIA(c), were iodinated and shown to specifically bind to brush-border membrane vesicles of both insect strains. Multiple change...

  18. Improved ligand binding energies derived from molecular dynamics: replicate sampling enhances the search of conformational space.

    Science.gov (United States)

    Adler, Marc; Beroza, Paul

    2013-08-26

    Does a single molecular trajectory provide an adequate sample conformational space? Our calculations indicate that for Molecular Mechanics--Poisson-Boltzmann Surface Area (MM-PBSA) measurement of protein ligand binding, a single molecular dynamics trajectory does not provide a representative sampling of phase space. For a single trajectory, the binding energy obtained by averaging over a number of molecular dynamics frames in an equilibrated system will converge after an adequate simulation time. A separate trajectory with nearly identical starting coordinates (1% randomly perturbed by 0.001 Å), however, can lead to a significantly different calculated binding energy. Thus, even though the calculated energy converges for a single molecular dynamics run, the variation across separate runs implies that a single run inadequately samples the system. The divergence in the trajectories is reflected in the individual energy components, such as the van der Waals and the electrostatics terms. These results indicate that the trajectories sample different conformations that are not in rapid exchange. Extending the length of the dynamics simulation does not resolve the energy differences observed between different trajectories. By averaging over multiple simulations, each with a nearly equivalent starting structure, we find the standard deviation in the calculated binding energy to be ∼1.3 kcal/mol. The work presented here indicates that combining MM-PBSA with multiple samples of the initial starting coordinates will produce more precise and accurate estimates of protein/ligand affinity. PMID:23845109

  19. Theoretical studies of binding of mannose-binding protein to monosaccharides

    Science.gov (United States)

    Aida-Hyugaji, Sachiko; Takano, Keiko; Takada, Toshikazu; Hosoya, Haruo; Kojima, Naoya; Mizuochi, Tsuguo; Inoue, Yasushi

    2004-11-01

    Binding properties of mannose-binding protein (MBP) to monosaccharides are discussed based on ab initio molecular orbital calculations for cluster models constructed. The calculated binding energies indicate that MBP has an affinity for N-acetyl- D-glucosamine, D-mannose, L-fucose, and D-glucose rather than D-galactose and N-acetyl- D-galactosamine, which is consistent with the biochemical experimental results. Electrostatic potential surfaces at the binding site of four monosaccharides having binding properties matched well with that of MBP. A vacant frontier orbital was found to be localized around the binding site of MBP, suggesting that MBP-monosaccharide interaction may occur through electrostatic and orbital interactions.

  20. To Bind or not to Bind: It’s in the Contract

    DEFF Research Database (Denmark)

    Tvarnø, Christina D.

    2016-01-01

    discusses, in a theoretical perspective, the legal reasoning behind the different partnering approaches, both from a historical and contract law perspective, and furthermore applies a game theoretical approach in evaluating binding versus non-binding partnering contracts. The analysis focuses on private......This article discusses the formalization of collaboration through partnering contracts in the construction industry in the USA, Great Britain and Denmark. The article compares the different types of collaborative partnering contracts in the three countries, and provides a conclusion on whether...... the collaborative partnering contract should be binding or non-binding, based on the three empirical contracts analyzed in this article. The partnering contracts in Great Britain and Denmark are legally binding, while in the USA the partnering agreements are non-binding charters or letters of intent. This article...