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Sample records for ck2 phosphorylation-dependent interaction

  1. Primary and secondary interactions between CK2alpha and CK2beta lead to ring-like structures in the crystals of the CK2 holoenzyme

    DEFF Research Database (Denmark)

    Niefind, Karsten; Issinger, Olaf-Georg

    2005-01-01

    a distinct aggregation propensity of CK2. We demonstrate here that in the CK2 holoenzyme crystals contacts between different CK2 tetramers exists which provide structural details of the secondary CK2alpha/CK2beta interactions. These mainly ionic interactions lead to trimeric rings of CK2 holoenzymes...

  2. Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase

    DEFF Research Database (Denmark)

    Sayed, M; Kim, S O; Salh, B S

    2000-01-01

    in the human cervical carcinoma HeLa cells by up to 8-fold, and this could be blocked by the p38 MAP kinase inhibitor SB203580. We show that p38alpha MAP kinase, in a phosphorylation-dependent manner, can directly interact with the alpha and beta subunits of CK2 to activate the holoenzyme through what appears...

  3. Interaction between CK2α and CK2β, the subunits of protein kinase CK2: thermodynamic contributions of key residues on the CK2α surface

    DEFF Research Database (Denmark)

    Raaf, Jennifer; Bischoff, Nils; Klopffleisch, Karsten;

    2011-01-01

    using isothermal titration calorimetry (ITC). With structure-guided alanine scanning mutagenesis we truncated individual side chains in the hydrophobic amino acid cluster located within the CK2α interface to identify experimentally the amino acids that dominate affinity. The ITC results indicate...

  4. Development of a high-throughput screening-compatible assay to identify inhibitors of the CK2alpha/CK2beta interaction

    DEFF Research Database (Denmark)

    Hochscherf, Jennifer; Lindenblatt, Dirk; Steinkrueger, Michaela;

    2015-01-01

    active site-directed approaches. The current article describes the development of a fluorescence anisotropy-based assay that mimics the principle of CK2 subunit interaction by using CK2alpha1-335 and the fluorescent probe CF-Ahx-Pc as a CK2beta analog. In addition, we identified new inhibitors able......Increased activity of protein kinase CK2 is associated with various types of cancer, neurodegenerative diseases, and chronic inflammation. In the search for CK2 inhibitors, attention has expanded toward compounds disturbing the interaction between CK2alpha and CK2beta in addition to established...... crystal structure of the Pc/CK2alpha1-335 complex. The dissociation constants obtained in the fluorescence anisotropy assay for binding of all compounds to human CK2alpha1-335 were validated by isothermal titration calorimetry. I-Pc was identified as the tightest binding ligand with a KD value of 240n...

  5. Structure of the human protein kinase CK2 catalytic subunit CK2α' and interaction thermodynamics with the regulatory subunit CK2β

    DEFF Research Database (Denmark)

    Bischoff, Nils; Olsen, Birgitte; Raaf, Jennifer;

    2011-01-01

    the limited biochemical knowledge about the second paralog (CK2α'), we developed a well-soluble catalytically active full-length mutant of human CK2α', characterized it by Michaelis-Menten kinetics and isothermal titration calorimetry, and determined its crystal structure to a resolution of 2 Å. The affinity......Protein kinase CK2 (formerly "casein kinase 2") is composed of a central dimer of noncatalytic subunits (CK2β) binding two catalytic subunits. In humans, there are two isoforms of the catalytic subunit (and an additional splicing variant), one of which (CK2α) is well characterized. To supplement...

  6. Interactions of protein kinase CK2beta subunit within the holoenzyme and with other proteins

    DEFF Research Database (Denmark)

    Kusk, M; Ahmed, R; Thomsen, B;

    1999-01-01

    in alpha-beta and beta-beta interactions. We also detected an intramolecular beta interaction within the amino acid stretch 132-165. Using CK2beta as a bait in a two-hybrid library screening several new putative cellular partners have been identified, among them the S6 kinase p90rsk, the putative tumor...

  7. Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

    Science.gov (United States)

    Na, Jung-Hyun; Lee, Won-Kyu; Kim, Yuyoung; Jeong, Cherlhyun; Song, Seung Soo; Cha, Sun-Shin; Han, Kyou-Hoon; Shin, Yeon-Kyun; Yu, Yeon Gyu

    2017-01-01

    Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. PMID:27297113

  8. Fas-associated factor 1 interacts with protein kinase CK2 in vivo upon apoptosis induction

    DEFF Research Database (Denmark)

    Guerra, B; Boldyreff, B; Issinger, O G

    2001-01-01

    We show here that in several different cell lines protein kinase CK2 and Fas-associated factor 1 (FAF1) exist together in a complex which is stable to high monovalent salt concentration. The CK2/FAF1 complex formation is significantly increased after induction of apoptosis with various DNA damaging...... the view that protein kinase CK2 plays an important role in certain steps of apoptosis....

  9. A subnanomolar fluorescent probe for protein kinase CK2 interaction studies

    DEFF Research Database (Denmark)

    Enkvist, Erki; Viht, Kaido; Bischoff, Nils

    2012-01-01

    Up-regulation of an acidophilic protein kinase, CK2, has been established in several types of cancer. This cognition has made CK2 an important target for drug development for cancer chemotherapy. The characterization of potential drug candidates, determination of the structure and clarification...

  10. A-Raf kinase is a new interacting partner of protein kinase CK2 beta subunit

    DEFF Research Database (Denmark)

    Boldyreff, B; Issinger, O G

    1997-01-01

    In a search for protein kinase CK2 beta subunit binding proteins using the two-hybrid system, more than 1000 positive clones were isolated. Beside clones for the alpha' and beta subunit of CK2, there were clones coding for a so far unknown protein, whose partial cDNA sequence was already deposite...

  11. A subnanomolar fluorescent probe for protein kinase CK2 interaction studies.

    Science.gov (United States)

    Enkvist, Erki; Viht, Kaido; Bischoff, Nils; Vahter, Jürgen; Saaver, Siiri; Raidaru, Gerda; Issinger, Olaf-Georg; Niefind, Karsten; Uri, Asko

    2012-11-21

    Up-regulation of an acidophilic protein kinase, CK2, has been established in several types of cancer. This cognition has made CK2 an important target for drug development for cancer chemotherapy. The characterization of potential drug candidates, determination of the structure and clarification of the functions of CK2 could be facilitated by the application of small-molecule fluorescent probes that bind to the active site of the enzyme with high affinity and selectivity. We have used a bisubstrate approach for the development of a highly potent inhibitor of CK2. 4,5,6,7-Tetrabromo-1H-benzimidazole was conjugated with peptides containing multiple aspartate residues via different linkers. The design of the inhibitors was by crystallographic analysis of the complex of an inhibitor with the catalytic subunit of the enzyme (CK2α). The inhibitory potency of the synthesized compounds was established in a kinetic assay that used thin layer chromatography for the measurement of the rate of phosphorylation of fluorescently labelled peptide 5-TAMRA-RADDSDDDDD. The most potent inhibitor, ARC-1502 (K(i) = 0.5 nM), revealed high selectivity for CK2α in a panel of 140 protein kinases. Labelling of ARC-1502 with PromoFluor-647 gave the fluorescent probe ARC-1504 that possessed subnanomolar affinity towards both CK2α and the holoenzyme. The probe was used in a fluorescence anisotropy-based binding assay to measure the concentration of CK2α and characterize non-labelled ligands binding to the active site of CK2α.

  12. A surface-plasmon-resonance analysis of polylysine interactions with a peptide substrate of protein kinase CK2 and with the enzyme

    OpenAIRE

    Benítez, María J.; Mier, Gerardo; Briones Fernández-Pola, Fernando; Moreno, Francisco J.; Juan S Jiménez

    1997-01-01

    The mechanism of protein kinase CK2 (CK2) activity stimulation by polylysine has been studied by surface plasmon resonance (SPR). The kinetics of the polylysine interaction with a peptide substrate of the enzyme, and with the enzyme itself, have been investigated. A peptide containing a threonine (T) residue surrounded by a cluster of negatively charged acidic [arginine (R) and glutamic acid (E)] residues, RRREEETEEE, and specifically phosphorylated by CK2, was selected. Polylysine interacts ...

  13. Protein kinase CK2 interacts at the neuromuscular synapse with Rapsyn, Rac1, 14-3-3γ, and Dok-7 proteins and phosphorylates the latter two.

    Science.gov (United States)

    Herrmann, Dustin; Straubinger, Marion; Hashemolhosseini, Said

    2015-09-11

    Previously, we demonstrated that the protein kinase CK2 associates with and phosphorylates the receptor tyrosine kinase MuSK (muscle specific receptor tyrosine kinase) at the neuromuscular junction (NMJ), thereby preventing fragmentation of the NMJs (Cheusova, T., Khan, M. A., Schubert, S. W., Gavin, A. C., Buchou, T., Jacob, G., Sticht, H., Allende, J., Boldyreff, B., Brenner, H. R., and Hashemolhosseini, S. (2006) Genes Dev. 20, 1800-1816). Here, we asked whether CK2 interacts with other proteins involved in processes at the NMJ, which would be consistent with the previous observation that CK2 appears enriched at the NMJ. We identified the following proteins to interact with protein kinase CK2: (a) the α and β subunits of the nicotinic acetylcholine receptors with weak interaction, (b) dishevelled (Dsh), and (c) another four proteins, Rapsyn, Rac1, 14-3-3γ, and Dok-7, with strong interaction. CK2 phosphorylated 14-3-3γ at serine residue 235 and Dok-7 at several serine residues but does not phosphorylate Rapsyn or Rac1. Furthermore, phosphomimetic Dok-7 mutants aggregated nicotinic acetylcholine receptors in C2C12 myotubes with significantly higher frequency than wild type Dok-7. Additionally, we mapped the interacting epitopes of all four binding partners to CK2 and thereby gained insights into the potential role of the CK2/Rapsyn interaction.

  14. Rational Design of Coumarin Derivatives as CK2 Inhibitors by Improving the Interaction with the Hinge Region.

    Science.gov (United States)

    Zhang, Na; Chen, Wen-Juan; Zhou, Yue; Zhao, Hongtao; Zhong, Ru-Gang

    2016-01-01

    Design of novel coumarin derivatives as CK2 inhibitors were attempted by targeting the interaction with the hinge region. A set of substituents capable of forming a hydrogen bond or halogen bond with the hinge region were screened in silico, and trifluoromethyl emerges as a promising motif by forming favorable electrostatic interaction and a presumable halogen bond with the hinge region. As proof of concept, three trifluoromethyl derivatives of coumarin were synthesized and tested in vitro. The results indicated that replacement of methyl by trifluoromethyl leads to a modest 5-fold improvement in potency, with the most active compound being 0.4 µM. The newly designed compounds were further screened on one lung cancer cell line A549, showing low micromolar anti-proliferative activity.

  15. Phosphorylation-dependent 14-3-3 protein interactions regulate CFTR biogenesis.

    Science.gov (United States)

    Liang, Xiubin; Da Paula, Ana Carina; Bozóky, Zoltán; Zhang, Hui; Bertrand, Carol A; Peters, Kathryn W; Forman-Kay, Julie D; Frizzell, Raymond A

    2012-03-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP/protein kinase A (PKA)-regulated chloride channel whose phosphorylation controls anion secretion across epithelial cell apical membranes. We examined the hypothesis that cAMP/PKA stimulation regulates CFTR biogenesis posttranslationally, based on predicted 14-3-3 binding motifs within CFTR and forskolin-induced CFTR expression. The 14-3-3β, γ, and ε isoforms were expressed in airway cells and interacted with CFTR in coimmunoprecipitation assays. Forskolin stimulation (15 min) increased 14-3-3β and ε binding to immature and mature CFTR (bands B and C), and 14-3-3 overexpression increased CFTR bands B and C and cell surface band C. In pulse-chase experiments, 14-3-3β increased the synthesis of immature CFTR, reduced its degradation rate, and increased conversion of immature to mature CFTR. Conversely, 14-3-3β knockdown decreased CFTR B and C bands (70 and 55%) and elicited parallel reductions in cell surface CFTR and forskolin-stimulated anion efflux. In vitro, 14-3-3β interacted with the CFTR regulatory region, and by nuclear magnetic resonance analysis, this interaction occurred at known PKA phosphorylated sites. In coimmunoprecipitation assays, forskolin stimulated the CFTR/14-3-3β interaction while reducing CFTR's interaction with coat protein complex 1 (COP1). Thus 14-3-3 binding to phosphorylated CFTR augments its biogenesis by reducing retrograde retrieval of CFTR to the endoplasmic reticulum. This mechanism permits cAMP/PKA stimulation to make more CFTR available for anion secretion.

  16. VCP phosphorylation-dependent interaction partners prevent apoptosis in Helicobacter pylori-infected gastric epithelial cells.

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    Cheng-Chou Yu

    Full Text Available Previous studies have demonstrated that valosin-containing protein (VCP is associated with H. pylori-induced gastric carcinogenesis. By identifying the interactome of VCP overexpressed in AGS cells using a subtractive proteomics approach, we aimed to characterize the cellular responses mediated by VCP and its functional roles in H. pylori-associated gastric cancer. VCP immunoprecipitations followed by proteomic analysis identified 288 putative interacting proteins, 18 VCP-binding proteins belonged to the PI3K/Akt signaling pathway. H. pylori infection increased the interaction between Akt and VCP, Akt-dependent phosphorylation of VCP, levels of ubiquitinated proteins, and aggresome formation in AGS cells. Furthermore, phosphorylated VCP co-localized with the aggresome, bound ubiquitinated proteins, and increased the degradation of cellular regulators to protect H. pylori-infected AGS cells from apoptosis. Our study demonstrates that VCP phosphorylation following H. pylori infection promotes both gastric epithelial cell survival, mediated by the PI3K/Akt pathway, and the degradation of cellular regulators. These findings provide novel insights into the mechanisms of H. pylori infection induced gastric carcinogenesis.

  17. Phosphorylation-dependent interactions between Crb2 and Chk1 are essential for DNA damage checkpoint.

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    Meng Qu

    2012-07-01

    Full Text Available In response to DNA damage, the eukaryotic genome surveillance system activates a checkpoint kinase cascade. In the fission yeast Schizosaccharomyces pombe, checkpoint protein Crb2 is essential for DNA damage-induced activation of downstream effector kinase Chk1. The mechanism by which Crb2 mediates Chk1 activation is unknown. Here, we show that Crb2 recruits Chk1 to double-strand breaks (DSBs through a direct physical interaction. A pair of conserved SQ/TQ motifs in Crb2, which are consensus phosphorylation sites of upstream kinase Rad3, is required for Chk1 recruitment and activation. Mutating both of these motifs renders Crb2 defective in activating Chk1. Tethering Crb2 and Chk1 together can rescue the SQ/TQ mutations, suggesting that the main function of these phosphorylation sites is promoting interactions between Crb2 and Chk1. A 19-amino-acid peptide containing these SQ/TQ motifs is sufficient for Chk1 binding in vitro when one of the motifs is phosphorylated. Remarkably, the same peptide, when tethered to DSBs by fusing with either recombination protein Rad22/Rad52 or multi-functional scaffolding protein Rad4/Cut5, can rescue the checkpoint defect of crb2Δ. The Rad22 fusion can even bypass the need for Rad9-Rad1-Hus1 (9-1-1 complex in checkpoint activation. These results suggest that the main role of Crb2 and 9-1-1 in DNA damage checkpoint signaling is recruiting Chk1 to sites of DNA lesions.

  18. p21WAF1/CIP1 interacts with protein kinase CK2

    DEFF Research Database (Denmark)

    Götz, C; Wagner, P; Issinger, O G;

    1996-01-01

    p21WAF1/CIP1 which belongs to a class of regulatory proteins that interact with cyclin dependent kinases is a potent inhibitor of these kinases. The inhibition of the cyclin dependent kinases induces an arrest of cells in the G phase of the cell cycle. In addition p21WAF1/CIP1 associates with PCNA...

  19. Novel role of phosphorylation-dependent interaction between FtsZ and FipA in mycobacterial cell division.

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    Kamakshi Sureka

    Full Text Available The bacterial divisome is a multiprotein complex. Specific protein-protein interactions specify whether cell division occurs optimally, or whether division is arrested. Little is known about these protein-protein interactions and their regulation in mycobacteria. We have investigated the interrelationship between the products of the Mycobacterium tuberculosis gene cluster Rv0014c-Rv0019c, namely PknA (encoded by Rv0014c and FtsZ-interacting protein A, FipA (encoded by Rv0019c and the products of the division cell wall (dcw cluster, namely FtsZ and FtsQ. M. smegmatis strains depleted in components of the two gene clusters have been complemented with orthologs of the respective genes of M. tuberculosis. Here we identify FipA as an interacting partner of FtsZ and FtsQ and establish that PknA-dependent phosphorylation of FipA on T77 and FtsZ on T343 is required for cell division under oxidative stress. A fipA knockout strain of M. smegmatis is less capable of withstanding oxidative stress than the wild type and showed elongation of cells due to a defect in septum formation. Localization of FtsQ, FtsZ and FipA at mid-cell was also compromised. Growth and survival defects under oxidative stress could be functionally complemented by fipA of M. tuberculosis but not its T77A mutant. Merodiploid strains of M. smegmatis expressing the FtsZ(T343A showed inhibition of FtsZ-FipA interaction and Z ring formation under oxidative stress. Knockdown of FipA led to elongation of M. tuberculosis cells grown in macrophages and reduced intramacrophage growth. These data reveal a novel role of phosphorylation-dependent protein-protein interactions involving FipA, in the sustenance of mycobacterial cell division under oxidative stress.

  20. Phosphorylation-Dependent PIH1D1 Interactions Define Substrate Specificity of the R2TP Cochaperone Complex

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    Zuzana Hořejší

    2014-04-01

    Full Text Available The R2TP cochaperone complex plays a critical role in the assembly of multisubunit machines, including small nucleolar ribonucleoproteins (snoRNPs, RNA polymerase II, and the mTORC1 and SMG1 kinase complexes, but the molecular basis of substrate recognition remains unclear. Here, we describe a phosphopeptide binding domain (PIH-N in the PIH1D1 subunit of the R2TP complex that preferentially binds to highly acidic phosphorylated proteins. A cocrystal structure of a PIH-N domain/TEL2 phosphopeptide complex reveals a highly specific phosphopeptide recognition mechanism in which Lys57 and 64 in PIH1D1, along with a conserved DpSDD phosphopeptide motif within TEL2, are essential and sufficient for binding. Proteomic analysis of PIH1D1 interactors identified R2TP complex substrates that are recruited by the PIH-N domain in a sequence-specific and phosphorylation-dependent manner suggestive of a common mechanism of substrate recognition. We propose that protein complexes assembled by the R2TP complex are defined by phosphorylation of a specific motif and recognition by the PIH1D1 subunit.

  1. Crystal structures of catalytic and regulatory subunits of rat protein kinase CK2

    Institute of Scientific and Technical Information of China (English)

    ZHOU WeiHong; SHEN YueQuan; QIN XiaoHong; YAN XiaoJie; XIE XingQiao; LI Liang; FANG ShaSha; LONG JiaFu; ADELMAN John; TANG Wei-Jen

    2009-01-01

    Protein kinase CK2 consists of two catalytic subunits (CK2α) and two regulatory subunits (CK2β). Here,we report the crystal structures of rat CK2α mutant (rCK2α-△C, 1-335) and CK2β(rCK2β). The overall topology of rCK2α-△C and rCK2βare very similar to the human enzyme, although large structural dif-ferences could be observed in the N-terminal domain of rCK2α-△C. Our reported structure of rCK2α-△C is in the close conformation state while the counterpart hCK2α is in the open conformation state, indi-cating the conformation of CK2α molecule has high plasticity. The structure of rCK2β represents the conformation of free CK2β. Upon CK2α binding, the C-terminal region undergoes a drastic conforma-tional change. The major region of interaction within the interface of CK2αCK2β may serve as a bridge to transmit the conformational change and thus regulate the activity of CK2α.

  2. Gene targeting of CK2 catalytic subunits

    Science.gov (United States)

    Lou, David Y.; Toselli, Paul; Landesman-Bollag, Esther; Dominguez, Isabel

    2013-01-01

    Protein kinase CK2 is a highly conserved and ubiquitous serine–threonine kinase. It is a tetrameric enzyme that is made up of two regulatory CK2β subunits and two catalytic subunits, either CK2α/CK2α, CK2α/ CK2α′, or CK2α′/CK2α′. Although the two catalytic subunits diverge in their C termini, their enzymatic activities are similar. To identify the specific function of the two catalytic subunits in development, we have deleted them individually from the mouse genome by homologous recombination. We have previously reported that CK2α′is essential for male germ cell development, and we now demonstrate that CK2α has an essential role in embryogenesis, as mice lacking CK2α die in mid-embryogenesis, with cardiac and neural tube defects. PMID:18594950

  3. Gene targeting of CK2 catalytic subunits.

    Science.gov (United States)

    Seldin, David C; Lou, David Y; Toselli, Paul; Landesman-Bollag, Esther; Dominguez, Isabel

    2008-09-01

    Protein kinase CK2 is a highly conserved and ubiquitous serine-threonine kinase. It is a tetrameric enzyme that is made up of two regulatory CK2beta subunits and two catalytic subunits, either CK2alpha/CK2alpha, CK2alpha/CK2alpha', or CK2alpha'/CK2alpha'. Although the two catalytic subunits diverge in their C termini, their enzymatic activities are similar. To identify the specific function of the two catalytic subunits in development, we have deleted them individually from the mouse genome by homologous recombination. We have previously reported that CK2alpha' is essential for male germ cell development, and we now demonstrate that CK2alpha has an essential role in embryogenesis, as mice lacking CK2alpha die in mid-embryogenesis, with cardiac and neural tube defects.

  4. Phosphorylation of the regulatory beta-subunit of protein kinase CK2 by checkpoint kinase Chk1: identification of the in vitro CK2beta phosphorylation site

    DEFF Research Database (Denmark)

    Kristensen, Lars P; Larsen, Martin Røssel; Højrup, Peter;

    2004-01-01

    The regulatory beta-subunit of protein kinase CK2 mediates the formation of the CK2 tetrameric form and it has functions independent of CK2 catalytic subunit through interaction with several intracellular proteins. Recently, we have shown that CK2beta associates with the human checkpoint kinase Chk...... by the modification of Thr213 but it does require the presence of an active Chk1 kinase....

  5. In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface

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    Benoît Bestgen

    2017-02-01

    Full Text Available Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’ subunits and two regulatory (β subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way.

  6. Protein kinase CK2 in health and disease: Protein kinase CK2: from structures to insights

    DEFF Research Database (Denmark)

    Niefind, K; Raaf, J; Issinger, Olaf-Georg

    2009-01-01

    Within the last decade, 40 crystal structures corresponding to protein kinase CK2 (former name 'casein kinase 2'), to its catalytic subunit CK2alpha and to its regulatory subunit CK2beta were published. Together they provide a valuable, yet by far not complete basis to rationalize the biochemical...... features of the enzyme, such as its constitutive activity, acidophilic substrate specificity, dual-cosubstrate specificity and its heterotetrameric quarternary structure. Comprehensive sets of structural superimpositions reveal that both CK2alpha and CK2beta are relatively rigid molecules. In CK2beta...... the critical region of CK2alpha recruitment is pre-formed in the unbound state. In CK2alpha the activation segment - a key element of protein kinase regulation - adapts invariably the typical conformation of the active enzymes. Recent structures of human CK2alpha revealed a surprising plasticity in the ATP...

  7. Analysis of Phosphorylation-dependent Protein Interactions of Adhesion and Degranulation Promoting Adaptor Protein (ADAP) Reveals Novel Interaction Partners Required for Chemokine-directed T cell Migration.

    Science.gov (United States)

    Kuropka, Benno; Witte, Amelie; Sticht, Jana; Waldt, Natalie; Majkut, Paul; Hackenberger, Christian P R; Schraven, Burkhart; Krause, Eberhard; Kliche, Stefanie; Freund, Christian

    2015-11-01

    Stimulation of T cells leads to distinct changes of their adhesive and migratory properties. Signal propagation from activated receptors to integrins depends on scaffolding proteins such as the adhesion and degranulation promoting adaptor protein (ADAP)(1). Here we have comprehensively investigated the phosphotyrosine interactome of ADAP in T cells and define known and novel interaction partners of functional relevance. While most phosphosites reside in unstructured regions of the protein, thereby defining classical SH2 domain interaction sites for master regulators of T cell signaling such as SLP76, Fyn-kinase, and NCK, other binding events depend on structural context. Interaction proteomics using different ADAP constructs comprising most of the known phosphotyrosine motifs as well as the structured domains confirm that a distinct set of proteins is attracted by pY571 of ADAP, including the ζ-chain-associated protein kinase of 70 kDa (ZAP70). The interaction of ADAP and ZAP70 is inducible upon stimulation either of the T cell receptor (TCR) or by chemokine. NMR spectroscopy reveals that the N-terminal SH2 domains within a ZAP70-tandem-SH2 construct is the major site of interaction with phosphorylated ADAP-hSH3(N) and microscale thermophoresis (MST) indicates an intermediate binding affinity (Kd = 2.3 μm). Interestingly, although T cell receptor dependent events such as T cell/antigen presenting cell (APC) conjugate formation and adhesion are not affected by mutation of Y571, migration of T cells along a chemokine gradient is compromised. Thus, although most phospho-sites in ADAP are linked to T cell receptor related functions we have identified a unique phosphotyrosine that is solely required for chemokine induced T cell behavior.

  8. CK2 Secreted by Leishmania braziliensis Mediates Macrophage Association Invasion: A Comparative Study between Virulent and Avirulent Promastigotes

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    Ana Madeira Brito Zylbersztejn

    2015-01-01

    Full Text Available CK2 is a protein kinase distributed in different compartments of Leishmania braziliensis: an externally oriented ecto-CK2, an intracellular CK2, and a secreted CK2. This latter form is constitutively secreted from the parasite (CsCK2, but such secretion may be highly enhanced by the association of specific molecules, including enzyme substrates, which lead to a higher enzymatic activity, called inductively secreted CK2 (IsCK2. Here, we examined the influence of secreted CK2 (sCK2 activity on the infectivity of a virulent L. braziliensis strain. The virulent strain presented 121-fold higher total CK2 activity than those found in an avirulent strain. The use of specific CK2 inhibitors (TBB, DRB, or heparin inhibited virulent parasite growth, whereas no effect was observed in the avirulent parasites. When these inhibitors were added to the interaction assays between the virulent L. braziliensis strain and macrophages, association index was drastically inhibited. Polyamines enhanced sCK2 activity and increased the association index between parasites and macrophages. Finally, sCK2 and the supernatant of the virulent strain increased the association index between the avirulent strain and macrophages, which was inhibited by TBB. Thus, the kinase enzyme CK2 seems to be important to invasion mechanisms of L. braziliensis.

  9. First inactive conformation of CK2 alpha, the catalytic subunit of protein kinase CK2

    DEFF Research Database (Denmark)

    Raaf, Jennifer; Issinger, Olaf-Georg; Niefind, Karsten

    2009-01-01

    (EPKs). To function as regulatory key components, EPKs normally exist in inactive ground states and are activated only upon specific signals. Typically, this activation is accompanied by large conformational changes in helix alpha C and in the activation segment, leading to a characteristic arrangement......The Ser/Thr kinase casein kinase 2 (CK2) is a heterotetrameric enzyme composed of two catalytic chains (CK2alpha, catalytic subunit of CK2) attached to a dimer of two noncatalytic subunits (CK2beta, noncatalytic subunit of CK2). CK2alpha belongs to the superfamily of eukaryotic protein kinases...... of catalytic key elements. For CK2alpha, however, no strict physiological control of activity is known. Accordingly, CK2alpha was found so far exclusively in the characteristic conformation of active EPKs, which is, in this case, additionally stabilized by a unique intramolecular contact between the N...

  10. Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme

    DEFF Research Database (Denmark)

    Niefind, K; Guerra, B; Ermakowa, I;

    2001-01-01

    subunits, which make no direct contact with one another. Each catalytic subunit interacts with both regulatory chains, predominantly via an extended C-terminal tail of the regulatory subunit. The CK2 structure is consistent with its constitutive activity and with a flexible role of the regulatory subunit......The crystal structure of a fully active form of human protein kinase CK2 (casein kinase 2) consisting of two C-terminally truncated catalytic and two regulatory subunits has been determined at 3.1 A resolution. In the CK2 complex the regulatory subunits form a stable dimer linking the two catalytic...... as a docking partner for various protein kinases. Furthermore it shows an inter-domain mobility in the catalytic subunit known to be functionally important in protein kinases and detected here for the first time directly within one crystal structure....

  11. Ability of CK2beta to selectively regulate cellular protein kinases

    DEFF Research Database (Denmark)

    Olsen, Birgitte; Guerra, Barbara

    2008-01-01

    additional phosphodegrons recognised by beta-TrCP. These events contribute to destabilise Wee1 at the onset of mitosis (Watanabe et al. Proc Natl Acad Sci USA 101:4419-4424, 2004). We show here that in addition to the ability of CK2 to phosphorylate Wee1 as reported earlier, the regulatory beta......-subunit of protein kinase CK2 can interact with Wee1 in high molecular mass complexes. Indirect immunofluorescence microscopy revealled subcellular co-localisation of CK2beta and Wee1 in the nucleus. Moreover, in vitro phosphorylation assays showed that CK2beta indirectly up-regulates the activity of CDK1...

  12. Peptides derived from human galectin-3 N-terminal tail interact with its carbohydrate recognition domain in a phosphorylation-dependent manner

    Energy Technology Data Exchange (ETDEWEB)

    Berbís, M. Álvaro [Chemical and Physical Biology Department, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain); André, Sabine [Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians University, 80539 Munich (Germany); Cañada, F. Javier [Chemical and Physical Biology Department, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain); Pipkorn, Rüdiger [Central Peptide Synthesis Unit, German Cancer Research Center, 69120 Heidelberg (Germany); Ippel, Hans [Department of Biochemistry, CARIM, University of Maastricht, Maastricht (Netherlands); Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455 (United States); Mayo, Kevin H. [Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455 (United States); Kübler, Dieter [Biomolecular Interactions, German Cancer Research Center, 69120 Heidelberg (Germany); Gabius, Hans-Joachim [Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians University, 80539 Munich (Germany); Jiménez-Barbero, Jesús, E-mail: jjbarbero@cib.csic.es [Chemical and Physical Biology Department, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain)

    2014-01-03

    Highlights: •Galectin-3 is composed of a carbohydrate recognition domain and an N-terminal tail. •Synthetic peptides derived from the tail are shown to interact with the CRD. •This interaction is modulated by Ser- and Tyr-phosphorylation of the peptides. -- Abstract: Galectin-3 (Gal-3) is a multi-functional effector protein that functions in the cytoplasm and the nucleus, as well as extracellularly following non-classical secretion. Structurally, Gal-3 is unique among galectins with its carbohydrate recognition domain (CRD) attached to a rather long N-terminal tail composed mostly of collagen-like repeats (nine in the human protein) and terminating in a short non-collagenous terminal peptide sequence unique in this lectin family and not yet fully explored. Although several Ser and Tyr sites within the N-terminal tail can be phosphorylated, the physiological significance of this post-translational modification remains unclear. Here, we used a series of synthetic (phospho)peptides derived from the tail to assess phosphorylation-mediated interactions with {sup 15}N-labeled Gal-3 CRD. HSQC-derived chemical shift perturbations revealed selective interactions at the backface of the CRD that were attenuated by phosphorylation of Tyr 107 and Tyr 118, while phosphorylation of Ser 6 and Ser 12 was essential. Controls with sequence scrambling underscored inherent specificity. Our studies shed light on how phosphorylation of the N-terminal tail may impact on Gal-3 function and prompt further studies using phosphorylated full-length protein.

  13. Identification of a Potent Allosteric Inhibitor of Human Protein Kinase CK2 by Bacterial Surface Display Library Screening.

    Science.gov (United States)

    Nienberg, Christian; Garmann, Claudia; Gratz, Andreas; Bollacke, Andre; Götz, Claudia; Jose, Joachim

    2017-01-05

    Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to identify non-ATP competitive inhibitors, a 12-mer peptide library of 6 × 10⁵ variants was displayed on the surface of E. coli by autodisplay. Screening of this peptide library on variants with affinity to CK2 was performed by fluorophore-conjugated CK2 and subsequent flow cytometry. Single cell sorting of CK2-bound E. coli yielded new peptide variants, which were tested on inhibition of CK2 by a CE-based assay. Peptide B2 (DCRGLIVMIKLH) was the most potent inhibitor of both, CK2 holoenzyme and the catalytic CK2α subunit (IC50 = 0.8 µM). Using different ATP concentrations and different substrate concentrations for IC50 determination, B2 was shown to be neither ATP- nor substrate competitive. By microscale thermophoresis (MST) the KD value of B2 with CK2α was determined to be 2.16 µM, whereas no binding of B2 to CK2β-subunit was detectable. To our surprise, besides inhibition of enzymatic activity, B2 also disturbed the interaction of CK2α with CK2β at higher concentrations (≥25 µM).

  14. Identification of a Potent Allosteric Inhibitor of Human Protein Kinase CK2 by Bacterial Surface Display Library Screening

    Directory of Open Access Journals (Sweden)

    Christian Nienberg

    2017-01-01

    Full Text Available Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to identify non-ATP competitive inhibitors, a 12-mer peptide library of 6 × 105 variants was displayed on the surface of E. coli by autodisplay. Screening of this peptide library on variants with affinity to CK2 was performed by fluorophore-conjugated CK2 and subsequent flow cytometry. Single cell sorting of CK2-bound E. coli yielded new peptide variants, which were tested on inhibition of CK2 by a CE-based assay. Peptide B2 (DCRGLIVMIKLH was the most potent inhibitor of both, CK2 holoenzyme and the catalytic CK2α subunit (IC50 = 0.8 µM. Using different ATP concentrations and different substrate concentrations for IC50 determination, B2 was shown to be neither ATP- nor substrate competitive. By microscale thermophoresis (MST the KD value of B2 with CK2α was determined to be 2.16 µM, whereas no binding of B2 to CK2β-subunit was detectable. To our surprise, besides inhibition of enzymatic activity, B2 also disturbed the interaction of CK2α with CK2β at higher concentrations (≥25 µM.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  16. Site-Specific Labeling of Protein Kinase CK2: Combining Surface Display and Click Chemistry for Drug Discovery Applications.

    Science.gov (United States)

    Nienberg, Christian; Retterath, Anika; Becher, Kira-Sophie; Saenger, Thorsten; Mootz, Henning D; Jose, Joachim

    2016-06-27

    Human CK2 is a heterotetrameric constitutively active serine/threonine protein kinase and is an emerging target in current anti-cancer drug discovery. The kinase is composed of two catalytic CK2α subunits and two regulatory CK2β subunits. In order to establish an assay to identify protein-protein-interaction inhibitors (PPI) of the CK2α/CK2β interface, a bioorthogonal click reaction was used to modify the protein kinase α-subunit with a fluorophore. By expanding the genetic code, the unnatural amino acid para azidophenylalanine (pAzF) could be incorporated into CK2α. Performing the SPAAC click reaction (Strain-Promoted Azide-Alkyne Cycloaddition) by the use of a dibenzylcyclooctyne-fluorophore (DBCO-fluorophore) led to a specifically labeled human protein kinase CK2α. This site-specific labeling does not impair the phosphorylation activity of CK2, which was evaluated by capillary electrophoresis. Furthermore a dissociation constant (KD) of 631 ± 86.2 nM was determined for the substrate αS1-casein towards CK2α. This labeling strategy was also applied to CK2β subunit on Escherichia coli, indicating the site-specific modifications of proteins on the bacterial cell surface when displayed by Autodisplay.

  17. Site-Specific Labeling of Protein Kinase CK2: Combining Surface Display and Click Chemistry for Drug Discovery Applications †

    Science.gov (United States)

    Nienberg, Christian; Retterath, Anika; Becher, Kira-Sophie; Saenger, Thorsten; Mootz, Henning D.; Jose, Joachim

    2016-01-01

    Human CK2 is a heterotetrameric constitutively active serine/threonine protein kinase and is an emerging target in current anti-cancer drug discovery. The kinase is composed of two catalytic CK2α subunits and two regulatory CK2β subunits. In order to establish an assay to identify protein-protein-interaction inhibitors (PPI) of the CK2α/CK2β interface, a bioorthogonal click reaction was used to modify the protein kinase α-subunit with a fluorophore. By expanding the genetic code, the unnatural amino acid para azidophenylalanine (pAzF) could be incorporated into CK2α. Performing the SPAAC click reaction (Strain-Promoted Azide-Alkyne Cycloaddition) by the use of a dibenzylcyclooctyne-fluorophore (DBCO-fluorophore) led to a specifically labeled human protein kinase CK2α. This site-specific labeling does not impair the phosphorylation activity of CK2, which was evaluated by capillary electrophoresis. Furthermore a dissociation constant (KD) of 631 ± 86.2 nM was determined for the substrate αS1-casein towards CK2α. This labeling strategy was also applied to CK2β subunit on Escherichia coli, indicating the site-specific modifications of proteins on the bacterial cell surface when displayed by Autodisplay. PMID:27355959

  18. Site-Specific Labeling of Protein Kinase CK2: Combining Surface Display and Click Chemistry for Drug Discovery Applications

    Directory of Open Access Journals (Sweden)

    Christian Nienberg

    2016-06-01

    Full Text Available Human CK2 is a heterotetrameric constitutively active serine/threonine protein kinase and is an emerging target in current anti-cancer drug discovery. The kinase is composed of two catalytic CK2α subunits and two regulatory CK2β subunits. In order to establish an assay to identify protein-protein-interaction inhibitors (PPI of the CK2α/CK2β interface, a bioorthogonal click reaction was used to modify the protein kinase α-subunit with a fluorophore. By expanding the genetic code, the unnatural amino acid para azidophenylalanine (pAzF could be incorporated into CK2α. Performing the SPAAC click reaction (Strain-Promoted Azide-Alkyne Cycloaddition by the use of a dibenzylcyclooctyne-fluorophore (DBCO-fluorophore led to a specifically labeled human protein kinase CK2α. This site-specific labeling does not impair the phosphorylation activity of CK2, which was evaluated by capillary electrophoresis. Furthermore a dissociation constant (KD of 631 ± 86.2 nM was determined for the substrate αS1-casein towards CK2α. This labeling strategy was also applied to CK2β subunit on Escherichia coli, indicating the site-specific modifications of proteins on the bacterial cell surface when displayed by Autodisplay.

  19. Protein kinase CK2: evidence for a protein kinase CK2beta subunit fraction, devoid of the catalytic CK2alpha subunit, in mouse brain and testicles

    DEFF Research Database (Denmark)

    Guerra, B; Siemer, S; Boldyreff, B;

    1999-01-01

    The highest CK2 activity was found in mouse testicles and brain, followed by spleen, liver, lung, kidney and heart. The activity values were directly correlated with the protein expression level of the CK2 subunits alpha (catalytic) and beta (regulatory). The alpha' subunit was only detected...... found for testicles and brain. The amount of CK2beta protein in brain in comparison to the other organs (except testicles) was estimated to be ca. 2-3-fold higher whereas the ratio of CK2beta between testicles and brain was estimated to be 3-4-fold. Results from the immunoprecipitation experiments...... support the notion for the existence of free CK2beta population and/or CK2beta in complex with other protein(s) present in brain and testicles. In all other mouse organs investigated, i.e. heart, lung, liver, kidney and spleen, no comparable amount of free CK2beta was observed. This is the first...

  20. CK2: a protein kinase in need of control

    DEFF Research Database (Denmark)

    Guerra, B; Boldyreff, B; Sarno, S;

    1999-01-01

    Protein kinase CK2 is a heterotetrameric alpha2beta2 Ser/Thr protein kinase with some features unusual among the eukaryotic protein kinases: (1) CK2 recognizes phosphoacceptor sites specified by several acidic determinants; (2) CK2 can use both ATP and GTP as phosphoryl donors; and (3...... response to nucleotide analogs. The increasing knowledge of CK2 structure-function relationships will allow the design of highly selective inhibitors of this pleiotropic kinase with oncogenic potential....

  1. RP1 is a phosphorylation target of CK2 and is involved in cell adhesion.

    Directory of Open Access Journals (Sweden)

    Frank Stenner

    Full Text Available RP1 (synonym: MAPRE2, EB2 is a member of the microtubule binding EB1 protein family, which interacts with APC, a key regulatory molecule in the Wnt signalling pathway. While the other EB1 proteins are well characterized the cellular function and regulation of RP1 remain speculative to date. However, recently RP1 has been implicated in pancreatic cancerogenesis. CK2 is a pleiotropic kinase involved in adhesion, proliferation and anti-apoptosis. Overexpression of protein kinase CK2 is a hallmark of many cancers and supports the malignant phenotype of tumor cells. In this study we investigate the interaction of protein kinase CK2 with RP1 and demonstrate that CK2 phosphorylates RP1 at Ser(236 in vitro. Stable RP1 expression in cell lines leads to a significant cleavage and down-regulation of N-cadherin and impaired adhesion. Cells expressing a Phospho-mimicking point mutant RP1-ASP(236 show a marked decrease of adhesion to endothelial cells under shear stress. Inversely, we found that the cells under shear stress downregulate endogenous RP1, most likely to improve cellular adhesion. Accordingly, when RP1 expression is suppressed by shRNA, cells lacking RP1 display significantly increased cell adherence to surfaces. In summary, RP1 phosphorylation at Ser(236 by CK2 seems to play a significant role in cell adhesion and might initiate new insights in the CK2 and EB1 family protein association.

  2. RP1 Is a Phosphorylation Target of CK2 and Is Involved in Cell Adhesion

    Science.gov (United States)

    Göttig, Stephan; Henschler, Reinhard; Markuly, Norbert; Kleber, Sascha; Faust, Michael; Mischo, Axel; Bauer, Stefan; Zweifel, Martin; Knuth, Alexander; Renner, Christoph; Wadle, Andreas

    2013-01-01

    RP1 (synonym: MAPRE2, EB2) is a member of the microtubule binding EB1 protein family, which interacts with APC, a key regulatory molecule in the Wnt signalling pathway. While the other EB1 proteins are well characterized the cellular function and regulation of RP1 remain speculative to date. However, recently RP1 has been implicated in pancreatic cancerogenesis. CK2 is a pleiotropic kinase involved in adhesion, proliferation and anti-apoptosis. Overexpression of protein kinase CK2 is a hallmark of many cancers and supports the malignant phenotype of tumor cells. In this study we investigate the interaction of protein kinase CK2 with RP1 and demonstrate that CK2 phosphorylates RP1 at Ser236 in vitro. Stable RP1 expression in cell lines leads to a significant cleavage and down-regulation of N-cadherin and impaired adhesion. Cells expressing a Phospho-mimicking point mutant RP1-ASP236 show a marked decrease of adhesion to endothelial cells under shear stress. Inversely, we found that the cells under shear stress downregulate endogenous RP1, most likely to improve cellular adhesion. Accordingly, when RP1 expression is suppressed by shRNA, cells lacking RP1 display significantly increased cell adherence to surfaces. In summary, RP1 phosphorylation at Ser236 by CK2 seems to play a significant role in cell adhesion and might initiate new insights in the CK2 and EB1 family protein association. PMID:23844040

  3. Structural and functional insights into the regulation mechanism of CK2 by IP6 and the intrinsically disordered protein Nopp140.

    Science.gov (United States)

    Lee, Won-Kyu; Son, Sang Hyeon; Jin, Bong-Suk; Na, Jung-Hyun; Kim, Soo-Youl; Kim, Kook-Han; Kim, Eunice Eunkyeong; Yu, Yeon Gyu; Lee, Hyung Ho

    2013-11-26

    Protein kinase CK2 is a ubiquitous kinase that can phosphorylate hundreds of cellular proteins and plays important roles in cell growth and development. Deregulation of CK2 is related to a variety of human cancers, and CK2 is regarded as a suppressor of apoptosis; therefore, it is a target of anticancer therapy. Nucleolar phosphoprotein 140 (Nopp140), which is an intrinsically disordered protein, interacts with CK2 and inhibits the latter's catalytic activity in vitro. Interestingly, the catalytic activity of CK2 is recovered in the presence of d-myo-inositol 1,2,3,4,5,6-hexakisphosphate (IP6). IP6 is widely distributed in animal cells, but the molecular mechanisms that govern its cellular functions in animal cells have not been completely elucidated. In this study, the crystal structure of CK2 in complex with IP6 showed that the lysine-rich cluster of CK2 plays an important role in binding to IP6. The biochemical experiments revealed that a Nopp140 fragment (residues 568-596) and IP6 competitively bind to the catalytic subunit of CK2 (CK2α), and phospho-Ser574 of Nopp140 significantly enhances its interaction with CK2α. Substitutions of K74E, K76E, and K77E in CK2α significantly reduced the interactions of CK2α with both IP6 and the Nopp140-derived peptide. Our study gives an insight into the regulation of CK2. In particular, our work suggests that CK2 activity is inhibited by Nopp140 and reactivated by IP6 by competitive binding at the substrate recognition site of CK2.

  4. Exploring the CK2 Paradox: Restless, Dangerous, Dispensable

    Science.gov (United States)

    Franchin, Cinzia; Borgo, Christian; Zaramella, Silvia; Cesaro, Luca; Arrigoni, Giorgio; Salvi, Mauro; Pinna, Lorenzo A.

    2017-01-01

    The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its “lateral” implication in a variety of signaling pathways is now soundly documented. At variance with many “onco-kinases”, CK2 is constitutively active, and no oncogenic CK2 mutant is known; still high CK2 activity correlates to neoplasia. Its pleiotropy and essential role may cast doubts on the actual “druggability” of CK2; however, a CK2 inhibitor is now in Phase II clinical trials for the treatment of cancer, and cell clones viable in the absence of CK2 are providing information about the mechanism by which cancer becomes addicted to high CK2 levels. A phosphoproteomics analysis of these CK2 null cells suggests that CK2 pleiotropy may be less pronounced than expected and supports the idea that the phosphoproteome generated by this kinase is flexible and not rigidly pre-determined. PMID:28117670

  5. Exploring the CK2 Paradox: Restless, Dangerous, Dispensable

    Directory of Open Access Journals (Sweden)

    Cinzia Franchin

    2017-01-01

    Full Text Available The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its “lateral” implication in a variety of signaling pathways is now soundly documented. At variance with many “onco-kinases”, CK2 is constitutively active, and no oncogenic CK2 mutant is known; still high CK2 activity correlates to neoplasia. Its pleiotropy and essential role may cast doubts on the actual “druggability” of CK2; however, a CK2 inhibitor is now in Phase II clinical trials for the treatment of cancer, and cell clones viable in the absence of CK2 are providing information about the mechanism by which cancer becomes addicted to high CK2 levels. A phosphoproteomics analysis of these CK2 null cells suggests that CK2 pleiotropy may be less pronounced than expected and supports the idea that the phosphoproteome generated by this kinase is flexible and not rigidly pre-determined.

  6. CK2α is essential for embryonic morphogenesis.

    Science.gov (United States)

    Dominguez, Isabel; Degano, Irene R; Chea, Kathleen; Cha, Julie; Toselli, Paul; Seldin, David C

    2011-10-01

    CK2 is a highly conserved serine-threonine kinase involved in biological processes such as embryonic development, circadian rhythms, inflammation, and cancer. Biochemical experiments have implicated CK2 in the control of several cellular processes and in the regulation of signal transduction pathways. Our laboratory is interested in characterizing the cellular, signaling, and molecular mechanisms regulated by CK2 during early embryonic development. For this purpose, animal models, including mice deficient in CK2 genes, are indispensable tools. Using CK2α gene-deficient mice, we have recently shown that CK2α is a critical regulator of mid-gestational morphogenetic processes, as CK2α deficiency results in defects in heart, brain, pharyngeal arch, tail bud, limb bud, and somite formation. Morphogenetic processes depend upon the precise coordination of essential cellular processes in which CK2 has been implicated, such as proliferation and survival. Here, we summarize the overall phenotype found in CK2α (-/- ) mice and describe our initial analysis aimed to identify the cellular processes affected in CK2α mutants.

  7. Thermodynamics parameters for binding of halogenated benzotriazole inhibitors of human protein kinase CK2α.

    Science.gov (United States)

    Winiewska, Maria; Kucińska, Katarzyna; Makowska, Małgorzata; Poznański, Jarosław; Shugar, David

    2015-10-01

    The interaction of human CK2α (hCK2α) with nine halogenated benzotriazoles, TBBt and its analogues representing all possible patterns of halogenation on the benzene ring of benzotriazole, was studied by biophysical methods. Thermal stability of protein-ligand complexes, monitored by calorimetric (DSC) and optical (DSF) methods, showed that the increase in the mid-point temperature for unfolding of protein-ligand complexes (i.e. potency of ligand binding to hCK2α) follow the inhibitory activities determined by biochemical assays. The dissociation constant for the ATP-hCK2α complex was estimated with the aid of microscale thermophoresis (MST) as 4.3±1.8 μM, and MST-derived dissociation constants determined for halogenated benzotriazoles, when converted according to known ATP concentrations, perfectly reconstruct IC50 values determined by the biochemical assays. Ligand-dependent quenching of tyrosine fluorescence, together with molecular modeling and DSC-derived heats of unfolding, support the hypothesis that halogenated benzotriazoles bind in at least two alternative orientations, and those that are efficient hCK2α inhibitors bind in the orientation which TBBt adopts in its complex with maize CK2α. DSC-derived apparent heat for ligand binding (ΔΔHbind) is driven by intermolecular electrostatic interactions between Lys68 and the triazole ring of the ligand, as indicated by a good correlation between ΔΔHbind and ligand pKa. Overall results, additionally supported by molecular modeling, confirm that a balance of hydrophobic and electrostatic interactions contribute predominantly (~40 kJ/mol), relative to possible intermolecular halogen/hydrogen bonding (less than 10 kJ/mol), in binding of halogenated benzotriazoles to the ATP-binding site of hCK2α. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

  8. CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock.

    Directory of Open Access Journals (Sweden)

    Teruya Tamaru

    Full Text Available Intracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we established a pivotal role for casein kinase (CK-2-mediated circadian BMAL1-Ser90 phosphorylation (BMAL1-P in regulating central and peripheral core clocks. Subsequent analysis of the underlying mechanism showed a novel role of CRY as a repressor for protein kinase. Co-immunoprecipitation experiments and real-time monitoring of protein-protein interactions revealed that CRY-mediated periodic binding of CK2β to BMAL1 inhibits BMAL1-Ser90 phosphorylation by CK2α. The FAD binding domain of CRY1, two C-terminal BMAL1 domains, and particularly BMAL1-Lys537 acetylation/deacetylation by CLOCK/SIRT1, were shown to be critical for CRY-mediated BMAL1-CK2β binding. Reciprocally, BMAL1-Ser90 phosphorylation is prerequisite for BMAL1-Lys537 acetylation. We propose a dual negative-feedback model in which a CRY-dependent CK2-driven posttranslational BMAL1-P-BMAL1 loop is an integral part of the core clock oscillator.

  9. Protein kinase CK2: a newcomer in the 'druggable kinome'.

    Science.gov (United States)

    Pagano, M A; Cesaro, L; Meggio, F; Pinna, L A

    2006-12-01

    The acronym CK2 (derived from the misnomer 'casein kinase' 2) denotes one of the most pleiotropic members of the eukaryotic protein kinase superfamily, characterized by an acidic consensus sequence in which a carboxylic acid (or pre-phosphorylated) side chain at position n+3 relative to the target serine/threonine residue plays a crucial role. The latest repertoire of CK2 substrates includes approx. 300 proteins, but the analysis of available phosphopeptide databases from different sources suggests that CK2 alone may be responsible for the generation of a much larger proportion (10-20%) of the eukaryotic phosphoproteome. Although for the time being CK2 is not included among protein kinases whose inhibitors are in clinical practice or in advanced clinical trials, evidence is accumulating that elevated CK2 constitutive activity co-operates to induce a number of pathological conditions, including cancer, infectious diseases, neurodegeneration and cardiovascular pathologies. The development and usage of cell-permeant, selective inhibitors discloses a scenario whereby CK2 plays a global anti-apoptotic role, which under special circumstances may lead to untimely and pathogenic cell survival.

  10. Inhibition of CK2 Activity by TCDD via Binding to ATP-competitive Binding Site of Catalytic Subunit:Insight from Computational Studies

    Institute of Scientific and Technical Information of China (English)

    XU Xian-jin; CANNISTRARO Salvatore; BIZZARRI Anna-rita; ZENG Yi; CHEN Wei-zu; WANG Cun-xin

    2013-01-01

    Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD),instead of the binding to aryl hydrocarbon receptor(AhR),have been taken into consideration.It has been recently shown that TCDD reduces rapidly the activity of CK2(casein kinase Ⅱ) both in vivo and in vitro.It is found that TCDD has high molecular similarities to the known inhibitors of CK2 catalytic subunit(CK2α).This suggests that TCDD could also be an ATP-competitive inhibitor of CK2α.In this work,docking TCDD to CK2 was carried out based on the two structures of CK2α from maize and human,respectively.The binding free energies of the predicted CK2α-TCDD complexes estimated by the molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA) method are from -85.1 kJ/mol to-114.3 kJ/mol for maize and are from-96.1 kJ/mol to-118.2 kJ/mol for human,which are comparable to those estimated for the known inhibitor and also ATP with CK2α.The energetic analysis also reveals that the van der Waals interaction is the dominant contribution to the binding free energy.These results are also useful for designing new drugs for a target of overexpressing CK2 in cancers.

  11. Phosphorylation of the Fas associated factor FAF1 by protein kinase CK2 and identification of serines 289 and 291 as the in vitro phosphorylation sites

    DEFF Research Database (Denmark)

    Jensen, H H; Hjerrild, M; Guerra, B;

    2001-01-01

    We previously identified the human Fas associated factor (FAF1) as one of the interacting partners of protein kinase CK2 beta subunit. Since FAF1 is a phosphoprotein we investigated whether it is a substrate for CK2. Here, we report the full length human FAF1 cDNA sequence, expression of FAF1 in ...

  12. Stimulation of Leishmania tropica protein kinase CK2 activities by platelet-activating factor (PAF).

    Science.gov (United States)

    Dutra, Patricia M L; Vieira, Danielle P; Meyer-Fernandes, Jose R; Silva-Neto, Mario A C; Lopes, Angela H

    2009-09-01

    Leishmania tropica is one of the causative agents of cutaneous leishmaniasis. Platelet-activating factor (PAF) is a phospholipid mediator in diverse biological and pathophysiological processes. Here we show that PAF promoted a three-fold increase on ecto-protein kinase and a three-fold increase on the secreted kinase activity of L. tropica live promastigotes. When casein was added to the reaction medium, along with PAF, there was a four-fold increase on the ecto-kinase activity. When live L. tropica promastigotes were pre-incubated for 30 min in the presence of PAF-plus casein, a six-fold increase on the secreted kinase activity was observed. Also, a protein released from L. tropica promastigotes reacted with polyclonal antibodies for the mammalian CK2 alpha catalytic subunit. Furthermore, in vitro mouse macrophage infection by L. tropica was doubled when promastigotes were pre-treated for 2 h with PAF. Similar results were obtained when the interaction was performed in the presence of purified CK2 or casein. TBB and DRB, CK2 inhibitors, reversed PAF enhancement of macrophage infection by L. tropica. WEB 2086, a competitive PAF antagonist, reversed all PAF effects here described. This study shows for the first time that PAF promotes the activation of two isoforms of CK2, secreted and membrane-bound, correlating these activities to infection of mouse macrophages.

  13. Linear motif atlas for phosphorylation-dependent signaling

    DEFF Research Database (Denmark)

    Miller, Martin Lee; Jensen, LJ; Diella, F;

    2008-01-01

    Systematic and quantitative analysis of protein phosphorylation is revealing dynamic regulatory networks underlying cellular responses to environmental cues. However, matching these sites to the kinases that phosphorylate them and the phosphorylation-dependent binding domains that may subsequently...... sequence models of linear motifs. The atlas is available as a community resource (http://netphorest.info)....

  14. Protein kinase CK2 structure-function relationship

    DEFF Research Database (Denmark)

    Boldyreff, B; Meggio, F; Pinna, L A

    1994-01-01

    Protein kinase CK2 subunits alpha and beta were expressed either separately or together in a bacterial expression system (pT7-7/BL21(DE3)) and purified to homogeneity. After mixing the subunits, a CK2 holoenzyme (alpha 2 beta 2) was spontaneously reconstituted, which displays identical features...... inactivated through urea, protease, and heat treatment. In contrast, the holoenzyme, either reconstituted or native, is much more stable when similar negative insults prevail. The beta subunit has at least three functions: (a) it is necessary for maximum activity of the enzyme under physiological salt...... conditions, (b) it protects the alpha subunit against denaturing agents or conditions, and (c) it alters the substrate specificity of the alpha subunit. By site-directed mutagenesis, certain functions of the beta subunit could be assigned to specific amino acids or domains. Twenty one mutants of the beta...

  15. The Alpha Catalytic Subunit of Protein Kinase CK2 Is Required for Mouse Embryonic Development▿

    Science.gov (United States)

    Lou, David Y.; Dominguez, Isabel; Toselli, Paul; Landesman-Bollag, Esther; O'Brien, Conor; Seldin, David C.

    2008-01-01

    Protein kinase CK2 (formerly casein kinase II) is a highly conserved and ubiquitous serine/threonine kinase that is composed of two catalytic subunits (CK2α and/or CK2α′) and two CK2β regulatory subunits. CK2 has many substrates in cells, and key roles in yeast cell physiology have been uncovered by introducing subunit mutations. Gene-targeting experiments have demonstrated that in mice, the CK2β gene is required for early embryonic development, while the CK2α′ subunit appears to be essential only for normal spermatogenesis. We have used homologous recombination to disrupt the CK2α gene in the mouse germ line. Embryos lacking CK2α have a marked reduction in CK2 activity in spite of the presence of the CK2α′ subunit. CK2α−/− embryos die in mid-gestation, with abnormalities including open neural tubes and reductions in the branchial arches. Defects in the formation of the heart lead to hydrops fetalis and are likely the cause of embryonic lethality. Thus, CK2α appears to play an essential and uncompensated role in mammalian development. PMID:17954558

  16. Protein kinase CK2 localizes to sites of DNA double-strand break regulating the cellular response to DNA damage

    Directory of Open Access Journals (Sweden)

    Olsen Birgitte B

    2012-03-01

    Full Text Available Abstract Background The DNA-dependent protein kinase (DNA-PK is a nuclear complex composed of a large catalytic subunit (DNA-PKcs and a heterodimeric DNA-targeting subunit Ku. DNA-PK is a major component of the non-homologous end-joining (NHEJ repair mechanism, which is activated in the presence of DNA double-strand breaks induced by ionizing radiation, reactive oxygen species and radiomimetic drugs. We have recently reported that down-regulation of protein kinase CK2 by siRNA interference results in enhanced cell death specifically in DNA-PKcs-proficient human glioblastoma cells, and this event is accompanied by decreased autophosphorylation of DNA-PKcs at S2056 and delayed repair of DNA double-strand breaks. Results In the present study, we show that CK2 co-localizes with phosphorylated histone H2AX to sites of DNA damage and while CK2 gene knockdown is associated with delayed DNA damage repair, its overexpression accelerates this process. We report for the first time evidence that lack of CK2 destabilizes the interaction of DNA-PKcs with DNA and with Ku80 at sites of genetic lesions. Furthermore, we show that CK2 regulates the phosphorylation levels of DNA-PKcs only in response to direct induction of DNA double-strand breaks. Conclusions Taken together, these results strongly indicate that CK2 plays a prominent role in NHEJ by facilitating and/or stabilizing the binding of DNA-PKcs and, possibly other repair proteins, to the DNA ends contributing to efficient DNA damage repair in mammalian cells.

  17. Developmental and growth defects in mice with combined deficiency of CK2 catalytic genes.

    Science.gov (United States)

    Landesman-Bollag, Esther; Belkina, Anna; Hovey, Beth; Connors, Edward; Cox, Charles; Seldin, David C

    2011-10-01

    The CK2 α and α' catalytic gene products have overlapping biochemical activity, but in vivo, their functions are very different. Deletion of both alleles of CK2α leads to mid-gestational embryonic lethality, while deletion of both alleles of CK2α' does not interfere with viability or development of embryos; however, adult CK2α'-/-males are infertile. To further elucidate developmental roles of CK2, and analyze functional overlap between the two catalytic genes, mice with combined knockouts were bred. Mice bearing any two CK2 catalytic alleles were phenotypically normal. However, inheritance of a single CK2α allele, without either CK2α' allele, resulted in partial embryonic lethality. Such mice that survived through embryogenesis were smaller at birth than littermate controls, and weighed less throughout life. However, their cardiac function and lifespan were normal. Fibroblasts derived from CK2α+/-CK2α'-/- embryos grew poorly in culture. These experiments demonstrate that combined loss of one CK2α allele and both CK2α' alleles leads to unique abnormalities of growth and development.

  18. Thermodynamic parameters for binding of some halogenated inhibitors of human protein kinase CK2

    Energy Technology Data Exchange (ETDEWEB)

    Winiewska, Maria; Makowska, Małgorzata [Institute of Biochemistry and Biophysics PAS, Warszawa (Poland); Maj, Piotr [Institute of Biochemistry and Biophysics PAS, Warszawa (Poland); Nencki Institute of Experimental Biology PAS, Warszawa (Poland); Wielechowska, Monika; Bretner, Maria [Warsaw University of Technology, Faculty of Chemistry, Warszawa (Poland); Poznański, Jarosław, E-mail: jarek@ibb.waw.pl [Institute of Biochemistry and Biophysics PAS, Warszawa (Poland); Shugar, David [Institute of Biochemistry and Biophysics PAS, Warszawa (Poland)

    2015-01-02

    Highlights: • Two new compounds being potential human CK2a inhibitors are studied. • Their IC50 values were determined in vitro. • The heats of binding and kbind were estimated using DSC. • The increased stability of protein–ligand complexes was followed by fluorescence. • Methylated TBBt derivative (MeBr3Br) is almost as active as TBBt. - Abstract: The interaction of human CK2α with a series of tetrabromobenzotriazole (TBBt) and tetrabromobenzimidazole (TBBz) analogs, in which one of the bromine atoms proximal to the triazole/imidazole ring is replaced by a methyl group, was studied by biochemical (IC{sub 50}) and biophysical methods (thermal stability of protein–ligand complex monitored by DSC and fluorescence). Two newly synthesized tri-bromo derivatives display inhibitory activity comparable to that of the reference compounds, TBBt and TBBz, respectively. DSC analysis of the stability of protein–ligand complexes shows that the heat of ligand binding (H{sub bind}) is driven by intermolecular electrostatic interactions involving the triazole/imidazole ring, as indicated by a strong correlation between H{sub bind} and ligand pK{sub a}. Screening, based on fluorescence-monitored thermal unfolding of protein–ligand complexes, gave comparable results, clearly identifying ligands that most strongly bind to the protein. Overall results, additionally supported by molecular modeling, confirm that a balance of hydrophobic and electrostatic interactions contribute predominantly, relative to possible intermolecular halogen bonding, in binding of the ligands to the CK2α ATP-binding site.

  19. Isomeric mono-, di-, and tri-bromobenzo-1H-triazoles as inhibitors of human protein kinase CK2α.

    Directory of Open Access Journals (Sweden)

    Romualda Wąsik

    Full Text Available To further clarify the role of the individual bromine atoms of 4,5,6,7-tetrabromotriazole (TBBt, a relatively selective inhibitor of protein kinase CK2, we have examined the inhibition (IC(50 of human CK2α by the two mono-, the four di-, and the two tri- bromobenzotriazoles relative to that of TBBt. Halogenation of the central vicinal C(5/C(6 atoms proved to be a key factor in enhancing inhibitory activity, in that 5,6-di-Br(2Bt and 4,5,6-Br(3Bt were almost as effective inhibitors as TBBt, notwithstanding their marked differences in pK(a for dissociation of the triazole proton. The decrease in pK(a on halogenation of the peripheral C(4/C(7 atoms virtually nullifies the gain due to hydrophobic interactions, and does not lead to a decrease in IC(50. Molecular modeling of structures of complexes of the ligands with the enzyme, as well as QSAR analysis, pointed to a balance of hydrophobic and electrostatic interactions as a discriminator of inhibitory activity. The role of halogen bonding remains debatable, as originally noted for the crystal structure of TBBt with CK2α (pdb1j91. Finally we direct attention to the promising applicability of our series of well-defined halogenated benzotriazoles to studies on inhibition of kinases other than CK2.

  20. Overexpression of nuclear protein kinase CK2 α catalytic subunit (CK2α as a poor prognosticator in human colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Kai-Yuan Lin

    Full Text Available BACKGROUND: Colorectal cancer (CRC is one of the most common malignancies but the current therapeutic approaches for advanced CRC are less efficient. Thus, novel therapeutic approaches are badly needed. The purpose of this study is to investigate the involvement of nuclear protein kinase CK2 α subunit (CK2α in tumor progression, and in the prognosis of human CRC. METHODOLOGY/PRINCIPAL FINDINGS: Expression levels of nuclear CK2α were analyzed in 245 colorectal tissues from patients with CRC by immunohistochemistry, quantitative real-time PCR and Western blot. We correlated the expression levels with clinicopathologic parameters and prognosis in human CRC patients. Overexpression of nuclear CK2α was significantly correlated with depth of invasion, nodal status, American Joint Committee on Cancer (AJCC staging, degree of differentiation, and perineural invasion. Patients with high expression levels of nuclear CK2α had a significantly poorer overall survival rate compared with patients with low expression levels of nuclear CK2α. In multi-variate Cox regression analysis, overexpression of nuclear CK2α was proven to be an independent prognostic marker for CRC. In addition, DLD-1 human colon cancer cells were employed as a cellular model to study the role of CK2α on cell growth, and the expression of CK2α in DLD-1 cells was inhibited by using siRNA technology. The data indicated that CK2α-specific siRNA treatment resulted in growth inhibition. CONCLUSIONS/SIGNIFICANCE: Taken together, overexpression of nuclear CK2α can be a useful marker for predicting the outcome of patients with CRC.

  1. Biochemical characterization of CK2alpha and alpha' paralogues and their derived holoenzymes: evidence for the existence of a heterotrimeric CK2alpha'-holoenzyme forming trimeric complexes

    DEFF Research Database (Denmark)

    Olsen, Birgitte; Rasmussen, Tine; Niefind, Karsten;

    2008-01-01

    cells, all others in Escherichia coli. IC(50) studies involving the established CK2 inhibitors DMAT, TBBt, TBBz, apigenin and emodin were carried out and the K(i) values calculated. Although the differences in the K(i) values found were modest, there was a general tendency showing that the CK2...

  2. Ablation of Protein Kinase CK2β in Skeletal Muscle Fibers Interferes with Their Oxidative Capacity

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    Nane Eiber

    2017-01-01

    Full Text Available The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be at least required for regular aggregation of nicotinic acetylcholine receptors, which serves as a hallmark for the presence of a postsynaptic apparatus. Here, we set out to determine whether any other feature accompanies CK2β-deficient muscle fibers. Hind limb muscles gastrocnemius, plantaris, and soleus of adult wildtype and CK2β-deficient mice were dissected, cross-sectioned, and stained histochemically by Gomori trichrome and for nicotinamide adenine dinucleotide (NADH dehydrogenase and succinate dehydrogenase (SDH enzymatic activities. A reduction of oxidative enzymatic activity was determined for CK2β-deficient muscle fibers in comparison with wildtype controls. Importantly, the CK2β-deficient fibers, muscle fibers that typically exhibit high NADH dehydrogenase and SDH activities, like slow-type fibers, showed a marked reduction in these activities. Altogether, our data indicate additional impairments in the absence of CK2β in skeletal muscle fibers, pointing to an eventual mitochondrial myopathy.

  3. The C-terminal domain of human grp94 protects the catalytic subunit of protein kinase CK2 (CK2alpha) against thermal aggregation. Role of disulfide bonds

    DEFF Research Database (Denmark)

    Roher, N; Miró, F; Boldyreff, B

    2001-01-01

    The C-terminal domain (residues 518-803) of the 94 kDa glucose regulated protein (grp94) was expressed in Escherichia coli as a fusion protein with a His6-N-terminal tag (grp94-CT). This truncated form of grp94 formed dimers and oligomers that could be dissociated into monomers by treatment...... with dithiothreitol. Grp94-CT conferred protection against aggregation on the catalytic subunit of protein kinase CK2 (CK2alpha), although it did not protect against thermal inactivation. This anti-aggregation effect of grp94-CT was concentration dependent, with full protection achieved at grp94-CT/CK2alpha molar...

  4. Expression and characterization of a recombinant maize CK-2 alpha subunit

    DEFF Research Database (Denmark)

    Boldyreff, B; Meggio, F; Dobrowolska, G

    1993-01-01

    to support the immunological data also by biochemical and biophysical experiments the availability of a recombinant CK-2 alpha from maize was a prerequisite. A maize cDNA clone of maize CK-2 alpha was expressed in the bacterial strain BL21 (DE3). The recombinant protein was purified to homogeneity; its...... molecular mass on one-dimensional SDS PAGE was estimated to be 36.5 kDa. The calculated molecular mass according to the amino acid composition is 39,228 Da (332 amino acids). The recombinant maize CK-2 alpha (rmCK-2 alpha) exhibited mostly the same properties as the recombinant human CK-2 alpha (rhCK-2...

  5. Purification and characterization of recombinant protein kinase CK2 from Zea mays expressed in Escherichia coli

    DEFF Research Database (Denmark)

    Riera, Marta; Pages, Montserrat; Issinger, Olaf Georg;

    2003-01-01

    Recombinant protein kinase subunits rmCK2alpha-1 and rmCK2beta-1 from Zea mays were expressed separately in Escherichia coli and assembled to a fully active tetrameric holoenzyme complex in vitro. The obtained maize holoenzyme was purified to homogeneity, biochemically characterized, and compared...

  6. Structure of protein kinase CK2: dimerization of the human beta-subunit

    DEFF Research Database (Denmark)

    Boldyreff, B; Mietens, U; Issinger, O G

    1996-01-01

    Protein kinase CK2 has been shown to be elevated in all so far investigated solid tumors and its catalytic subunit has been shown to serve as an oncogene product. CK2 is a heterotetrameric serine-threonine kinase composed of two catalytic (alpha and/or alpha') and two regulatory beta...

  7. The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design.

    Science.gov (United States)

    Cozza, Giorgio

    2017-02-20

    Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by "trial and error testing". In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising.

  8. INTERACCIONES INTRA E INTERMOLECULARES DE LA PROTEINAQUINASA CK2: ESTUDIO ESTRUCTURAL Y FUNCIONAL DE DOMINIOS ESPECIFICOS.

    OpenAIRE

    TAPIA PINEDA, JULIO CESAR

    2003-01-01

    La proteinaquinasa CK2 es una enzima ubicua en el mundo eucariótico, formada por la asociación de subunidades catalíticas a o a' y regulatorias l en las combinaciones a22, a'22 o aa' 2 . La diferencia estructural fundamental entre las subunidades CK2a de 190p.

  9. Structure of the gene encoding the murine protein kinase CK2 beta subunit

    DEFF Research Database (Denmark)

    Boldyreff, B; Issinger, O G

    1995-01-01

    The mouse protein kinase CK2 beta subunit gene (Csnk2b) is composed of seven exons contained within 7874 bp. The exon and intron lengths extend from 76 to 321 and 111 to 1272 bp, respectively. The lengths of the murine coding exons correspond exactly to the lengths of the exons in the human CK2...

  10. Emerging roles of protein kinase CK2 in abscisic acid (ABA signaling

    Directory of Open Access Journals (Sweden)

    Belmiro eVilela

    2015-11-01

    Full Text Available The phytohormone abscisic acid (ABA regulates many aspects of plant growth and development as well as responses to multiple stresses. Post-translational modifications such as phosphorylation or ubiquitination have pivotal roles in the regulation of ABA signaling. In addition to the positive regulator sucrose non-fermenting-1 related protein kinase 2 (SnRK2, the relevance of the role of other protein kinases, such as CK2, has been recently highlighted. We have recently established that CK2 phosphorylates the maize ortholog of open stomata 1 OST1, ZmOST1, suggesting a role of CK2 phosphorylation in the control of ZmOST1 protein degradation (Vilela et al., 2015. CK2 is a pleiotropic enzyme involved in multiple developmental and stress-responsive pathways. This review summarizes recent advances that taken together suggest a prominent role of protein kinase CK2 in ABA signaling and related processes.

  11. Protein kinase CK2 and its role in cellular proliferation, development and pathology

    DEFF Research Database (Denmark)

    Guerra, B; Issinger, O G

    1999-01-01

    Protein kinase CK2 is a pleiotropic, ubiquitous and constitutively active protein kinase that can use both ATP and GTP as phosphoryl donors with specificity for serine/threonine residues in the vicinity of acidic amino acids. Recent results show that the enzyme is involved in transcription...... conserved throughout evolution. Furthermore the existence of different CK2beta-related proteins together with the observation of deregulated CK2beta levels in tumor cells and the reported association of CK2beta protein with key proteins in signal transduction, e.g. A-Raf, Mos, pg90rsk etc. are suggestive...... for an additional physiological role of CK2beta protein beside being the regulatory compound in the tetrameric holoenzyme....

  12. Dominant-negative CK2alpha induces potent effects on circadian rhythmicity.

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    Elaine M Smith

    2008-01-01

    Full Text Available Circadian clocks organize the precise timing of cellular and behavioral events. In Drosophila, circadian clocks consist of negative feedback loops in which the clock component PERIOD (PER represses its own transcription. PER phosphorylation is a critical step in timing the onset and termination of this feedback. The protein kinase CK2 has been linked to circadian timing, but the importance of this contribution is unclear; it is not certain where and when CK2 acts to regulate circadian rhythms. To determine its temporal and spatial functions, a dominant negative mutant of the catalytic alpha subunit, CK2alpha(Tik, was targeted to circadian neurons. Behaviorally, CK2alpha(Tik induces severe period lengthening (approximately 33 h, greater than nearly all known circadian mutant alleles, and abolishes detectable free-running behavioral rhythmicity at high levels of expression. CK2alpha(Tik, when targeted to a subset of pacemaker neurons, generates period splitting, resulting in flies exhibiting both long and near 24-h periods. These behavioral effects are evident even when CK2alpha(Tik expression is induced only during adulthood, implicating an acute role for CK2alpha function in circadian rhythms. CK2alpha(Tik expression results in reduced PER phosphorylation, delayed nuclear entry, and dampened cycling with elevated trough levels of PER. Heightened trough levels of per transcript accompany increased protein levels, suggesting that CK2alpha(Tik disturbs negative feedback of PER on its own transcription. Taken together, these in vivo data implicate a central role of CK2alpha function in timing PER negative feedback in adult circadian neurons.

  13. Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex.

    Science.gov (United States)

    Rozovski, Uri; Harris, David M; Li, Ping; Liu, Zhiming; Jain, Preetesh; Veletic, Ivo; Ferrajoli, Alessandra; Burger, Jan; O'Brien, Susan; Bose, Prithviraj; Thompson, Philip; Jain, Nitin; Wierda, William; Keating, Michael J; Estrov, Zeev

    2017-01-27

    In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that co-immunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T-cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK co-expressed in CLL, but not in normal B- or T-cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus.

  14. GTP plus water mimic ATP in the active site of protein kinase CK2

    DEFF Research Database (Denmark)

    Niefind, K; Pütter, M; Guerra, B;

    1999-01-01

    The structures of the catalytic subunit of protein kinase CK2 from Zea mays complexed with Mg2+ and with analogs of ATP or GTP were determined to 2.2 A resolution. Unlike most other protein kinases, CK2 from various sources shows 'dual-cosubstrate specificity', that is, the ability to efficiently...... use either ATP or GTP as a cosubstrate. The structures of these complexes demonstrate that water molecules are critical to switch the active site of CK2 from an ATP- to a GTP-compatible state. An understanding of the structural basis of dual-cosubstrate specificity may help in the design of drugs...

  15. CK2 phosphorylation of eukaryotic translation initiation factor 5 potentiates cell cycle progression

    OpenAIRE

    Homma, Miwako Kato; Wada, Ikuo; Suzuki, Toshiyuki; Yamaki, Junko; Krebs, Edwin G.; Homma, Yoshimi

    2005-01-01

    Casein kinase 2 (CK2) is a ubiquitous eukaryotic Ser/Thr protein kinase that plays an important role in cell cycle progression. Although its function in this process remains unclear, it is known to be required for the G1 and G2/M phase transitions in yeast. Here, we show that CK2 activity changes notably during cell cycle progression and is increased within 3 h of serum stimulation of quiescent cells. During the time period in which it exhibits high enzymatic activity, CK2 associates with and...

  16. Exploiting the repertoire of CK2 inhibitors to target DYRK and PIM kinases.

    Science.gov (United States)

    Cozza, Giorgio; Sarno, Stefania; Ruzzene, Maria; Girardi, Cristina; Orzeszko, Andrzej; Kazimierczuk, Zygmunt; Zagotto, Giuseppe; Bonaiuto, Emanuela; Di Paolo, Maria Luisa; Pinna, Lorenzo A

    2013-07-01

    Advantage has been taken of the relative promiscuity of commonly used inhibitors of protein kinase CK2 to develop compounds that can be exploited for the selective inhibition of druggable kinases other than CK2 itself. Here we summarize data obtained by altering the scaffold of CK2 inhibitors to give rise to novel selective inhibitors of DYRK1A and to a powerful cell permeable dual inhibitor of PIM1 and CK2. In the former case one of the new compounds, C624 (naphto [1,2-b]benzofuran-5,9-diol) displays a potency comparable to that of the first-in-class DYRK1A inhibitor, harmine, lacking however the drawback of drastically inhibiting monoamine oxidase-A (MAO-A) as harmine does. On the other hand the promiscuous CK2 inhibitor 4,5,6,7-tetrabromo-1H-benzimidazole (TBI,TBBz) has been derivatized with a sugar moiety to generate a 1-(β-D-2'-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) compound which inhibits PIM1 and CK2 with comparably high efficacy (IC50 valuescancer cells consistent with concomitant inhibition of both its onco-kinase targets. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).

  17. CK2 blockade causes MPNST cell apoptosis and promotes degradation of β-catenin.

    Science.gov (United States)

    Kendall, Jed J; Chaney, Katherine E; Patel, Ami V; Rizvi, Tilat A; Largaespada, David A; Ratner, Nancy

    2016-08-16

    Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that are a major cause of mortality of Neurofibromatosis type 1 (NF1) patients. MPNST patients have few therapeutic options available and only complete surgical resection can be curative. MPNST formation and survival are dependent on activated β-catenin signaling. The goal of this study was to determine if inhibition of the CK2 enzyme can be therapeutically exploited in MPNSTs, given CK2's role in mainta ining oncogenic phenotypes including stabilization of β-catenin. We found that CK2α is over-expressed in MPNSTs and is critical for maintaining cell survival, as the CK2 inhibitor, CX-4945 (Silmitasertib), and shRNA targeting CK2α each significantly reduce MPNST cell viability. These effects were preceded by loss of critical signaling pathways in MPNSTs, including destabilization of β-catenin and TCF8. CX-4945 administration in vivo slowed tumor growth and extends survival time. We conclude that CK2 inhibition is a promising approach to blocking β-catenin in MPNST cells, although combinatorial therapies may be required for maximal efficacy.

  18. Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2.

    Science.gov (United States)

    Jabor Gozzi, Gustavo; Bouaziz, Zouhair; Winter, Evelyn; Daflon-Yunes, Nathalia; Aichele, Dagmar; Nacereddine, Abdelhamid; Marminon, Christelle; Valdameri, Glaucio; Zeinyeh, Waël; Bollacke, Andre; Guillon, Jean; Lacoudre, Aline; Pinaud, Noël; Cadena, Silvia M; Jose, Joachim; Le Borgne, Marc; Di Pietro, Attilio

    2015-01-08

    A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations.

  19. CK2 phosphorylation of eukaryotic translation initiation factor 5 potentiates cell cycle progression

    Science.gov (United States)

    Homma, Miwako Kato; Wada, Ikuo; Suzuki, Toshiyuki; Yamaki, Junko; Krebs, Edwin G.; Homma, Yoshimi

    2005-01-01

    Casein kinase 2 (CK2) is a ubiquitous eukaryotic Ser/Thr protein kinase that plays an important role in cell cycle progression. Although its function in this process remains unclear, it is known to be required for the G1 and G2/M phase transitions in yeast. Here, we show that CK2 activity changes notably during cell cycle progression and is increased within 3 h of serum stimulation of quiescent cells. During the time period in which it exhibits high enzymatic activity, CK2 associates with and phosphorylates a key molecule for translation initiation, eukaryotic translation initiation factor (eIF) 5. Using MS, we show that Ser-389 and -390 of eIF5 are major sites of phosphorylation by CK2. This is confirmed using eIF5 mutants that lack CK2 sites; the phosphorylation levels of mutant eIF5 proteins are significantly reduced, relative to WT eIF5, both in vitro and in vivo. Expression of these mutants reveals that they have a dominant-negative effect on phosphorylation of endogenous eIF5, and that they perturb synchronous progression of cells through S to M phase, resulting in a significant reduction in growth rate. Furthermore, the formation of mature eIF5/eIF2/eIF3 complex is reduced in these cells, and, in fact, restricted diffusional motion of WT eIF5 was almost abolished in a GFP-tagged eIF5 mutant lacking CK2 phosphorylation sites, as measured by fluorescence correlation spectroscopy. These results suggest that CK2 may be involved in the regulation of cell cycle progression by associating with and phosphorylating a key molecule for translation initiation. PMID:16227438

  20. Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Drygin, Denis, E-mail: ddrygin@cylenepharma.com; Ho, Caroline B.; Omori, Mayuko; Bliesath, Joshua; Proffitt, Chris; Rice, Rachel; Siddiqui-Jain, Adam; O' Brien, Sean; Padgett, Claire; Lim, John K.C.; Anderes, Kenna; Rice, William G.; Ryckman, David

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer We examine the potential cross-talk between CK2 and IL-6. Black-Right-Pointing-Pointer Inhibition of CK2 by siRNA or CX-4945 inhibits expression of IL-6 in models of IBC. Black-Right-Pointing-Pointer Treatment of IBC patient in the clinic with CX-4945 reduces her IL-6 plasma levels. Black-Right-Pointing-Pointer We demonstrate that CK2 is a potential therapeutic target for IL-6 driven diseases. -- Abstract: Inflammatory breast cancer is driven by pro-angiogenic and pro-inflammatory cytokines. One of them Interleukin-6 (IL-6) is implicated in cancer cell proliferation and survival, and promotes angiogenesis, inflammation and metastasis. While IL-6 has been shown to be upregulated by several oncogenes, the mechanism behind this phenomenon is not well characterized. Here we demonstrate that the pleotropic Serine/Threonine kinase CK2 is implicated in the regulation of IL-6 expression in a model of inflammatory breast cancer. We used siRNAs targeted toward CK2 and a selective small molecule inhibitor of CK2, CX-4945, to inhibit the expression and thus suppress the secretion of IL-6 in in vitro as well as in vivo models. Moreover, we report that in a clinical trial, CX-4945 was able to dramatically reduce IL-6 levels in plasma of an inflammatory breast cancer patient. Our data shed a new light on the regulation of IL-6 expression and position CX-4945 and potentially other inhibitors of CK2, for the treatment of IL-6-driven cancers and possibly other diseases where IL-6 is instrumental, including rheumatoid arthritis.

  1. Protein kinase CK2α catalytic subunit ameliorates diabetic renal inflammatory fibrosis via NF-κB signaling pathway.

    Science.gov (United States)

    Huang, Junying; Chen, Zhiquan; Li, Jie; Chen, Qiuhong; Li, Jingyan; Gong, Wenyan; Huang, Jiani; Liu, Peiqing; Huang, Heqing

    2017-02-23

    Activation of casein kinase 2 (CK2) is closely linked to the body disturbance of carbohydrate metabolism and inflammatory reaction. The renal chronic inflammatory reaction in the setting of diabetes is one of the important hallmarks of diabetic renal fibrosis. However, it remains unknown whether CK2 influences the process of diabetic renal fibrosis. The current study is aimed to investigate if CK2α ameliorates renal inflammatory fibrosis in diabetes via NF-κB pathway. To explore potential regulatory mechanism of CK2α, the expression and activity of CK2α, which were studied by plasmid transfection, selective inhibitor, small-interfering RNA (siRNA) and adenovirus infection in vitro or in vivo, were analyzed by means of western blotting (WB), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The following findings were observed: (1) Expression of CK2α was upregulated in kidneys of db/db and KKAy diabetic mice; (2) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression suppressed high glucose-induced expressions of FN and ICAM-1 in glomerular mesangial cells (GMCs); (3) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression not only restrained IκB degradation, but also suppressed HG-induced nuclear accumulation, transcriptional activity and DNA binding activity of NF-κB in GMCs; (4) Treatment of TBB or CK2α RNAi adenovirus infection ameliorated renal fibrosis in diabetic animals; (5) Treatment of TBB or CK2α RNAi adenovirus infection suppressed IκB degradation and NF-κB nuclear accumulation in glomeruli of diabetic animals. This study indicates the essential role of CK2α in regulating the diabetic renal pathological process of inflammatory fibrosis via NF-κB pathway, and inhibition of CK2α may serve as a promising therapeutic strategy for diabetic nephropathy.

  2. CK2 phosphorylates Sec31 and regulates ER-To-Golgi trafficking.

    Directory of Open Access Journals (Sweden)

    Mayuko Koreishi

    Full Text Available Protein export from the endoplasmic reticulum (ER is an initial and rate-limiting step of molecular trafficking and secretion. This is mediated by coat protein II (COPII-coated vesicles, whose formation requires small GTPase Sar1 and 6 Sec proteins including Sec23 and Sec31. Sec31 is a component of the outer layer of COPII coat and has been identified as a phosphoprotein. The initiation and promotion of COPII vesicle formation is regulated by Sar1; however, the mechanism regulating the completion of COPII vesicle formation followed by vesicle release is largely unknown. Hypothesizing that the Sec31 phosphorylation may be such a mechanism, we identified phosphorylation sites in the middle linker region of Sec31. Sec31 phosphorylation appeared to decrease its association with ER membranes and Sec23. Non-phosphorylatable mutant of Sec31 stayed longer at ER exit sites and bound more strongly to Sec23. We also found that CK2 is one of the kinases responsible for Sec31 phosphorylation because CK2 knockdown decreased Sec31 phosphorylation, whereas CK2 overexpression increased Sec31 phosphorylation. Furthermore, CK2 knockdown increased affinity of Sec31 for Sec23 and inhibited ER-to-Golgi trafficking. These results suggest that Sec31 phosphorylation by CK2 controls the duration of COPII vesicle formation, which regulates ER-to-Golgi trafficking.

  3. Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure.

    Science.gov (United States)

    Shinoda, Kosaku; Ohyama, Kana; Hasegawa, Yutaka; Chang, Hsin-Yi; Ogura, Mayu; Sato, Ayaka; Hong, Haemin; Hosono, Takashi; Sharp, Louis Z; Scheel, David W; Graham, Mark; Ishihama, Yasushi; Kajimura, Shingo

    2015-12-01

    Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under β3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the β3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes.

  4. Expression, purification and crystallization of the catalytic subunit of protein kinase CK2 from Zea mays

    DEFF Research Database (Denmark)

    Guerra, B; Niefind, K; Pinna, L A

    1998-01-01

    a = 142.6, b = 61.3, c = 45.6 A, beta = 103.3 degrees and diffract X-rays to at least 2.0 A resolution. The calculated crystal packing parameter is Vm = 2.47 A3 Da-1 suggesting that one CK2alpha molecule is contained in the asymmetric unit and that the solvent content of the unit cell is 50%.......The catalytic (alpha) subunit of protein kinase CK2 (CK2alpha) was originally cloned and overexpressed in the Escherichia coli strain pT7-7/BL21(DE3). The protein has been purified to homogeneity and crystallized. The crystals belong to the monoclinic space group C2, they have unit-cell parameters...

  5. Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma.

    Science.gov (United States)

    Zhou, Bingying; Ritt, Daniel A; Morrison, Deborah K; Der, Channing J; Cox, Adrienne D

    2016-08-19

    The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the α catalytic subunit (CK2α, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2α protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2α in drug resistance to Food and Drug Administration-approved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2α decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2α sensitized cells to inhibitor treatment. CK2α-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2α post-translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2α, that RAF-MEK inhibitor resistance did not rely on CK2α kinase catalytic function, and both wild-type and kinase-inactive CK2α maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase-inactive CK2α bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2α increases KSR facilitation of ERK phosphorylation. Accordingly, CK2α did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2α that promotes resistance to RAF- and MEK-targeted therapies.

  6. Conformational plasticity of the catalytic subunit of protein kinase CK2 and its consequences for regulation and drug design

    DEFF Research Database (Denmark)

    Niefind, Karsten; Issinger, Olaf-Georg

    2010-01-01

    well to the constitutive activity of the enzyme, meaning, its independence from phosphorylation or other characteristic control factors. Most CK2alpha structures are based on the enzyme from Zea mays, supplemented by an increasing number of human CK2alpha structures. In the latter a surprising...... molecule seems to favour the partially and fully inactive states. This observation may be exploited to design effective and selective CK2 inhibitors....

  7. Protein Kinase CK2 Expression Predicts Relapse Survival in ERα Dependent Breast Cancer, and Modulates ERα Expression in Vitro

    OpenAIRE

    2015-01-01

    The heterotetrameric protein kinase CK2 has been associated with oncogenic transformation, and our previous studies have shown that it may affect estrogenic signaling. Here, we investigate the role of the protein kinase CK2 in regulating ERα (estrogen receptor α) signaling in breast cancer. We determined the correlation of CK2α expression with relapse free breast cancer patient survival utilizing Kaplan Meier Plotter (kmplot.com/analysis/) to mine breast cancer microarrays repositories. Patie...

  8. Cloning and purification of protein kinase CK2 recombinant alpha and beta subunits from the Mediterranean fly Ceratitis capitata.

    Science.gov (United States)

    Kouyanou-Koutsoukou, Sophia; Baier, Andrea; Kolaitis, Regina-Maria; Maniatopoulou, Evanthia; Thanopoulou, Konstantina; Szyszka, Ryszard

    2011-10-01

    The Mediterranean fruit fly Ceratitis capitata is an insect capable of wreaking extensive damage to a wide range of fruit crops. Protein kinase CK2 is a ubiquitous Ser/Thr kinase that is highly conserved among eukaryotes; it is a heterotetramer composed of two catalytic (α) and a dimer of regulatory (β) subunits. We present here the construction of the cDNA molecules of the CK2α and CK2β subunits from the medfly C. capitata by the 5'/3' RACE and RT-PCR methods, respectively. CcCK2α catalytic subunit presents the characteristic and conserved features of a typical protein kinase, similar to the regulatory CcCK2β subunit, that also possess the conserved features of regulatory CK2β subunits, as revealed by comparison of their predicted amino acid sequences with other eukaryotic species. The recombinant CcCK2α and CcCK2β proteins were purified by affinity chromatography to homogeneity, after overexpression in Escherichia coli. CcCK2α is capable to utilize GTP and its activity and is inhibited by polyanions and stimulated by polycations in phosphorylation assays, using purified acidic ribosomal protein P1 as a substrate.

  9. Proteomic Analysis of Calcium- and Phosphorylation-dependentCalmodulin Complexes in Mammalian Cells

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Deok-Jin; Wang, Daojing

    2006-05-26

    Protein conformational changes due to cofactor binding (e.g. metal ions, heme) and/or posttranslational modifications (e.g. phosphorylation) modulate dynamic protein complexes. Calmodulin (CaM) plays an essential role in regulating calcium (Ca{sup 2+}) signaling and homeostasis. No systematic approach on the identification of phosphorylation-dependent Ca{sup 2+}/CaM binding proteins has been published. Herein, we report a proteome-wide study of phosphorylation-dependent CaM binding proteins from mammalian cells. This method, termed 'Dynamic Phosphoprotein Complex Trapping', 'DPPC Trapping' for short, utilizes a combination of in vivo and in vitro assays. The basic strategy is to drastically shift the equilibrium towards endogenous phosphorylation of Ser, Thr, and Tyr at the global scale by inhibiting corresponding phosphatases in vivo. The phosphorylation-dependent calmodulin-binding proteins are then trapped in vitro in a Ca{sup 2+}-dependent manner by CaM-Sepharose chromatography. Finally, the isolated calmodulin-binding proteins are separated by SDS-PAGE and identified by LC/MS/MS. In parallel, the phosphorylation-dependent binding is visualized by silver staining and/or Western blotting. Using this method, we selectively identified over 120 CaM-associated proteins including many previously uncharacterized. We verified ubiquitin-protein ligase EDD1, inositol 1, 4, 5-triphosphate receptor type 1 (IP{sub 3}R1), and ATP-dependent RNA helicase DEAD box protein 3 (DDX3), as phosphorylation-dependent CaM binding proteins. To demonstrate the utilities of our method in understanding biological pathways, we showed that pSer/Thr of IP{sub 3}R1 in vivo by staurosporine-sensitive kinase(s), but not by PKA/PKG/PKC, significantly reduced the affinity of its Ca{sup 2+}-dependent CaM binding. However, pSer/Thr of IP{sub 3}R1 did not substantially affect its Ca{sup 2+}-independent CaM binding. We further showed that phosphatase PP1, but not PP2A or PP2B

  10. Synthesis of novel polybrominated benzimidazole derivatives-potential CK2 inhibitors with anticancer and proapoptotic activity.

    Science.gov (United States)

    Łukowska-Chojnacka, Edyta; Wińska, Patrycja; Wielechowska, Monika; Poprzeczko, Martyna; Bretner, Maria

    2016-02-15

    The efficient method for the synthesis of novel cell permeable inhibitors of protein kinase CK2 with anticancer and proapoptotic activity has been developed. A series of polybrominated benzimiadazole derivatives substituted by various cyanoalkyl groups have been synthesized. Cyanoethyl derivatives were obtained by Michael type addition of 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole to acrylonitrile, whilst cyanomethyl, cyanopropyl and cyanobutyl analogs by N-alkylation of 4,5,6,7-tetrabromo-1H-benzimidazole and 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole with appropriate cyanoalkyl halides. The inhibitory activity against protein kinase rhCK2α catalytic subunit and cytotoxicity against two human cancer cell lines: acute lymphocytic leukemia (CCRF-CEM) and breast (MCF-7) were evaluated for all newly synthesized compounds. Additionally, the proapoptotic activity toward leukemia cells and intracellular inhibition of CK2 for the most cytotoxic derivatives have been performed, demonstrating 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole as a new selective inhibitor of rhCK2 with twenty-fold better proapoptotic activity than parental compound (TBBi).

  11. Regulation of taurine transport systems by protein kinase CK2 in mammalian cells

    DEFF Research Database (Denmark)

    Lambert, Ian Henry; Hansen, Daniel Bloch

    2011-01-01

    Maintaining cell volume is critical for cellular function yet shift in cell volume is a prerequisite for mitosis and apoptosis. The ubiquitously and evolutionary conserved serine/threonine kinase CK2 promotes cell survival and suppresses apoptosis. The present review describes how mammalian cells...

  12. Two putative protein kinase CK2 phosphorylation sites are important for Myf-5 activity

    DEFF Research Database (Denmark)

    Winter, B; Kautzner, I; Issinger, O G;

    1997-01-01

    Myf-5, a member of a family of muscle-specific transcription factors, is important for myogenic cell determination and differentiation. Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites ...

  13. Crystal structure of the catalytic subunit of protein kinase CK2 from Zea mays at 2.1 A resolution

    DEFF Research Database (Denmark)

    Niefind, K; Guerra, B; Pinna, L A

    1998-01-01

    and probably contributes to the constitutively active nature of CK2. The active centre is occupied by a partially disordered ATP molecule with the adenine base attached to a novel binding site of low specificity. This finding explains the observation that CK2, unlike other protein kinases, can use both ATP...

  14. Targeting CK2-driven non-oncogene addiction in B-cell tumors.

    Science.gov (United States)

    Mandato, E; Manni, S; Zaffino, F; Semenzato, G; Piazza, F

    2016-11-24

    Genetic mutations of oncogenes often underlie deranged cell growth and altered differentiation pathways leading to malignant transformation of B-lymphocytes. However, addiction to oncogenes is not the only drive to lymphoid tumor pathogenesis. Dependence on non-oncogenes, which act by propelling basic mechanisms of cell proliferation and survival, has also been recognized in the pathobiology of lymphoid leukemias, lymphomas and multiple myeloma. Among the growing number of molecules that may uphold non-oncogene addiction, a key place is increasingly being recognized to the serine-threonine kinase CK2. This enzyme is overexpressed and overactive in B-acute lymphoblastic leukemia, multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphomas, such as mantle cell, follicular, Burkitt's and diffuse large B-cell lymphomas. In these tumors, CK2 may serve the activity of oncogenes, similar to BCR-ABL and c-MYC, control the activation of critical signaling cascades, such as NF-κB (nuclear factor-κB), STAT3 (signal transducer and activator of transcription 3) and PTEN/PI3K/AKT (phosphatase and tensin homolog protein/phosphoinositide 3-kinase/AKR thymoma), and sustain multiple cellular stress-elicited pathways, such as the proteotoxic stress, unfolded protein and DNA-damage responses. CK2 has also been shown to have an essential role in tuning signals derived from the stromal tumor microenvironment. Not surprisingly, targeting CK2 in lymphoid tumor cell lines or mouse xenograft models can boost the cytotoxic effects of both conventional chemotherapeutics and novel agents, similar to heat-shock protein 90, proteasome and tyrosine kinases inhibitors. In this review, we summarize the evidence indicating how CK2 embodies most of the features of a cancer growth-promoting non-oncogene, focusing on lymphoid tumors. We further discuss the preclinical data of the use of small ATP-competitive CK2 inhibitors, which hold the promise to be additional options in novel drug

  15. Crystallization and preliminary characterization of crystals of human protein kinase CK2

    DEFF Research Database (Denmark)

    Niefind, K; Guerra, B; Ermakowa, I;

    2000-01-01

    The heterotetrameric recombinant holoenzyme of human protein kinase CK2 was purified to homogeneity. It degraded spontaneously to a stable and fully active state in which the catalytic subunit was about 5 kDa smaller than the wild type. The degraded enzyme was crystallized using polyethylene glycol...... 3350 as precipitant. The crystals belong to the hexagonal space group P6(3). They have unit-cell parameters a = b = 176.0, c = 93.6 A and diffract X-rays to at least 3.5 A resolution. The calculated crystal packing parameter is V(M) = 3.22 A(3) Da(-1), suggesting that one CK2 tetramer is contained...

  16. CK2(beta)tes gene encodes a testis-specific isoform of the regulatory subunit of casein kinase 2 in Drosophila melanogaster

    DEFF Research Database (Denmark)

    Kalmykova, Alla I; Shevelyov, Yuri Y; Polesskaya, Oksana O

    2002-01-01

    An earlier described CK2(beta)tes gene of Drosophila melanogaster is shown to encode a male germline specific isoform of regulatory beta subunit of casein kinase 2. Western-analysis using anti-CK2(beta)tes Ig revealed CK2(beta)tes protein in Drosophila testes extract. Expression of a CK2(beta...... and coimmunoprecipitation analysis of protein extract from Drosophila testes, we demonstrated an association between CK2(beta)tes and CK2alpha. Northern-analysis has shown that another regulatory (beta') subunit found recently in D. melanogaster genome is also testis-specific. Thus, we describe the first example of two...

  17. CK2 phosphorylation inactivates DNA binding by the papillomavirus E1 and E2 proteins.

    Science.gov (United States)

    Schuck, Stephen; Ruse, Cristian; Stenlund, Arne

    2013-07-01

    Papillomaviruses have complex life cycles that are understood only superficially. Although it is well established that the viral E1 and E2 proteins play key roles in controlling viral transcription and DNA replication, how these factors are regulated is not well understood. Here, we demonstrate that phosphorylation by the protein kinase CK2 controls the biochemical activities of the bovine papillomavirus E1 and E2 proteins by modifying their DNA binding activity. Phosphorylation at multiple sites in the N-terminal domain in E1 results in the loss of sequence-specific DNA binding activity, a feature that is also conserved in human papillomavirus (HPV) E1 proteins. The bovine papillomavirus (BPV) E2 protein, when phosphorylated by CK2 on two specific sites in the hinge, also loses its site-specific DNA binding activity. Mutation of these sites in E2 results in greatly increased levels of latent viral DNA replication, indicating that CK2 phosphorylation of E2 is a negative regulator of viral DNA replication during latent viral replication. In contrast, mutation of the N-terminal phosphorylation sites in E1 has no effect on latent viral DNA replication. We propose that the phosphorylation of the N terminus of E1 plays a role only in vegetative viral DNA replication, and consistent with such a role, caspase 3 cleavage of E1, which has been shown to be necessary for vegetative viral DNA replication, restores the DNA binding activity to phosphorylated E1.

  18. Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism.

    Science.gov (United States)

    Granovsky, Alexey E; Clark, Matthew C; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

    2009-03-01

    Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.

  19. Protein Kinase CK2 Expression Predicts Relapse Survival in ERα Dependent Breast Cancer, and Modulates ERα Expression in Vitro

    Directory of Open Access Journals (Sweden)

    Marlon D. Williams

    2015-12-01

    Full Text Available The heterotetrameric protein kinase CK2 has been associated with oncogenic transformation, and our previous studies have shown that it may affect estrogenic signaling. Here, we investigate the role of the protein kinase CK2 in regulating ERα (estrogen receptor α signaling in breast cancer. We determined the correlation of CK2α expression with relapse free breast cancer patient survival utilizing Kaplan Meier Plotter (kmplot.com/analysis/ to mine breast cancer microarrays repositories. Patients were stratified according to ERα status, histological grade, and hormonal therapy. Luciferase reporter assays and flow cytometry were implemented to determine the impact of CK2 inhibition on ERE-mediated gene expression and expression of ERα protein. CK2α expression is associated with shorter relapse free survival among ERα (+ patients with grade 1 or 2 tumors, as well as among those patients receiving hormonal therapy. Biochemical inhibition of CK2 activity results in increased ER-transactivation as well as increased expression among ERα (+ and ERα (− breast cancer cell lines. These findings suggest that CK2 may contribute to estrogen-independent cell proliferation and breast tumor progression, and may potentially serve as a biomarker and pharmacological target in breast cancer.

  20. Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses

    DEFF Research Database (Denmark)

    Fritz, Gerhard; Issinger, Olaf-Georg; Olsen, Birgitte Brinkmann

    2009-01-01

    Targeting protein kinases as a therapeutic approach to treat various diseases, especially cancer is currently a fast growing business. Although many inhibitors are available, exhibiting remarkable potency, the major challenge is their selectivity. Here we show that the protein kinase CK2 inhibitors...... viability and inhibition of endogenous CK2 activity in the absence and presence of the anti-cancer drug cisplatin. The strongest effect on viability was observed with resorufin. In contrast to resorufin, TBB protected cells from cisplatin-induced cell killing. Furthermore, the inhibition of endogenous CK2...

  1. Phosphorylation-dependent translocation of glycogen synthase to a novel structure during glycogen resynthesis

    DEFF Research Database (Denmark)

    Prats, Clara; Cadefau, Joan A; Cussó, Roser;

    2005-01-01

    . Both enzymes are regulated by reversible phosphorylation and by allosteric effectors. However, evidence in the literature indicates that changes in muscle GS and GPh intracellular distribution may constitute a new regulatory mechanism of glycogen metabolism. Already in the 1960s, it was proposed...... structures that were not present in basal muscle, and we present evidence that indicate that they are products of actin cytoskeleton remodeling. Furthermore, for the first time, we show a phosphorylation-dependent intracellular distribution of GS. Here, we present evidence of a new regulatory mechanism...

  2. Nanoencapsulated anti-CK2 small molecule drug or siRNA specifically targets malignant cancer but not benign cells.

    Science.gov (United States)

    Trembley, Janeen H; Unger, Gretchen M; Korman, Vicci L; Tobolt, Diane K; Kazimierczuk, Zygmunt; Pinna, Lorenzo A; Kren, Betsy T; Ahmed, Khalil

    2012-02-01

    CK2, a pleiotropic Ser/Thr kinase, is an important target for cancer therapy. We tested our novel tenfibgen-based nanocapsule for delivery of the inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) and an siRNA directed against both CK2α and α' catalytic subunits to prostate cancer cells. We present data on the TBG nanocapsule itself and on CK2 inhibition or downregulation in treated cells, including effects on Nuclear Factor-kappa B (NF-κB) p65. By direct comparison of two CK2-directed cargos, our data provide proof that the TBG encapsulation design for delivery of drugs specifically to cancer cells has strong potential for small molecule- and nucleic acid-based cancer therapy.

  3. Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells.

    Directory of Open Access Journals (Sweden)

    Sofia Zanin

    Full Text Available CK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-4945 and CX-5011 have proved to be very potent, selective and effective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacy of these compounds to overcome drug resistance, a major reasons of cancer therapy failure. Here we address this point, by studying their effects in several tumor cell lines, each available as variant R resistant to drug-induced apoptosis, and normal-sensitive variant S. We found that the inhibition of endogenous CK2 was very similar in S and R treated cells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptotic response was induced both in S and R variants of each pairs. Moreover, the combined treatment of CX-4945 plus vinblastine was able to sensitize to vinblastine R cells that are otherwise almost insensitive to this conventional antitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR cells was greatly increased by CX-4945.In summary, we demonstrated that all the R variants are sensitive to CX-4945 and CX-5011; since some of the treated R lines express the extrusion pump Pgp, often responsible of the MDR phenotype, we can also conclude that the two inhibitors can successfully overcome the MDR phenomenon.

  4. Protein Kinase CK2 Regulates Cytoskeletal Reorganization during Ionizing Radiation-Induced Senescence of Human Mesenchymal Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Daojing; Jang, Deok-Jin

    2009-08-21

    Human mesenchymal stem cells (hMSC) are critical for tissue regeneration. How hMSC respond to genotoxic stresses and potentially contribute to aging and cancer remain underexplored. We demonstrated that ionizing radiation induced cellular senescence of hMSC over a period of 10 days, showing a critical transition between day 3 and day 6. This was confirmed by senescence-associated beta-galactosidase (SA-{beta}-gal) staining, protein expression profiles of key cell cycle regulators (retinoblastoma (Rb) protein, p53, p21{sup waf1/Cip1}, and p16{sup INK4A}), and senescence-associated secretory phenotypes (SASPs) (IL-8, IL-12, GRO, and MDC). We observed dramatic cytoskeletal reorganization of hMSC through reduction of myosin-10, redistribution of myosin-9, and secretion of profilin-1. Using a SILAC-based phosphoproteomics method, we detected significant reduction of myosin-9 phosphorylation at Ser1943, coinciding with its redistribution. Importantly, through treatment with cell permeable inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT)), and gene knockdown using RNA interference, we identified CK2, a kinase responsible for myosin-9 phosphorylation at Ser1943, as a key factor contributing to the radiation-induced senescence of hMSC. We showed that individual knockdown of CK2 catalytic subunits CK2{alpha} and CK2{alpha}{prime} induced hMSC senescence. However, only knockdown of CK2{alpha} resulted in morphological phenotypes resembling those of radiation-induced senescence. These results suggest that CK2{alpha} and CK2{alpha}{prime} play differential roles in hMSC senescence progression, and their relative expression might represent a novel regulatory mechanism for CK2 activity.

  5. Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2.

    Science.gov (United States)

    Syniugin, Anatolii R; Ostrynska, Olga V; Chekanov, Maksym O; Volynets, Galyna P; Starosyla, Sergiy A; Bdzhola, Volodymyr G; Yarmoluk, Sergiy M

    2016-01-01

    In this article, the derivatives of 3-quinoline carboxylic acid were studied as inhibitors of protein kinase CK2. Forty-three new compounds were synthesized. Among them 22 compounds inhibiting CK2 with IC50 in the range from 0.65 to 18.2 μM were identified. The most active inhibitors were found among tetrazolo-quinoline-4-carboxylic acid and 2-aminoquinoline-3-carboxylic acid derivatives.

  6. The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses

    Directory of Open Access Journals (Sweden)

    Yusuke Kanamaru

    2012-01-01

    Full Text Available To maintain cellular homeostasis, cells are equipped with precise systems that trigger the appropriate stress responses. Mitochondria not only provide cellular energy but also integrate stress response signaling pathways, including those regulating cell death. Several lines of evidence suggest that the mitochondrial proteins that function in this process, such as Bcl-2 family proteins in apoptosis and phosphoglycerate mutase family member 5 (PGAM5 in necroptosis, are regulated by several kinases. It has also been suggested that the phosphorylation-dependent regulation of mitochondrial fission machinery, dynamin-related protein 1 (Drp1, facilitates appropriate cellular stress responses. However, mitochondria themselves are also damaged by various stresses. To avoid the deleterious effects exerted by damaged mitochondria, cells remove these mitochondria in a selective autophagic degradation process called mitophagy. Interestingly, several kinases, such as PTEN-induced putative kinase 1 (PINK1 in mammals and stress-responsive mitogen-activated protein (MAP kinases in yeast, have recently been shown to be involved in mitophagy. In this paper, we focus on the phosphorylation-dependent regulation of mitochondrial proteins and discuss the roles of this regulation in the mitochondrial and cellular stress responses.

  7. Resorufin: a lead for a new protein kinase CK2 inhibitor

    DEFF Research Database (Denmark)

    Sandholt, Iben Skjøth; Olsen, Birgitte Brinkmann; Guerra, Barbara;

    2009-01-01

    treatment with 40 mol/l resorufin led to 15-20% dead cells; however, no caspase-mediated apoptosis was observed. In the case of the colorectal carcinoma HCT116 cell line, a similar picture was obtained, yet, when resorufin was administered to cells treated with doxorubicin, apoptosis was strongly induced...... other kinases by 90%. The IC50 values determined for the CK2 holoenzymes were 1.5 mol/l and for the free catalytic subunits ca. 4 mol/l. Altogether four cell lines were subjected to resorufin and emodin treatment. In the case of the three prostate carcinoma cell lines (PC-3, DU-145, LNCaP), 24 h...... within 24 h. Endogenous protein kinase CK2 was inhibited by resorufin by ca. 80% in the three prostate cell lines. In the case of the HCT116 cells, the inhibition was only 40% supporting the notion of cell line-specific selectivity. Moreover, we analysed the effect of resorufin and emodin on selected...

  8. Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality

    DEFF Research Database (Denmark)

    Buchou, Thierry; Vernet, Muriel; Blond, Olivier

    2003-01-01

    Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory beta subunit, CK2beta, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2beta gene in m....... Thus, our study demonstrates that in mammals, CK2beta is essential for viability at the cellular level, possibly because it acquired new functions during evolution.......Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory beta subunit, CK2beta, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2beta gene...

  9. Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice

    Science.gov (United States)

    Ferrer-Font, Laura; Villamañan, Lucia; Arias-Ramos, Nuria; Vilardell, Jordi; Plana, Maria; Ruzzene, Maria; Pinna, Lorenzo A.; Itarte, Emilio; Arús, Carles; Candiota, Ana Paula

    2017-01-01

    Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response. PMID:28208677

  10. Detection of phospho-sites generated by protein kinase CK2 in CFTR: mechanistic aspects of Thr1471 phosphorylation.

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    Andrea Venerando

    Full Text Available By mass spectrometry analysis of mouse Cystic Fibrosis Transmembrane-conductance Regulator (mCFTR expressed in yeast we have detected 21 phosphopeptides accounting for 22 potential phospho-residues, 12 of which could be unambiguously assigned. Most are conserved in human CFTR (hCFTR and the majority cluster in the Regulatory Domain, lying within consensus sequences for PKA, as identified in previous mammalian studies. This validates our yeast expression model. A number of phospho-residues were novel and human conserved, notably mouse Ser670, Ser723, Ser737, and Thr1467, that all lie in acidic sequences, compatible with their phosphorylation by protein kinase CK2. Thr1467 is localized in the C-terminal tail, embedded in a functionally important and very acidic sequence (EETEEE which displays an optimal consensus for protein kinase CK2. Herein, we show that Thr1467, homologous to human Thr1471 is readily phosphorylated by CK2. Indeed a 42 amino acid peptide encompassing the C-terminal segment of human CFTR is readily phosphorylated at Thr1471 with favorable kinetics (Km 1.7 µM by CK2 holoenzyme, but neither by its isolated catalytic subunit nor by other acidophilic Ser/Thr kinases (CK1, PLK2/3, GCK/FAM20C. Our finding that by treating CFTR expressing BHK cells with the very specific CK2 inhibitor CX4945, newly synthesized wild type CFTR (and even more its Phe508del mutant accumulates more abundantly than in the absence of CK2 inhibitor, supports the conclusion that phosphorylation of CFTR by CK2 correlates with decreased stability of the protein.

  11. Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice

    Directory of Open Access Journals (Sweden)

    Laura Ferrer-Font

    2017-02-01

    Full Text Available Glioblastoma (GBM causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2 contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129 phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05 was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6 when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6 and controls (22.5 ± 1.2, n = 6. Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.

  12. Phosphorylation-dependent regulation of plant chromatin and chromatin-associated proteins

    KAUST Repository

    Bigeard, Jean

    2014-07-10

    In eukaryotes, most of the DNA is located in the nucleus where it is organized with histone proteins in a higher order structure as chromatin. Chromatin and chromatin-associated proteins contribute to DNA-related processes such as replication and transcription as well as epigenetic regulation. Protein functions are often regulated by PTMs among which phosphorylation is one of the most abundant PTM. Phosphorylation of proteins affects important properties, such as enzyme activity, protein stability, or subcellular localization. We here describe the main specificities of protein phosphorylation in plants and review the current knowledge on phosphorylation-dependent regulation of plant chromatin and chromatin-associated proteins. We also outline some future challenges to further elucidate protein phosphorylation and chromatin regulation.

  13. Different Persistence of the Cellular Effects Promoted by Protein Kinase CK2 Inhibitors CX-4945 and TDB

    Directory of Open Access Journals (Sweden)

    Cristina Girardi

    2015-01-01

    Full Text Available We compare the cellular efficacy of two selective and cell permeable inhibitors of the antiapoptotic kinase CK2. One inhibitor, CX-4945, is already in clinical trials as antitumor drug, while the other, TDB, has been recently successfully employed to demonstrate the implication of CK2 in cellular (disregulation. We found that, upon treatment of cancer cells with these compounds, the extent of inhibition of endocellular CK2 is initially comparable but becomes significantly different after the inhibitors are removed from the cellular medium: while in CX-4945 treated cells CK2 activity is restored to control level after 24 h, in the case of TDB it is still strongly reduced after 4 days from removal. The biological effects of the two inhibitors have been analyzed by performing clonogenic, spheroid formation, and wound-healing assays: we observed a permanent inhibition of cell survival and migration in TDB-treated cells even after the inhibitor removal, while in the case of CX-4945 only its maintenance for the whole duration of the assay insured a persisting effect. We suggest that the superiority of TDB in maintaining kinase activity inhibited and perpetuating the consequent effects is an added value to be considered when planning new therapies based on CK2 targeting.

  14. Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors.

    Science.gov (United States)

    Cozza, Giorgio; Gianoncelli, Alessandra; Bonvini, Paolo; Zorzi, Elisa; Pasquale, Riccardo; Rosolen, Angelo; Pinna, Lorenzo A; Meggio, Flavio; Zagotto, Giuseppe; Moro, Stefano

    2011-12-09

    Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (K(i)=20 nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, K(i)=60 nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a K(i) value of 7 nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments.

  15. Different Persistence of the Cellular Effects Promoted by Protein Kinase CK2 Inhibitors CX-4945 and TDB

    Science.gov (United States)

    Girardi, Cristina; Ottaviani, Daniele; Pinna, Lorenzo A.; Ruzzene, Maria

    2015-01-01

    We compare the cellular efficacy of two selective and cell permeable inhibitors of the antiapoptotic kinase CK2. One inhibitor, CX-4945, is already in clinical trials as antitumor drug, while the other, TDB, has been recently successfully employed to demonstrate the implication of CK2 in cellular (dis)regulation. We found that, upon treatment of cancer cells with these compounds, the extent of inhibition of endocellular CK2 is initially comparable but becomes significantly different after the inhibitors are removed from the cellular medium: while in CX-4945 treated cells CK2 activity is restored to control level after 24 h, in the case of TDB it is still strongly reduced after 4 days from removal. The biological effects of the two inhibitors have been analyzed by performing clonogenic, spheroid formation, and wound-healing assays: we observed a permanent inhibition of cell survival and migration in TDB-treated cells even after the inhibitor removal, while in the case of CX-4945 only its maintenance for the whole duration of the assay insured a persisting effect. We suggest that the superiority of TDB in maintaining kinase activity inhibited and perpetuating the consequent effects is an added value to be considered when planning new therapies based on CK2 targeting. PMID:26558259

  16. CK2 phosphorylation of human centrins 1 and 2 regulates their binding to the DNA repair protein XPC, the centrosomal protein Sfi1 and the phototransduction protein transducin β.

    Science.gov (United States)

    Grecu, Dora; Assairi, Liliane

    2014-01-01

    Centrins are calcium-binding proteins that can interact with several cellular targets (Sfi1, XPC, Sac3 and transducin β) through the same hydrophobic triad. However, two different orientations of the centrin-binding motif have been observed: W(1)xxL(4)xxxL(8) for XPC (xeroderma pigmentosum group C protein) and the opposite orientation L(8)xxxL(4)xxW(1) for Sfi1 (suppressor of fermentation-induced loss of stress resistance protein 1), Sac3 and transducin β. Centrins are also phosphorylated by several protein kinases, among which is CK2. The purpose of this study was to determine the binding mechanism of human centrins to three targets (transducin β, Sfi1 and XPC), and the effects of in vitro phosphorylation by CK2 of centrins 1 and 2 with regard to this binding mechanism. We identified the centrin-binding motif at the COOH extremity of transducin β. Human centrin 1 binds to transducin β only in the presence of calcium with a binding constant lower than the binding constant observed for Sfi1 and for XPC. The affinity constants of centrin 1 were 0.10 10(6) M(-1), 249 10(6) M(-1) and 52.5 10(6) M(-1) for Trd, R17-Sfi1 and P17-XPC respectively. CK2 phosphorylates human centrin 1 at residue T138 and human centrin 2 at residues T138 and S158. Consequently CK2 phosphorylation abolished the binding of centrin 1 to transducin β and reduced the binding to Sfi1 and XPC. CK2 phosphorylation of centrin 2 at T138 and S158 abolished the binding to Sfi1 as assessed using a C-HsCen2 T138D-S158D phosphomimetic form of centrin 2.

  17. CK2 phosphorylation of human centrins 1 and 2 regulates their binding to the DNA repair protein XPC, the centrosomal protein Sfi1 and the phototransduction protein transducin β

    Science.gov (United States)

    Grecu, Dora; Assairi, Liliane

    2014-01-01

    Centrins are calcium-binding proteins that can interact with several cellular targets (Sfi1, XPC, Sac3 and transducin β) through the same hydrophobic triad. However, two different orientations of the centrin-binding motif have been observed: W1xxL4xxxL8 for XPC (xeroderma pigmentosum group C protein) and the opposite orientation L8xxxL4xxW1 for Sfi1 (suppressor of fermentation-induced loss of stress resistance protein 1), Sac3 and transducin β. Centrins are also phosphorylated by several protein kinases, among which is CK2. The purpose of this study was to determine the binding mechanism of human centrins to three targets (transducin β, Sfi1 and XPC), and the effects of in vitro phosphorylation by CK2 of centrins 1 and 2 with regard to this binding mechanism. We identified the centrin-binding motif at the COOH extremity of transducin β. Human centrin 1 binds to transducin β only in the presence of calcium with a binding constant lower than the binding constant observed for Sfi1 and for XPC. The affinity constants of centrin 1 were 0.10 106 M−1, 249 106 M−1 and 52.5 106 M−1 for Trd, R17-Sfi1 and P17-XPC respectively. CK2 phosphorylates human centrin 1 at residue T138 and human centrin 2 at residues T138 and S158. Consequently CK2 phosphorylation abolished the binding of centrin 1 to transducin β and reduced the binding to Sfi1 and XPC. CK2 phosphorylation of centrin 2 at T138 and S158 abolished the binding to Sfi1 as assessed using a C-HsCen2 T138D-S158D phosphomimetic form of centrin 2. PMID:24918055

  18. CK2 phosphorylation of human centrins 1 and 2 regulates their binding to the DNA repair protein XPC, the centrosomal protein Sfi1 and the phototransduction protein transducin β

    Directory of Open Access Journals (Sweden)

    Dora Grecu

    2014-01-01

    Full Text Available Centrins are calcium-binding proteins that can interact with several cellular targets (Sfi1, XPC, Sac3 and transducin β through the same hydrophobic triad. However, two different orientations of the centrin-binding motif have been observed: W1xxL4xxxL8 for XPC (xeroderma pigmentosum group C protein and the opposite orientation L8xxxL4xxW1 for Sfi1 (suppressor of fermentation-induced loss of stress resistance protein 1, Sac3 and transducin β. Centrins are also phosphorylated by several protein kinases, among which is CK2. The purpose of this study was to determine the binding mechanism of human centrins to three targets (transducin β, Sfi1 and XPC, and the effects of in vitro phosphorylation by CK2 of centrins 1 and 2 with regard to this binding mechanism. We identified the centrin-binding motif at the COOH extremity of transducin β. Human centrin 1 binds to transducin β only in the presence of calcium with a binding constant lower than the binding constant observed for Sfi1 and for XPC. The affinity constants of centrin 1 were 0.10 106 M−1, 249 106 M−1 and 52.5 106 M−1 for Trd, R17-Sfi1 and P17-XPC respectively. CK2 phosphorylates human centrin 1 at residue T138 and human centrin 2 at residues T138 and S158. Consequently CK2 phosphorylation abolished the binding of centrin 1 to transducin β and reduced the binding to Sfi1 and XPC. CK2 phosphorylation of centrin 2 at T138 and S158 abolished the binding to Sfi1 as assessed using a C-HsCen2 T138D-S158D phosphomimetic form of centrin 2.

  19. Effects of siRNA specific to the protein kinase CK2α on apoptosis of laryngeal carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    WANG Jian-ting; GONG Shu-sheng

    2012-01-01

    Background The relationship between apoptosis and tumors is a major focus in cancer research.RNA interference (RNAi) technology has emerged as a very potent tool to generate cellular knockdown phenotypes of a desired gene.The aim of this study was to explore the effect of siRNA specific to the protein casein kinase 2a (CK2α) on apoptosis of laryngeal carcinoma cells and to explore possible mechanisms.Methods An siRNA expression plasmid specific to CK2α,psiRNA-hH1neo-CK2a,and a non-specific siRNA expression plasmid,psiRNA-hH1neo-cont,were constructed and transfected into Hep-2 cells by a lipofectamine method.The mRNA and protein levels of CK2a in transfected cells were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analysis.Apoptosis was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double-staining methods.The morphological changes to Hep-2 cells were observed under transmission electron microscopy (TEM).The levels of Bcl-2 and Bax proteins were measured by Western blotting analysis.Results Levels of CK2a mRNA and protein were significantly decreased in the psiRNA-hHlneo-CK2α group compared to the other groups (P <0.05).The apoptotic rate of the psiRNA-hHlneo-CK2a transfected group was significantly higher compared to that in the untransfected group and the siRNA-hH1neo-cont transfected group (25.66%±0.83%,3.66%±0.43%,and 5.18%±0.22%) (P <0.05).Compared with the untransfected group and the siRNA-hH1neo-cont transfected group,the psiRNA-hH1neo-CK2a transfected group presented with classical ultrastructural features of apoptosis,such as karyopyknosis,chromatic agglutination adjacent to the nuclear membrane,and apoptotic bodies.Compared with the other two groups,the level of Bcl-2 protein in the psiRNA-hH1neo-CK2α transfected group was decreased (0.20±0.09 vs.0.72±0.16,0.56±0.11,P <0.01),while the Bax protein level was increased (0.81±0.17 vs.0.26±0.12,0.33±0

  20. 抑制CK2增加Sorbitol引起的肺癌细胞凋亡

    Institute of Scientific and Technical Information of China (English)

    齐昕; 徐晓光; 蒋颖超

    2014-01-01

    目的:探讨抑制CK2对雷帕霉素引起的肺癌细胞凋亡的影响。方法选用人肺癌A549细胞,MTT方法检测单独利用山梨醇( Sor-bitol)或者联合CK2抑制剂TBB对A549细胞活性的影响,Western印迹检测单独利用 Sorbitol或者联合 CK2抑制剂TBB凋亡相关蛋白 caspase-3和PARP,以及线粒体凋亡相关蛋白细胞色素C表达水平的影响。结果 MTT结果显示,Sorbitol可以显著引起A549细胞活性下降,并呈现时间依赖性和剂量依赖性。 Western印迹结果显示,Sorbitol可以引起凋亡相关蛋白Cleaved PARP、Cleaved caspase-3以及细胞色素C表达水平明显上升。 MTT结果显示,联合应用CK2抑制剂可以明显增加Sorbitol,引起细胞活性降低。 Western印迹显示,与单独给予Sorbitol比较,联合应用CK2抑制剂 TBB,凋亡相关蛋白Cleaved PARP、Cleaved caspase-3进一步增加。结论 CK2抑制剂TBB可提高人肺癌A549细胞对Sorbitol的敏感性。

  1. Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen–Glucose Deprivation/Reperfusion

    Directory of Open Access Journals (Sweden)

    Shuangxi Liu

    2016-10-01

    Full Text Available Annexin-1 (ANXA1 has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1. These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated α-E-catenin and the binding of casein kinase II (CK2 with α-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2-26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target α-E-catenin phosphorylation is involved in this process.

  2. The phosphorylation-dependent regulation of nuclear SREBP1 during mitosis links lipid metabolism and cell growth

    Science.gov (United States)

    Bengoechea-Alonso, Maria Teresa; Ericsson, Johan

    2016-01-01

    ABSTRACT The SREBP transcription factors are major regulators of lipid metabolism. Disturbances in lipid metabolism are at the core of several health issues facing modern society, including cardiovascular disease, obesity and diabetes. In addition, the role of lipid metabolism in cancer cell growth is receiving increased attention. Transcriptionally active SREBP molecules are unstable and rapidly degraded in a phosphorylation-dependent manner by Fbw7, a ubiquitin ligase that targets several cell cycle regulatory proteins for degradation. We have previously demonstrated that active SREBP1 is stabilized during mitosis. We have now delineated the mechanisms involved in the stabilization of SREBP1 in mitotic cells. This process is initiated by the phosphorylation of a specific serine residue in nuclear SREBP1 by the mitotic kinase Cdk1. The phosphorylation of this residue creates a docking site for a separate mitotic kinase, Plk1. Plk1 interacts with nuclear SREBP1 in mitotic cells and phosphorylates a number of residues in the C-terminal domain of the protein, including a threonine residue in close proximity of the Fbw7 docking site in SREBP1. The phosphorylation of these residues by Plk1 blocks the interaction between SREBP1 and Fbw7 and attenuates the Fbw7-dependent degradation of nuclear SREBP1 during cell division. Inactivation of SREBP1 results in a mitotic defect, suggesting that SREBP1 could regulate cell division. We propose that the mitotic phosphorylation and stabilization of nuclear SREBP1 during cell division provides a link between lipid metabolism and cell proliferation. Thus, the current study provides additional support for the emerging hypothesis that SREBP-dependent lipid metabolism may be important for cell growth. PMID:27579997

  3. Protein kinase CK2 inhibition is associated with the destabilization of HIF-1α in human cancer cells

    DEFF Research Database (Denmark)

    Guerra, Barbara; Rasmussen, Tine D. L.; Schnitzler, Alexander

    2015-01-01

    Screening for protein kinase CK2 inhibitors of the structural diversity compound library (DTP NCI/NIH) led to the discovery of 4-[(E)-(fluoren-9-ylidenehydrazinylidene)-methyl]benzoic acid (E9). E9 induces apoptotic cell death in various cancer cell lines and upon hypoxia, the compound suppresses...... CK2-catalyzed HSP90/Cdc37 phosphorylation and induces HIF-1alpha degradation. Furthermore, E9 exerts a strong anti-tumour activity by inducing necrosis in murine xenograft models underlining its potential to be used for cancer treatment in future clinical studies. Crystal structure analysis of human...

  4. Low-density crystal packing of human protein kinase CK2 catalytic subunit in complex with resorufin or other ligands

    DEFF Research Database (Denmark)

    Klopffleisch, Karsten; Issinger, Olaf Georg; Niefind, Karsten

    2012-01-01

    adopts a closed conformation correlating to a canonically established catalytic spine as is typical for eukaryotic protein kinases. In the corresponding crystal packing the hinge/helix αD region is nearly unaffected by crystal contacts, so that largely unbiased conformational adaptions are possible....... This is documented by published human CK2α structures with the same crystal packing but with an open hinge/helix αD region, one of which has been redetermined here with a higher symmetry. An overview of all published human CK2α crystal packings serves as the basis for a discussion of the factors that determine...

  5. The crystal structure of the complex of Zea mays alpha subunit with a fragment of human beta subunit provides the clue to the architecture of protein kinase CK2 holoenzyme

    DEFF Research Database (Denmark)

    Battistutta, R; Sarno, S; De Moliner, E

    2000-01-01

    The crystal structure of a complex between the catalytic alpha subunit of Zea mays CK2 and a 23-mer peptide corresponding the C-terminal sequence 181-203 of the human CK2 regulatory beta subunit has been determined at 3.16-A resolution. The complex, composed of two alpha chains and two peptides......, presents a molecular twofold axis, with each peptide interacting with both alpha chains. In the derived model of the holoenzyme, the regulatory subunits are positioned on the opposite side with respect to the opening of the catalytic sites, that remain accessible to substrates and cosubstrates. The beta...... subunit can influence the catalytic activity both directly and by promoting the formation of the alpha2 dimer, in which each alpha chain interacts with the active site of the other. Furthermore, the two active sites are so close in space that they can simultaneously bind and phosphorylate two...

  6. The functional interplay between protein kinase CK2 and CCA1 transcriptional activity is essential for clock temperature compensation in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Sergi Portolés

    2010-11-01

    Full Text Available Circadian rhythms are daily biological oscillations driven by an endogenous mechanism known as circadian clock. The protein kinase CK2 is one of the few clock components that is evolutionary conserved among different taxonomic groups. CK2 regulates the stability and nuclear localization of essential clock proteins in mammals, fungi, and insects. Two CK2 regulatory subunits, CKB3 and CKB4, have been also linked with the Arabidopsis thaliana circadian system. However, the biological relevance and the precise mechanisms of CK2 function within the plant clockwork are not known. By using ChIP and Double-ChIP experiments together with in vivo luminescence assays at different temperatures, we were able to identify a temperature-dependent function for CK2 modulating circadian period length. Our study uncovers a previously unpredicted mechanism for CK2 antagonizing the key clock regulator CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1. CK2 activity does not alter protein accumulation or subcellular localization but interferes with CCA1 binding affinity to the promoters of the oscillator genes. High temperatures enhance the CCA1 binding activity, which is precisely counterbalanced by the CK2 opposing function. Altering this balance by over-expression, mutation, or pharmacological inhibition affects the temperature compensation profile, providing a mechanism by which plants regulate circadian period at changing temperatures. Therefore, our study establishes a new model demonstrating that two opposing and temperature-dependent activities (CCA1-CK2 are essential for clock temperature compensation in Arabidopsis.

  7. The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation

    DEFF Research Database (Denmark)

    Guerra, B; Götz, C; Wagner, P

    1997-01-01

    The oncogene product MDM2 can be phosphorylated by protein kinase CK2 in vitro 0.5-1 mol of phosphate were incorporated per mol MDM2 protein. The catalytic subunit of protein kinase CK2 (alpha-subunit) catalyzed the incorporation of twice as much phosphate into the MDM2 protein as it was obtained...... with the holoenzyme. Polylysine stimulated MDM2 phosphorylation by CK2 holoenzyme threefold in contrast to the alpha-subunit-catalyzed MDM2 phosphorylation which was reduced by about 66% when polylysine was added. Full length p53, but also a peptide representing a C-terminal fragment of the tumor suppressor gene......(264-393) was on the average close to twofold and inhibition in the case of the alpha-subunit-catalyzed MDM2 phosphorylation was about 40%. Phosphorylation of MDM2 by CK2 holoenzyme in the presence of the p21(WAF1/CIP1), known to be a potent inhibitor of cyclin-dependent protein kinases, also led to a significant reduction...

  8. Protein kinase CK2 mutants defective in substrate recognition. Purification and kinetic analysis

    DEFF Research Database (Denmark)

    Sarno, S; Vaglio, P; Meggio, F

    1996-01-01

    Five mutants of protein kinase CK2 alpha subunit in which altogether 14 basic residues were singly to quadruply replaced by alanines (K74A,K75A,K76A,K77A; K79A, R80A,K83A; R191A,R195A,K198A; R228A; and R278A, K279A,R280A) have been purified to near homogeneity either as such or after addition...... of the recombinant beta subunit. By this latter procedure five mutated tetrameric holoenzymes were obtained as judged from their subunit composition, sedimentation coefficient on sucrose gradient ultracentrifugation, and increased activity toward a specific peptide substrate as compared with the isolated alpha...... subunits. The kinetic constants and the phosphorylation efficiencies (V(max)/Km) of all the mutants with the parent peptide RRRADDSDDDDD and a series of derivatives, in which individual aspartic acids were replaced by alanines, have been determined. Three mutants, namely K74A,K75A,K76A,K77A; K79A, R80A,K83...

  9. GSK-3 and CK2 Kinases Converge on Timeless to Regulate the Master Clock

    Directory of Open Access Journals (Sweden)

    Deniz Top

    2016-07-01

    Full Text Available The molecular clock relies on a delayed negative feedback loop of transcriptional regulation to generate oscillating gene expression. Although the principal components of the clock are present in all circadian neurons, different neuronal clusters have varying effects on rhythmic behavior, suggesting that the clocks they house are differently regulated. Combining biochemical and genetic techniques in Drosophila, we identify a phosphorylation program native to the master pacemaker neurons that regulates the timing of nuclear accumulation of the Period/Timeless repressor complex. GSK-3/SGG binds and phosphorylates Period-bound Timeless, triggering a CK2-mediated phosphorylation cascade. Mutations that block the hierarchical phosphorylation of Timeless in vitro also delay nuclear accumulation in both tissue culture and in vivo and predictably change rhythmic behavior. This two-kinase phosphorylation cascade is anatomically restricted to the eight master pacemaker neurons, distinguishing the regulatory mechanism of the molecular clock within these neurons from the other clocks that cooperate to govern behavioral rhythmicity.

  10. HDAC2 phosphorylation-dependent KIf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs

    Institute of Scientific and Technical Information of China (English)

    Bin Zheng; Mei Han; Ya-nan Shu; Yimg-jie Li; Sui-bing Miao; Xin-hua Zhang; Hui-jing Shi; Tian zhang; Jin-kun Wen

    2011-01-01

    Abnormal proliferation of vascular smooth muscle cells (VSMCs) occurs in hypertension,atherosclerosis and restenosis after angioplasty,leading to pathophysiological vascular remodeling.As an important growth arrest gene,p21 plays critical roles in vascular remodeling.Regulation of p21 expression by retinoic acid receptor (RAR) and its ligand has important implications for control of pathological vascular remodeling.Nevertheless,the mechanism of RAR-mediated p21 expression in VSMCs remains poorly understood.Here,we show that,under basal conditions,RARa forms a complex with histone deacetylase 2 (HDAC2) and Krüppel-like factor 5 (KIf5) at the p21 promoter to inhibit its expression.Upon RARα agonist stimulation,HDAC2 is phosphorylated by CK2α.Phosphorylation of HDAC2,on the one hand,promotes its dissociation from RARα,thus allowing the liganded-RARα to interact with co-activators; on the other hand,it increases its interaction with KIf5,thus leading to deacetylation of Klf5.Deacetylation of KIf5 facilitates its dissociation from thep21 promoter,relieving its repressive effect on thep21 promoter.Interference with HDAC2 phosphorylation by either CK2α knockdown or the use of phosphorylation-deficient mutant of HDAC2 prevents the dissociation of KIf5 from the p21 promoter and impairs RAR agonist-induced p21 activation.Our results reveal a novel mechanism involving a phosphorylation-deacetylation cascade that functions to remove the basal repression complex from the p21 promoter upon RAR agonlst treatment,allowing for optimum agonistinduced p21 expression.

  11. Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues.

    Science.gov (United States)

    Qaiser, Fatima; Trembley, Janeen H; Sadiq, Sarah; Muhammad, Iqbal; Younis, Rubina; Hashmi, Shoaib Naiyar; Murtaza, Badar; Rector, Thomas S; Naveed, Abdul Khaliq; Ahmed, Khalil

    2016-09-01

    Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease.

  12. Casein kinase Ⅱ interacts with prion protein in vitro and forms complex with na-tive prion protein in vivo

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The most essential and crucial step during the pathogenesis of transmissible spongiform encephalopathy is the conformational change of cellular prion protein to pathologic isoform. Casein kinase Ⅱ (CK2) is a ubiquitously expressed and evolutiouarily conserved pleiotropic protein kinase that is essential for viability. To explore the possible molecular interaction between CK2 and prion protein (PrP), the full-length sequences of human CK2α and CK2β complementary DNA were amplified with reverse transcription-polymerase chain reaction using the total messenger RNA from cell line SH-SY5Y as the template; then, the fusion proteins histidine-CK2α and glutathione S-transferase-histidine-CK2β were expressed in Escherichia coll. The interaction between CK2 and PrP was evaluated with co-immunoprecipi-tation and pull-down assays. The results demonstrated that recombinant PrP bound specifically with CK2α, but not with CK2β. The native CK2 and PrP in hamster brains interacted with each other, forming protein complexes. Three different glycosylated forms of PrP (diglycosylated, monoglycosylated and unglycosylated PrP) from normal brains interacted with the CK2α subunit, though the unglycosylated PrP seemed to have a stronger binding ability with CK2α subunit. The domain responsible for interacting with CK2α was located at the C-terminal segment of PrP (residues 91-231). This study proposed reliable experimental data for the molecular interaction between PrP and CK2α (both in recombinant and native categories), scientific clues for further assessing the potential biological significance of the PrP-CK2 interaction, and the possible role of CK2 in the pathogenesis of prion diseases.

  13. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

    Science.gov (United States)

    Pizzi, Marco; Piazza, Francesco; Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Rugge, Massimo; Semenzato, Gianpietro; Pileri, Stefano A

    2015-03-30

    Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.

  14. Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2.

    Science.gov (United States)

    Vahter, Jürgen; Viht, Kaido; Uri, Asko; Enkvist, Erki

    2017-02-28

    Structurally diverse inhibitors of the protein kinase CK2 are required for regulation of this ubiquitous protein to establish biological roles of the enzyme which catalyzes the phosphorylation of a vast number of substrate proteins. In this article we disclose a series of new bisubstrate inhibitors of CK2 that are structurally represented by the oligo(l-Asp) peptide conjugates of benzo[c][2,6]naphthyridine-8-carboxylic acid. This fragment originated from CX-4945, the first in class inhibitor taken to clinical trials. The most potent conjugates possessed two-digit picomolar affinity and clear selectivity for CK2α in a panel of 140 protein kinases. Labeling of the inhibitors with a fluorescent dye yielded probes for a fluorescence anisotropy-based binding/displacement assay which can be used for analysis of CK2 and precise determination of affinity of the highly potent (tight-binding) CK2-targeting inhibitors.

  15. Prolonged insulin stimulation down-regulates GLUT4 through oxidative stress-mediated retromer inhibition by a protein kinase CK2-dependent mechanism in 3T3-L1 adipocytes.

    Science.gov (United States)

    Ma, Jinhui; Nakagawa, Yuko; Kojima, Itaru; Shibata, Hiroshi

    2014-01-03

    Although insulin acutely stimulates glucose uptake by promotion of GLUT4 translocation from intracellular compartments to the plasma membrane in adipocytes and muscles, long term insulin stimulation causes GLUT4 depletion that is particularly prominent in the insulin-responsive GLUT4 storage compartment. This effect is caused mainly by accelerated lysosomal degradation of GLUT4, although the mechanism is not fully defined. Here we show that insulin acutely induced dissociation of retromer components from the low density microsomal membranes of 3T3-L1 adipocytes that was accompanied by disruption of the interaction of Vps35 with sortilin. This insulin effect was dependent on the activity of protein kinase CK2 but not phosphatidylinositol 3-kinase or extracellular signal-regulated kinase 1/2. Knockdown of Vps26 decreased GLUT4 to a level comparable with that with insulin stimulation for 4 h. Vps35 with a mutation in the CK2 phosphorylation motif (Vps35-S7A) was resistant to insulin-induced dissociation from the low density microsomal membrane, and its overexpression attenuated GLUT4 down-regulation with insulin. Furthermore, insulin-generated hydrogen peroxide was an upstream mediator of the insulin action on retromer and GLUT4. These results suggested that insulin-generated oxidative stress switches the GLUT4 sorting direction to lysosomes through inhibition of the retromer function in a CK2-dependent manner.

  16. Oncogenic potential of CK2α and its regulatory role in EGF-induced HDAC2 expression in human liver cancer.

    Science.gov (United States)

    Kim, Hyung S; Chang, Young G; Bae, Hyun J; Eun, Jung W; Shen, Qingyu; Park, Se J; Shin, Woo C; Lee, Eun K; Park, Soha; Ahn, Young M; Park, Won S; Lee, Jung Y; Nam, Suk W

    2014-02-01

    Histone deacetylase 2 (HDAC2) is aberrantly regulated and plays a pivotal role in the development of hepatocellular carcinoma (HCC) through regulation of cell-cycle components at the transcriptional level, but the underlying mechanism leading to oncogenic HDAC2 remains unknown. In this study, we show that expression of CK2α (casein kinase II α subunit) was up-regulated in a large cohort of human HCC patients, and that high expression of CK2α was significantly associated with poor prognosis of HCC patients in terms of five-year overall survival. It was also found that CK2α over-expression positively correlated with HDAC2 over-expression in a subset of HCCs. We observed that treatment with epidermal growth factor (EGF) elicited an increase in CK2α expression and Akt phosphorylation, causing induction of HDAC2 expression in liver cancer cells. It was also observed that ectopic expression of dominant-negative CK2α blocked EGF-induced HDAC2 expression, and that ectopic CK2α expression attenuated the suppressive effect of Akt knockdown on HDAC2 expression in liver cancer cells. Targeted disruption of CK2α influenced the cell cycle, causing a significant increase in the number of liver cancer cells remaining in G₂/M phase, and suppressed growth via repression of Cdc25c and cyclin B in liver cancer cells. Taken together, our findings suggest the oncogenic potential of CK2α in liver tumorigenesis. Furthermore, a regulatory mechanism for HDAC2 expression is proposed whereby EGF induces transcriptional activation of HDAC2 by CK2α/Akt activation in liver cancer cells. Therefore, this makes CK2α a promising target in cancer therapy.

  17. Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2.

    Science.gov (United States)

    Guillon, Jean; Le Borgne, Marc; Rimbault, Charlotte; Moreau, Stéphane; Savrimoutou, Solène; Pinaud, Noël; Baratin, Sophie; Marchivie, Mathieu; Roche, Séverine; Bollacke, Andre; Pecci, Adali; Alvarez, Lautaro; Desplat, Vanessa; Jose, Joachim

    2013-07-01

    Herein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxaline-carboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC50 in the micro- and sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl)amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.

  18. Cystic fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual allosteric control over the master kinase CK2

    Science.gov (United States)

    Pagano, Mario A.; Marin, Oriano; Cozza, Giorgio; Sarno, Stefania; Meggio, Flavio; Treharne, Kate J.; Mehta, Anil; Pinna, Lorenzo A.

    2011-01-01

    Cystic fibrosis mostly follows a single Phe508 deletion in CFTR (cystic fibrosis transmembrane regulator) (CFTRΔF508), thereby causing premature fragmentation of the nascent protein with concomitant alterations of diverse cellular functions. We show that CK2, the most pleiotropic protein kinase, undergoes allosteric control of its different cellular forms in the presence of short CFTR peptides encompassing the Phe508 deletion: these CFTRΔF508 peptides drastically inhibit the isolated catalytic subunit (α) of the kinase and yet up-regulate the holoenzyme, composed of two catalytic and two non-catalytic (β) subunits. Remarkable agreement between in silico docking and our biochemical data point to different sites for the CFTRΔF508 peptide binding on isolated CK2α and on CK2β assembled into the holoenzyme, suggesting that CK2 targeting may be perturbed in cells expressing CFTRΔF508; this could shed light on some pleiotropic aspects of cystic fibrosis disease. PMID:19925455

  19. A Proteomic Approach to Identify Phosphorylation-Dependent Targets of BRCT Domains

    Science.gov (United States)

    2008-03-01

    targets To develop the BiFC technology for screening for BRCT- BRCA1 interacting proteins in mammalian cells, we constructed expression...domain To screen for BRCA1-BRCT interacting proteins using BiFC, we undertook several approaches. In the last report, we described a reduction approach...candidate BRCT- interacting proteins . Indeed, we obtained many cell clones that exhibited either strong or weak fluorescence, indicating that these

  20. Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer

    Science.gov (United States)

    Nelson, Nadine; Szekeres, Karoly; Iclozan, Cristina; Rivera, Ivannie Ortiz; McGill, Andrew; Johnson, Gbemisola; Nwogu, Onyekachi

    2017-01-01

    Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros

  1. Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining

    Directory of Open Access Journals (Sweden)

    Samer Haidar

    2017-01-01

    Full Text Available Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada. This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione, a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 µM.

  2. Tenfibgen ligand nanoencapsulation delivers bi-functional anti-CK2 RNAi oligomer to key sites for prostate cancer targeting using human xenograft tumors in mice.

    Directory of Open Access Journals (Sweden)

    Janeen H Trembley

    Full Text Available Protected and specific delivery of nucleic acids to malignant cells remains a highly desirable approach for cancer therapy. Here we present data on the physical and chemical characteristics, mechanism of action, and pilot therapeutic efficacy of a tenfibgen (TBG-shell nanocapsule technology for tumor-directed delivery of single stranded DNA/RNA chimeric oligomers targeting CK2αα' to xenograft tumors in mice. The sub-50 nm size TBG nanocapsule (s50-TBG is a slightly negatively charged, uniform particle of 15 - 20 nm size which confers protection to the nucleic acid cargo. The DNA/RNA chimeric oligomer (RNAi-CK2 functions to decrease CK2αα' expression levels via both siRNA and antisense mechanisms. Systemic delivery of s50-TBG-RNAi-CK2 specifically targets malignant cells, including tumor cells in bone, and at low doses reduces size and CK2-related signals in orthotopic primary and metastatic xenograft prostate cancer tumors. In conclusion, the s50-TBG nanoencapsulation technology together with the chimeric oligomer targeting CK2αα' offer significant promise for systemic treatment of prostate malignancy.

  3. INHIBITORY EFFECT AND KINETIC ANALYSIS OF SODIUM QUERCETIN-7,4′-DISULPHATE ON RECOMBINANT HUMAN PROTEIN KINASE CK2 HOLOENZYME%槲皮素-7,4′-二硫酸酯钠对重组人CK2全酶的抑制作用及动力学分析

    Institute of Scientific and Technical Information of China (English)

    刘新光; 梁念慈; 刘文; 佘戟; 莫丽儿

    2002-01-01

    目的观察槲皮素-7,4′-二硫酸酯钠(sodium quercetin-7,4′-disulphate,SQDS)对重组人CK2全酶的直接作用及酶动力学机制.方法通过测定转移到CK2底物上的[γ-32P]ATP的32P放射活度检测不同条件下的重组人CK2全酶的活性.结果重组人CK2是一种Ca2+,cAMP和cGMP等第二信使非依赖性蛋白激酶,与天然CK2的性质一致.SQDS对重组人CK2全酶有很强的抑制作用,IC50为4.4 μmol·L-1,抑制作用大于已知CK2抑制剂DRB和A3.CK2的动力学研究表明:SQDS与ATP和酪蛋白分别呈竞争性和非竞争性抑制作用.结论 SQDS是有效的CK2抑制剂,对于开发更有效的CK2抑制剂及将SQDS用于临床提供了一定的实验依据.

  4. Systematic diversification of benzylidene heterocycles yields novel inhibitor scaffolds selective for Dyrk1A, Clk1 and CK2.

    Science.gov (United States)

    Mariano, Marica; Hartmann, Rolf W; Engel, Matthias

    2016-04-13

    The dual-specificity tyrosine-regulated kinase 1A (Dyrk1A) has gathered much interest as a pharmacological target in Alzheimer's disease (AD), but it plays a role in malignant brain tumors as well. As both diseases are multi-factorial, further protein kinases, such as Clk1 and CK2, were proposed to contribute to the pathogenesis. We designed a new class of α-benzylidene-γ-butyrolactone inhibitors that showed low micromolar potencies against Dyrk1A and/or Clk1 and a good selectivity profile among the most frequently reported off-target kinases. A systematic replacement of the heterocyclic moiety gave access to further inhibitor classes with interesting selectivity profiles, demonstrating that the benzylidene heterocycles provide a versatile tool box for developing inhibitors of the CMGC kinase family members Dyr1A/1B, Clk1/4 and CK2. Efficacy for the inhibition of Dyrk1A-mediated tau phosphorylation was demonstrated in a cell-based assay. Multi-targeted but not non-specific kinase inhibitors were also obtained, that co-inhibited the lipid kinases PI3Kα/γ. These compounds were shown to inhibit the proliferation of U87MG cells in the low micromolar range. Based on the molecular properties, the inhibitors described here hold promise for CNS activity.

  5. A Proteomic Approach to Identify Phosphorylation-Dependent Targets of BRCT Domains

    Science.gov (United States)

    2009-03-01

    HRP or anti-V5- HRP antibodies. (c) TPP1 promotes TIN2–TRF2 interaction in insect cells. Sf9 cells were coinfected with His-TRF2 and His-TIN2...Expression Systems. Sf9 cells (5 106) were coinfected with His-TRF2, His-TIN2, and increasing amounts of His-TPP1 baculoviruses. At 3 days after

  6. Attenuation of Phosphorylation-dependent Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Disease-causing Mutations at the Transmission Interface*

    Science.gov (United States)

    Chin, Stephanie; Yang, Donghe; Miles, Andrew J.; Eckford, Paul D. W.; Molinski, Steven; Wallace, B. A.; Bear, Christine E.

    2017-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) is a multidomain membrane protein that functions as a phosphorylation-regulated anion channel. The interface between its two cytosolic nucleotide binding domains and coupling helices conferred by intracellular loops extending from the channel pore domains has been referred to as a transmission interface and is thought to be critical for the regulated channel activity of CFTR. Phosphorylation of the regulatory domain of CFTR by protein kinase A (PKA) is required for its channel activity. However, it was unclear if phosphorylation modifies the transmission interface. Here, we studied purified full-length CFTR protein using spectroscopic techniques to determine the consequences of PKA-mediated phosphorylation. Synchrotron radiation circular dichroism spectroscopy confirmed that purified full-length wild-type CFTR is folded and structurally responsive to phosphorylation. Intrinsic tryptophan fluorescence studies of CFTR showed that phosphorylation reduced iodide-mediated quenching, consistent with an effect of phosphorylation in burying tryptophans at the transmission interface. Importantly, the rate of phosphorylation-dependent channel activation was compromised by the introduction of disease-causing mutations in either of the two coupling helices predicted to interact with nucleotide binding domain 1 at the interface. Together, these results suggest that phosphorylation modifies the interface between the catalytic and pore domains of CFTR and that this modification facilitates CFTR channel activation. PMID:28003367

  7. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7).

    Science.gov (United States)

    Sundqvist, Anders; Bengoechea-Alonso, Maria T; Ye, Xin; Lukiyanchuk, Vasyl; Jin, Jianping; Harper, J Wade; Ericsson, Johan

    2005-06-01

    The sterol regulatory element binding protein (SREBP) family of transcription factors controls cholesterol and lipid metabolism. The nuclear forms of these proteins are rapidly degraded by the ubiquitin-proteasome pathway, but the signals and factors required for this are unknown. Here, we identify a phosphodegron in SREBP1a that serves as a recognition motif for the SCF(Fbw7) ubiquitin ligase. Fbw7 interacts with nuclear SREBP1a and enhances its ubiquitination and degradation in a manner dependent on the phosphorylation of T426 and S430 by GSK-3. Fbw7 also degrades nuclear SREBP1c and SREBP2, and inactivation of endogenous Fbw7 results in stabilization of nuclear SREBP1 and -2, enhanced expression of SREBP target genes, enhanced synthesis of cholesterol and fatty acids, and enhanced receptor-mediated uptake of LDL. Thus, our results suggest that Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors.

  8. Attenuation of Phosphorylation-dependent Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Disease-causing Mutations at the Transmission Interface.

    Science.gov (United States)

    Chin, Stephanie; Yang, Donghe; Miles, Andrew J; Eckford, Paul D W; Molinski, Steven; Wallace, B A; Bear, Christine E

    2017-02-03

    Cystic fibrosis transmembrane conductance regulator (CFTR) is a multidomain membrane protein that functions as a phosphorylation-regulated anion channel. The interface between its two cytosolic nucleotide binding domains and coupling helices conferred by intracellular loops extending from the channel pore domains has been referred to as a transmission interface and is thought to be critical for the regulated channel activity of CFTR. Phosphorylation of the regulatory domain of CFTR by protein kinase A (PKA) is required for its channel activity. However, it was unclear if phosphorylation modifies the transmission interface. Here, we studied purified full-length CFTR protein using spectroscopic techniques to determine the consequences of PKA-mediated phosphorylation. Synchrotron radiation circular dichroism spectroscopy confirmed that purified full-length wild-type CFTR is folded and structurally responsive to phosphorylation. Intrinsic tryptophan fluorescence studies of CFTR showed that phosphorylation reduced iodide-mediated quenching, consistent with an effect of phosphorylation in burying tryptophans at the transmission interface. Importantly, the rate of phosphorylation-dependent channel activation was compromised by the introduction of disease-causing mutations in either of the two coupling helices predicted to interact with nucleotide binding domain 1 at the interface. Together, these results suggest that phosphorylation modifies the interface between the catalytic and pore domains of CFTR and that this modification facilitates CFTR channel activation.

  9. Analyzing phosphorylation-dependent regulation of subcellular localization and transcriptional activity of transcriptional coactivator NT-PGC-1α.

    Science.gov (United States)

    Chang, Ji Suk; Gettys, Thomas W

    2013-01-01

    Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is a nuclear transcriptional coactivator that regulates the genes involved in energy metabolism. Recent evidence has been provided that alternative splicing of PPARGC1A gene produces a functional but predominantly cytosolic isoform of PGC-1α (NT-PGC-1α). We have demonstrated that transcriptional coactivation capacity of NT-PGC-1α is directly correlated with its nuclear localization in a PKA phosphorylation-dependent manner. In this chapter, we describe quantitative imaging analysis methods that are developed to measure the relative fluorescence intensity of the protein of interest in the nucleus and cytoplasm in a single cell and the frequency distribution of nuclear/cytoplasmic intensity ratios in the population of cells, respectively. This chapter also describes transient cotransfection and dual-luciferase reporter gene assay that examine the ability of coactivators to activate the transcriptional activity of transcription factors.

  10. Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer

    Science.gov (United States)

    Wang, Yi-Ting; Pan, Szu-Hua; Tsai, Chia-Feng; Kuo, Ting-Chun; Hsu, Yuan-Ling; Yen, Hsin-Yung; Choong, Wai-Kok; Wu, Hsin-Yi; Liao, Yen-Chen; Hong, Tse-Ming; Sung, Ting-Yi; Yang, Pan-Chyr; Chen, Yu-Ju

    2017-01-01

    Although EGFR tyrosine kinase inhibitors (TKIs) have demonstrated good efficacy in non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, most patients develop intrinsic and acquired resistance. We quantitatively profiled the phosphoproteome and proteome of drug-sensitive and drug-resistant NSCLC cells under gefitinib treatment. The construction of a dose-dependent responsive kinase-substrate network of 1548 phosphoproteins and 3834 proteins revealed CK2-centric modules as the dominant core network for the potential gefitinib resistance-associated proteins. CK2 knockdown decreased cell survival in gefitinib-resistant NSCLCs. Using motif analysis to identify the CK2 core sub-network, we verified that elevated phosphorylation level of a CK2 substrate, HMGA1 was a critical node contributing to EGFR-TKI resistance in NSCLC cell. Both HMGA1 knockdown or mutation of the CK2 phosphorylation site, S102, of HMGA1 reinforced the efficacy of gefitinib in resistant NSCLC cells through reactivation of the downstream signaling of EGFR. Our results delineate the TKI resistance-associated kinase-substrate network, suggesting a potential therapeutic strategy for overcoming TKI-induced resistance in NSCLC. PMID:28290473

  11. Redox modulation of tyrosine phosphorylation-dependent neutrophil adherence to endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Thibodeau, Paul A. [INSERM U479 Phagocytes et Reponses Inflammatoires, Faculte de Medecine, Universite Paris VII-Denis Diderot, 16, rue Henri Huchard, 75870 Paris, Cedex 18 (France)]. E-mail: pathibodeau@hotmail.com; Gozin, Alexia [INSERM U479 Phagocytes et Reponses Inflammatoires, Faculte de Medecine, Universite Paris VII-Denis Diderot, 16, rue Henri Huchard, 75870 Paris, Cedex 18 (France); Gougerot-Pocidalo, Marie-Anne [INSERM U479 Phagocytes et Reponses Inflammatoires, Faculte de Medecine, Universite Paris VII-Denis Diderot, 16, rue Henri Huchard, 75870 Paris, Cedex 18 (France); Pasquier, Catherine [INSERM U479 Phagocytes et Reponses Inflammatoires, Faculte de Medecine, Universite Paris VII-Denis Diderot, 16, rue Henri Huchard, 75870 Paris, Cedex 18 (France)

    2005-02-01

    Reactive oxygen species (ROS) are now well known to be involved in an increased interaction between neutrophils and endothelial cells. Previously, we have shown that the increased adhesion of neutrophils to ROS-stimulated endothelial cells involves an increase in tyrosine phosphorylation of the focal adhesion kinase, p125{sup FAK}, and several cytoskeleton proteins. This review article focuses on the involvement of adhesion molecules in the increased adhesion of neutrophils to ROS-stimulated endothelial cells, on the oxygen species responsible for this adhesion, and on the intracellular signaling pathway leading to the modification of the cytoskeleton by ROS. The evidence from our laboratory and others describing these events is summarized. Finally, the future perspectives that need to be explored in order to inhibit or reduce the ROS-mediated adhesion of neutrophils to endothelial cells are addressed.

  12. Inhibitory effect and its kinetic analysis of tyrphostin AG1478 on recombinant human protein kinase CK2 holoenzyme%Tyrphostin AG1478对重组人蛋白激酶CK2全酶的抑制作用及其动力学分析

    Institute of Scientific and Technical Information of China (English)

    刘新光; 梁念慈

    2002-01-01

    目的:观察Tyrphostin AG1478[4-(3-氯苯胺基)-6,7-二甲氧喹唑啉]对重组人蛋白激酶CK2全酶的直接作用及其酶动力学机制.方法:在体外等摩尔数混合重组蛋白激酶CK2 α和β亚基构成CK2全酶,在不同条件下测定CK2的活性.CK2活性通过测定转移到CK2底物上的[γ-32P]ATP或[γ-32P]GTP的32P放射活度来检测.结果:重组人CK2是一种Ca2+、[KG*2]cAMP和cGMP等第二信使非依赖性蛋白激酶,与天然CK2的性质一致.AG1478对重组人CK2全酶具有很强的抑制作用,IC50为25.9 μmol/L,抑制作用接近于已知的CK2抑制剂N-(2-氨乙基)-5-氯萘-1-硫胺(A3),稍小于5,6-二氯-1-β-呋喃糖苯并咪唑(DRB).AG1478对重组人CK2的动力学研究表明:它与GTP和酪蛋白均呈竞争性抑制作用,是一种双底物抑制剂.结论:AG1478不仅是高效特异的表皮生长因子受体酪氨酸蛋白激酶的抑制剂,而且也是一种新型有效的蛋白激酶CK2抑制剂.重组人蛋白激酶CK2可作为一种较为简便的筛选和开发有效CK2抑制剂的分子靶点.%AIM: To study the direct effect of tyrphostin AG1478[4-( 3-chloroanilino )-6, 7-dimethoxyquinazoline ] on re-combinant human protein kinase CK2 holoenzyme and itskinetics. METHODS: Recombinant human proteinkinase CK2 α and β subunits were mixed at equal molar ratio and CK2 holoenzyme were reconstituted. The CK2activity was assayed by detecting incorporation of [γ-32P]ATP or [γ-32P]GTP into substrates in various conditions. RESULTS: These results demonstrated that the recombinant human CK2 was a second messengers (Ca2+ , cAMP, and cGMP)-independent protein kinase,the characterization and function of the reconstituted holoenzyme were consistent with those of native CK2. AG1478 strongly inhibited the holoenzyme activity of recombinant human protein kinase CK2 with IC50 of 25.9μmol/L, the inhibition is very close to that of N-(2-aminoethyl )-5-chloronaphthalene-l-sulfonamide ( A3 ),but less potent than that of 5

  13. The regulatory beta-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis

    DEFF Research Database (Denmark)

    Yde, C W; Olsen, B B; Meek, D

    2008-01-01

    Cell-cycle transition from the G(2) phase into mitosis is regulated by the cyclin-dependent protein kinase 1 (CDK1) in complex with cyclin B. CDK1 activity is controlled by both inhibitory phosphorylation, catalysed by the Myt1 and Wee1 kinases, and activating dephosphorylation, mediated by the CDC...... interference results in delayed cell-cycle progression at the onset of mitosis. Knockdown of CK2beta causes stabilization of Wee1 and increased phosphorylation of CDK1 at the inhibitory Tyr15. PLK1-Wee1 association is an essential event in the degradation of Wee1 in unperturbed cell cycle. We have found...... regulatory subunit, identifying it as a new component of signaling pathways that regulate cell-cycle progression at the entry of mitosis.Oncogene advance online publication, 12 May 2008; doi:10.1038/onc.2008.146....

  14. A specific inhibitor of protein kinase CK2 delays gamma-H2Ax foci removal and reduces clonogenic survival of irradiated mammalian cells

    Directory of Open Access Journals (Sweden)

    Huber Peter E

    2011-02-01

    Full Text Available Abstract Background The protein kinase CK2 sustains multiple pro-survival functions in cellular DNA damage response and its level is tightly regulated in normal cells but elevated in cancers. Because CK2 is thus considered as potential therapeutic target, DNA double-strand break (DSB formation and rejoining, apoptosis induction and clonogenic survival was assessed in irradiated mammalian cells upon chemical inhibition of CK2. Methods MRC5 human fibroblasts and WIDR human colon carcinoma cells were incubated with highly specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB, or mock-treated, 2 hours prior to irradiation. DSB was measured by pulsed-field electrophoresis (PFGE as well as gamma-H2AX foci formation and removal. Apoptosis induction was tested by DAPI staining and sub-G1 flow cytometry, survival was quantified by clonogenic assay. Results TBB treatment did not affect initial DNA fragmention (PFGE; up to 80 Gy or foci formation (1 Gy. While DNA fragment rejoining (PFGE was not inhibited by the drug, TBB clearly delayed gamma-H2AX foci disappearence during postirradiation incubation. No apoptosis induction could be detected for up to 38 hours for both cell lines and exposure conditions (monotherapies or combination, but TBB treatment at this moderately toxic concentration of 20 μM (about 40% survival enhanced radiation-induced cell killing in the clonogenic assay. Conclusions The data imply a role of CK2 in gamma-H2AX dephosporylation, most likely through its known ability to stimulate PP2A phosphatase, rather than DSB rejoining. The slight but definite clonogenic radiosensitization by TBB does apparently not result from interference with an apoptosis suppression function of CK2 in these cells but could reflect inhibitor-induced uncoupling of DNA damage response decay from break ligation.

  15. Isolation and characterization of a monoclonal anti-protein kinase CK2 beta-subunit antibody of the IgG class for the direct detection of CK2 beta-subunit in tissue cultures of various mammalian species and human tumors

    DEFF Research Database (Denmark)

    Nastainczyk, W; Schmidt-Spaniol, I; Boldyreff, B;

    1995-01-01

    -subunit or in the CK2 holoenzyme (alpha 2 beta 2). Here, concentrations of the first antibody of 1 ng/ml still allowed the detection of the subunit. Immunoblotting of crude cellular extracts from various tissue cultures (man, mouse, and hamster), from human tumors, and the nonneoplastic tissue allowed the detection...... of the CK2 beta-subunit. The detected epitope of this antibody was, as determined by the epitope analysis technique, 123GLSDI127....

  16. Ck2-Dependent Phosphorylation Is Required to Maintain Pax7 Protein Levels in Proliferating Muscle Progenitors.

    Directory of Open Access Journals (Sweden)

    Natalia González

    Full Text Available Skeletal muscle regeneration and long term maintenance is directly link to the balance between self-renewal and differentiation of resident adult stem cells known as satellite cells. In turn, satellite cell fate is influenced by a functional interaction between the transcription factor Pax7 and members of the MyoD family of muscle regulatory factors. Thus, changes in the Pax7-to-MyoD protein ratio may act as a molecular rheostat fine-tuning acquisition of lineage identity while preventing precocious terminal differentiation. Pax7 is expressed in quiescent and proliferating satellite cells, while its levels decrease sharply in differentiating progenitors Pax7 is maintained in cells (reacquiring quiescence. While the mechanisms regulating Pax7 levels based on differentiation status are not well understood, we have recently described that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4, thus promoting proteasome-dependent Pax7 degradation in differentiating satellite cells. Here we show that Pax7 levels are maintained in proliferating muscle progenitors by a mechanism involving casein kinase 2-dependent Pax7 phosphorylation at S201. Point mutations preventing S201 phosphorylation or casein kinase 2 inhibition result in decreased Pax7 protein in proliferating muscle progenitors. Accordingly, this correlates directly with increased Pax7 ubiquitination. Finally, Pax7 down regulation induced by casein kinase 2 inhibition results in precocious myogenic induction, indicating early commitment to terminal differentiation. These observations highlight the critical role of post translational regulation of Pax7 as a molecular switch controlling muscle progenitor fate.

  17. Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels.

    Science.gov (United States)

    Vacher, Helene; Trimmer, James S

    2011-11-01

    Voltage-gated ion channels are a diverse family of signaling proteins that mediate rapid electrical signaling events. Among these, voltage-gated potassium or Kv channels are the most diverse partly due to the large number of principal (or α) subunits and auxiliary subunits that can assemble in different combinations to generate Kv channel complexes with distinct structures and functions. The diversity of Kv channels underlies much of the variability in the active properties between different mammalian central neurons and the dynamic changes that lead to experience-dependent plasticity in intrinsic excitability. Recent studies have revealed that Kv channel α subunits and auxiliary subunits are extensively phosphorylated, contributing to additional structural and functional diversity. Here, we highlight recent studies that show that auxiliary subunits exert some of their profound effects on dendritic Kv4 and axonal Kv1 channels through phosphorylation-dependent mechanisms, either due to phosphorylation on the auxiliary subunit itself or by influencing the extent and/or impact of α subunit phosphorylation. The complex effects of auxiliary subunits and phosphorylation provide a potent mechanism to generate additional diversity in the structure and function of Kv4 and Kv1 channels, as well as allowing for dynamic reversible regulation of these important ion channels.

  18. Determination of mRNA, and protein levels of p53, MDM2 and protein kinase CK2 subunits in F9 cells after treatment with the apoptosis-inducing drugs cisplatin and carboplatin

    DEFF Research Database (Denmark)

    Siemer, S; Ornskov, D; Guerra, B

    1999-01-01

    Protein kinase CK2 is a pleiotropic serine/threonine kinase which has been shown to phosphorylate numerous substrates. Evidence is accumulating that CK2 may exist complexed to a variety of cellular proteins, e.g. p53, MDM2, and A-Raf. Here, we explored the effects of the chemotherapeutic drugs...... cisplatin and carboplatin on the mRNA and protein levels of p53, MDM2 and CK2 in a murine teratocarcinoma cell line F9. Northern and Western blot analyses were performed and the CK2 activity was determined. The degree of apoptosis after drug treatment was assessed using the TUNEL test. Six hours after...

  19. CK2 abrogates the inhibitory effects of PRH/HHEX on prostate cancer cell migration and invasion and acts through PRH to control cell proliferation

    Science.gov (United States)

    Siddiqui, Y H; Kershaw, R M; Humphreys, E H; Assis Junior, E M; Chaudhri, S; Jayaraman, P-S; Gaston, K

    2017-01-01

    PRH/HHEX (proline-rich homeodomain protein/haematopoietically expressed homeobox protein) is a transcription factor that controls cell proliferation, cell differentiation and cell migration. Our previous work has shown that in haematopoietic cells, Protein Kinase CK2-dependent phosphorylation of PRH results in the inhibition of PRH DNA-binding activity, increased cleavage of PRH by the proteasome and the misregulation of PRH target genes. Here we show that PRH and hyper-phosphorylated PRH are present in normal prostate epithelial cells, and that hyper-phosphorylated PRH levels are elevated in benign prostatic hyperplasia, prostatic adenocarcinoma, and prostate cancer cell lines. A reduction in PRH protein levels increases the motility of normal prostate epithelial cells and conversely, PRH over-expression inhibits prostate cancer cell migration and blocks the ability of these cells to invade an extracellular matrix. We show that CK2 over-expression blocks the repression of prostate cancer cell migration and invasion by PRH. In addition, we show that PRH knockdown in normal immortalised prostate cells results in an increase in the population of cells capable of colony formation in Matrigel, as well as increased cell invasion and decreased E-cadherin expression. Inhibition of CK2 reduces PRH phosphorylation and reduces prostate cell proliferation but the effects of CK2 inhibition on cell proliferation are abrogated in PRH knockdown cells. These data suggest that the increased phosphorylation of PRH in prostate cancer cells increases both cell proliferation and tumour cell migration/invasion. PMID:28134934

  20. Inhibition of nucleoside diphosphate kinase activity by in vitro phosphorylation by protein kinase CK2. Differential phosphorylation of NDP kinases in HeLa cells in culture

    DEFF Research Database (Denmark)

    Biondi, R M; Engel, M; Sauane, M

    1996-01-01

    that in vitro protein kinase CK2 catalyzed phosphorylation of human NDPK A inhibits its enzymatic activity by inhibiting the first step of its ping-pong mechanism of catalysis: its autophosphorylation. Upon in vivo 32P labeling of HeLa cells, we observed that both human NDPKs, A and B, were autophosphorylated...

  1. The catalytic subunit of human protein kinase CK2 structurally deviates from its maize homologue in complex with the nucleotide competitive inhibitor emodin

    DEFF Research Database (Denmark)

    Raaf, Jennifer; Klopffleisch, Karsten; Issinger, Olaf-Georg;

    2008-01-01

    in the ATP-binding loop, whereas human CK2alpha shows its largest adaptations in the hinge region connecting the two main domains of the protein kinase core. These observations emphasize the importance of local plasticity for ligand binding and demonstrate that two orthologues of an enzyme can behave quite...

  2. Characterization of protein kinase CK2 protein subunits and p53 in F9 teratocarcinoma cells in the absence and presence of cisplatin

    DEFF Research Database (Denmark)

    Küpper, M; Köster, M; Schmidt-Spaniol, I

    1994-01-01

    The effect of cis-diaminedichloroplatinum(II) (cisplatin) on the induction of p53 and protein kinase CK2 activity was studied in the mouse teratocarcinoma cell line F9. Treatment of the cells with the chemotherapeutic agent cisplatin led to the detection of p53 3 h after addition of the drug. F9 ...

  3. Phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) serine-511 by the combined action of tyrosine kinases and CK2: the implication of tyrosine-512 and phenylalanine-508.

    Science.gov (United States)

    Cesaro, Luca; Marin, Oriano; Venerando, Andrea; Donella-Deana, Arianna; Pinna, Lorenzo A

    2013-12-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) harbors, close to Phe-508, whose deletion is the commonest cause of cystic fibrosis, a conserved potential CK2 phospho-acceptor site (Ser511), which however is not susceptible to phosphorylation by CK2. To shed light on this apparent paradox, a series of systematically substituted peptides encompassing Ser511 were assayed for their ability to be phosphorylated. The main outcomes of our study are the following: (a) Tyr512 plays a prominent role as a negative determinant as its replacement by Ala restores Ser511 phosphorylation by CK2; (b) an even more pronounced phosphorylation of Ser511 is promoted if Tyr512 is replaced by phospho-tyrosine instead of alanine; (c) Tyr512 and, to a lesser extent, Tyr515 are readily phosphorylated by Lyn, a protein tyrosine kinase of the Src family, in a manner which is enhanced by the concomitant Phe508 deletion. Collectively taken, our data, in conjunction with the notion that Tyr515 is phosphorylated in vivo, disclose the possibility that CFTR Ser511 can be phosphorylated by the combined action of tyrosine kinases and CK2 and disclose a new mechanism of hierarchical phosphorylation where the role of the priming kinase is that of removing negative determinant(s).

  4. Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells.

    Science.gov (United States)

    Manni, Sabrina; Brancalion, Alessandra; Mandato, Elisa; Tubi, Laura Quotti; Colpo, Anna; Pizzi, Marco; Cappellesso, Rocco; Zaffino, Fortunato; Di Maggio, Speranza Antonia; Cabrelle, Anna; Marino, Filippo; Zambello, Renato; Trentin, Livio; Adami, Fausto; Gurrieri, Carmela; Semenzato, Gianpietro; Piazza, Francesco

    2013-01-01

    CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.

  5. Mitotic Activation of a Novel Histone Deacetylase 3-Linker Histone H1.3 Protein Complex by Protein Kinase CK2.

    Science.gov (United States)

    Patil, Hemangi; Wilks, Carrie; Gonzalez, Rhiannon W; Dhanireddy, Sudheer; Conrad-Webb, Heather; Bergel, Michael

    2016-02-12

    Histone deacetylase 3 (HDAC3) and linker histone H1 are involved in both chromatin compaction and the regulation of mitotic progression. However, the mechanisms by which HDAC3 and H1 regulate mitosis and the factors controlling HDAC3 and H1 activity during mitosis are unclear. Furthermore, as of now, no association between class I, II, or IV (non-sirtuin) HDACs and linker histones has been reported. Here we describe a novel HDAC3-H1.3 complex containing silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor 1 (N-CoR) that accumulated in synchronized HeLa cells in late G2 phase and mitosis. Nonetheless, the deacetylation activity by HDAC3 in the complex was evident only in mitotic complexes. HDAC3 associated with H1.3 was highly phosphorylated on Ser-424 only during mitosis. Isolation of inactive HDAC3-H1.3 complexes from late G2 phase cells, and phosphorylation of HDAC3 in the complexes at serine 424 by protein kinase CK2 (also known as casein kinase 2) activated the HDAC3 in vitro. In vivo, CK2α and CK2α' double knockdown cells demonstrated a significant decrease in HDAC3 Ser-424 phosphorylation during mitosis. HDAC3 and H1.3 co-localized in between the chromosomes, with polar microtubules and spindle poles during metaphase through telophase, and partially co-localized with chromatin during prophase and interphase. H1 has been reported previously to associate with microtubules and, therefore, could potentially function in targeting HDAC3 to the microtubules. We suggest that phosphorylation of HDAC3 in the complex by CK2 during mitosis activates the complex for a dual role: compaction of the mitotic chromatin and regulation of polar microtubules dynamic instability.

  6. 左卡尼汀对特发性弱精子症精子质量及蛋白激酶CK2活性的影响%Effects of Levocarnitine on sperm quality and activity of protein kinase CK2 in patients with idiopathic asthenozoospermia

    Institute of Scientific and Technical Information of China (English)

    黄雪坤; 尚慧玲; 黄娟华; 刘建霞; 张四友

    2011-01-01

    目的 研究左卡尼汀对特发性弱精子症精子质量及蛋白激酶CK2活性的影响,从而探讨其可能的作用机制.方法 利用计算机辅助精子分析(CASA)系统对35例特发性弱精子症患者接受左卡尼汀(1 g/次,tid)治疗前、治疗3个月后和15例健康男性的精液进行分析;提取精子总蛋白,利用同位素掺入法检测精子蛋白激酶CK2活性.结果 左卡尼汀能显著提高特发性弱精子症患者精子的活动率、前向性运动精子百分率(a+b级)、曲线运动速度(VCL)、直线运动速度(VSL)和平均路径运动速度(VAP).左卡尼汀治疗前CK2活性每分钟计算值为1445±431,治疗后为2209±502,治疗后精液CK2活性明显升高(P<0.05).治疗前后CK2活性变化与治疗前后精子活动率(r=0.45,P<0.05)、a+b级(r=0.58,P<0.01)、VCL(r=0.43,P<0.05)、VSL(r=0.40,P<0.05)、VAP(r=0.41,P<0.05)变化均呈正相关性.结论 左卡尼汀能显著提高特发性弱精子症精子质量,其作用机制可能是增加了蛋白激酶CK2活性.%Objective To study the effects of Levocarnitine on sperm quality and activity of protein kinase CK2 in patients with idiopathic asthenozoospermia , and further explore the possible molecular mechanisms. Methods Sperms, obtained from 35 idiopathic asthenozoospermia patients before and after treated with Levocarnitine ( 1 g/time, tid) for 3 months and 15 healthy fertile men, were analyzed by computer-aid semen analysis ( CASA ) system. In addition, protein was extracted from those sperm samples and the CK2 activity was assayed by detecting incorporation of 32P of [ 7- P] ATP into the substrate. Results The sperm in idiopathic asthenozoospermia patients treated with Levocarnitine showed a significant increase in sperm progressive motility , grade a + b sperm percent, curvilinear velocity ( VCL) , straight-line velocity (VSL) and average path velocity (VAP). CK2 activity in idiopathic asthenozoospermia patients after treated with Levocarnitine

  7. Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block

    DEFF Research Database (Denmark)

    Hansen, Klaus; Farkas, T; Lukas, J;

    2001-01-01

    The retinoblastoma (pRb)-related p130 pocket protein is a regulator of cell growth and differentiation, and a candidate tumour suppressor. Both pRb and p130 operate through interactions with cellular proteins, including the E2F transcription factors. While such interactions are controlled...

  8. Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis.

    Science.gov (United States)

    Perera, Yasser; Pedroso, Seidy; Borras-Hidalgo, Orlando; Vázquez, Dania M; Miranda, Jamilet; Villareal, Adelaida; Falcón, Viviana; Cruz, Luis D; Farinas, Hernán G; Perea, Silvio E

    2015-06-01

    B23/NPM is a multifunctional nucleolar protein frequently overexpressed, mutated, or rearranged in neoplastic tissues. B23/NPM is involved in diverse biological processes and is mainly regulated by heteroligomer association and posttranslational modification, phosphorylation being a major posttranslational event. While the role of B23/NPM in supporting and/or driving malignant transformation is widely recognized, the particular relevance of its CK2-mediated phosphorylation remains unsolved. Interestingly, the pharmacologic inhibition of such phosphorylation event by CIGB-300, a clinical-grade peptide drug, was previously associated to apoptosis induction in tumor cell lines. In this work, we sought to identify the biological processes modulated by CIGB-300 in a lung cancer cell line using subtractive suppression hybridization and subsequent functional annotation clustering. Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis (ES = 8.4, p NPM in cancer cells, revealing at the same time the potentialities of its pharmacological manipulation for cancer therapy. Finally, this work also suggests several candidate gene biomarkers to be evaluated during the clinical development of the anti-CK2 peptide CIGB-300.

  9. Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

    Science.gov (United States)

    Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

    2013-01-01

    Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

  10. Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90

    Directory of Open Access Journals (Sweden)

    Xu Yuan-Ji

    2011-08-01

    Full Text Available Abstract Background Multiple myeloma (MM is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined. Results In this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat. Conclusions Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

  11. [Participation of proteinkinase CK2 in regulation of human erythrocytes plasma membrane redox system activity: relative contribution of ca(2+)-dependent and ca(2+)-independent mechanisms of its activation].

    Science.gov (United States)

    Iakovenko, I N; Zhirnov, V V; Kozachenko, O P; Shablykin, O V; Brovarets', V S

    2012-01-01

    Involvement of protein kinase CK2 (2.7.11.1) in modulation of live cells trans-plasma membrane electron transport was first discovered. Using human erythrocytes a decrease of plasma membrane redox system (PMRS) activity is shown under the action of specific protein kinase CK2 inhibitors. Using inhibitory analysis the activity regulation of human erythrocytes PMRS by Ca(2+)-dependent and Ca(2+)-independent mechanisms were investigated. It was shown that functional Ca(2+)-antagonists (nitrendipine and calmidazolium) significantly increased, and functional Ca(2+)-agonists to some extent reduced or did not affect the trans-plasma membrane electron transport in these cells.

  12. Safety and preliminary efficacy data of a novel Casein Kinase 2 (CK2 peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies

    Directory of Open Access Journals (Sweden)

    Alonso Daniel F

    2009-05-01

    Full Text Available Abstract Background Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL, the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2 phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies. Methods Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 – 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated. Results No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression

  13. p53 and the ribosomal protein L5 participate in high molecular mass complex formation with protein kinase CK2 in murine teratocarcinoma cell line F9 after serum stimulation and cisplatin treatment

    DEFF Research Database (Denmark)

    Guerra, B; Issinger, O G

    1998-01-01

    Using the murine teratocarcinoma cell line F9 we investigated the influence of serum stimulation and cisplatin treatment on the p53, CK2, MDM2 levels. Both treatments led to an increase of p53, though with different kinetics; the other proteins investigated were not affected. We present direct...

  14. Decreased Degradation of Internalized Follicle-Stimulating Hormone Caused by Mutation of Aspartic Acid 6.30550 in a Protein Kinase-CK2 Consensus Sequence in the Third Intracellular Loop of Human Follicle-Stimulating Hormone Receptor1

    Science.gov (United States)

    Kluetzman, Kerri S.; Thomas, Richard M.; Nechamen, Cheryl A.; Dias, James A.

    2011-01-01

    A naturally occurring mutation in follicle-stimulating hormone receptor (FSHR) gene has been reported: an amino acid change to glycine occurs at a conserved aspartic acid 550 (D550, D567, D6.30567). This residue is contained in a protein kinase-CK2 consensus site present in human FSHR (hFSHR) intracellular loop 3 (iL3). Because CK2 has been reported to play a role in trafficking of some receptors, the potential roles for CK2 and D550 in FSHR function were evaluated by generating a D550A mutation in the hFSHR. The hFSHR-D550A binds hormone similarly to WT-hFSHR when expressed in HEK293T cells. Western blot analyses showed lower levels of mature hFSHR-D550A. Maximal cAMP production of both hFSHR-D550A as well as the naturally occurring mutation hFSHR-D550G was diminished, but constitutive activity was not observed. Unexpectedly, when 125I-hFSH bound to hFSHR-D550A or hFSHR-D550G, intracellular accumulation of radiolabeled FSH was observed. Both sucrose and dominant-negative dynamin blocked internalization of radiolabeled FSH and its commensurate intracellular accumulation. Accumulation of radiolabeled FSH in cells transfected with hFSHR-D550A is due to a defect in degradation of hFSH as measured in pulse chase studies, and confocal microscopy imaging revealed that FSH accumulated in large intracellular structures. CK2 kinase activity is not required for proper degradation of internalized FSH because inhibition of CK2 kinase activity in cells expressing hFSHR did not uncouple degradation of internalized radiolabeled FSH. Additionally, the CK2 consensus site in FSHR iL3 is not required for binding because CK2alpha coimmunoprecipitated with hFSHR-D550A. Thus, mutation of D550 uncouples the link between internalization and degradation of hFSH. PMID:21270425

  15. Insights from soft X-rays: the chlorine and sulfur sub-structures of a CK2alpha/DRB complex.

    Science.gov (United States)

    Raaf, Jennifer; Issinger, Olaf-Georg; Niefind, Karsten

    2008-09-01

    The diffraction pattern of a protein crystal is normally a product of the interference of electromagnetic waves scattered by electrons of the crystalline sample. The diffraction pattern undergoes systematic changes in case additionally X-ray absorption occurs, meaning if the wavelength of the primary X-ray beam is relatively close to the absorption edge of selected elements of the sample. The resulting effects are summarized as "anomalous dispersion" and can be always observed with "soft" X-rays (wavelength around 2 A) since they match the absorption edges of sulfur and chlorine. A particularly useful application of this phenomenon is the experimental detection of the sub-structures of the anomalous scatterers in protein crystals. We demonstrate this here with a crystal of a C-terminally truncated variant of human CK2alpha to which two molecules of the inhibitor 5,6-dichloro-1-beta-D-ribo-furanosyl-benzimidazole (DRB) are bound. The structure of this co-crystal has been solved recently. For this study we measured an additional diffraction data set at a wavelength of 2 A which showed strong anomalous dispersion effects. On the basis of these effects we detected all sulfur atoms of the protein, the two liganded DRB molecules and a total of 16 additional chloride ions some of them emerging at positions filled with water molecules in previous structure determinations. A number of chloride ions are bound to structural and functional important locations fitting to the constitutive activity and the acidophilic substrate specificity of the enzyme.

  16. Basic residues in the 74-83 and 191-198 segments of protein kinase CK2 catalytic subunit are implicated in negative but not in positive regulation by the beta-subunit

    DEFF Research Database (Denmark)

    Sarno, S; Vaglio, P; Marin, O;

    1997-01-01

    by the beta-subunit many fold more than that of alpha wild type, while extrastimulation by beta mutant D55L56E57A, observable with alpha wild type, is abolished with these mutants. These data support the conclusion that down regulation by the acidic residues clustered in the N-terminal moiety of beta...... sensitive to inhibition by either beta-subunit or its N-terminal, CK2beta-(1-77)-peptide, while its stimulation by the C-terminal peptide, CK2beta-(155-215), is comparable to that of alpha wild type. These observations suggest an indirect role of Val66 in conferring to the alpha-subunit a conformation less...

  17. 酪蛋白激酶2结合并磷酸化ataxin-3%Casein kinase 2 interacts with and phosphorylates ataxin-3

    Institute of Scientific and Technical Information of China (English)

    陶瑞松; 费尔康; 应征; 王洪枫; 王光辉

    2008-01-01

    目的 马查多-约瑟夫病/脊髓小脑共济失调3型,是由MJDI基因产物ataxin-3的C-末端的多聚谷氨酰胺发生重复扩展突变而引起的一种常染色体显性遗传的神经退行性疾病,目前它的发病机制还不清楚.很多研究表明磷酸化修饰作用在很多神经退行性疾病的发病过程中起到重要作用,然而已知可以磷酸化ataxin-3的激酶仍然很少.本研究的目的是探讨酪蛋白激酶2(Casein kinase 2,CK2)对于ataxin-3的磷酸化作用.方法 通过GST pulldown和免疫共沉淀技术鉴定ataxin-3和CK2的相互作用.通过体外磷酸化技术检测CK2对ataxin-3的磷酸化.结果 (1)正常和扩展突变型ataxin-3在体外与CK2α、β亚单位均发生相互作用;(2)在293细胞中正常和扩展突变型ataxin-3只和CK2β亚单位相互作用,而与α亚单位没有结合;(3)正常和扩展突变型ataxin-3都可以被CK2磷酸化.结论 Ataxin-3是蛋白激酶CK2的底物.%Objective Machado-Joseph disease(MJD)/Spinocerebellar ataxia type 3(SCA3)is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJDI gene product,ataxin-3.The precise mechanism of the MJD/SCA3 pathogenesis remains unclear.A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases.However,few kinases are known to phosphorylate ataxin-3.The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 (CK2).Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase (GST) pull-down assay and co-immunoprecipition assay.The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays.Results (1) Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro.(2) In 293 cells,both wild type and expanded ataxin-3 interacted with CK2β,but not CK2α.(3) CK2 phosphorylated wild type and

  18. Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin

    DEFF Research Database (Denmark)

    Kriajevska, M; Bronstein, I B; Scott, D J

    2000-01-01

    A role for EF-hand calcium-binding protein Mts1 (S100A4) in the phosphorylation and the assembly of myosin filaments was studied. The nonmuscle myosin molecules form bipolar filaments, which interact with actin filaments to produce a contractile force. Phosphorylation of the myosin plays...

  19. Phosphorylation-dependent differential regulation of plant growth, cell death, and innate immunity by the regulatory receptor-like kinase BAK1

    DEFF Research Database (Denmark)

    Schwessinger, Benjamin; Roux, Milena; Kadota, Yasuhiro;

    2011-01-01

    Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine-rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe the different......Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine-rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe...... the differential regulation of three different BAK1-dependent signaling pathways by a novel allele of BAK1, bak1-5. Innate immune signaling mediated by the BAK1-dependent RKs FLS2 and EFR is severely compromised in bak1-5 mutant plants. However, bak1-5 mutants are not impaired in BR signaling or cell death control...... of FLS2 or EFR with BAK1 in planta, revealing another pathway specific mechanistic difference. The specific suppression of FLS2- and EFR-dependent signaling in bak1-5 is not due to a differential interaction of BAK1-5 with the respective ligand-binding RK but requires BAK1-5 kinase activity. Overall our...

  20. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner.

    Science.gov (United States)

    Eckford, Paul D W; Li, Canhui; Ramjeesingh, Mohabir; Bear, Christine E

    2012-10-26

    The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe.

  1. Protein kinase CK2 in human diseases

    DEFF Research Database (Denmark)

    Guerra, Barbara; Issinger, Olaf-Georg

    2008-01-01

    in various disease processes including cancer has been gained in recent years, and the present review may help to further elucidate its aberrant role in many disease states. Its peculiar structural features [3-9] may be advantageous in designing tailor-made compounds with the possibility to specifically...

  2. The binding site for regulatory 14-3-3 protein in plant plasma membrane H+-ATPase: Involvement of a region promoting phosphorylation-independent interaction in addition to the phosphorylation-dependent C-terminal end

    DEFF Research Database (Denmark)

    Fuglsang, Anja T; Borch, Jonas; Bych, Katrine;

    2003-01-01

    of the Arabidopsis plasma membrane H+-ATPase isoform 2 (AHA2). Following site-directed mutagenesis within the 45 C-terminal residues of AHA2, we conclude that, in addition to the 946YpTV motif, a number of residues located further upstream are required for phosphorylation-independent binding of 14-3-3. Among these...

  3. Ras-induced and extracellular signal-regulated kinase 1 and 2 phosphorylation-dependent isomerization of protein tyrosine phosphatase (PTP)-PEST by PIN1 promotes FAK dephosphorylation by PTP-PEST.

    Science.gov (United States)

    Zheng, Yanhua; Yang, Weiwei; Xia, Yan; Hawke, David; Liu, David X; Lu, Zhimin

    2011-11-01

    Protein tyrosine phosphatase (PTP)-PEST is a critical regulator of cell adhesion and migration. However, the mechanism by which PTP-PEST is regulated in response to oncogenic signaling to dephosphorylate its substrates remains unclear. Here, we demonstrate that activated Ras induces extracellular signal-regulated kinase 1 and 2-dependent phosphorylation of PTP-PEST at S571, which recruits PIN1 to bind to PTP-PEST. Isomerization of the phosphorylated PTP-PEST by PIN1 increases the interaction between PTP-PEST and FAK, which leads to the dephosphorylation of FAK Y397 and the promotion of migration, invasion, and metastasis of v-H-Ras-transformed cells. These findings uncover an important mechanism for the regulation of PTP-PEST in activated Ras-induced tumor progression.

  4. INTERACT

    DEFF Research Database (Denmark)

    Jochum, Elizabeth; Borggreen, Gunhild; Murphey, TD

    This paper considers the impact of visual art and performance on robotics and human-computer interaction and outlines a research project that combines puppetry and live performance with robotics. Kinesics—communication through movement—is the foundation of many theatre and performance traditions...... interaction between a human operator and an artificial actor or agent. We can apply insights from puppetry to develop culturally-aware robots. Here we describe the development of a robotic marionette theatre wherein robotic controllers assume the role of human puppeteers. The system has been built, tested...

  5. Murine gammaherpesvirus 68 ORF75c contains ubiquitin E3 ligase activity and requires PML SUMOylation but not other known cellular PML regulators, CK2 and E6AP, to mediate PML degradation

    OpenAIRE

    Sewatanon, Jaturong; Ling, Paul D.

    2013-01-01

    All gammaherpsviruses encode at least one gene related to the cellular formylglycinamide ribonucleotide amidotransferase (FGARAT) enzyme but their biological roles are relatively unknown. The murine gammaherpesvirus 68 (MHV68) vFGARAT, ORF75c, mediates a proteasome-dependent degradation of the antiviral promyelocytic leukemia (PML) protein by an unknown mechanism, which is addressed in this study. We found that ORF75c interacts weakly with PML and SUMO-modified forms of PML are important for ...

  6. Interactions

    DEFF Research Database (Denmark)

    The main theme of this anthology is the unique interaction between mathematics, physics and philosophy during the beginning of the 20th century. Seminal theories of modern physics and new fundamental mathematical structures were discovered or formed in this period. Significant physicists such as ...... also key figures in the philosophical discussions of nature and science - from philosophical tendencies like logical empiricism via critical rationalism to various neo-Kantian trends....

  7. Characterization of CK2 holoenzyme variants with regard to crystallization

    DEFF Research Database (Denmark)

    Guerra, B; Niefind, K; Ermakowa, I;

    2001-01-01

    severely. One of the approaches chosen was the production of a chimeric holoenzyme made up from a human regulatory subunit and a catalytic subunit from Z. mays. The plant catalytic subunit, in contrast to the human counterpart is very stable and does not undergo this kind of degradation. The second...

  8. Interaction of aluminum with PHFtau in Alzheimer's disease neurofibrillary degeneration evidenced by desferrioxamine-assisted chelating autoclave method.

    Science.gov (United States)

    Murayama, H; Shin, R W; Higuchi, J; Shibuya, S; Muramoto, T; Kitamoto, T

    1999-09-01

    To demonstrate that aluminum III (Al) interacts with PHFtau in neurofibrillary degeneration (NFD) of Alzheimer's disease (AD) brain, we developed a "chelating autoclave method" that allows Al chelation by using trivalent-cationic chelator desferrioxamine. Its application to AD brain sections before Morin histochemistry for Al attenuated the positive fluorescence of neurofibrillary tangles, indicating Al removal from them. This method, applied for immunostaining with phosphorylation-dependent anti-tau antibodies, significantly enhanced the PHFtau immunoreactivity of the NFD. These results suggest that each of the phosphorylated epitopes in PHFtau are partially masked by Al binding. Incubation of AD sections with AlCl(3) before Morin staining revealed Al accumulation with association to neurofibrillary tangles. Such incubation before immunostaining with the phosphorylation-dependent anti-tau antibodies abolished the immunolabeling of the NFD and this abolition was reversed by the Al chelation. These findings indicate cumulative Al binding to and thereby antigenic masking of the phosphorylated epitopes of PHFtau. Al binding was further documented for electrophoretically-resolved PHFtau on immunoblots, indicating direct Al binding to PHFtau. In vitro aggregation by AlCl(3) was observed for PHFtau but was lost on dephosphorylation of PHFtau. Taken together, phosphorylation-dependent and direct PHFtau-Al interaction occurs in the NFD of the AD brain.

  9. Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions.

    Science.gov (United States)

    Bozoky, Zoltan; Krzeminski, Mickael; Muhandiram, Ranjith; Birtley, James R; Al-Zahrani, Ateeq; Thomas, Philip J; Frizzell, Raymond A; Ford, Robert C; Forman-Kay, Julie D

    2013-11-19

    Intrinsically disordered proteins play crucial roles in regulatory processes and often function as protein interaction hubs. Here, we present a detailed characterization of a full-length disordered hub protein region involved in multiple dynamic complexes. We performed NMR, CD, and fluorescence binding studies on the nonphosphorylated and highly PKA-phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) regulatory region, a ∼200-residue disordered segment involved in phosphorylation-dependent regulation of channel trafficking and gating. Our data provide evidence for dynamic, phosphorylation-dependent, multisite interactions of various segments of the regulatory region for its intra- and intermolecular partners, including the CFTR nucleotide binding domains 1 and 2, a 42-residue peptide from the C terminus of CFTR, the SLC26A3 sulphate transporter and antisigma factor antagonist (STAS) domain, and 14-3-3β. Because of its large number of binding partners, multivalent binding of individually weak sites facilitates rapid exchange between free and bound states to allow the regulatory region to engage with different partners and generate a graded or rheostat-like response to phosphorylation. Our results enrich the understanding of how disordered binding segments interact with multiple targets. We present structural models consistent with our data that illustrate this dynamic aspect of phospho-regulation of CFTR by the disordered regulatory region.

  10. Phosphorylation-dependent Trafficking of Plasma Membrane Proteins in Animal and Plant Cells

    Institute of Scientific and Technical Information of China (English)

    Remko Offringa; and Fang Huang

    2013-01-01

    In both unicellular and multicellular organisms, transmembrane (TM) proteins are sorted to and retained at specific membrane domains by endomembrane trafficking mechanisms that recognize sorting signals in the these proteins. The trafficking and distribution of plasma membrane (PM)-localized TM proteins (PM proteins), especially of those PM proteins that show an asymmetric distribution over the PM, has received much attention, as their proper PM localization is crucial for elementary signaling and transport processes, and defects in their localization often lead to severe disease symptoms or developmental defects. The subcellular localization of PM proteins is dynamically regulated by post-translational modifications, such as phosphorylation and ubiquitination. These modificaitons mostly occur on sorting signals that are located in the larger cytosolic domains of the cargo proteins. Here we review the effects of phosphorylation of PM proteins on their trafficking, and present the key examples from the animal field that have been subject to studies for already several decades, such as that of aquaporin 2 and the epidermal growth factor receptor. Our knowledge on cargo trafficking in plants is largely based on studies of the family of PIN FORMED (PIN) carriers that mediate the efflux of the plant hormone auxin. We will review what is known on the subcellular distribution and trafficking of PIN proteins, with a focus on how this is modulated by phosphorylation, and identify and discuss analogies and differences in trafficking with the well-studied animal examples.

  11. Perilipin Promotes HSL-Mediated Adipocyte Lipolysis via Phosphorylation-dependent and Independent Mechanisms

    Science.gov (United States)

    Hormone-sensitive lipase (HSL) is the predominant lipase effector of catecholamine-stimulated lipolysis in adipocytes. HSL-dependent lipolysis, in response to catecholamines, is mediated by protein kinase A (PKA)-dependent phosphorylation of perilipin A (Peri A), an essential lipid droplet (LD)-ass...

  12. Inflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation.

    Science.gov (United States)

    Schmid, Tobias; Bajer, Magdalena M; Blees, Johanna S; Eifler, Lisa K; Milke, Larissa; Rübsamen, Daniela; Schulz, Kathrin; Weigert, Andreas; Baker, Alyson R; Colburn, Nancy H; Brüne, Bernhard

    2011-10-01

    The tumor suppressor programmed cell death 4 (Pdcd4) is lost in various tumor tissues. Loss of Pdcd4 has been associated with increased tumorigenic potential and tumor progression. While various mechanisms of Pdcd4 regulation have been described, the effect of an inflammatory tumor microenvironment on Pdcd4 protein expression has not been characterized so far. In the present study, we aimed to elucidate the molecular mechanisms of Pdcd4 protein regulation in tumor cells under inflammatory conditions. 12-O-tetradecanoylphorbol 13-acetate-induced differentiation of human U937 monocytes increased the expression and secretion of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-6 and IL-8. Exposure to conditioned medium (CM) of these activated macrophages markedly decreased Pdcd4 protein expression in various tumor cells. Similarly, indirect coculture with such activated U937 monocyte-derived macrophages resulted in the loss of Pdcd4 protein in tumor cells. Decreased Pdcd4 protein levels were attributable to enhanced proteasomal degradation, diminishing Pdcd4 protein half-life. Proteasomal degradation required activation of phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling. Since macrophage-CM sufficed to induce Pdcd4 degradation, Pdcd4 downregulation was determined to be an indirect unidirectional effect of the macrophages on the tumor cells. Pdcd4 protein expression was also attenuated in vivo in mouse colon tissue in response to dextran sodium sulfate-induced colitis. In summary, we characterized PI3K-mTOR-dependent proteasome-mediated Pdcd4 degradation in tumor cells in the inflammatory tumor microenvironment. Consequently, stabilization of Pdcd4 protein could provide a promising novel avenue for therapeutics targeting inflammation-associated tumors.

  13. Activation of the yeast Hippo pathway by phosphorylation-dependent assembly of signaling complexes.

    Science.gov (United States)

    Rock, Jeremy M; Lim, Daniel; Stach, Lasse; Ogrodowicz, Roksana W; Keck, Jamie M; Jones, Michele H; Wong, Catherine C L; Yates, John R; Winey, Mark; Smerdon, Stephen J; Yaffe, Michael B; Amon, Angelika

    2013-05-17

    Scaffold-assisted signaling cascades guide cellular decision-making. In budding yeast, one such signal transduction pathway called the mitotic exit network (MEN) governs the transition from mitosis to the G1 phase of the cell cycle. The MEN is conserved and in metazoans is known as the Hippo tumor-suppressor pathway. We found that signaling through the MEN kinase cascade was mediated by an unusual two-step process. The MEN kinase Cdc15 first phosphorylated the scaffold Nud1. This created a phospho-docking site on Nud1, to which the effector kinase complex Dbf2-Mob1 bound through a phosphoserine-threonine binding domain, in order to be activated by Cdc15. This mechanism of pathway activation has implications for signal transmission through other kinase cascades and might represent a general principle in scaffold-assisted signaling.

  14. Phosphorylation-dependent trafficking of plasma membrane proteins in animal and plant cells.

    Science.gov (United States)

    Offringa, Remko; Huang, Fang

    2013-09-01

    In both unicellular and multicellular organisms, transmembrane (TM) proteins are sorted to and retained at specific membrane domains by endomembrane trafficking mechanisms that recognize sorting signals in the these proteins. The trafficking and distribution of plasma membrane (PM)-localized TM proteins (PM proteins), especially of those PM proteins that show an asymmetric distribution over the PM, has received much attention, as their proper PM localization is crucial for elementary signaling and transport processes, and defects in their localization often lead to severe disease symptoms or developmental defects. The subcellular localization of PM proteins is dynamically regulated by post-translational modifications, such as phosphorylation and ubiquitination. These modificaitons mostly occur on sorting signals that are located in the larger cytosolic domains of the cargo proteins. Here we review the effects of phosphorylation of PM proteins on their trafficking, and present the key examples from the animal field that have been subject to studies for already several decades, such as that of aquaporin 2 and the epidermal growth factor receptor. Our knowledge on cargo trafficking in plants is largely based on studies of the family of PIN FORMED (PIN) carriers that mediate the efflux of the plant hormone auxin. We will review what is known on the subcellular distribution and trafficking of PIN proteins, with a focus on how this is modulated by phosphorylation, and identify and discuss analogies and differences in trafficking with the well-studied animal examples.

  15. Phosphorylation-dependent down-regulation of apolipoprotein A5 by insulin

    Energy Technology Data Exchange (ETDEWEB)

    Nowak, Maxine; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Rommens, Corinne; Martin, Genevieve; Duran-Sandoval, Daniel; Staels, Bart; Rubin, Edward M.; Pennacchio, Len A.; Taskinen, Marja-Riitta; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2004-02-15

    The apolipoprotein A5 (APOA5) gene has been shown to be important in lowering plasma triglyceride levels. Since several studies have shown that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 gene is regulated by insulin. We show here that cell and mouse treatments with insulin down-regulated APOA5 expression in a dose-dependent manner. Furthermore, we determined that insulin decreases APOA5 promoter activity and subsequent deletion analyses revealed an E-box-containing fragment. We showed that Upstream Stimulatory Factors, USF1/USF2, bind to the identified E-box in the APOA5 promoter. Moreover, in cotransfection studies, USF1 stimulates APOA5 promoter activity. The treatment with insulin reduces the binding of USF1/USF2 to APOA5 promoter. The inhibition of PI3K pathway with wortmannin abolished the insulin s effect on APOA5 gene transcription. Using oligoprecipitation method of USF from nuclear extracts, we demonstrated that phosphorylated USF1 failed to bind to APOA5 promoter. This indicates that the APOA5 gene transrepression by insulin involves a phosphorylation of USF through PI3K, that modulate their binding to APOA5 promoter and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in healthy men shows a decrease of the plasma ApoAV level. These data suggest a potential mechanism involving APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.

  16. CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock

    NARCIS (Netherlands)

    T. Tamaru (Teruya); M. Hattori (Mitsuru); K. Honda (Kousuke); Y. Nakahata (Yasukazu); P. Sassone-Corsi (Paolo); G.T.J. van der Horst (Gijsbertus); T. Ozawa (Takeaki); K. Takamatsu (Ken)

    2015-01-01

    textabstractIntracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we establi

  17. Mapping the residues of protein kinase CK2 implicated in substrate recognition

    DEFF Research Database (Denmark)

    Sarno, S; Boldyreff, B; Marin, O

    1995-01-01

    , hampering the calculation of kinetic parameters. In contrast 3 mutants (K74-77A, K79R80K83A and R191,195K198A) phosphorylated the peptide with reduced efficiency accounted for by increased Km and decreased Vmax values. By using derivatives of the RRRADDSDDDDD peptide in which individual aspartyl residues...... were variably replaced by alanine(s) and two peptide substrates derived from I-2 (KYRIREQESSGEEDSDL and RRKDLHDDEEDEEMSETADGE) it was shown that mutations in the 191-198, 74-77 and 79-83 regions were the least detrimental whenever the acidic determinants were lacking at positions +1, +4/+5 and +3...

  18. Analysis of Presenilin 1 and 2 interacting proteins in mouse cerebral cortex during development.

    Science.gov (United States)

    Kumar, Ashish; Thakur, M K

    2014-11-01

    In our previous report, we showed that Presenilin (PS)1 and 2 have differential expression profile from early embryonic stages till adulthood in mouse cerebral cortex, suggesting that both of these proteins are crucial for brain development. Genetic manipulation studies have also shown the involvement of PS1 in brain development, but PS2 remains largely unexplored. In order to understand how PS1 and 2 mediate developmental functions, we have investigated the interaction of PS1 and 2 with proteins of mouse cerebral cortex during development. Co-immunoprecipitation (Co-IP) combined with MALDI-MS/MS analysis revealed 12 interacting partners of PS1 and 11 partners of PS2. The interacting proteins were different for PS1 and 2, and involved in cell division, glycolysis, cell adhesion and protein trafficking. Densitometric analysis of protein bands visualized after SDS-PAGE separation of Co-IP proteins revealed variation in their amount and degree of interaction during different developmental stages of mice. Further, immunoblot based validation of PS1 interacting protein Notch-1 showed maximum interaction at embryonic day (E) 12.5, decline at E18.5, upregulation from postnatal day 0 (P0) to P20 and thereafter reduction at P45 and 20 weeks. In-silico analysis of PS and its interacting proteins indicated conformation based interaction through common type of secondary structures having alpha helical, extended beta strand and random coil, and CK2, PKC phosphorylation and myristoylation motifs. Taken together, our study showed that PS1 and PS2 interact to varying extent with different proteins of mouse cerebral cortex and suggests their interaction based on specific conformation and involvement in diverse functions essential for the brain development.

  19. Interactions between Casein kinase Iepsilon (CKIepsilon and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity.

    Directory of Open Access Journals (Sweden)

    Caroline Lund Dahlberg

    Full Text Available BACKGROUND: Members of the Casein Kinase I (CKI family of serine/threonine kinases regulate diverse biological pathways. The seven mammalian CKI isoforms contain a highly conserved kinase domain and divergent amino- and carboxy-termini. Although they share a preferred target recognition sequence and have overlapping expression patterns, individual isoforms often have specific substrates. In an effort to determine how substrates recognize differences between CKI isoforms, we have examined the interaction between CKIepsilon and two substrates from different signaling pathways. METHODOLOGY/PRINCIPAL FINDINGS: CKIepsilon, but not CKIalpha, binds to and phosphorylates two proteins: Period, a transcriptional regulator of the circadian rhythms pathway, and Disheveled, an activator of the planar cell polarity pathway. We use GST-pull-down assays data to show that two key residues in CKIalpha's kinase domain prevent Disheveled and Period from binding. We also show that the unique C-terminus of CKIepsilon does not determine Dishevelled's and Period's preference for CKIepsilon nor is it essential for binding, but instead plays an auxillary role in stabilizing the interactions of CKIepsilon with its substrates. We demonstrate that autophosphorylation of CKIepsilon's C-terminal tail prevents substrate binding, and use mass spectrometry and chemical crosslinking to reveal how a phosphorylation-dependent interaction between the C-terminal tail and the kinase domain prevents substrate phosphorylation and binding. CONCLUSIONS/SIGNIFICANCE: The biochemical interactions between CKIepsilon and Disheveled, Period, and its own C-terminus lead to models that explain CKIepsilon's specificity and regulation.

  20. Collocated Interaction

    DEFF Research Database (Denmark)

    E. Fischer, Joel; Porcheron, Martin; Lucero, Andrés;

    2016-01-01

    , and wearable technologies, spaces and spatial interaction, and those interested in the social aspects of interaction, such as conversation analysis and ethnomethodology. These communities have matured considerably, and produced significant exemplars of systems, methods, and studies concerned with collocated...

  1. Identification of a phosphorylation-dependent nuclear localization motif in interferon regulatory factor 2 binding protein 2.

    Directory of Open Access Journals (Sweden)

    Allen C T Teng

    Full Text Available BACKGROUND: Interferon regulatory factor 2 binding protein 2 (IRF2BP2 is a muscle-enriched transcription factor required to activate vascular endothelial growth factor-A (VEGFA expression in muscle. IRF2BP2 is found in the nucleus of cardiac and skeletal muscle cells. During the process of skeletal muscle differentiation, some IRF2BP2 becomes relocated to the cytoplasm, although the functional significance of this relocation and the mechanisms that control nucleocytoplasmic localization of IRF2BP2 are not yet known. METHODOLOGY/PRINCIPAL FINDINGS: Here, by fusing IRF2BP2 to green fluorescent protein and testing a series of deletion and site-directed mutagenesis constructs, we mapped the nuclear localization signal (NLS to an evolutionarily conserved sequence (354ARKRKPSP(361 in IRF2BP2. This sequence corresponds to a classical nuclear localization motif bearing positively charged arginine and lysine residues. Substitution of arginine and lysine with negatively charged aspartic acid residues blocked nuclear localization. However, these residues were not sufficient because nuclear targeting of IRF2BP2 also required phosphorylation of serine 360 (S360. Many large-scale phosphopeptide proteomic studies had reported previously that serine 360 of IRF2BP2 is phosphorylated in numerous human cell types. Alanine substitution at this site abolished IRF2BP2 nuclear localization in C(2C(12 myoblasts and CV1 cells. In contrast, substituting serine 360 with aspartic acid forced nuclear retention and prevented cytoplasmic redistribution in differentiated C(2C(12 muscle cells. As for the effects of these mutations on VEGFA promoter activity, the S360A mutation interfered with VEGFA activation, as expected. Surprisingly, the S360D mutation also interfered with VEGFA activation, suggesting that this mutation, while enforcing nuclear entry, may disrupt an essential activation function of IRF2BP2. CONCLUSIONS/SIGNIFICANCE: Nuclear localization of IRF2BP2 depends on phosphorylation near a conserved NLS. Changes in phosphorylation status likely control nucleocytoplasmic localization of IRF2BP2 during muscle differentiation.

  2. Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function.

    Science.gov (United States)

    Wei, Zelan; Qi, Ji; Dai, Yunxiu; Bowen, Wayne D; Mousseau, Darrell D

    2009-01-01

    The antipsychotic drug haloperidol is still used to treat psychosis and "agitation", often with devastating consequences, particularly in geriatric and pre-demented patients. Cytotoxicity induced by haloperidol has been associated with induction of Bcl-XS, a pro-apoptotic member of the Bcl-2 family, as well as with modulation of the Akt pro-survival pathway. Using preneuronal PC12 and primary neuronal cultures, we show that haloperidol inactivates Akt. This induces the dephosphorylation of serine residues in Bcl-XS and promotes its association with the mitochondrial voltage-dependent anion channel (VDAC), as well as with cytochrome c- and caspase-3-dependent events. These events are sensitive to expression of constitutively active Akt. Mutation of Serine106 (Ser106), which is flanked by a putative Akt motif, hinders the association of the Bcl-XS protein with Akt, but promotes its association with VDAC. The dephosphorylation mimic, Bcl-XS(Ser106Ala), induces caspase-dependent PC12 and neuronal cell apoptosis. In contrast, Bcl-XS(Ser106Ala) induces a significant loss of VDAC expression, and cytochrome c- and caspase-independent toxicity in the non-neuronal HEK293A cells. We link haloperidol and Akt to Bcl-XS-sensitive toxicity via cell line-dependent mitochondrial events centering on VDAC. This clearly mitigates the chronic use of haloperidol in neuropsychiatric populations, but supports its use as a potential acute therapeutic in cancer, where apoptosis is desirable.

  3. Involvement of redox- and phosphorylation-dependent pathways in osmotic adaptation in sperm cells of euryhaline tilapia.

    Science.gov (United States)

    Morita, Masaya; Nakajima, Ayako; Takemura, Akihiro; Okuno, Makoto

    2011-06-15

    Sperm cells involved in fertilisation must tolerate hypo-osmotic and hyper-osmotic environments. Euryhaline tilapia (Oreochromis mossambicus) can acclimatise to and reproduce in freshwater and seawater because its sperm are able to adapt to these differing osmotic environments. In this study, we found that the dephosphorylation of sperm proteins in O. mossambicus correlated with the activation of flagellar motility when sperm were exposed to hypotonic or hypertonic conditions, and that differences in phosphorylation may reflect adaptations to a given osmotic environment. Of the sperm proteins that were dephosphorylated, the phosphorylation pattern of an 18 kDa protein, identified as the superoxide anion scavenger Cu/Zn superoxide dismutase (Cu/Zn SOD), was different in freshwater- and seawater-acclimatised tilapia sperm. Cu/Zn SOD was distributed from the sperm head to the flagellum. Additionally, differences were observed between freshwater and seawater tilapia in the nitration of tyrosine residues (which might be mediated by SOD) in sperm flagellar proteins in response to osmotic shock. These results demonstrate that reactive-oxygen-species-dependent mechanisms contribute to both osmotic tolerance and the activation of flagellar motility.

  4. AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis.

    Science.gov (United States)

    Höpker, Katja; Hagmann, Henning; Khurshid, Safiya; Chen, Shuhua; Hasskamp, Pia; Seeger-Nukpezah, Tamina; Schilberg, Katharina; Heukamp, Lukas; Lamkemeyer, Tobias; Sos, Martin L; Thomas, Roman K; Lowery, Drew; Roels, Frederik; Fischer, Matthias; Liebau, Max C; Resch, Ulrike; Kisner, Tülay; Röther, Fabian; Bartram, Malte P; Müller, Roman Ulrich; Fabretti, Francesca; Kurschat, Peter; Schumacher, Björn; Gaestel, Matthias; Medema, René H; Yaffe, Michael B; Schermer, Bernhard; Reinhardt, H Christian; Benzing, Thomas

    2012-10-17

    Following genotoxic stress, cells activate a complex signalling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumour suppressor p53 lies at the heart of this DNA damage response. However, it remains incompletely understood, which signalling molecules dictate the choice between these different cellular outcomes. Here, we identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. In xenograft experiments, mice exhibit a dramatically enhanced response of AATF-depleted tumours following genotoxic chemotherapy with adriamycin. The exogenous expression of a phospho-mimicking AATF point mutant results in marked adriamycin resistance in vivo. Nuclear AATF enrichment appears to be selected for in p53-proficient endometrial cancers. Furthermore, focal copy number gains at the AATF locus in neuroblastoma, which is known to be almost exclusively p53-proficient, correlate with an adverse prognosis and reduced overall survival. These data identify the p38/MK2/AATF signalling module as a critical repressor of p53-driven apoptosis and commend this pathway as a target for DNA damage-sensitizing therapeutic regimens.

  5. Sedimentary Features of Minerals of the CK-2 Drill in the North of Luobupo Salt Lake, Xinjiang province%新疆罗布泊罗北洼地CK-2孔盐类沉积特征

    Institute of Scientific and Technical Information of China (English)

    高东林; 李秉孝; 山发寿

    2001-01-01

    新疆罗布泊罗北洼地主要有粉砂、粘土沉积,硫酸盐沉积和氯化物沉积。其中硫酸盐(主要为钙芒硝)沉积占主导地位,钻孔岩芯中微细层理发育。研究分析表明,罗北洼地为一长期动荡的浅水沉积环境;钾资源以液体矿为主:25kaB.P.-10KaB.P.为该洼地湖泊的演化末期,属于盐湖阶段。%There are mainly three kinds of sedimentary minerals: fine-sand,sulphates, and chlorides. Among them, sulphates(Glauberite) are most in quantity. Through studying, the deposit environment of low-lying area was long-period unrestful, potassium resources mainly store in liquid, and in 25ka B.P.—10ka B.P.,the evolution of the area came into last phase, belong to salt lake stage.

  6. Floor interaction

    DEFF Research Database (Denmark)

    Petersen, Marianne Graves; Krogh, Peter; Ludvigsen, Martin;

    2005-01-01

    Within architecture, there is a long tradition of careful design of floors. The design has been concerned with both decorating floors and designing floors to carry information. Ubiquitous computing technology offers new opportunities for designing interactive floors. This paper presents three...... different interactive floor concepts. Through an urban perspective it draws upon the experiences of floors in architecture, and provides a set of design issues for designing interactive floors....

  7. Explicit Interaction

    DEFF Research Database (Denmark)

    Löwgren, Jonas; Eriksen, Mette Agger; Linde, Per

    2006-01-01

    as an interpretation of palpability, comprising usability as well as patient empowerment and socially performative issues. We present a prototype environment for video recording during physiotherapeutical consultation which illustrates our current thoughts on explicit interaction and serves as material for further......We report an ongoing study of palpable computing to support surgical rehabilitation, in the general field of interaction design for ubiquitous computing. Through explorative design, fieldwork and participatory design techniques, we explore the design principle of explicit interaction...

  8. Playful Interaction

    DEFF Research Database (Denmark)

    2003-01-01

    The video Playful Interaction describes a future architectural office, and envisions ideas and concepts for playful interactions between people, materials and appliances in a pervasive and augmented working environment. The video both describes existing developments, technologies and designs...... as well as ideas not yet implemented such as playful modes of interaction with an augmented ball. Playful Interaction has been used as a hybrid of a vision video and a video prototype (1). Externally the video has been used to visualising our new ideas, and internally the video has also worked to inspire...

  9. Interactive benchmarking

    DEFF Research Database (Denmark)

    Lawson, Lartey; Nielsen, Kurt

    2005-01-01

    We discuss individual learning by interactive benchmarking using stochastic frontier models. The interactions allow the user to tailor the performance evaluation to preferences and explore alternative improvement strategies by selecting and searching the different frontiers using directional...... in the suggested benchmarking tool. The study investigates how different characteristics on dairy farms influences the technical efficiency....

  10. Aesthetic interaction

    DEFF Research Database (Denmark)

    Petersen, Marianne Graves; Iversen, Ole Sejer; Krogh, Peter;

    2004-01-01

    There is a growing interest in considering aesthetic aspects in the design of interactive systems. A set of approaches are emerging each representing different applications of the terminology as well as different inherent assumptions on the role of the user, designer and interaction ideals....... In this paper, we use the concept of Pragmatist Aesthetics to provide a framework for distinguishing between different approaches to aesthetics. Moreover, we use our own design cases to illustrate how pragmatist aesthetics is a promising path to follow in the context of designing interactive systems......, as it promotes aesthetics of use, rather than aesthetics of appearance. We coin this approach in the perspective of aesthetic interaction. Finally we make the point that aesthetics is not re-defining everything known about interactive systems. We provide a framework placing this perspective among other...

  11. Thermodynamics of the interaction between Alzheimer's disease related tau protein and DNA.

    Directory of Open Access Journals (Sweden)

    Sergio Camero

    Full Text Available Tau hyperphosphorylation can be considered as one of the hallmarks of Alzheimer's disease and other tauophaties. Besides its well-known role as a microtubule associated protein, Tau displays a key function as a protector of genomic integrity in stress situations. Phosphorylation has been proven to regulate multiple processes including nuclear translocation of Tau. In this contribution, we are addressing the physicochemical nature of DNA-Tau interaction including the plausible influence of phosphorylation. By means of surface plasmon resonance (SPR we measured the equilibrium constant and the free energy, enthalpy and entropy changes associated to the Tau-DNA complex formation. Our results show that unphosphorylated Tau binding to DNA is reversible. This fact is in agreement with the protective role attributed to nuclear Tau, which stops binding to DNA once the insult is over. According to our thermodynamic data, oscillations in the concentration of dephosphorylated Tau available to DNA must be the variable determining the extent of Tau binding and DNA protection. In addition, thermodynamics of the interaction suggest that hydrophobicity must represent an important contribution to the stability of the Tau-DNA complex. SPR results together with those from Tau expression in HEK cells show that phosphorylation induces changes in Tau protein which prevent it from binding to DNA. The phosphorylation-dependent regulation of DNA binding is analogous to the Tau-microtubules binding inhibition induced by phosphorylation. Our results suggest that hydrophobicity may control Tau location and DNA interaction and that impairment of this Tau-DNA interaction, due to Tau hyperphosphorylation, could contribute to Alzheimer's pathogenesis.

  12. Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

    Science.gov (United States)

    Carmona, Guillaume; Perera, Upamali; Gillett, Cheryl; Naba, Alexandra; Law, Ah-Lai; Sharma, Ved P.; Wang, Jian; Wyckoff, Jeffrey; Balsamo, Michele; Mosis, Fuad; De Piano, Mario; Monypenny, James; Woodman, Natalie; McConnell, Russell E.; Mouneimne, Ghassan; Van Hemelrijck, Mieke; Cao, Yihai; Condeelis, John; Hynes, Richard O.; Gertler, Frank B.; Krause, Matthias

    2016-01-01

    Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlates with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation, and matrix degradation were impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not Ena/VASP is required for random 2D cell migration. We identify a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, while Src-dependent phosphorylation enhances binding to Scar/WAVE but not Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of EGF gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis. PMID:26996666

  13. Programming Interactivity

    CERN Document Server

    Noble, Joshua

    2012-01-01

    Ready to create rich interactive experiences with your artwork, designs, or prototypes? This is the ideal place to start. With this hands-on guide, you'll explore several themes in interactive art and design-including 3D graphics, sound, physical interaction, computer vision, and geolocation-and learn the basic programming and electronics concepts you need to implement them. No previous experience is necessary. You'll get a complete introduction to three free tools created specifically for artists and designers: the Processing programming language, the Arduino microcontroller, and the openFr

  14. Interaction graphs

    DEFF Research Database (Denmark)

    Seiller, Thomas

    2016-01-01

    Interaction graphs were introduced as a general, uniform, construction of dynamic models of linear logic, encompassing all Geometry of Interaction (GoI) constructions introduced so far. This series of work was inspired from Girard's hyperfinite GoI, and develops a quantitative approach that should...... be understood as a dynamic version of weighted relational models. Until now, the interaction graphs framework has been shown to deal with exponentials for the constrained system ELL (Elementary Linear Logic) while keeping its quantitative aspect. Adapting older constructions by Girard, one can clearly define...... "full" exponentials, but at the cost of these quantitative features. We show here that allowing interpretations of proofs to use continuous (yet finite in a measure-theoretic sense) sets of states, as opposed to earlier Interaction Graphs constructions were these sets of states were discrete (and finite...

  15. Neutrino Interactions

    CERN Document Server

    McFarland, Kevin

    2008-01-01

    This manuscript summarizes a series of three lectures on interactions of neutrinos . The lectures begin with a pedagogical foundation and then explore topics of interest to current and future neutrino oscillation and cross-section experiments.

  16. Embarrassing Interactions

    DEFF Research Database (Denmark)

    Deterding, Sebastian; Lucero, Andrés; Holopainen, Jussi;

    2015-01-01

    Wherever the rapid evolution of interactive technologies disrupts standing situational norms, creates new, often unclear situational audiences, or crosses cultural boundaries, embarrassment is likely. This makes embarrassment a fundamental adoption and engagement hurdle, but also a creative design...

  17. Hadronic Interactions

    CERN Document Server

    Yamazaki, Takeshi

    2015-01-01

    Understanding hadronic interactions is crucial for investigating the properties of unstable hadrons, since measuring physical quantities for unstable hadrons including the resonance mass and decay width requires simultaneous calculations of final scattering states. Recent studies of hadronic scatterings and decays are reviewed from this point of view. The nuceon-nucleon and multi-nucleon interactions are very important to understand the formation of nucleus from the first principle of QCD. These interactions have been studied mainly by two methods, due originally to L\\"uscher and to HALQCD. The results obtained from the two methods are compared in three channels, $I=2$ two-pion, H-dibaryon, and two-nucleon channels. So far the results from the two methods for the two-nucleon channels are different even at the level of the presence or absence of bound states. We then discuss possible uncertainties in each method. Recent results on the binding energy for helium nuclei are also reviewed.

  18. Interaction Widget

    DEFF Research Database (Denmark)

    Ingstrup, Mads

    2003-01-01

    This pattern describes the idea of making a user interface of discrete, reusable entities---here called interaction widgets. The idea behind widgets is described using two perspectives, that of the user and that of the developer. It is the forces from these two perspectives that are balanced in t...... in the pattern. The intended audience of the pattern is developers and researchers within the field of human computer interaction.......This pattern describes the idea of making a user interface of discrete, reusable entities---here called interaction widgets. The idea behind widgets is described using two perspectives, that of the user and that of the developer. It is the forces from these two perspectives that are balanced...

  19. Interactive governance

    DEFF Research Database (Denmark)

    Sørensen, Eva; Torfing, Jacob; Peters, B. Guy

    Governance has become one of the most commonly used concepts in contemporary political science. It is, however, often used to mean a variety of different things. This book helps to clarify this conceptual muddle by concentrating on one variety of governance-interactive governance. The authors argue...... that although the state may remain important for many aspects of governing, interactions between state and society represent an important, and perhaps increasingly important, dimension of governance. These interactions may be with social actors such as networks, with market actors or with other governments......, but all these forms represent means of governing involving mixtures of state action with the actions of other entities.This book explores thoroughly this meaning of governance, and links it to broader questions of governance. In the process of explicating this dimension of governance the authors also...

  20. Programming Interactivity

    CERN Document Server

    Noble, Joshua

    2009-01-01

    Make cool stuff. If you're a designer or artist without a lot of programming experience, this book will teach you to work with 2D and 3D graphics, sound, physical interaction, and electronic circuitry to create all sorts of interesting and compelling experiences -- online and off. Programming Interactivity explains programming and electrical engineering basics, and introduces three freely available tools created specifically for artists and designers: Processing, a Java-based programming language and environment for building projects on the desktop, Web, or mobile phonesArduino, a system t

  1. Kinesthetic Interaction

    DEFF Research Database (Denmark)

    Fogtmann, Maiken Hillerup; Fritsch, Jonas; Kortbek, Karen Johanne

    2008-01-01

    Within the Human-Computer Interaction community there is a growing interest in designing for the whole body in interaction design. The attempts aimed at addressing the body have very different outcomes spanning from theoretical arguments for understanding the body in the design process, to more...... to reveal bodily potential in relation to three design themes – kinesthetic development, kinesthetic means and kinesthetic disorder; and seven design parameters – engagement, sociality, movability, explicit motivation, implicit motivation, expressive meaning and kinesthetic empathy. The framework is a tool...

  2. Audiovisual Interaction

    DEFF Research Database (Denmark)

    Karandreas, Theodoros-Alexandros

    importance of each modality with respect to the overall quality evaluation. The results show that this was not due to specific interactions between stimuli but rather because the auditory modality dominated over the visual modality. Furthermore, for all experiments where less than optimal stimuli...

  3. Interactive Storytelling

    DEFF Research Database (Denmark)

    Schoenau-Fog, Henrik; Reng, Lars

    2015-01-01

    This book constitutes the refereed proceedings of the 8th International Conference on Interactive Digital Storytelling, ICIDS 2015, held in Copenhagen, Denmark, in November/December 2015. The 18 revised full papers and 13 short papers presented together with 9 posters, 9 workshop descriptions, an...

  4. Interactive Astronomy.

    Science.gov (United States)

    Martin, Jean K.

    1997-01-01

    Presents guiding principles for developing interactive lessons for the World Wide Web. Describes "Amazing Space: Education Online from the Hubble Space Telescope", a program where students study spectacular Hubble Space Telescope images of stars and star-forming regions to learn about the life cycle of stars and the creation of atoms. (JRH)

  5. Adhesion and degranulation promoting adapter protein (ADAP is a central hub for phosphotyrosine-mediated interactions in T cells.

    Directory of Open Access Journals (Sweden)

    Marc Sylvester

    Full Text Available TCR stimulation leads to an increase in cellular adhesion among other outcomes. The adhesion and degranulation promoting adapter protein (ADAP is known to be rapidly phosphorylated after T cell stimulation and relays the TCR signal to adhesion molecules of the integrin family. While three tyrosine phosphorylation sites have been characterized biochemically, the binding capabilities and associated functions of several other potential phosphotyrosine motifs remain unclear. Here, we utilize in vitro phosphorylation and mass spectrometry to map novel phosphotyrosine sites in the C-terminal part of human ADAP (486-783. Individual tyrosines were then mutated to phenylalanine and their relevance for cellular adhesion and migration was tested experimentally. Functionally important tyrosine residues include two sites within the folded hSH3 domains of ADAP and two at the C-terminus. Furthermore, using a peptide pulldown approach in combination with stable isotope labeling in cell culture (SILAC we identified SLP-76, PLCgamma, PIK3R1, Nck, CRK, Gads, and RasGAP as phospho-dependent binding partners of a central YDDV motif of ADAP. The phosphorylation-dependent interaction between ADAP and Nck was confirmed by yeast two-hybrid analysis, immunoprecipitation and binary pulldown experiments, indicating that ADAP directly links integrins to modulators of the cytoskeleton independent of SLP-76.

  6. The effect of polylysine on casein-kinase-2 activity is influenced by both the structure of the protein/peptide substrates and the subunit composition of the enzyme

    DEFF Research Database (Denmark)

    Meggio, F; Boldyreff, B; Marin, O;

    1992-01-01

    alpha subunit. The concentration of polylysine required for half-maximal stimulation is comparable to CK2 concentration and increases by increasing CK2 concentration, suggesting that polylysine primarily interacts with the enzyme, rather than with the peptide substrate.......The mechanism by which polybasic peptides stimulate the activity of casein kinase 2 (CK2) has been studied by comparing the effect of polylysine on the phosphorylation of a variety of protein and peptide substrates by the native CK2 holoenzyme and by its recombinant catalytic alpha subunit, either...... phosphorylated by either CK2 holoenzyme or the recombinant alpha subunit with 5.8-fold and 2.8-fold stimulation by polylysine, respectively. The recombinant beta subunit of CK2 is itself a good exogenous substrate for the enzyme, its phosphorylation, however, is inhibited rather than enhanced by polylysine...

  7. Interacting Electrons

    Science.gov (United States)

    Martin, Richard M.; Reining, Lucia; Ceperley, David M.

    2016-06-01

    Preface; Part I. Interacting Electrons: Beyond the Independent-Particle Picture: 1. The many electron problem: introduction; 2. Signatures of electron correlation; 3. Concepts and models for interacting electrons; Part II. Foundations of Theory for Many-Body Systems: 4. Mean fields and auxiliary systems; 5. Correlation functions; 6. Many-body wavefunctions; 7. Particles and quasi-particles; 8. Functionals in many-particle physics; Part III. Many-Body Green's Function Methods: 9. Many-body perturbation theory: expansion in the interaction; 10. Many-body perturbation theory via functional derivatives; 11. The RPA and the GW approximation for the self-energy; 12. GWA calculations in practice; 13. GWA calculations: illustrative results; 14. RPA and beyond: the Bethe-Salpeter equation; 15. Beyond the GW approximation; 16. Dynamical mean field theory; 17. Beyond the single-site approximation in DMFT; 18. Solvers for embedded systems; 19. Characteristic hamiltonians for solids with d and f states; 20. Examples of calculations for solids with d and f states; 21. Combining Green's functions approaches: an outlook; Part IV. Stochastic Methods: 22. Introduction to stochastic methods; 23. Variational Monte Carlo; 24. Projector quantum Monte Carlo; 25. Path integral Monte Carlo; 26. Concluding remarks; Part V. Appendices: A. Second quantization; B. Pictures; C. Green's functions: general properties; D. Matsubara formulation for Green's functions for T ̸= 0; E. Time-ordering, contours, and non-equilibrium; F. Hedin's equations in a basis; G. Unique solutions in Green's function theory; H. Properties of functionals; I. Auxiliary systems and constrained search; J. Derivation of the Luttinger theorem; K. Gutzwiller and Hubbard approaches; References; Index.

  8. Interactive Governance

    DEFF Research Database (Denmark)

    Bang, Henrik

    2016-01-01

    Governance analysis has exploded in recent years, and it has become nearly impossible to tell what difference the concept and practice of governance makes from those of government and state. In addition governance analysis has been placed more and more in the shadow of the new institutionalisms and...... and growth. However, interactive governance is not a property or effect of institutions; nor does it apply solely to those individuals who seek success above everything else. It is connective more than individualistic or collectivistic in nature; and it manifests a governability capacity which...

  9. Sibling interaction.

    Science.gov (United States)

    Balsam, Rosemary H

    2013-01-01

    Sibling interactions traditionally were conceived psychoanalytically in "vertical" and parentified oedipal terms and overlooked in their own right, for complicated reasons (Colonna and Newman 1983). Important work has been done to right this, from the 1980s and onward, with conferences and writings. Juliet Mitchell's 2000 and, in particular, her 2003 books, for example, have brought "lateral" sibling relations forcefully to the forefront of insights, especially about sex and violence, with the added interdisciplinary impact of illuminating upheaval in global community interactions as well as having implications for clinicians. A clinical example from the analysis of an adult woman with a ten-years-younger sister will show here how we need both concepts to help us understand complex individual psychic life. The newer "lateral" sibling emphasis, including Mitchell's "Law of the Mother" and "seriality," can be used to inform the older "vertical" take, to enrich the full dimensions of intersubjective oedipal and preoedipal reciprocities that have been foundational in shaping that particular analysand's inner landscape. Some technical recommendations for heightening sensitivity to the import of these dynamics will be offered along the way here, by invoking Hans Loewald's useful metaphor of the analytic situation as theater.

  10. Electromagnetic interactions

    CERN Document Server

    Bosanac, Slobodan Danko

    2016-01-01

    This book is devoted to theoretical methods used in the extreme circumstances of very strong electromagnetic fields. The development of high power lasers, ultrafast processes, manipulation of electromagnetic fields and the use of very fast charged particles interacting with other charges requires an adequate theoretical description. Because of the very strong electromagnetic field, traditional theoretical approaches, which have primarily a perturbative character, have to be replaced by descriptions going beyond them. In the book an extension of the semi-classical radiation theory and classical dynamics for particles is performed to analyze single charged atoms and dipoles submitted to electromagnetic pulses. Special attention is given to the important problem of field reaction and controlling dynamics of charges by an electromagnetic field.

  11. Electromagnetic interactions

    Energy Technology Data Exchange (ETDEWEB)

    Bosanac, Slobodan Danko [Ruder Boskovic Institute, Zagreb (Croatia). Physical Chemistry

    2016-07-01

    This book is devoted to theoretical methods used in the extreme circumstances of very strong electromagnetic fields. The development of high power lasers, ultrafast processes, manipulation of electromagnetic fields and the use of very fast charged particles interacting with other charges requires an adequate theoretical description. Because of the very strong electromagnetic field, traditional theoretical approaches, which have primarily a perturbative character, have to be replaced by descriptions going beyond them. In the book an extension of the semi-classical radiation theory and classical dynamics for particles is performed to analyze single charged atoms and dipoles submitted to electromagnetic pulses. Special attention is given to the important problem of field reaction and controlling dynamics of charges by an electromagnetic field.

  12. Designing "Interaction": How Do Interaction Design Students Address Interaction?

    Science.gov (United States)

    Karlgren, Klas; Ramberg, Robert; Artman, Henrik

    2016-01-01

    Interaction design is usually described as being concerned with interactions with and through artifacts but independent of a specific implementation. Design work has been characterized as a conversation between the designer and the situation and this conversation poses a particular challenge for interaction design as interactions can be elusive…

  13. Cloud Interactions

    Science.gov (United States)

    2004-01-01

    [figure removed for brevity, see original site] Released 1 July 2004 The atmosphere of Mars is a dynamic system. Water-ice clouds, fog, and hazes can make imaging the surface from space difficult. Dust storms can grow from local disturbances to global sizes, through which imaging is impossible. Seasonal temperature changes are the usual drivers in cloud and dust storm development and growth. Eons of atmospheric dust storm activity has left its mark on the surface of Mars. Dust carried aloft by the wind has settled out on every available surface; sand dunes have been created and moved by centuries of wind; and the effect of continual sand-blasting has modified many regions of Mars, creating yardangs and other unusual surface forms. This image was acquired during mid-spring near the North Pole. The linear water-ice clouds are now regional in extent and often interact with neighboring cloud system, as seen in this image. The bottom of the image shows how the interaction can destroy the linear nature. While the surface is still visible through most of the clouds, there is evidence that dust is also starting to enter the atmosphere. Image information: VIS instrument. Latitude 68.4, Longitude 258.8 East (101.2 West). 38 meter/pixel resolution. Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time. NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara

  14. KinomeXplorer: an integrated platform for kinome biology studies

    DEFF Research Database (Denmark)

    Horn, Heiko; Schoof, Erwin; Kim, Jinho;

    2014-01-01

    A letter to the editor is presented related to the KinomeXplorer, an integrated platform providing workflows to efficiently analyze phosphorylation dependent interaction networks or kinase signaling networks.......A letter to the editor is presented related to the KinomeXplorer, an integrated platform providing workflows to efficiently analyze phosphorylation dependent interaction networks or kinase signaling networks....

  15. Unification of Electromagnetic Interactions and Gravitational Interactions

    Institute of Scientific and Technical Information of China (English)

    WUNing

    2002-01-01

    Unified theory of gravitational interactions and electromagnetic interactions is discussed in this paper.Based on gauge principle,electromagnetic interactions and gravitational interactions are formulated in the same manner and are unified in a semi-direct product group of U(1) Abelian gauge group and gravitational gauge group.

  16. Unification of Electromagnetic Interactions and Gravitational Interactions

    Institute of Scientific and Technical Information of China (English)

    WU Ning

    2002-01-01

    Unified theory of gravitational interactions and electromagnetic interactions is discussed in this paper.Based on gauge principle, electromagnetic interactions and gravitational interactions are formulated in the same mannerand are unified in a semi-direct product group of U(1) Abelian gauge group and gravitational gauge group.

  17. Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.

    Science.gov (United States)

    Carmona, G; Perera, U; Gillett, C; Naba, A; Law, A-L; Sharma, V P; Wang, J; Wyckoff, J; Balsamo, M; Mosis, F; De Piano, M; Monypenny, J; Woodman, N; McConnell, R E; Mouneimne, G; Van Hemelrijck, M; Cao, Y; Condeelis, J; Hynes, R O; Gertler, F B; Krause, M

    2016-09-29

    Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.

  18. Erioflorin stabilizes the tumor suppressor Pdcd4 by inhibiting its interaction with the E3-ligase β-TrCP1.

    Science.gov (United States)

    Blees, Johanna S; Bokesch, Heidi R; Rübsamen, Daniela; Schulz, Kathrin; Milke, Larissa; Bajer, Magdalena M; Gustafson, Kirk R; Henrich, Curtis J; McMahon, James B; Colburn, Nancy H; Schmid, Tobias; Brüne, Bernhard

    2012-01-01

    Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70(S6K1)-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition.

  19. Erioflorin stabilizes the tumor suppressor Pdcd4 by inhibiting its interaction with the E3-ligase β-TrCP1.

    Directory of Open Access Journals (Sweden)

    Johanna S Blees

    Full Text Available Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70(S6K1-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin, it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target and HIF-1α (a pVHL-target, implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition.

  20. Drug Interaction API

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Interaction API is a web service for accessing drug-drug interactions. No license is needed to use the Interaction API. Currently, the API uses DrugBank for its...

  1. Problem of interactions: electromagnetic particles interaction

    CERN Document Server

    Sannikov-Proskuryakov, S S

    2001-01-01

    The electromagnetic interactions between charged particles are derived on the basis of the particles dynamic theory, proposed in the work of Sannikov. The electromagnetic interactions exist only in the relativistic model of the bihamiltonian system, based on the Heisenberg algebra. Existence of this type of interactions is connected with the U sub e (1)-degeneration of the basic state of the relativistic bihamiltonian system, lying in the basis of the given theory

  2. Interactive pinball business

    DEFF Research Database (Denmark)

    Buur, Jacob; Gudiksen, Sune Klok

    2012-01-01

    Interaction design expands into new fields. Interaction design and business model innovation is a promising meeting of disciplines: Many businesses see the need to rethink their ways of doing business, and, as business models pose highly dynamic and interactive problems, interaction design has much...

  3. PIC: Protein Interactions Calculator.

    Science.gov (United States)

    Tina, K G; Bhadra, R; Srinivasan, N

    2007-07-01

    Interactions within a protein structure and interactions between proteins in an assembly are essential considerations in understanding molecular basis of stability and functions of proteins and their complexes. There are several weak and strong interactions that render stability to a protein structure or an assembly. Protein Interactions Calculator (PIC) is a server which, given the coordinate set of 3D structure of a protein or an assembly, computes various interactions such as disulphide bonds, interactions between hydrophobic residues, ionic interactions, hydrogen bonds, aromatic-aromatic interactions, aromatic-sulphur interactions and cation-pi interactions within a protein or between proteins in a complex. Interactions are calculated on the basis of standard, published criteria. The identified interactions between residues can be visualized using a RasMol and Jmol interface. The advantage with PIC server is the easy availability of inter-residue interaction calculations in a single site. It also determines the accessible surface area and residue-depth, which is the distance of a residue from the surface of the protein. User can also recognize specific kind of interactions, such as apolar-apolar residue interactions or ionic interactions, that are formed between buried or exposed residues or near the surface or deep inside.

  4. Designing for mobile interaction

    DEFF Research Database (Denmark)

    Nazzi, Elena

    2009-01-01

    The theme of this PhD project is designing for mobile interaction with devices and services, for the accessing, making, and sharing of information, taking into account the dynamic physical and social settings that embrace this interaction. To narrow down this theme, the whole project focuses...... on the exploitation of social interaction --- in particular among senior citizens --- to enhance and support mobile interaction....

  5. Aggregation of Ribosomal Protein S6 at Nucleolus Is Cell Cycle-Controlled and Its Function in Pre-rRNA Processing Is Phosphorylation Dependent.

    Science.gov (United States)

    Zhang, Duo; Chen, Hui-Peng; Duan, Hai-Feng; Gao, Li-Hua; Shao, Yong; Chen, Ke-Yan; Wang, You-Liang; Lan, Feng-Hua; Hu, Xian-Wen

    2016-07-01

    Ribosomal protein S6 (rpS6) has long been regarded as one of the primary r-proteins that functions in the early stage of 40S subunit assembly, but its actual role is still obscure. The correct forming of 18S rRNA is a key step in the nuclear synthesis of 40S subunit. In this study, we demonstrate that rpS6 participates in the processing of 30S pre-rRNA to 18S rRNA only when its C-terminal five serines are phosphorylated, however, the process of entering the nucleus and then targeting the nucleolus does not dependent its phosphorylation. Remarkably, we also find that the aggregation of rpS6 at the nucleolus correlates to the phasing of cell cycle, beginning to concentrate in the nucleolus at later S phase and disaggregate at M phase. J. Cell. Biochem. 117: 1649-1657, 2016. © 2015 Wiley Periodicals, Inc.

  6. RKIP phosphorylation-dependent ERK1 activation stimulates adipogenic lipid accumulation in 3T3-L1 preadipocytes overexpressing LC3.

    Science.gov (United States)

    Hahm, Jong Ryeal; Ahmed, Mahmoud; Kim, Deok Ryong

    2016-09-01

    3T3-L1 preadipocytes undergo adipogenesis in response to treatment with dexamethaxone, 1-methyl-3-isobutylxanthine, and insulin (DMI) through activation of several adipogenic transcription factors. Many autophagy-related proteins are also highly activated in the earlier stages of adipogenesis, and the LC3 conjugation system is required for formation of lipid droplets. Here, we investigated the effect of overexpression of green fluorescent protein (GFP)-LC3 fusion protein on adipogenesis. Overexpression of GFP-LC3 in 3T3-L1 preadipocytes using poly-l-lysine-assisted adenoviral GFP-LC3 transduction was sufficient to produce intracellular lipid droplets. Indeed, GFP-LC3 overexpression stimulated expression of some adipogenic transcription factors (e.g., C/EBPα or β, PPARγ, SREBP2). In particular, SREBP2 was highly activated in preadipocytes transfected with adenoviral GFP-LC3. Also, phosphorylation of Raf kinase inhibitory protein (RKIP) at serine 153, consequently stimulating extracellular-signal regulated kinase (ERK)1 activity, was significantly increased during adipogenesis induced by either poly-l-lysine-assisted adenoviral GFP-LC3 transduction or culture in the presence of dexamethasone, 1-methyl-3-isobutylxanthine, and insulin. Furthermore, RKIP knockdown promoted ERK1 and PPARγ activation, and significantly increased the intracellular accumulation of triacylglycerides in DMI-induced adipogenesis. In conclusion, GFP-LC3 overexpression in 3T3-L1 preadipocytes stimulates adipocyte differentiation via direct modulation of RKIP-dependent ERK1 activity.

  7. Investigating the Role of Akt1 in Prostate Cancer Development Through Phosphorylation-Dependent Regulation of Skp2 Stability and Oncogenic Function

    Science.gov (United States)

    2010-09-01

    mice to cancer development [12]. However, in contrast with known tumor suppressor genes such as p53 or Rb, homozygous loss or silencing of the p27 gene ...cases loss of this differentiated state plays a major role in promoting tumorigenesis, and p27 has been demonstrated to be a critical player. KPC has... Genes Dev 2004, 18(21):2573-2580.Page 6 of 8 (page number not for citation purposes) Cell Division 2009, 4:11 http://www.celldiv.com/content/4/1/115

  8. Tyrosine phosphorylation-dependent activation of phosphatidylinositide 3-kinase occurs upstream of Ca^(2+)-signalling induced by Fcy receptor cross-linking in human neutrophils

    NARCIS (Netherlands)

    Vossebeld, Paula J. M.; Homburg, Christa H. E.; Schweizer, R.C.; Ibarrola, Iñaki; Kessler, Jan; Koenderman, L.; Roos, Dirk; Verhoeven, Arthur J.

    2002-01-01

    The effect of wortmannin on IgG-receptor (FcyR)-mediated stimulation of human neutrophils was investigated. The Ca^(2+) influx induced by clustering of both Fcy receptors was inhibited by wortmannin, as was the release of Ca^(2+) from intracellular stores. Wortmannin also inhibited, with the same ef

  9. Interaction for visualization

    CERN Document Server

    Tominski, Christian

    2015-01-01

    Visualization has become a valuable means for data exploration and analysis. Interactive visualization combines expressive graphical representations and effective user interaction. Although interaction is an important component of visualization approaches, much of the visualization literature tends to pay more attention to the graphical representation than to interaction.The goal of this work is to strengthen the interaction side of visualization. Based on a brief review of general aspects of interaction, we develop an interaction-oriented view on visualization. This view comprises five key as

  10. Interactive CFD simulations

    OpenAIRE

    Duque Lombana, Juan Fernando

    2007-01-01

    This project is about the development of an implementable Interactive Computer Fluid Dynamics methodology -- The range of this work begins with an overview of the current status of computational fluid dynamics simulation software and methodologies, continues with an introduction to what interactive and interactivity mean, develops an all original interactive CFD methodology to follow for the solution of fluid scenarios and finally, the description of the implementation of an interactive solve...

  11. Bile acid interactions with cholangiocytes

    Institute of Scientific and Technical Information of China (English)

    Xuefeng Xia; Heather Francis; Shannon Glaser; Gianfranco Alpini; Gene LeSage

    2006-01-01

    Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2)is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3,an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, OstαOstβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliaryplexus back to hepatocytes for re-secretion into bile.This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines.Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogenactivated protein (MAP) kinase and extracellular signalregulated protein kinase (ERK) intracellular signals.Bile acids significantly alter cholangiocyte secretion,proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals,and in some instances trigger opposing effects on cholangiocyte secretion

  12. Casein kinase 2α regulates multidrug resistance-associated protein 1 function via phosphorylation of Thr249.

    Science.gov (United States)

    Stolarczyk, Elzbieta I; Reiling, Cassandra J; Pickin, Kerry A; Coppage, Ryan; Knecht, Marc R; Paumi, Christian M

    2012-09-01

    We have shown previously that the function of Ycf1p, yeast ortholog of multidrug resistance-associated protein 1 (MRP1), is regulated by yeast casein kinase 2α (Cka1p) via phosphorylation at Ser251. In this study, we explored whether casein kinase 2α (CK2α), the human homolog of Cka1p, regulates MRP1 by phosphorylation at the semiconserved site Thr249. Knockdown of CK2α in MCF7-derived cells expressing MRP1 [MRP1 CK2α(-)] resulted in increased doxorubicin sensitivity. MRP1-dependent transport of leukotriene C(4) and estradiol-17β-d-glucuronide into vesicles derived from MRP1 CK2α(-) cells was decreased compared with MRP1 vesicles. Moreover, mutation of Thr249 to alanine (MRP1-T249A) also resulted in decreased MRP1-dependent transport, whereas a phosphomimicking mutation (MRP1-T249E) led to dramatic increase in MRP1-dependent transport. Studies in tissue culture confirmed these findings, showing increased intracellular doxorubicin accumulation in MRP1 CK2α(-) and MRP1-T249A cells compared with MRP1 cells. Inhibition of CK2 kinase by 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole resulted in increased doxorubicin accumulation in MRP1 cells, but not in MRP1 CK2α(-), MRP1-T249A, or MRP1-T249E cells, suggesting that CK2α regulates MRP1 function via phosphorylation of Thr249. Indeed, CK2α and MRP1 interact physically, and recombinant CK2 phosphorylates MRP1-derived peptide in vitro in a Thr249-dependent manner, whereas knockdown of CK2α results in decreased phosphorylation at MRP1-Thr249. The role of CK2 in regulating MRP1 was confirmed in other cancer cell lines where CK2 inhibition decreased MRP1-mediated efflux of doxorubicin and increased doxorubicin cytotoxicity. This study supports a model in which CK2α potentiates MRP1 function via direct phosphorylation of Thr249.

  13. Interactive Pinball Business

    DEFF Research Database (Denmark)

    Buur, Jacob; Gudiksen, Sune

    2012-01-01

    Interaction design expands into new fields. Interaction design and business model innovation is a promising meeting of disciplines: Many businesses see the need to rethink their ways of doing business, and, as business models pose highly dynamic and interactive problems, interaction design has much...... to offer. This paper compares ‘tangible business models’ in the form of pinball-like contraptions, designed by interaction design students with those developed by groups of professionals around concrete business issues. We will show how the interactive models encourage business people to play...... with hypotheses and experiment with scenarios as a way of innovating their business models, and why this is so....

  14. Phosphorylation of murine double minute clone 2 (MDM2) protein at serine-267 by protein kinase CK2 in vitro and in cultured cells

    DEFF Research Database (Denmark)

    Hjerrild, M; Milne, D; Dumaz, N

    2001-01-01

    Murine double minute clone 2 oncoprotein (MDM2) is a key component in the regulation of the tumour suppressor p53. MDM2 mediates the ubiqutination of p53 in the capacity of an E3 ligase and targets p53 for rapid degradation by the proteasome. Stress signals which impinge on p53, leading to its...... activation, promote disruption of the p53-MDM2 complex, as in the case of ionizing radiation, or block MDM2 synthesis and thereby reduce cellular MDM2 levels, as in the case of UV radiation. It is therefore likely that MDM2, which is known to be modified by ubiquitination, SUMOylation and multi......,6-dichlororibofuranosylbenzimidazole. Radiolabelling of cells expressing tagged recombinant wild-type MDM2 or a S267A (Ser(267)-->Ala) mutant, followed by phosphopeptide analysis, confirmed that Ser(267) is a cellular target for phosphorylation. Ser(267) mutants are still able to direct the degradation of p53, but in a slightly...

  15. Protein kinase CK2 phosphorylates the Fas-associated factor FAF1 in vivo and influences its transport into the nucleus

    DEFF Research Database (Denmark)

    Olsen, Birgitte B; Jessen, Vibeke; Højrup, Peter;

    2003-01-01

    is phosphorylated in vivo. Furthermore, we analyzed putative physiological functions of FAF1 phosphorylation. The ability of FAF1 to potentiate Fas-induced apoptosis is not influenced by the FAF1 phosphorylation status; however, the nuclear import of a phosphorylation-deficient FAF1 mutant was delayed in comparison...

  16. Interacting agents in finance

    NARCIS (Netherlands)

    C. Hommes

    2008-01-01

    Interacting agents in finance represent a behavioural, agent-based approach in which financial markets are viewed as complex adaptive systems consisting of many boundedly rational agents interacting through simple heterogeneous investment strategies, constantly adapting their behaviour in response t

  17. Health Data Interactive (HDI)

    Data.gov (United States)

    U.S. Department of Health & Human Services — Health Data Interactive (HDI) presents a broad range of important public health indicators through an interactive web-based application that provides access to...

  18. Sea Turtle Interaction Report

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Sea Turtle Interaction Report is a report sent out in pdf format to authorized individuals that summarizes sea turtle interactions in the longline fishery. The...

  19. Gestalt Interactional Groups

    Science.gov (United States)

    Harman, Robert L.; Franklin, Richard W.

    1975-01-01

    Gestalt therapy in groups is not limited to individual work in the presence of an audience. Describes several ways to involve gestalt groups interactionally. Interactions described focus on learning by doing and discovering, and are noninterpretive. (Author/EJT)

  20. Diachronic Perspective and Interaction

    DEFF Research Database (Denmark)

    Marchetti, Emanuela; Valente, Andrea

    . An ongoing participatory inquiry is being conducted, to explore deeper forms of learning and communication for historical museums. Our hypothesis is that the diachronic perspective on historical processes, defined as social interaction within the environment through time, is a key missing element....... Explorations of more interactive representations of the diachronic perspective, through play and tangible interaction, may foster a dialogue with young visitors. Therefore, a new interactive installation is being designed, intended as a tool to enrich learning, allowing children to experience historical...

  1. Gaze Interactive Building Instructions

    DEFF Research Database (Denmark)

    Hansen, John Paulin; Ahmed, Zaheer; Mardanbeigi, Diako

    We combine eye tracking technology and mobile tablets to support hands-free interaction with digital building instructions. As a proof-of-concept we have developed a small interactive 3D environment where one can interact with digital blocks by gaze, keystroke and head gestures. Blocks may be moved...

  2. Interactivity: A Forgotten Art?

    Science.gov (United States)

    Sims, Rod

    1997-01-01

    This paper promotes further discussion and analysis of interactivity in learning environments and contains a classification of interaction types appropriate for consideration in multimedia settings. Through an examination of related factors associated with navigation and control, a matrix of interactive dimensions is proposed. (Author)

  3. Device-less interaction

    NARCIS (Netherlands)

    Monaci, G.; Triki, M.; Sarroukh, B.E.

    2009-01-01

    This document describes the results of a technology survey for device-less interaction. The Device-less Interaction project (2007-307) aims at providing interaction options for future home appliances without resorting to a remote control or any other dedicated control device. The target home applia

  4. Interaction and Language Acquisition

    Institute of Scientific and Technical Information of China (English)

    孙红叶

    2016-01-01

    Based on Long's Interaction Hypothesis (IH), the paper examines the aspects of interaction that might facilitate natu-ralistic language development and goes further to propose features of interaction that could encourage classroom second lan-guage acquisition, in the hope that improved classroom interation will enhance teaching effectiveness in language classroom.

  5. Dynamic Interactive Learning Systems

    Science.gov (United States)

    Sabry, Khaled; Barker, Jeff

    2009-01-01

    This paper reviews and discusses the notions of interactivity and dynamicity of learning systems in relation to information technologies and design principles that can contribute to interactive and dynamic learning. It explores the concept of dynamic interactive learning systems based on the emerging generation of information as part of a…

  6. The Interactive Learning Toolkit: supporting interactive classrooms

    Science.gov (United States)

    Dutta, S.; McCauley, V.; Mazur, E.

    2004-05-01

    Research-based interactive learning techniques have dramatically improved student understanding. We have created the 'Interactive Learning Toolkit' (ILT), a web-based learning management system, to help implement two such pedagogies: Just in Time Teaching and Peer Instruction. Our main goal in developing this toolkit is to save the instructor time and effort and to use technology to facilitate the interaction between the students and the instructor (and between students themselves). After a brief review of both pedagogies, we will demonstrate the many exciting new features of the ILT. We will show how technology can not only implement, but also supplement and improve these pedagogies. We would like acknowdge grants from NSF and DEAS, Harvard University

  7. Food-drug interactions

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    Interactions between food and drugs may inadvertently reduce or increase the drug effect. The majority of clinically relevant food-drug interactions are caused by food-induced changes in the bioavailability of the drug. Since the bioavailability and clinical effect of most drugs are correlated......, the bioavailability is an important pharmacokinetic effect parameter. However, in order to evaluate the clinical relevance of a food-drug interaction, the impact of food intake on the clinical effect of the drug has to be quantified as well. As a result of quality review in healthcare systems, healthcare providers...... are increasingly required to develop methods for identifying and preventing adverse food-drug interactions. In this review of original literature, we have tried to provide both pharmacokinetic and clinical effect parameters of clinically relevant food-drug interactions. The most important interactions are those...

  8. Grasp interaction with tablets

    CERN Document Server

    Wolf, Katrin

    2015-01-01

    This book presents guidelines for a future device type: a tablet that allows ergonomic front- and back-of-device interaction. These guidelines help designers and developers of user interfaces to build ergonomic applications for tablet devices, in particular for devices that enable back-of-device interaction. In addition, manufacturers of tablet devices obtain arguments that back-of-device interaction is a promising extension of the interaction design space and results in increased input capabilities, enriched design possibilities, and proven usability. The guidelines are derived from empirical studies and developed to fit the users’ skills to the way the novel device type is held. Three particular research areas that are relevant to develop design guidelines for tablet interaction are investigated: ergonomic gestures, interaction areas, and pointing techniques.

  9. Two interacting Hofstadter butterflies

    OpenAIRE

    Barelli, Armelle; Bellissard, Jean; Jacquod, Philippe; Shepelyansky, Dima L.

    1996-01-01

    The problem of two interacting particles in a quasiperiodic potential is addressed. Using analytical and numerical methods, we explore the spectral properties and eigenstates structure from the weak to the strong interaction case. More precisely, a semiclassical approach based on non commutative geometry techniques permits to understand the intricate structure of such a spectrum. An interaction induced localization effect is furthermore emphasized. We discuss the application of our results on...

  10. Interactions in multispecies biofilms

    DEFF Research Database (Denmark)

    Burmølle, Mette; Ren, Dawei; Bjarnsholt, Thomas;

    2014-01-01

    The recent focus on complex bacterial communities has led to the recognition of interactions across species boundaries. This is particularly pronounced in multispecies biofilms, where synergistic interactions impact the bacterial distribution and overall biomass produced. Importantly, in a number...... of settings, the interactions in a multispecies biofilm affect its overall function, physiology, or surroundings, by resulting in enhanced resistance, virulence, or degradation of pollutants, which is of significant importance to human health and activities. The underlying mechanisms causing these synergistic...

  11. Interactive Strategy-Making

    DEFF Research Database (Denmark)

    Andersen, Torben Juul

    2015-01-01

    to failed communication and execution of the planned actions. However, effective strategy-making comprises both central reasoning from forward-looking planning considerations and decentralised responses to emerging events as interacting elements in a dynamic adaptive system. The interaction between......This article outlines an interactive strategy-making model that combines central reasoning with ongoing learning from decentralised responses. The management literature often presents strategy as implementing an optimal plan identified through rational analysis and ascribes potential shortcomings...

  12. Quantum interaction. Proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Bruza, Peter [Queensland Univ. of Technology, Brisbane (Australia). Faculty of Science and Technology; Sofge, Donald [Navy Center for Applied Research in Artificial Intelligence, Washington, DC (United States). Naval Research Lab.; Lawless, William [Paine Coll., Augusta, GA (United States); Rijsbergen, Keith van [Glasgow Univ. (United Kingdom). Dept. of Computing Science; Klusch, Matthias (eds.) [German Research Center for Artificial Intelligence, Saarbruecken (Germany)

    2009-07-01

    This book constitutes the refereed proceedings of the Third International Symposium on Quantum Interaction, QI 2009, held in Saarbruecken, Germany, in March 2009. The 21 revised full papers presented together with the 3 position papers were carefully reviewed and selected from numerous submissions. The papers show the cross-disciplinary nature of quantum interaction covering topics such as computation, cognition, decision theory, information retrieval, information systems, social interaction, computational linguistics and finance. (orig.)

  13. Two interacting Hofstadter butterflies

    Energy Technology Data Exchange (ETDEWEB)

    Barelli, A.; Bellissard, J. [Laboratoire de Physique Quantique, UMR 5626 du CNRS, Universite Paul Sabatier, F-31062 Toulouse Cedex (France); Jacquod, P. [Institut de Physique, Universite de Neuchatel, CH-2000 Neuchatel (Switzerland), Confederation Helvetique; Shepelyansky, D.L. [Laboratoire de Physique Quantique, UMR 5626 du CNRS, Universite Paul Sabatier, F-31062 Toulouse Cedex (France)

    1997-04-01

    The problem of two interacting particles in a quasiperiodic potential is addressed. Using analytical and numerical methods, we explore the spectral properties and eigenstates structure from the weak to the strong interaction case. More precisely, a semiclassical approach based on noncommutative geometry techniques is used to understand the intricate structure of such a spectrum. An interaction induced localization effect is furthermore emphasized. We discuss the application of our results on a two-dimensional model of two particles in a uniform magnetic field with on-site interaction. {copyright} {ital 1997} {ital The American Physical Society}

  14. Framing interactive methods

    DEFF Research Database (Denmark)

    2011-01-01

    Two paradigms of organization and leadership is outlined and compared. A theoretical model of interactive leadership is developed, combining learning, knowledge flow, leadership and organizational principles....

  15. Philosophy of Interaction

    DEFF Research Database (Denmark)

    Svanæs, Dag

    2011-01-01

    This is an encyclopedia entry for the Interaction-Design.org free IxD encyclopedia. The topic of the entry is the application of the philosophy of Heidegger and Merleau-Ponty to a theory of interactivity. Comments by Don Norman and Eva Hornecker.......This is an encyclopedia entry for the Interaction-Design.org free IxD encyclopedia. The topic of the entry is the application of the philosophy of Heidegger and Merleau-Ponty to a theory of interactivity. Comments by Don Norman and Eva Hornecker....

  16. Vision-based interaction

    CERN Document Server

    Turk, Matthew

    2013-01-01

    In its early years, the field of computer vision was largely motivated by researchers seeking computational models of biological vision and solutions to practical problems in manufacturing, defense, and medicine. For the past two decades or so, there has been an increasing interest in computer vision as an input modality in the context of human-computer interaction. Such vision-based interaction can endow interactive systems with visual capabilities similar to those important to human-human interaction, in order to perceive non-verbal cues and incorporate this information in applications such

  17. Proxemic Mobile Collocated Interactions

    DEFF Research Database (Denmark)

    Porcheron, Martin; Lucero, Andrés; Quigley, Aaron

    2016-01-01

    and their digital devices (i.e. the proxemic relationships). Building on the ideas of proxemic interactions, this workshop is motivated by the concept of ‘proxemic mobile collocated interactions’, to harness new or existing technologies to create engaging and interactionally relevant experiences. Such approaches......Recent research on mobile collocated interactions has been looking at situations in which collocated users engage in collaborative activities using their mobile devices. However, existing practices fail to fully account for the culturally-dependent spatial relationships between people...... in exploring proxemics and mobile collocated interactions....

  18. Drug-nutrient interactions.

    Science.gov (United States)

    Chan, Lingtak-Neander

    2013-07-01

    Drug-nutrient interactions are defined as physical, chemical, physiologic, or pathophysiologic relationships between a drug and a nutrient. The causes of most clinically significant drug-nutrient interactions are usually multifactorial. Failure to identify and properly manage drug-nutrient interactions can lead to very serious consequences and have a negative impact on patient outcomes. Nevertheless, with thorough review and assessment of the patient's history and treatment regimens and a carefully executed management strategy, adverse events associated with drug-nutrient interactions can be prevented. Based on the physiologic sequence of events after a drug or a nutrient has entered the body and the mechanism of interactions, drug-nutrient interactions can be categorized into 4 main types. Each type of interaction can be managed using similar strategies. The existing data that guide the clinical management of most drug-nutrient interactions are mostly anecdotal experience, uncontrolled observations, and opinions, whereas the science in understanding the mechanism of drug-nutrient interactions remains limited. The challenge for researchers and clinicians is to increase both basic and higher level clinical research in this field to bridge the gap between the science and practice. The research should aim to establish a better understanding of the function, regulation, and substrate specificity of the nutrient-related enzymes and transport proteins present in the gastrointestinal tract, as well as assess how the incidence and management of drug-nutrient interactions can be affected by sex, ethnicity, environmental factors, and genetic polymorphisms. This knowledge can help us develop a true personalized medicine approach in the prevention and management of drug-nutrient interactions.

  19. Child Computer Interaction SIG

    DEFF Research Database (Denmark)

    Read, Janet; Hourcade, Juan Pablo; Markopoulos, Panos

    The discipline of Child Computer Interaction (CCI) has been steadily growing and it is now firmly established as a community in its own right, having the annual IDC (Interaction and Design for Children) conference and its own journal and also enjoying its role as a highly recognisable and vibrant...

  20. Visualizing Dispersion Interactions

    Science.gov (United States)

    Gottschalk, Elinor; Venkataraman, Bhawani

    2014-01-01

    An animation and accompanying activity has been developed to help students visualize how dispersion interactions arise. The animation uses the gecko's ability to walk on vertical surfaces to illustrate how dispersion interactions play a role in macroscale outcomes. Assessment of student learning reveals that students were able to develop…

  1. Progress on Multiple Interactions

    CERN Document Server

    Skands, P Z

    2004-01-01

    We report on the development of a new model for the underlying event in hadron-hadron collisions. The model includes parton showers for all interactions, as well as non-trivial flavour, momentum, and colour correlations between interaction initiators and beam remnant partons.

  2. Moving into an interaction

    DEFF Research Database (Denmark)

    Mortensen, Kristian; Hazel, Spencer

    2014-01-01

    Opening an interaction is a crucial step in establishing and maintaining social relationships. In this paper we describe how participants in an institutional setting, a help desk counter for exchange students at an international university, literally move into interaction. This is accomplished...

  3. INTERACT Station Catalogue - 2015

    DEFF Research Database (Denmark)

    INTERACT stations are located in all major environmental envelopes of the Arctic providing an ideal platform for studying climate change and its impact on the environment and local communities. Since alpine environments face similar changes and challenges as the Arctic, the INTERACT network also ...

  4. Storyboarding Multimedia Interactions.

    Science.gov (United States)

    Martin, Linda C.

    2000-01-01

    Understanding how to include interactivity when designing multimedia-based training (MBT) storyboards is a major key for a successful MBT. Discusses the basic formats of interactions and when to use each format. Describes how to storyboard and areas to address, including: the display area, prompts, branching, programming and graphics notes,…

  5. Interactive Visualization of Dependencies

    Science.gov (United States)

    Moreno, Camilo Arango; Bischof, Walter F.; Hoover, H. James

    2012-01-01

    We present an interactive tool for browsing course requisites as a case study of dependency visualization. This tool uses multiple interactive visualizations to allow the user to explore the dependencies between courses. A usability study revealed that the proposed browser provides significant advantages over traditional methods, in terms of…

  6. Contribution of casein kinase 2 and spleen tyrosine kinase to CFTR trafficking and protein kinase A-induced activity.

    Science.gov (United States)

    Luz, Simão; Kongsuphol, Patthara; Mendes, Ana Isabel; Romeiras, Francisco; Sousa, Marisa; Schreiber, Rainer; Matos, Paulo; Jordan, Peter; Mehta, Anil; Amaral, Margarida D; Kunzelmann, Karl; Farinha, Carlos M

    2011-11-01

    Previously, the pleiotropic "master kinase" casein kinase 2 (CK2) was shown to interact with CFTR, the protein responsible for cystic fibrosis (CF). Moreover, CK2 inhibition abolished CFTR conductance in cell-attached membrane patches, native epithelial ducts, and Xenopus oocytes. CFTR possesses two CK2 phosphorylation sites (S422 and T1471), with unclear impact on its processing and trafficking. Here, we investigated the effects of mutating these CK2 sites on CFTR abundance, maturation, and degradation coupled to effects on ion channel activity and surface expression. We report that CK2 inhibition significantly decreased processing of wild-type (wt) CFTR, with no effect on F508del CFTR. Eliminating phosphorylation at S422 and T1471 revealed antagonistic roles in CFTR trafficking: S422 activation versus T1471 inhibition, as evidenced by a severe trafficking defect for the T1471D mutant. Notably, mutation of Y512, a consensus sequence for the spleen tyrosine kinase (SYK) possibly acting in a CK2 context adjacent to the common CF-causing defect F508del, had a strong effect on both maturation and CFTR currents, allowing the identification of this kinase as a novel regulator of CFTR. These results reinforce the importance of CK2 and the S422 and T1471 residues for regulation of CFTR and uncover a novel regulation of CFTR by SYK, a recognized controller of inflammation.

  7. Magnetic interactions between nanoparticles

    DEFF Research Database (Denmark)

    Mørup, Steen; Hansen, Mikkel Fougt; Frandsen, Cathrine

    2010-01-01

    We present a short overview of the influence of inter-particle interactions on the properties of magnetic nanoparticles. Strong magnetic dipole interactions between ferromagnetic or ferrimagnetic particles, that would be superparamagnetic if isolated, can result in a collective state...... of nanoparticles. This collective state has many similarities to spin-glasses. In samples of aggregated magnetic nanoparticles, exchange interactions are often important and this can also lead to a strong suppression of superparamagnetic relaxation. The temperature dependence of the order parameter in samples...... of strongly interacting hematite nanoparticles or goethite grains is well described by a simple mean field model. Exchange interactions between nanoparticles with different orientations of the easy axes can also result in a rotation of the sub-lattice magnetization directions....

  8. Laser-surface interactions

    CERN Document Server

    Ganeev, Rashid A

    2014-01-01

    This book is about the interaction of laser radiation with various surfaces at variable parameters of radiation. As a basic principle of classification we chose the energetic or intensity level of interaction of laser radiation with the surfaces. These two characteristics of laser radiation are the most important parameters defining entire spectrum of the processes occurring on the surfaces during interaction with electromagnetic waves. This is a first book containing a whole spectrum of the laser-surface interactions distinguished by the ranges of used laser intensity. It combines the surface response starting from extremely weak laser intensities (~1 W cm-2) up to the relativistic intensities (~1020 W cm-2 and higher). The book provides the basic information about lasers and acquaints the reader with both common applications of laser-surface interactions (laser-related printers, scanners, barcode readers, discs, material processing, military, holography, medicine, etc) and unusual uses of the processes on t...

  9. Human Work Interaction Design

    DEFF Research Database (Denmark)

    Lopes, Arminda; Ørngreen, Rikke

    This book constitutes the thoroughly refereed post-conference proceedings of the Third IFIP WG 13.6 Working Conference on Human Work Interaction Design, HWID 2012, held in Copenhagen, Denmark, in December 2012. The 16 revised papers presented were carefully selected for inclusion in this volume. ......, and mobile probing. They have been organized in the following topical sections: work analysis: dimensions and methods; interactions, models and approaches; and evaluations, interactions and applications.......This book constitutes the thoroughly refereed post-conference proceedings of the Third IFIP WG 13.6 Working Conference on Human Work Interaction Design, HWID 2012, held in Copenhagen, Denmark, in December 2012. The 16 revised papers presented were carefully selected for inclusion in this volume....... The papers reflect many different areas and address many complex and diverse work domains, ranging from medical user interfaces, work and speech interactions at elderly care facilities, greenhouse climate control, navigating through large oil industry engineering models, crisis management, library usability...

  10. Extrasolar Planet Interactions

    CERN Document Server

    Barnes, Rory

    2008-01-01

    The dynamical interactions of planetary systems may be a clue to their formation histories. Therefore, the distribution of these interactions provides important constraints on models of planet formation. We focus on each system's apsidal motion and proximity to dynamical instability. Although only ~25 multiple planet systems have been discovered to date, our analyses in these terms have revealed several important features of planetary interactions. 1) Many systems interact such that they are near the boundary between stability and instability. 2) Planets tend to form such that at least one planet's eccentricity periodically drops to near zero. 3) Mean-motion resonant pairs would be unstable if not for the resonance. 4) Scattering of approximately equal mass planets is unlikely to produce the observed distribution of apsidal behavior. 5) Resonant interactions may be identified through calculating a system's proximity to instability, regardless of knowledge of angles such as mean longitude and longitude of peri...

  11. Interaction English Teaching Model

    Institute of Scientific and Technical Information of China (English)

    穆宇娜

    2013-01-01

      Malash—Thomas pointed out“Interaction is a process in which people and things act upon each other through their ac⁃tions.”According to different subjects, interaction can be divided into human-computer interaction, people-people interaction and learner-content interaction. According to different forms, interactions can be divided into one-one interaction, one-more interac⁃tion and more-more interaction.“Interaction Education”means that teachers are leading parts and students are the center of class. During teaching process, teachers must lead students to discover. Demands from students can encourage teachers to inspire con⁃versely.Thus it can form a close communication between teachers and students. Teaching and learning are realized in a happy and harmonious atmosphere. Successful English teaching must take new bilateral teaching as the first part, which should let the func⁃tion of the two most important elements develop fully. Teachers should grasp opportunities to guide. Teaching methods need to be flexible, and contents of teaching need to be vivid;students should be keen to think, to participate actively, and can break the tradi⁃tion to produce fresh ideas, and in that situation the capability of students can develop fully. The educational model refers to the simplified description of detailed teaching activities. Possessing dual functions of theory and practice, the educational model is the manifestation of theoretical teaching method. The combination of interaction and educational model which are mentioned above form the“interactive teaching”model. With the coming of economic globalization and integration of science and technology, now communications are increasing with each passing day. If you want to take part in or to get in touch with others, you must use lan⁃guage. English has been learnt for 10 years in Middle school and in college, but it can’t be spoken very fluently. That is a realistic picture as the result of an

  12. Sketches in Embodied Interaction

    DEFF Research Database (Denmark)

    Erkut, Cumhur; Dahl, Sofia; Triantafyllidis, Georgios

    2014-01-01

    We present an approach for teaching and designing embodied interaction based on interactive sketches. We have combined the mover perspective and felt experiences of movement with advanced technologies (multi-agents, physical simulations) in a generative design session. We report our activities...... and provide a simple example as a design outcome. The variety and the qualities of the initial ideas indicate that this approach might provide a better foundation for our participants, compared to the approaches that focus only on technologies. The interactive sketches were demonstrated at the conference....

  13. Media Facades beyond Interaction

    DEFF Research Database (Denmark)

    Fritsch, Jonas

    2008-01-01

    As part of a the research project Digital Urban Living [www.digitalurbanliving.dk], we have taken part in the design of two large-scale installations that employ interactive technologies to facilitate participation and foster social interactions in public, urban settings. We present the two cases......, Aarhus by Light and Projected Poetry, and discuss the future trajectory of our work in this field, as well as some of our findings regarding the challenges of designing large-scale public interactive installations. In doing so, we specifically highlight the possibilities in relation to designing...

  14. Dendrimer-surfactant interactions.

    Science.gov (United States)

    Cheng, Yiyun; Zhao, Libo; Li, Tianfu

    2014-04-28

    In this article, we reviewed the interactions between dendrimers and surfactants with particular focus on the interaction mechanisms and physicochemical properties of the yielding dendrimer-surfactant aggregates. In order to provide insight into the behavior of dendrimers in biological systems, the interactions of dendrimers with bio-surfactants such as phospholipids in bulk solutions, in solid-supported bilayers and at the interface of phases or solid-states were discussed. Applications of the dendrimer-surfactant aggregates as templates to guide the synthesis of nanoparticles and in drug or gene delivery were also mentioned.

  15. Prostate Cell Specific Regulation of Androgen Receptor Phosphorylation In Vivo

    Science.gov (United States)

    2006-11-01

    analysis indicates that the screen is preferentially isolating proteins with a known role in gene transcription and we are currently assessing the phosphorylation- dependence of the putative AR interacting proteins .

  16. Chasing Ecological Interactions

    Science.gov (United States)

    2016-01-01

    Basic research on biodiversity has concentrated on individual species—naming new species, studying distribution patterns, and analyzing their evolutionary relationships. Yet biodiversity is more than a collection of individual species; it is the combination of biological entities and processes that support life on Earth. To understand biodiversity we must catalog it, but we must also assess the ways species interact with other species to provide functional support for the Tree of Life. Ecological interactions may be lost well before the species involved in those interactions go extinct; their ecological functions disappear even though they remain. Here, I address the challenges in studying the functional aspects of species interactions and how basic research is helping us address the fast-paced extinction of species due to human activities. PMID:27631692

  17. Interaction Before Agriculture

    DEFF Research Database (Denmark)

    Richter, Tobias; Garrard, Andrew; Allcock, Samantha

    2011-01-01

    This article discusses social interaction in the Epipalaeolithic of southwest Asia. Discussions of contact, social relationships and social organization have primarily focused on the Pre-Pottery Neolithic and are often considered to represent typical hallmarks of emergent farming societies...

  18. Interactive Office user's manual

    Science.gov (United States)

    Montgomery, Edward E.; Lowers, Benjamin; Nabors, Terri L.

    1990-01-01

    Given here is a user's manual for Interactive Office (IO), an executive office tool for organization and planning, written specifically for Macintosh. IO is a paperless management tool to automate a related group of individuals into one productive system.

  19. ENTREPRENEURSHIP AS SOCIAL INTERACTION

    DEFF Research Database (Denmark)

    Larsen, Henry; Lima, Patricia; Olsen, Bente

    2013-01-01

    This paper aims to explore how entrepreneurs work with innovation; to explore and develop attention points in understanding entrepreneurship as social processes of interaction between people. Through interviews and engagement with entrepreneurs and key stakeholders, their actual social practices...... and the influence on the progress as innovators are explored. It is focused on a new local activity in a Danish town, named the I-factory which has within a year gathered almost 40 entrepreneurs. As a part of the interaction, there were created activities to encourage even more collaboration. We see...... entrepreneurship as socially constructed through local interactions between players and identify key themes in these interactions within the organisation, such as leadership, becoming part of the initiative and trust/mistrust. By doing so, this paper contributes to an understanding of entrepreneurship as social...

  20. Atomic & Molecular Interactions

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-07-12

    The Gordon Research Conference (GRC) on Atomic & Molecular Interactions was held at Roger Williams University, Bristol, RI. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  1. Space for Interaction

    DEFF Research Database (Denmark)

    Jørgensen, Mariane Ellen; Folmer, Mette Blicher; Mullins, Michael

    SPACE FOR INTERACTION QUALIFYING GROUP TREATMENT FOR PATIENTS WITH CHRONIC PAIN THROUGH OPTIMIZATION(?) OF SPACE. A RANDOMIZED PILOT STUDY. In a Ph-D. Mariane Ellen Jørgensen / Nurse + psykoterapist / maej@rn.dk / Pain Center / Aalborg University Hospital / Denmark / Mette Blicher Folmer...... Building Research Institute / Aalborg University / Denmark AIM Research shows the hospital space has significance for human healing processes and the physical environment can have both positive and negative impact on the interaction between patients and staff. In order to qualify treatment for patients...... with chronic pain, the effect and experience of two different rooms for group therapy were compared. Three hypotheses were tested: 1) Room decor affects the interaction and thus the psychotherapeutic group therapy 2) The meaning of space for the interaction could be measured on the effect of treatment 3...

  2. Patient - patient interaction

    DEFF Research Database (Denmark)

    Birkelund, Regner; Søndergaard Larsen, Lene

    2013-01-01

    Aim:  The aim of this study is to provide an understanding of the significance of hospitalized patients’ interpersonal interaction with fellow patients in an infectious disease ward in a large Danish hospital. Method:  A qualitative approach was selected using participant observation and semi...... subcategories representing significance of patients’ interaction with fellow patients. Results:  The qualitative analysis resulted in two main categories: (i) Caring for fellow patients and (ii) Sharing illness information with fellow patients. Each of the main categories was elucidated through several...... subcategories. Our findings clearly showed that interpersonal interaction with fellow patients was of utmost importance when it came to care and support and when they needed information about their illness. Typically, the interpersonal interaction was experienced as giving and referred to in positive terms...

  3. Unparticle self-interactions

    CERN Document Server

    Georgi, Howard

    2009-01-01

    We develop techniques for studying the effects of self-interactions in the conformal sector of an unparticle model. Their physics is encoded in the higher n-point functions of the conformal theory. We study inclusive processes and argue that the inclusive production of unparticle stuff in standard model processes due to the unparticle self-interactions can be decomposed using the conformal partial wave expansion and its generalizations into a sum over contributions from the production of various kinds of unparticle stuff, corresponding to different primary conformal operators. Such processes typically involve the production of unparticle stuff associated with operators other than those to which the standard model couples directly. Thus just as interactions between particles allow scattering processes to produce new particles in the final state, so unparticle self-interactions cause the production of various kinds of unparticle stuff. We discuss both inclusive and exclusive methods for computing these processe...

  4. Theory of gravitational interactions

    CERN Document Server

    Gasperini, Maurizio

    2013-01-01

    This reference textbook is an up-to-date and self-contained introduction to the theory of gravitational interactions. The first part of the book follows the traditional presentation of general relativity as a geometric theory of the macroscopic gravitational field. A second, advanced part then discusses the deep analogies (and differences) between a geometric theory of gravity and the gauge theories of the other fundamental interactions. This fills a gap which is present in the context of the traditional approach to general relativity, and which usually makes students puzzled about the role of gravity. The necessary notions of differential geometry are reduced to the minimum, leaving more room for those aspects of gravitational physics of current phenomenological and theoretical interest, such as the properties of gravitational waves, the gravitational interactions of spinors, and the supersymmetric and higher-dimensional generalization of the Einstein equations. Theory of Gravitational Interactions will be o...

  5. Interactive Sample Book (ISB)

    DEFF Research Database (Denmark)

    Heimdal, Elisabeth Jacobsen; Lenau, Torben Anker; Guglielmi, Michel

    2009-01-01

    involving designers and engineers. It is carried out by Elisabeth Heimdal as her Master thesis from Design & Innovation, The Technical University of Denmark. Collaboration partners are the design bureau Diffus, textile designer Priya Mani, master student in medialogy at AAU Marija Andonovska and DTU......, with the aim of exploring and communicating some of the possibilities within interactive textiles. The applications for interactive textiles range from medical applications to architecture, and from the fashion industry to costume design. In relation to the sample book, focus will be on texture, lightning...... and senses in relation to integrated decoration and function primarily to indoor applications. The result of the project will be a number of interactive textiles, to be gathered in an interactive sample book (ISB), in a similar way as the sample books of wallpapers one can take home from the shop and choose...

  6. Neutrino Self-Interactions

    CERN Document Server

    Hasenkamp, Jasper

    2016-01-01

    We propose a theory that equips the active neutrinos with interactions among themselves that are at least three orders of magnitude stronger than the weak interaction. We introduce an Abelian gauge group $U(1)_x$ with vacuum expectation value $v_x \\lesssim \\mathcal{O}(100 \\textrm{ MeV})$. An asymmetric mass matrix implements the active neutrinos as massless mass eigenstates carrying "effective" charges. To stabilize $v_x$, supersymmetry breaking is mediated via loops to the additional sector with the only exception of xHiggs terms. No Standard Model interaction eigenstate carries $U(1)_x$ charge. Thus the dark photon's kinetic mixing is two-loop suppressed.With only simple and generic values of dimensionless parameters, our theory might explain the high-energy neutrino spectrum observed by IceCube including the PeV neutrinos. We comment on the imposing opportunity to incorporate a self-interacting dark matter candidate.

  7. Interactive Energy Planning

    DEFF Research Database (Denmark)

    Blarke, Morten Boje

    2006-01-01

    anchoring along the shores of the land of communications and collaboration. Whether or not a particular typology is applicable, theory and praxis are establishing standpoints, which strengthens our understanding of the planning complex, and which should inspire improved energy planning methodologies...... and tools. This paper presents an “Interactive Energy Planning” framework, which is intended to support interactivity in planning, building on important theoretical and experimental advances in planning. In particular, the paper explores the potential significance of allowing a critical perspective...... on context analysis and problem-orientation to define the course of the planning process, and deploying value-rational planning tools primarily as a platform for interactivity. The focus on interactivity in energy planning will allow contemporary government planners, consultants, researchers...

  8. Mobile Collocated Interactions

    DEFF Research Database (Denmark)

    Lucero, Andrés; Clawson, James; Lyons, Kent

    2015-01-01

    Mobile devices such as smartphones and tablets were originally conceived and have traditionally been utilized for individual use. Research on mobile collocated interactions has been looking at situations in which collocated users engage in collaborative activities using their mobile devices, thus...... going from personal/individual toward shared/multiuser experiences and interactions. However, computers are getting smaller, more powerful, and closer to our bodies. Therefore, mobile collocated interactions research, which originally looked at smartphones and tablets, will inevitably include ever......-smaller computers, ones that can be worn on our wrists or other parts of the body. The focus of this workshop is to bring together a community of researchers, designers and practitioners to explore the potential of extending mobile collocated interactions to the use of wearable devices....

  9. Interaction as Negotiation

    DEFF Research Database (Denmark)

    Kristensen, Jannie Friis; Nielsen, Christina

    In this paper we discuss recent developments in interaction design principles for ubiquitous computing environments, specifically implications related to situated and mobile aspects of work. We present 'Interaction through Negotiation' as a general Human-Computer Interaction (HCI) paradigm, aimed...... at ubiquitous/pervasive technology and environments, with focus on facilitating negotiation in and between webs of different artifacts, humans and places. This approach is concerned with the way technology presents itself to us, both as physical entities and as conceptual entities, as well as the relations...... on several extensive empirical case studies, as well as co-operative design-sessions, we present a reflective analysis providing insights into results of the "Interaction through Negotiation" design approach in action. A very promising area of application is exception handling in pervasive computing...

  10. Interactive Biplot Construction

    OpenAIRE

    Frederic Udina

    2005-01-01

    We analyze and discuss how a generic software to produce biplot graphs should be designed. We describe a data structure appropriate to include the biplot description and we specify the algorithm(s) to be used for several biplot types. We discuss the options the software should offer to the user in two different environments. In a highly interactive environment the user should be able to specify many graphical options and also to change them using the usual interactive tools. The resulting gra...

  11. Interacting Agegraphic Dark Energy

    OpenAIRE

    Wei, Hao; Cai, Rong-Gen

    2007-01-01

    A new dark energy model, named "agegraphic dark energy", has been proposed recently, based on the so-called K\\'{a}rolyh\\'{a}zy uncertainty relation, which arises from quantum mechanics together with general relativity. In this note, we extend the original agegraphic dark energy model by including the interaction between agegraphic dark energy and pressureless (dark) matter. In the interacting agegraphic dark energy model, there are many interesting features different from the original agegrap...

  12. Human-machine interactions

    Science.gov (United States)

    Forsythe, J. Chris; Xavier, Patrick G.; Abbott, Robert G.; Brannon, Nathan G.; Bernard, Michael L.; Speed, Ann E.

    2009-04-28

    Digital technology utilizing a cognitive model based on human naturalistic decision-making processes, including pattern recognition and episodic memory, can reduce the dependency of human-machine interactions on the abilities of a human user and can enable a machine to more closely emulate human-like responses. Such a cognitive model can enable digital technology to use cognitive capacities fundamental to human-like communication and cooperation to interact with humans.

  13. Quantum interaction. Selected papers

    Energy Technology Data Exchange (ETDEWEB)

    Atmanspacher, Harald [Eidgenoessische Technische Hochschule, Zurich (Switzerland); Haven, Emmanuel [Leicester Univ. (United Kingdom). School of Management; Kitto, Kirsty [Queensland Univ. of Technology, Brisbane, QLD (Australia); Raine, Derek (ed.) [Leicester Univ. (United Kingdom). Centre for Interdisciplinary Science

    2014-07-01

    This book constitutes the refereed proceedings of the 7th International Conference on Quantum Interaction, QI 2013, held in Leicester, UK, in July 2013. The 31 papers presented in this book were carefully selected from numerous submissions. The papers cover various topics on quantum interaction and revolve around four themes: information processing/retrieval/semantic representation and logic; cognition and decision making; finance/economics and social structures and biological systems.

  14. Interaction with geospatial data

    OpenAIRE

    SCHOENING, Johannes

    2015-01-01

    My research interest lies at the interaction between human-computer interaction (HCI) and geoinformatics. I am interested in developing new methods and novel user interfaces to navigate through spatial information. This article will give a brief overview on my past and current research topics and streams. Generally speaking, geography is playing an increasingly important role in computer science and also in the field of HCI ranging from social computing to natural user interfaces (NUIs). At t...

  15. Beam-Material Interaction

    Energy Technology Data Exchange (ETDEWEB)

    Mokhov, N. V. [Fermilab; Cerutti, F. [CERN

    2016-01-01

    Th is paper is motivated by the growing importance of better understanding of the phenomena and consequences of high-intensity energetic particle beam interactions with accelerator, generic target, and detector components. It reviews the principal physical processes of fast-particle interactions with matter, effects in materials under irradiation, materials response, related to component lifetime and performance, simulation techniques, and methods of mitigating the impact of radiation on the components and environment in challenging current and future applications.

  16. Extrasolar planet interactions

    Science.gov (United States)

    Barnes, Rory; Greenberg, Richard

    2008-05-01

    The dynamical interactions of planetary systems may be a clue to their formation histories. Therefore, the distribution of these interactions provides important constraints on models of planet formation. We focus on each system's apsidal motion and proximity to dynamical instability. Although only 25 multiple planet systems have been discovered to date, our analyses in these terms have revealed several important features of planetary interactions. 1) Many systems interact such that they are near the boundary between stability and instability. 2) Planets tend to form such that at least one planet's eccentricity periodically drops to near zero. 3) Mean-motion resonant pairs would be unstable if not for the resonance. 4) Scattering of approximately equal mass planets is unlikely to produce the observed distribution of apsidal behavior. 5) Resonant interactions may be identified through calculating a system's proximity to instability, regardless of knowledge of angles such as mean longitude and longitude of periastron (e.g. GJ 317 b and c are probably in a 4:1 resonance). These properties of planetary systems have been identified through calculation of two parameters that describe the interaction. The apsidal interaction can be quantified by determining how close a planet is to an apsidal separatrix (a boundary between qualitatively different types of apsidal oscillations, e.g. libration or circulation of the major axes). This value can be calculated through short numerical integrations. The proximity to instability can be measured by comparing the observed orbital elements to an analytic boundary that describes a type of stability known as Hill stability. We have set up a website dedicated to presenting the most up-to-date information on dynamical interactions: http://www.lpl.arizona.edu/~rory/research/xsp/dynamics.

  17. Beam-Material Interaction

    CERN Document Server

    Mokhov, N.V.

    2016-01-01

    Th is paper is motivated by the growing importance of better understanding of the phenomena and consequences of high- intensity energetic particle beam interactions with accelerator, generic target , and detector components. It reviews the principal physical processes of fast-particle interactions with matter, effects in materials under irradiation, materials response, related to component lifetime and performance, simulation techniques, and methods of mitigating the impact of radiation on the components and envir onment in challenging current and future application

  18. Sperm-egg interaction.

    Science.gov (United States)

    Evans, Janice P

    2012-01-01

    A crucial step of fertilization is the sperm-egg interaction that allows the two gametes to fuse and create the zygote. In the mouse, CD9 on the egg and IZUMO1 on the sperm stand out as critical players, as Cd9(-/-) and Izumo1(-/-) mice are healthy but infertile or severely subfertile due to defective sperm-egg interaction. Moreover, work on several nonmammalian organisms has identified some of the most intriguing candidates implicated in sperm-egg interaction. Understanding of gamete membrane interactions is advancing through characterization of in vivo and in vitro fertilization phenotypes, including insights from less robust phenotypes that highlight potential supporting (albeit not absolutely essential) players. An emerging theme is that there are varied roles for gamete molecules that participate in sperm-egg interactions. Such roles include not only functioning as fusogens, or as adhesion molecules for the opposite gamete, but also functioning through interactions in cis with other proteins to regulate membrane order and functionality.

  19. Interactions between photodegradation components

    Directory of Open Access Journals (Sweden)

    Abdollahi Yadollah

    2012-09-01

    Full Text Available Abstract Background The interactions of p-cresol photocatalytic degradation components were studied by response surface methodology. The study was designed by central composite design using the irradiation time, pH, the amount of photocatalyst and the p-cresol concentration as variables. The design was performed to obtain photodegradation % as actual responses. The actual responses were fitted with linear, two factor interactions, cubic and quadratic model to select an appropriate model. The selected model was validated by analysis of variance which provided evidences such as high F-value (845.09, very low P-value (2 = 0.999, adjusted R-squared (Radj2 = 0.998, predicted R-squared (Rpred2 = 0.994 and the adequate precision (95.94. Results From the validated model demonstrated that the component had interaction with irradiation time under 180 min of the time while the interaction with pH was above pH 9. Moreover, photocatalyst and p-cresol had interaction at minimal amount of photocatalyst (p-cresol. Conclusion These variables are interdependent and should be simultaneously considered during the photodegradation process, which is one of the advantages of the response surface methodology over the traditional laboratory method.

  20. Strongly interacting Fermi gases

    Directory of Open Access Journals (Sweden)

    Bakr W.

    2013-08-01

    Full Text Available Strongly interacting gases of ultracold fermions have become an amazingly rich test-bed for many-body theories of fermionic matter. Here we present our recent experiments on these systems. Firstly, we discuss high-precision measurements on the thermodynamics of a strongly interacting Fermi gas across the superfluid transition. The onset of superfluidity is directly observed in the compressibility, the chemical potential, the entropy, and the heat capacity. Our measurements provide benchmarks for current many-body theories on strongly interacting fermions. Secondly, we have studied the evolution of fermion pairing from three to two dimensions in these gases, relating to the physics of layered superconductors. In the presence of p-wave interactions, Fermi gases are predicted to display toplogical superfluidity carrying Majorana edge states. Two possible avenues in this direction are discussed, our creation and direct observation of spin-orbit coupling in Fermi gases and the creation of fermionic molecules of 23Na 40K that will feature strong dipolar interactions in their absolute ground state.

  1. Interactive Karyotyping Training

    Directory of Open Access Journals (Sweden)

    Ashwin Kotwaliwale

    2013-01-01

    Full Text Available Despite the wide use of newer techniques in genetic diagnostics, there remains a need for technologists to learn human chromosome morphology, identify abnormal metaphases and report clinical abnormalities. Global short age of cytogenetic trainers and a time consuming training process makes Karyotyping training difficult. We have developed a web based interactive Karyotyping training tool, KaryoTutor©, that allows technologists to learn karyotyping in an interactive environment and aids the trainer in the training process. KaryoTutor©provides visual clues for identifying abnormal chromosomes, provides instant test scores and includes a reference library of ideograms,sample chromosome images and reference materials. Trainees are able to recursively work on a case till a satisfactory result is achieved,with KaryoTutor providing interactive inputs.Additionally, trainers can assign cases and monitor trainee progress using audit trail management and other administrative features.

  2. Sonic Interaction Design

    DEFF Research Database (Denmark)

    created for such contexts as mobile music, sensorimotor learning, rehabilitation, and gaming. The goal is not only to extend the existing research and pedagogical approaches to SID but also to foster domains of practice for sound designers, architects, interaction designers, media artists, product......Sound is an integral part of every user experience but a neglected medium in design disciplines. Design of an artifact’s sonic qualities is often limited to the shaping of functional, representational, and signaling roles of sound. The interdisciplinary field of sonic interaction design (SID...... aspects of sonic experience. Sonic Interaction Design gathers contributions from scholars, artists, and designers working at the intersections of fields ranging from electronic music to cognitive science. They offer both theoretical considerations of key themes and case studies of products and systems...

  3. Gene-environment interaction.

    Science.gov (United States)

    Manuck, Stephen B; McCaffery, Jeanne M

    2014-01-01

    With the advent of increasingly accessible technologies for typing genetic variation, studies of gene-environment (G×E) interactions have proliferated in psychological research. Among the aims of such studies are testing developmental hypotheses and models of the etiology of behavioral disorders, defining boundaries of genetic and environmental influences, and identifying individuals most susceptible to risk exposures or most amenable to preventive and therapeutic interventions. This research also coincides with the emergence of unanticipated difficulties in detecting genetic variants of direct association with behavioral traits and disorders, which may be obscured if genetic effects are expressed only in predisposing environments. In this essay we consider these and other rationales for positing G×E interactions, review conceptual models meant to inform G×E interpretations from a psychological perspective, discuss points of common critique to which G×E research is vulnerable, and address the role of the environment in G×E interactions.

  4. Electroweak interactions at LEP

    CERN Document Server

    Swain, J D

    2000-01-01

    The electroweak interactions are based on an extension of the electromagnetic (Maxwell) interactions, realized in a rather odd way so that the symmetries of the theory are not immediately obvious. This "broken" theory has been the subject of intense investigation at LEP, and has passed all tests with flying colours. These lectures are meant to complement the many excellent presentations of the standard SU(2)/sub L/*U(1)/sub Y/ electroweak interactions in three main ways: first to clarify the physical meaning of symmetries in particle physics, second, to summarize the recent tests of the standard model using LEP data, and finally to look at possible roles of gravity in understanding mass. (10 refs).

  5. Neutrino interactions with nuclei

    CERN Document Server

    Leitner, T; Mosel, U; Alvarez-Ruso, L

    2008-01-01

    Current long baseline experiments aim at measuring neutrino oscillation parameters with a high precision. A critical quantity is the neutrino energy which can not be measured directly but has to be reconstructed from the observed hadrons. A good knowledge of neutrino-nucleus interactions is thus necessary to minimize the systematic uncertainties in neutrino fluxes, backgrounds and detector responses. In particular final-state interactions inside the target nucleus modify considerably the particle yields through rescattering, charge-exchange and absorption. Nuclear effects can be described with our coupled channel GiBUU transport model where the neutrino first interacts with a bound nucleon producing secondary particles which are then transported out of the nucleus. In this contribution, we give some examples for the application of our model focusing in particular on the MiniBooNE and K2K experiments.

  6. Interactive Topology Optimization

    DEFF Research Database (Denmark)

    Nobel-Jørgensen, Morten

    Interactivity is the continuous interaction between the user and the application to solve a task. Topology optimization is the optimization of structures in order to improve stiffness or other objectives. The goal of the thesis is to explore how topology optimization can be used in applications...... in an interactive and intuitive way. By creating such applications with an intuitive and simple user interface we allow non-engineers like designers and architects to easily experiment with boundary conditions, design domains and other optimization settings. This is in contrast to commercial topology optimization...... software where the users are assumed to be well-educated both in the finite element method and topology optimization. This dissertation describes how various topology optimization methods have been used for creating cross-platform applications with high performance. The user interface design is based...

  7. Interactive Information Retrieval

    DEFF Research Database (Denmark)

    Borlund, Pia

    2013-01-01

    The paper introduces the research area of interactive information retrieval (IIR) from a historical point of view. Further, the focus here is on evaluation, because much research in IR deals with IR evaluation methodology due to the core research interest in IR performance, system interaction...... and satisfaction with retrieved information. In order to position IIR evaluation, the Cranfield model and the series of tests that led to the Cranfield model are outlined. Three iconic user-oriented studies and projects that all have contributed to how IIR is perceived and understood today are presented......: The MEDLARS test, the Book House fiction retrieval system, and the OKAPI project. On this basis the call for alternative IIR evaluation approaches motivated by the three revolutions (the cognitive, the relevance, and the interactive revolutions) put forward by Robertson & Hancock-Beaulieu (1992) is presented...

  8. Dike/Drift Interactions

    Energy Technology Data Exchange (ETDEWEB)

    E. Gaffiney

    2004-11-23

    This report presents and documents the model components and analyses that represent potential processes associated with propagation of a magma-filled crack (dike) migrating upward toward the surface, intersection of the dike with repository drifts, flow of magma in the drifts, and post-magma emplacement effects on repository performance. The processes that describe upward migration of a dike and magma flow down the drift are referred to as the dike intrusion submodel. The post-magma emplacement processes are referred to as the post-intrusion submodel. Collectively, these submodels are referred to as a conceptual model for dike/drift interaction. The model components and analyses of the dike/drift interaction conceptual model provide the technical basis for assessing the potential impacts of an igneous intrusion on repository performance, including those features, events, and processes (FEPs) related to dike/drift interaction (Section 6.1).

  9. Acting, interacting, enacting

    DEFF Research Database (Denmark)

    Hazel, Spencer

    2015-01-01

    This study followed the rehearsals of a 2014 Copenhagen theatre production of Margaret Edson’s play WIT. The play depicts the palliative care provision of a woman diagnosed with advanced ovarian cancer, with an important theme of the narrative centering around the dehumanizing practices that result...... from professional medical treatment of the body, rather than of the person. I adopt an interaction analytic approach to investigate how theatre practitioners develop representations of interaction in clinical environments. The article introduces one practice from the theatre rehearsal setting – doing...

  10. Generalized interaction in multigravity

    CERN Document Server

    Duplij, Steven

    2013-01-01

    A general approach to description of multigravity models in D-dimensional space-time is presented. Different possibilities of generalization of the invariant volume are given. Then a most general form of the interaction potential is constructed, which for bigravity coincides with the Pauli-Fierz model. A thorough analysis of the model along the 3+1 expansion formalism is done. It is shown that the absence of ghosts the considered bigravity model is equivalent in the weak field limit to the massive gravity (the Pauli-Fierz model). Thus, on the concrete example it is shown, that the interaction between metrics leads to nonvanishing mass of graviton.

  11. Urban Interaction Design

    DEFF Research Database (Denmark)

    Brynskov, Martin; Bermúdez, Juan Carlos Carvajal; Fernández, Manu;

    This book is an effort to explore the newly emerging field of urban interaction design that addresses these issues. In the first part of the book, 'Foundations', we look into its origins. Where do its practitioners come from? How are they working together? What methodologies do they bring...... to the table? What are the key concepts they are addressing in their work? In the second part of the book named 'Trends', we go into current developments in the networked city and how urban interaction design as a field addresses these. Taken together, these sections will not give the definite definition...

  12. Interactive Shape Design

    CERN Document Server

    Cani, Marie-Paule; Wyvill, Geoff

    2008-01-01

    Providing an intuitive modeling system, which would enable us to communicate about any free-form shape we have in mind at least as quickly as with real-world tools, is one of the main challenges of digital shape design. The user should ideally be able to create, deform, and progressively add details to a shape, without being aware of the underlying mathematical representation nor being tied by any constraint on the geometrical or topological nature of the model. This book presents the field of interactive shape design from this perspective. Since interactively creating a shape builds on the hu

  13. Empowered interaction through creativity

    DEFF Research Database (Denmark)

    Hasselblad, Stefan; Petersson, Eva; Brooks, Tony

    2007-01-01

    This paper reflects upon a case study where exploration, play and empowerment in interactive therapy sessions with audio and visual stimuli resulted in achievement, self-esteem and a shared pride between a young adult with profound and multiple learning disabilities (PMLD), his mother and the spe......This paper reflects upon a case study where exploration, play and empowerment in interactive therapy sessions with audio and visual stimuli resulted in achievement, self-esteem and a shared pride between a young adult with profound and multiple learning disabilities (PMLD), his mother...

  14. Interacting binary stars

    CERN Document Server

    Sahade, Jorge; Ter Haar, D

    1978-01-01

    Interacting Binary Stars deals with the development, ideas, and problems in the study of interacting binary stars. The book consolidates the information that is scattered over many publications and papers and gives an account of important discoveries with relevant historical background. Chapters are devoted to the presentation and discussion of the different facets of the field, such as historical account of the development in the field of study of binary stars; the Roche equipotential surfaces; methods and techniques in space astronomy; and enumeration of binary star systems that are studied

  15. Thoughts on Interaction Design

    CERN Document Server

    Kolko, Jon

    2009-01-01

    Interaction Designers-whether practicing as Usability Engineers, Visual Interface Designers, or Information Architects-attempt to understand and shape human behavior in order to design products that are at once usable, useful, and desirable. Although the value of design is now recognized as essential to product development, the field is often misunderstood by managers and other team members, who don't understand a designer's role in a team. This can cause inefficient and ineffective products. Thoughts on Interaction Design gives individuals engaged in this profession the dialogue to justify t

  16. Virtual Interactive Space (VIS)

    DEFF Research Database (Denmark)

    Brooks, Anthony Lewis

    2015-01-01

    This paper shares code that enables the making of a Virtual Interactive Space (VIS) where the skin of the invisible active sensor area is dynamically responsive to the velocity of a limb e.g. hand. Used in proprioception training of movement the patch is at the core of the author’s Reafferentation...

  17. Exploring governmentality as interaction

    DEFF Research Database (Denmark)

    Fahnøe, Kristian

    2010-01-01

    Based on my ongoing work in relation my PhD thesis this paper examines how the Foucauldian concept of governmentality as social control can be understood as interaction among individuals in institutional settings. In theoretical terms the paper examines how governmentality can be conceptualized f...

  18. [Fluoroquinolones. Drug interactions].

    Science.gov (United States)

    Rusu, G; Dănilă, G

    2000-01-01

    This review summarizes clinically relevant drug-drug interactions for fluoroquinolones: antiacids containing aluminum and magnesium salts, iron or zinc preparations, sucralfate, cimetidine, ranitidine, warfarina, cyclosporin, rifampin, oral contraceptive steroids, benzodiazepine, probenecid, beta-lactam antibiotics, nonsteroidal anti-inflammatory drugs, metronidazole, theophylline, caffeine.

  19. CONCEPT OF DRUG INTERACTION

    Directory of Open Access Journals (Sweden)

    Singh Nidhi

    2012-07-01

    Full Text Available Drug interaction is an increasingly important cause of adverse reactions (ADR, and is the modification of the effect of one drug (object by the prior or concomitant administration of another drug (precipitant drug. Drug interaction may either enhance or diminish the intended effect of one or both drugs. For example severe haemorrhage may occur if warfarin and salicylates (asprin are combined. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Many other drugs, act as precipitants or objects, and a number of drugs act as both. The aim of present review is to throw light on the concept of drug interaction.

  20. Highly interactive distributed visualization

    NARCIS (Netherlands)

    Scarpa, M.; Belleman, R.G.; Sloot, P.M.A.; de Laat, C.T.A.M.

    2006-01-01

    We report on our iGrid2005 demonstration, called the "Dead Cat Demo"; an example of a highly interactive augmented reality application consisting of software services distributed over a wide-area, high-speed network. We describe our design decisions, analyse the implications of the design on applica

  1. Experiencing affective interactive art

    NARCIS (Netherlands)

    Bialoskorski, Leticia S.S.; Westerink, Joyce H.D.M.; Broek, van den Egon L.

    2010-01-01

    The progress in the field of affective computing enables the realization of affective art. This paper describes the affective interactive art system Mood Swings, which interprets and visualizes affect expressed by a person. Mood Swings is founded on the integration of a framework for affective move

  2. Socially aware interactive playgrounds

    NARCIS (Netherlands)

    Moreno, Alejandro; Delden, van Robby; Poppe, Ronald; Reidsma, Dennis

    2013-01-01

    Interactive playgrounds are technology-enhanced installations that aim to provide rich game experiences for children by combining the benefits of traditional playgrounds with those of digital games. These game experiences could be attained by addressing three design considerations: context-awareness

  3. Multiactivity in Social Interaction

    DEFF Research Database (Denmark)

    Day, Dennis; Wagner, Johannes

    2014-01-01

    Doing more than one thing at the same time – a phenomenon that is often called ‘multitasking’ – is characteristic to many situations in everyday and professional life. Although we all experience it, its real time features remain understudied. Multiactivity in Social Interaction: Beyond multitasking...

  4. Electromagnetic interaction of metamaterials

    Science.gov (United States)

    Canales, Peter R.

    The observation of extraordinary transmission through subwavelength apertures has propelled a great interest in understanding its nature. It defies classical theories of electromagnetic interaction by demanding a closer examination of the surface properties. Traditionally, as surface features become much smaller in size than a single wavelength of interest, the structure is essentially continuous. Any periodic subwavelength corrugation or aperture array should not interact strongly with an incident field and therefore not contribute to any significant transmission through the film. We find that this is not always the case and that we may tune the surface geometry at these scales to affect the overall medium behavior. It is possible that a material may transcend its own natural properties and, in essence, become a metamaterial. The following analysis examines the concepts of metamaterials from a fundamental viewpoint. It does not seek to disrupt classical theories but instead demonstrates their validity to describe a new phenomenon. Several theories have been proposed that offer unique surface interactions as evidence of enhanced transmission. It is proposed that a fundamental Maxwell representation is sufficient in predicting the interaction of an electromagnetic wave with a metamaterial. In particular, a formalism has been developed to analyze enhanced transmission through a metallic grating structure. To experimentally validate this model, a fabrication procedure has been developed that allows for the production of quality thick film structures with subwavelength features. Finally, the analysis of metamaterials looks towards the RF spectrum to demonstrate a novel design to achieve conformal waveguides and antennas.

  5. Dimensions of Group Interaction

    Science.gov (United States)

    Dawidowicz, Paula

    2008-01-01

    The correlation between positive and negative group interactions and one or another of individuals' attitudes or characteristics--moral development, critical thinking, resilience, and self efficacy--has been examined previously. However, no systemic examination of individuals' development of patterns of these characteristics and those patterns'…

  6. Interactive Foresight Simulation

    DEFF Research Database (Denmark)

    Hansen, Mette Sanne; Rasmussen, Lauge Baungaard; Jacobsen, Peter

    2016-01-01

    The Combined Simulation Approach (CSA) is a way to evaluate risks and address potential unforeseen problems in a more interactive way than what is often observed in practice in companies or sectors. The approach is based on a combination of scenario analysis and discrete-event computer simulation...

  7. Interactive Playgrounds for Children

    NARCIS (Netherlands)

    Poppe, Ronald; Delden, van Robby; Moreno, Alejandro; Reidsma, Dennis; Nijholt, Anton

    2014-01-01

    Play is an important factor in the life of children. It plays a role in their cognitive, social, and physical development, and provides entertaining and fulfilling activities in itself. As with any field of human endeavor, interactive technology has a huge potential for transforming and enhancing pl

  8. Aesthetics of Mundane Interactions

    NARCIS (Netherlands)

    Vyas, D.M.; Hassenzahl, M.

    2008-01-01

    John Dewey’s pragmatist aesthetics is used as a conceptual basis for designing new technologies that support staff-members’ mundane social interactions in an academic department. From this perspective, aesthetics is seen as a broader phenomenon that encompasses experiential aspects of staff-members’

  9. Interactive Architecture #1

    NARCIS (Netherlands)

    Oosterhuis, K.; Xia, X.

    2007-01-01

    The iA bookzine series will consist of twelve issues, bi-annually published over a period of six years under the supervision of Prof. ir. Kas Oosterhuis, director of the Hperbody at the Delft University of Technology. Interactive Architecture - from here on abbreviated as iA - is NOT simply archite

  10. Alkane dimers interaction

    DEFF Research Database (Denmark)

    Ferrighi, Lara; Madsen, Georg Kent Hellerup; Hammer, Bjørk

    2010-01-01

    The interaction energies of a series of n-alkane dimers, from methane to decane, have been investigated with Density Functional Theory (DFT), using the MGGA-M06-L density functional. The results are compared both to the available wavefunction-based values as well as to dispersion corrected DFT...

  11. TIDE-TSUNAMI INTERACTIONS

    Directory of Open Access Journals (Sweden)

    Zygmunt Kowalik

    2006-01-01

    Full Text Available In this paper we investigate important dynamics defining tsunami enhancement in the coastal regions and related to interaction with tides. Observations and computations of the Indian Ocean Tsunami usually show amplifications of the tsunami in the near-shore regions due to water shoaling. Additionally, numerous observations depicted quite long ringing of tsunami oscillations in the coastal regions, suggesting either local resonance or the local trapping of the tsunami energy. In the real ocean, the short-period tsunami wave rides on the longer-period tides. The question is whether these two waves can be superposed linearly for the purpose of determining the resulting sea surface height (SSH or rather in the shallow water they interact nonlinearly, enhancing/reducing the total sea level and currents. Since the near–shore bathymetry is important for the run-up computation, Weisz and Winter (2005 demonstrated that the changes of depth caused by tides should not be neglected in tsunami run-up considerations. On the other hand, we hypothesize that much more significant effect of the tsunami-tide interaction should be observed through the tidal and tsunami currents. In order to test this hypothesis we apply a simple set of 1-D equations of motion and continuity to demonstrate the dynamics of tsunami and tide interaction in the vicinity of the shelf break for two coastal domains: shallow waters of an elongated inlet and narrow shelf typical for deep waters of the Gulf of Alaska.

  12. Connectionist Interaction Information Retrieval.

    Science.gov (United States)

    Dominich, Sandor

    2003-01-01

    Discussion of connectionist views for adaptive clustering in information retrieval focuses on a connectionist clustering technique and activation spreading-based information retrieval model using the interaction information retrieval method. Presents theoretical as well as simulation results as regards computational complexity and includes…

  13. Unparticle self-interactions

    Science.gov (United States)

    Georgi, Howard; Kats, Yevgeny

    2010-02-01

    We develop techniques for studying the effects of self-interactions in the conformal sector of an unparticle model. Their physics is encoded in the higher n-point functions of the conformal theory. We study inclusive processes and argue that the inclusive production of unparticle stuff in standard model processes due to the unparticle self-interactions can be decomposed using the conformal partial wave expansion and its generalizations into a sum over contributions from the production of various kinds of unparticle stuff, corresponding to different primary conformal operators. Such processes typically involve the production of unparticle stuff associated with operators other than those to which the standard model couples directly. Thus just as interactions between particles allow scattering processes to produce new particles in the final state, so unparticle self-interactions cause the production of various kinds of unparticle stuff. We discuss both inclusive and exclusive methods for computing these processes. The resulting picture, we believe, is a step towards understanding what unparticle stuff “looks like” because it is quite analogous to way we describe the production and scattering of ordinary particles in quantum field theory, with the primary conformal operators playing the role of particles and the coefficients in the conformal partial wave expansion (and its generalization to include more fields) playing the role of amplitudes. We exemplify our methods in the 2D toy model that we discussed previously in which the Banks-Zaks theory is exactly solvable.

  14. Fibronectin-cell interactions

    DEFF Research Database (Denmark)

    Couchman, J R; Austria, M R; Woods, A

    1990-01-01

    Fibronectins are widespread extracellular matrix and body fluid glycoproteins, capable of multiple interactions with cell surfaces and other matrix components. Their structure at a molecular level has been resolved, yet there are still many unanswered questions regarding their biologic activity i...

  15. Interactive Tabletops in Education

    Science.gov (United States)

    Dillenbourg, Pierre; Evans, Michael

    2011-01-01

    Interactive tabletops are gaining increased attention from CSCL researchers. This paper analyses the relation between this technology and teaching and learning processes. At a global level, one could argue that tabletops convey a socio-constructivist flavor: they support small teams that solve problems by exploring multiple solutions. The…

  16. Interactive Digital Signal Processor

    Science.gov (United States)

    Mish, W. H.

    1985-01-01

    Interactive Digital Signal Processor, IDSP, consists of set of time series analysis "operators" based on various algorithms commonly used for digital signal analysis. Processing of digital signal time series to extract information usually achieved by applications of number of fairly standard operations. IDSP excellent teaching tool for demonstrating application for time series operators to artificially generated signals.

  17. Gaze interaction from bed

    DEFF Research Database (Denmark)

    Hansen, John Paulin; San Agustin, Javier; Jensen, Henrik Tomra Skovsgaard Hegner

    2011-01-01

    This paper presents a low-cost gaze tracking solution for bedbound people composed of free-ware tracking software and commodity hardware. Gaze interaction is done on a large wall-projected image, visible to all people present in the room. The hardware equipment leaves physical space free to assist...

  18. Protein-protein interactions

    DEFF Research Database (Denmark)

    Byron, Olwyn; Vestergaard, Bente

    2015-01-01

    Responsive formation of protein:protein interaction (PPI) upon diverse stimuli is a fundament of cellular function. As a consequence, PPIs are complex, adaptive entities, and exist in structurally heterogeneous interplays defined by the energetic states of the free and complexed protomers......, are reported. The aim is to depict how the elucidation of the interplay of structures requires the interplay of methods....

  19. Interactive Purchasing Situations

    NARCIS (Netherlands)

    Groote Schaarsberg, M.; Borm, P.E.M.; Hamers, H.J.M.; Reijnierse, J.H.

    2012-01-01

    Abstract: This paper introduces a new class of interactive cooperative purchasing situations and provides an explicit alternative characterization of the nucleolus of cooperative games, which offers an alternative to Kohlberg (1971). In our cooperative purchasing situation, the unit price of a commo

  20. Electronically Enhanced Classroom Interaction.

    Science.gov (United States)

    Draper, Stephen; Cargill, Julie; Cutts, Quintin

    A design rationale for introducing electronic equipment (a group response system) for student interaction in lecture theaters is presented, linking the instructional design to theory. The effectiveness of the equipment for learning depends mostly on what pedagogic method is employed. Various alternative types are introduced, including: assessment;…

  1. Interaction in Information Systems - Beyond Human-Computer Interaction

    DEFF Research Database (Denmark)

    Bækgaard, Lars

    The purpose of this paper is to discuss and analyze the role of interaction in information systems. Interaction represents dynamic relations between actors and other elements in information systems. We introduce a semi-formal notation that we use to describe a set of interaction patterns and we...... illustrate how the notation can be used to describe mediated interaction. We use the interaction patterns to evaluate a set of modeling languages. No single language supports all relevant aspects of interaction modeling. We use the interaction patterns to identify to general and supplementary forms...... of interaction-interaction based on exchange of objects and interaction based on exchange of commands. None of the modeling languages that we analyze support both forms in a rich way....

  2. Interaction Design for Public Spaces

    DEFF Research Database (Denmark)

    Kortbek, Karen Johanne

    2008-01-01

    In this abstract I describe the doctorial research project "Interaction Design for Public Spaces". The objective of the project is to explore and design interaction contexts in culture related public spaces such as museums, experience centres and festivals. As a perspective on this domain, I...... will help interaction designers when designing for bodily movement, and communicating and staging interactive content in public spaces....

  3. Interactive Parallel and Distributed Processing

    DEFF Research Database (Denmark)

    Lund, Henrik Hautop; Pagliarini, Luigi

    2010-01-01

    We present the concept of interactive parallel and distributed processing, and the challenges that programmers face in designing interactive parallel and distributed systems. Specifically, we introduce the challenges that are met and the decisions that need to be taken with respect...... to distributedness, master dependency, software behavioural models, adaptive interactivity, feedback, connectivity, topology, island modeling, and user interaction. We introduce the system of modular interactive tiles as a tool for easy, fast, and flexible exploration of these issues, and through examples show how...... to implement interactive parallel and distributed processing with different software behavioural models such as open loop, randomness based, rule based, user interaction based, AI and ALife based software....

  4. Student interaction in workshops

    DEFF Research Database (Denmark)

    Evers, Winie

    2014-01-01

    A kind of teaching for active learning has been experimented with at SDU Sønderborg as part of the course Supply Chain Dynamics. In this course the students learn about complex systems, system dynamics as well as supply chain instability and oscillation, the course lecturer invited the author...... to experiment with novel workshop methods and techniques, where objects are used to illustrate and model business issues (Heinemann et al, 2011, Buur et al, 2013). The idea was to see how students could be engaged in a different and more interactive way to learn about these topics, by assigning the students...... teaching should reflect this diversity by embracing and experimenting with multiple forms, including activation of students by students’ interaction and manipulation with objects....

  5. Interacting Galaxies with MOND

    CERN Document Server

    Tiret, O

    2007-01-01

    We compare N-body simulations performed in MOND with analogs in Newtonian gravity with dark matter (DM). We have developed a code which solves the Poisson equation in both gravity models. It is a grid solver using adaptive mesh refinement techniques, allowing us to study isolated galaxies as well as interacting galaxies. Galaxies in MOND are found to form bars faster and stronger than in the DM model. In Newton dynamics, it is difficult to reproduce the observed high frequency of strong bars, while MOND appears to fit better the observations. Galaxy interactions and mergers, such as the Antennae, are also simulated with Newton and MOND dynamics. In the latter, dynamical friction is much weaker, and merging time-scales are longer. The formation of tidal dwarf galaxies in tidal tails are also compared in MOND and Newton+DM models.

  6. Neutrinophilic nonstandard interactions

    Science.gov (United States)

    Farzan, Yasaman; Heeck, Julian

    2016-09-01

    We construct UV-complete models for nonstandard neutrino interactions mediated by a sub-GeV gauge boson Z' coupled to baryon number B or B -L . A flavor-dependent Z' coupling to neutrinos is induced by mixing a U (1 )'-charged Dirac fermion with the active neutrinos, naturally suppressing flavor violation or nonuniversality of the charged leptons to the loop level. We show that these models can give rise to large flavor-conserving as well as flavor-violating nonstandard neutral-current neutrino interactions potentially observable in current or future oscillation experiments such as DUNE without being in conflict with other constraints such as neutrino scattering or lepton-flavor-violating decays. In particular, the LMA-Dark solution to the solar-neutrino anomaly can be obtained for U (1 )B, but not for U (1 )B-L.

  7. Multiparton Interactions and Rescattering

    CERN Document Server

    Corke, Richard

    2009-01-01

    The concept of multiple partonic interactions in hadronic events is vital for the understanding of both minimum-bias and underlying-event physics. The area is rather little studied, however, and current models offer a far from complete coverage, even of the effects we know ought to be there. In this article we address one such topic, namely that of rescattering, where an already scattered parton is allowed to take part in another subsequent scattering. A framework for rescattering is introduced for the Pythia 8 event generator and fully integrated with normal multiparton interactions and initial- and final-state radiation. Using this model, the effects on event structure are studied, and distributions are shown both for minimum-bias and jet events.

  8. Interactive White Board

    Directory of Open Access Journals (Sweden)

    Asadullah Khan Praveen Kumar Arun Nair Rishi R Hegde

    2012-02-01

    Full Text Available Visual Screen uses an inexpensive technique to transform an ordinary screen into a touch screen[1] using an ordinary camera[2]. The system can fullfill many tasks such as controlling a remote large display, and simulating a physical keyboard[4]. Users can naturally use their fingers or other tip pointers to issue commands and type texts. In many intelligent environments, instead of using conventional mice[3], keyboards[4] and joysticks[5], people are looking for an intuitive, immersive and cost-efficient interaction device. We describe two vision-based interface systems[10]. The first, Visual Screen, uses an inexpensive technique to transform an ordinary screen into a touch screen[1] using an ordinary camera[2], and a user can use his/her finger to interact with the computer. Touch screens[1] are very convenient because one can directly point to where it is interesting. No conventional mice[3] are needed.

  9. Interactional Expertise and Embodiment

    CERN Document Server

    Collins, Harry

    2016-01-01

    In Part 1 of this paper, I introduce the idea of interactional expertise while in Part 2, I focus on its implications for philosophical theories of the importance of the body in forming our conceptual world. I argue that the way philosophers have dealt with the body turns attention away from the most important questions and that we cannot answer these questions without making the notion of socialisation, and therefore interactional expertise, a central concept in our thinking. This makes language at least as important, and often more important than bodily practice in our understanding of the world. The notion of a disembodied socialised agent leads in the direction of interesting questions while the notion of an embodied but unsocialised human actor is unimaginable.

  10. Dynamics of interacting diseases

    CERN Document Server

    Sanz, Joaquín; Meloni, Sandro; Moreno, Yamir

    2014-01-01

    Current modeling of infectious diseases allows for the study of complex and realistic scenarios that go from the population to the individual level of description. Most epidemic models however assume that the spreading process takes place on a single level (be it a single population, a meta-population system or a network of contacts). The latter is in part a consequence of our still limited knowledge about the interdependency of the many mechanisms and factors involved in disease spreading. In particular, interdependent contagion phenomena can only be addressed if we go beyond the scheme one pathogen-one network. In this paper, we study a model that allows describing the spreading dynamics of two concurrent diseases and apply it to a paradigmatic case of disease-disease interaction: the interaction between AIDS and Tuberculosis. Specifically, we characterize analytically the epidemic thresholds of the two diseases for different scenarios and also compute the temporal evolution characterizing the unfolding dyn...

  11. Intelligent Interactive Multimedia

    CERN Document Server

    Watanabe, Toyohide; Takahashi, Naohisa; 5th International Conference on Intelligent Interactive Multimedia Systems and Services

    2012-01-01

    This volume contains the Proceedings of the 5th International Conference on Intelligent Interactive Multimedia Systems and Services (KES-IIMSS-12).  The Conference was jointly organised by Nagoya University in Japan and the KES International organisation, and held in the attractive city of Gifu.   The KES-IIMSS conference series, (series chairs Prof. Maria Virvou and Prof. George Tsihrintzis), presents novel research in various areas of intelligent multimedia system relevant to the development of a new generation of interactive, user-centric devices and systems.  The aim of the conference is to provide an internationally respected forum for scientific research in the technologies and applications of this new and dynamic research area.

  12. Theory of gravitational interactions

    CERN Document Server

    Gasperini, Maurizio

    2017-01-01

    This is the second edition of a well-received book that is a modern, self-contained introduction to the theory of gravitational interactions. The new edition includes more details on gravitational waves of cosmological origin, the so-called brane world scenario, and gravitational time-delay effects. The first part of the book follows the traditional presentation of general relativity as a geometric theory of the macroscopic gravitational field, while the second, more advanced part discusses the deep analogies (and differences) between a geometric theory of gravity and the “gauge” theories of the other fundamental interactions. This fills a gap within the traditional approach to general relativity which usually leaves students puzzled about the role of gravity. The required notions of differential geometry are reduced to the minimum, allowing room for aspects of gravitational physics of current phenomenological and theoretical interest, such as the properties of gravitational waves, the gravitational inter...

  13. Interactive protein manipulation

    Energy Technology Data Exchange (ETDEWEB)

    SNCrivelli@lbl.gov

    2003-07-01

    We describe an interactive visualization and modeling program for the creation of protein structures ''from scratch''. The input to our program is an amino acid sequence -decoded from a gene- and a sequence of predicted secondary structure types for each amino acid-provided by external structure prediction programs. Our program can be used in the set-up phase of a protein structure prediction process; the structures created with it serve as input for a subsequent global internal energy minimization, or another method of protein structure prediction. Our program supports basic visualization methods for protein structures, interactive manipulation based on inverse kinematics, and visualization guides to aid a user in creating ''good'' initial structures.

  14. Ultrahigh energy neutrino interactions

    Science.gov (United States)

    Domokos, G.; Elliot, B.; Kovesi-Domokos, S.; Mrenna, S.

    1990-03-01

    Ultrahigh energy neutrinos are valuable probes of physics beyond the Standard Model. Neutrinos of the highest energies are emitted by point sources in the sky. We review briefly the predictions of the Standard Model concerning neutrino interactions. We further argue that a number of preon models designed to overcome some difficulties of the Standard Model leads to a blurring of the distinction between leptons and quarks. As a consequence, at sufficiently high energies neutrinos acquire ``anomalous'' interactions. While this phenomenon can probably explain the observed muon excess in extensive air showers (EAS), it can be also tested by studying the absorption of the primaries on the cosmic microwave background. We discuss some observations to be performed in the search of such ``new physics'' beyond the Standard Model.

  15. Interactive Information Retrieval:

    DEFF Research Database (Denmark)

    Borlund, Pia

    This presentation addresses methodological issues of interactive information retrieval (IIR) evaluation in terms of what it entails to study users' use and interaction with IR systems, as well as their satisfaction with retrieved information. In particular, the presentation focuses on test design......, and it takes a look into the toolbox of IIR test design with reference to data collection methods and test procedure. It calls for careful and well-planned studies to qualify the knowledgebase generated as a result of the conducted IIR studies. The presentation further reflects on the need for an updated...... IIR from the perspective of search dedication and task load in order to also include everyday life information seeking? With this presentation, the IIR community is invited to an exchange of ideas and is encouraged to engage in collaborations with the solving of these (and other) issues to our joint...

  16. Ligand-Receptor Interactions

    CERN Document Server

    Bongrand, Pierre

    2008-01-01

    The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the ...

  17. Interactive Chemical Reactivity Exploration

    CERN Document Server

    Haag, Moritz P; Bosson, Mael; Redon, Stephane; Reiher, Markus

    2014-01-01

    Elucidating chemical reactivity in complex molecular assemblies of a few hundred atoms is, despite the remarkable progress in quantum chemistry, still a major challenge. Black-box search methods to find intermediates and transition-state structures might fail in such situations because of the high-dimensionality of the potential energy surface. Here, we propose the concept of interactive chemical reactivity exploration to effectively introduce the chemist's intuition into the search process. We employ a haptic pointer device with force-feedback to allow the operator the direct manipulation of structures in three dimensions along with simultaneous perception of the quantum mechanical response upon structure modification as forces. We elaborate on the details of how such an interactive exploration should proceed and which technical difficulties need to be overcome. All reactivity-exploration concepts developed for this purpose have been implemented in the Samson programming environment.

  18. Interactions faibles en harmonie

    CERN Multimedia

    1978-01-01

    Des résultats de haute précision obtenus à Stanford ouvrent la voie vers une unification des interactions faible et électromagnétique ; Présentation à la Conférence neutrino d'Oxford de nouveaux résultats en accord avec la théorie de la synthèse des forces faible et électro- magnétique

  19. ELEMENTARY PARTICLE INTERACTIONS

    Energy Technology Data Exchange (ETDEWEB)

    EFREMENKO, YURI; HANDLER, THOMAS; KAMYSHKOV, YURI; SIOPSIS, GEORGE; SPANIER, STEFAN

    2013-07-30

    The High-Energy Elementary Particle Interactions group at UT during the last three years worked on the following directions and projects: Collider-based Particle Physics; Neutrino Physics, particularly participation in “NOνA”, “Double Chooz”, and “KamLAND” neutrino experiments; and Theory, including Scattering amplitudes, Quark-gluon plasma; Holographic cosmology; Holographic superconductors; Charge density waves; Striped superconductors; and Holographic FFLO states.

  20. Scoping Agriculture, Wetland Interactions

    OpenAIRE

    2015-01-01

    Agriculture is identified as the main cause of wetland degradation and loss. Using a drivers, pressures, state changes, impacts and responses (DPSIR) framework to analyze 90 cases drawn from all parts of the world and all wetland types, this report assesses the character of agriculture - wetlands interactions (AWIs) and their impacts in socio-economic and ecosystem services terms. The report is a technical framework that is used to scope out the relevance and nature of AWIs, identify response...

  1. Pharmacokinetic interactions with thiazolidinediones.

    Science.gov (United States)

    Scheen, André J

    2007-01-01

    Type 2 diabetes mellitus is a complex disease combining defects in insulin secretion and insulin action. New compounds called thiazolidinediones or glitazones have been developed for reducing insulin resistance. After the withdrawal of troglitazone because of liver toxicity, two compounds are currently used in clinical practice, rosiglitazone and pioglitazone. These compounds are generally used in combination with other pharmacological agents. Because they are metabolised via cytochrome P450 (CYP), glitazones are exposed to numerous pharmacokinetic interactions. CYP2C8 and CYP3A4 are the main isoenzymes catalysing biotransformation of pioglitazone (as with troglitazone), whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. For both rosiglitazone and pioglitazone, the most relevant interactions have been described in healthy volunteers with rifampicin (rifampin), which results in a significant decrease of area under the plasma concentration-time curve [AUC] (54-65% for rosiglitazone, p<0.001; 54% for pioglitazone, p<0.001), and with gemfibrozil, which results in a significant increase of AUC (130% for rosiglitazone, p<0.001; 220-240% for pioglitazone, p<0.001). The relevance of such drug-drug interactions in patients with type 2 diabetes remains to be evaluated. However, in the absence of clinical data, it is prudent to reduce the dosage of each glitazone by half in patients treated with gemfibrozil. Conversely, rosiglitazone and pioglitazone do not seem to significantly affect the pharmacokinetics of other compounds. Although some food components have also been shown to potentially interfere with drugs metabolised with the CYP system, no published study deals specifically with these possible CYP-mediated food-drug interactions with glitazones.

  2. Orbital interactions in chemistry

    CERN Document Server

    Albright, Thomas A; Whangbo, Myung-Hwan

    2013-01-01

    Explains the underlying structure that unites all disciplines in chemistry Now in its second edition, this book explores organic, organometallic, inorganic, solid state, and materials chemistry, demonstrating how common molecular orbital situations arise throughout the whole chemical spectrum. The authors explore the relationships that enable readers to grasp the theory that underlies and connects traditional fields of study within chemistry, thereby providing a conceptual framework with which to think about chemical structure and reactivity problems. Orbital Interactions

  3. Designing for interaction

    OpenAIRE

    2004-01-01

    At present, the design of computer-supported group-based learning (CS)GBL) is often based on subjective decisions regarding tasks, pedagogy and technology, or concepts such as ‘cooperative learning’ and ‘collaborative learning’. Critical review reveals these concepts as insufficiently substantial to serve as a basis for (CS)GBL design. Furthermore, the relationship between outcome and group interaction is rarely specified a priori. Thus, there is a need for a more systematic approach to desig...

  4. Neutrino Interactions with Nuclei

    CERN Document Server

    Leitner, T; Mosel, U; Alvarez-Ruso, L

    2007-01-01

    We investigate neutrino-nucleus collisions at intermediate energies incorporating quasi-elastic scattering and the excitation of 13 resonances as elementary processes, taking into account medium effects such as Fermi motion, Pauli blocking, mean-field potentials and in-medium spectral functions. A coupled-channel treatment of final state interactions is achieved with the GiBUU transport model. Results for inclusive reactions, neutrino- and electron-induced, as well as for pion production and nucleon knockout are presented.

  5. Interactive Mathematics Textbooks

    DEFF Research Database (Denmark)

    Sinclair, Robert

    1999-01-01

    We claim that important considerations have been overlooked in designinginteractive mathematics educational software in the past.In particular,most previous work has concentrated on how to make use ofpre-existing software in mathematics education, rather than firstasking the more...... fundamentalquestion of which requirements mathematics education puts on software, and thendesigning software to fulfil these requirements.We present a working prototype system which takes a script defining an interactivemathematicaldocument and then provides a reader with an interactive realization of thatdocument....

  6. Wave-Ice interaction

    Institute of Scientific and Technical Information of China (English)

    沈奚海莉

    2001-01-01

    The growth and movement of sea ice cover are influenced by the presence of wave field. Inturn, the wave field is influenced by the presence of ice cover. Their interaction is not fully understood.In this paper, we discuss some current understanding on wave attenuation when it propagates through frag-mented ice cover, ice drift due to the wave motion, and the growth characteristics of ice cover in wave field.

  7. Brain-gut interactions.

    OpenAIRE

    Bonaz, Bruno

    1994-01-01

    International audience; Our digestive tract has an autonomous functioning but also has a bidirectional relation with our brain known as brain-gut interactions. This communication is mediated by the autonomous nervous system, i.e., the sympathetic and parasympathetic nervous systems, with a mixed afferent and efferent component, and the circumventricular organs located outside the blood-brain barrier. The vagus nerve, known as the principal component of the parasympathetic nervous system, is a...

  8. Renormalizability and nonrenormalizable interactions

    Institute of Scientific and Technical Information of China (English)

    YAO Hai-Bo; WU Shi-Shu

    2009-01-01

    Arguments are provided which show that extension of renormalizability in quantum field theory is possible. By an appropriate choice of effective Lagrangian, a dressed Feynman propagator is obtained. In this scheme, higher order Feynman diagrams become self-convergent and nonrenormalizable interactions become renormalizable. As an example, the vacuum fluctuation effects on p meson mass for the vector-tensor coupling model is discussed. It is found that the result can agree with the experimental value when coupling constant is adjusted.

  9. Model Checking Feature Interactions

    DEFF Research Database (Denmark)

    Le Guilly, Thibaut; Olsen, Petur; Pedersen, Thomas;

    2015-01-01

    This paper presents an offline approach to analyzing feature interactions in embedded systems. The approach consists of a systematic process to gather the necessary information about system components and their models. The model is first specified in terms of predicates, before being refined to t...... to timed automata. The consistency of the model is verified at different development stages, and the correct linkage between the predicates and their semantic model is checked. The approach is illustrated on a use case from home automation....

  10. A specific A/T polymorphism in Western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interactions.

    Science.gov (United States)

    Zhang, Xue-Song; Tegtmeyer, Nicole; Traube, Leah; Jindal, Shawn; Perez-Perez, Guillermo; Sticht, Heinrich; Backert, Steffen; Blaser, Martin J

    2015-02-01

    Helicobacter pylori persistently colonizes the human stomach, with mixed roles in human health. The CagA protein, a key host-interaction factor, is translocated by a type IV secretion system into host epithelial cells, where its EPIYA tyrosine phosphorylation motifs (TPMs) are recognized by host cell kinases, leading to multiple host cell signaling cascades. The CagA TPMs have been described as type A, B, C or D, each with a specific conserved amino acid sequence surrounding EPIYA. Database searching revealed strong non-random distribution of the B-motifs (including EPIYA and EPIYT) in Western H. pylori isolates. In silico analysis of Western H. pylori CagA sequences provided evidence that the EPIYT B-TPMs are significantly less associated with gastric cancer than the EPIYA B-TPMs. By generating and using a phosphorylated CagA B-TPM-specific antibody, we demonstrated the phosphorylated state of the CagA B-TPM EPIYT during H. pylori co-culture with host cells. We also showed that within host cells, CagA interaction with phosphoinositol 3-kinase (PI3-kinase) was B-TPM tyrosine-phosphorylation-dependent, and the recombinant CagA with EPIYT B-TPM had higher affinity to PI3-kinase and enhanced induction of AKT than the isogenic CagA with EPIYA B-TPM. Structural modeling of the CagA B-TPM motif bound to PI3-kinase indicated that the threonine residue at the pY+1 position forms a side-chain hydrogen bond to N-417 of PI3-kinase, which cannot be formed by alanine. During co-culture with AGS cells, an H. pylori strain with a CagA EPIYT B-TPM had significantly attenuated induction of interleukin-8 and hummingbird phenotype, compared to the isogenic strain with B-TPM EPIYA. These results suggest that the A/T polymorphisms could regulate CagA activity through interfering with host signaling pathways related to carcinogenesis, thus influencing cancer risk.

  11. A specific A/T polymorphism in Western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interactions.

    Directory of Open Access Journals (Sweden)

    Xue-Song Zhang

    2015-02-01

    Full Text Available Helicobacter pylori persistently colonizes the human stomach, with mixed roles in human health. The CagA protein, a key host-interaction factor, is translocated by a type IV secretion system into host epithelial cells, where its EPIYA tyrosine phosphorylation motifs (TPMs are recognized by host cell kinases, leading to multiple host cell signaling cascades. The CagA TPMs have been described as type A, B, C or D, each with a specific conserved amino acid sequence surrounding EPIYA. Database searching revealed strong non-random distribution of the B-motifs (including EPIYA and EPIYT in Western H. pylori isolates. In silico analysis of Western H. pylori CagA sequences provided evidence that the EPIYT B-TPMs are significantly less associated with gastric cancer than the EPIYA B-TPMs. By generating and using a phosphorylated CagA B-TPM-specific antibody, we demonstrated the phosphorylated state of the CagA B-TPM EPIYT during H. pylori co-culture with host cells. We also showed that within host cells, CagA interaction with phosphoinositol 3-kinase (PI3-kinase was B-TPM tyrosine-phosphorylation-dependent, and the recombinant CagA with EPIYT B-TPM had higher affinity to PI3-kinase and enhanced induction of AKT than the isogenic CagA with EPIYA B-TPM. Structural modeling of the CagA B-TPM motif bound to PI3-kinase indicated that the threonine residue at the pY+1 position forms a side-chain hydrogen bond to N-417 of PI3-kinase, which cannot be formed by alanine. During co-culture with AGS cells, an H. pylori strain with a CagA EPIYT B-TPM had significantly attenuated induction of interleukin-8 and hummingbird phenotype, compared to the isogenic strain with B-TPM EPIYA. These results suggest that the A/T polymorphisms could regulate CagA activity through interfering with host signaling pathways related to carcinogenesis, thus influencing cancer risk.

  12. Campylobacter-Acanthamoeba interactions.

    Science.gov (United States)

    Vieira, Ana; Seddon, Alan M; Karlyshev, Andrey V

    2015-05-01

    Campylobacter jejuni is a foodborne pathogen recognized as the major cause of human bacterial enteritis. Undercooked poultry products and contaminated water are considered as the most important sources of infection. Some studies suggest transmission and survival of this bacterial pathogen may be assisted by the free-living protozoa Acanthamoeba. The latter is known to play the role of a host for various pathogenic bacteria, protecting them from harsh environmental conditions. Importantly, there is a similarity between the mechanisms of bacterial survival within amoebae and macrophages, making the former a convenient tool for the investigation of the survival of pathogenic bacteria in the environment. However, the molecular mechanisms involved in the interaction between Campylobacter and Acanthamoeba are not well understood. Whilst some studies suggest the ability of C. jejuni to survive within the protozoa, the other reports support an extracellular mode of survival only. In this review, we focus on the studies investigating the interaction between Campylobacter and Acanthamoeba, address some reasons for the contradictory results, and discuss possible implications of these results for epidemiology. Additionally, as the molecular mechanisms involved remain unknown, we also suggest possible factors that may be involved in this process. Deciphering the molecular mechanisms of pathogen-protozoa interaction will assist in a better understanding of Campylobacter lifestyle and in the development of novel antibacterial drugs.

  13. Intercultural Interaction and Handicrafts

    Directory of Open Access Journals (Sweden)

    Mine CAN

    2015-07-01

    Full Text Available Technological developments in the world since the mid - 20th century, has increased intercultural communication and the whole world today has been informed of the existence of societies even in the most remote corners of the world. With increase in globaliza tion in cultural context, the importance of local differences has emerged more today. As a result, a process has initiated in which the similarities with differences, localization with the universalization and modernization with the tradition experienced s imutaneously and intercultural interaction has become inevitable and a natural phenomenon. However, handicrafts has been affected by cultural interactions negatively and the mistakes done caused the national culture and identities to weaken. For this reaso n, the necessity of experience of changing and developing in the frame of development with identity, transformation and cultural heritage today is emphasized. To be protected from the negative effects of the global interaction, many government produce prot ection and sustenance contracts, laws and projects by engaging in various initiatives. In the study, subjects is discussed with the examples of successful countries that aim to promote their local cultures globally and provide income.

  14. Pharmacological interactions of vasoconstrictors.

    Science.gov (United States)

    Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

    2009-01-01

    This article is the first of a series on pharmacological interactions involving medicaments commonly prescribed and/or used in odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessity for the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increase in medicament consumption by the general population. There is a demographic change with greater life expectancy and patients have increased chronic health problems and therefore have increased medicament intake. The presence of adrenaline (epinephrine) and other vasoconstrictors in local odontological anaesthetics is beneficial in relation to the duration and depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might produce pharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicament administered exogenically which the odontologist should be aware of, especially because of the risk of consequent adverse reactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include all medicaments, legal as well as illegal, taken by the patient.

  15. Transactional interactive multimedia banner

    Science.gov (United States)

    Shae, Zon-Yin; Wang, Xiping; von Kaenel, Juerg

    2000-05-01

    Advertising in TV broadcasting has shown that multimedia is a very effective means to present merchandise and attract shoppers. This has been applied to the Web by including animated multimedia banner ads on web pages. However, the issues of coupling interactive browsing, shopping, and secure transactions e.g. from inside a multimedia banner, have only recently started to being explored. Currently there is an explosively growing amount of back-end services available (e.g., business to business commerce (B2B), business to consumer (B2C) commerce, and infomercial services) in the Internet. These services are mostly accessible through static HTML web pages at a few specific web portals. In this paper, we will investigate the feasibility of using interactive multimedia banners as pervasive access point for the B2C, B2B, and infomercial services. We present a system architecture that involves a layer of middleware agents functioning as the bridge between the interactive multimedia banners and back-end services.

  16. Representation, interaction, and intersubjectivity.

    Science.gov (United States)

    Alterman, Richard

    2007-09-10

    What the participants share, their common "sense" of the world, creates a foundation, a framing, an orientation that enables human actors to see and act in coordination with one another. For recurrent activities, the methods the participants use to understand each other as they act change, making the intersubjective space in which actors operate richer and easier to produce. This article works through some of the issues that emerge from a close examination of intersubjectivity as it is managed through representation and interaction. The data that are presented document, in detail, a sequence of related interactions, within and across episodes of cooperation, where continuity and change can be observed. The emergence of conversational structure and coordinating representations are significant milestones in the long-term development of a representational practice that support the runtime co-construction of intersubjective space. Conversational structures emerge interactively to mediate recurrent points of coordination in the domain activity, and only secondarily the conversation itself. Coordinating representations change the representational practice of the participants by making it easier to manage their "shared view" of the collective work, enabling the participants to make progress, expand the field of the common activity, while exhibiting more control of if and when explicit grounding occurs.

  17. Web Interactive Campus Map

    Directory of Open Access Journals (Sweden)

    Marylene S. Eder

    2015-03-01

    Full Text Available Abstract Interactive campus map is a web based application that can be accessed through a web browser. With the Google Map Application Programming Interface availability of the overlay function has been taken advantage to create custom map functionalities. Collection of building points were gathered for routing and to create polygons which serves as a representation of each building. The previous campus map provides a static visual representation of the campus. It uses legends building name and its corresponding building number in providing information. Due to its limited capabilities it became a realization to the researchers to create an interactive campus map.Storing data about the building room and staff information and university events and campus guide are among the primary features that this study has to offer. Interactive Web-based Campus Information System is intended in providing a Campus Information System.It is open to constant updates user-friendly for both trained and untrained users and capable of responding to all needs of users and carrying out analyses. Based on the data gathered through questionnaires researchers analyzed the results of the test survey and proved that the system is user friendly deliver information to users and the important features that the students expect.

  18. Bacteria-surface interactions.

    Science.gov (United States)

    Tuson, Hannah H; Weibel, Douglas B

    2013-05-14

    The interaction of bacteria with surfaces has important implications in a range of areas, including bioenergy, biofouling, biofilm formation, and the infection of plants and animals. Many of the interactions of bacteria with surfaces produce changes in the expression of genes that influence cell morphology and behavior, including genes essential for motility and surface attachment. Despite the attention that these phenotypes have garnered, the bacterial systems used for sensing and responding to surfaces are still not well understood. An understanding of these mechanisms will guide the development of new classes of materials that inhibit and promote cell growth, and complement studies of the physiology of bacteria in contact with surfaces. Recent studies from a range of fields in science and engineering are poised to guide future investigations in this area. This review summarizes recent studies on bacteria-surface interactions, discusses mechanisms of surface sensing and consequences of cell attachment, provides an overview of surfaces that have been used in bacterial studies, and highlights unanswered questions in this field.

  19. On the Dark Sector Interactions

    CERN Document Server

    Cai, Rong-Gen

    2009-01-01

    The nature of dark energy (DE) is still unknown. It is possible that there exists some interaction between DE and dark matter (DM), and a suitable interaction can alleviate the coincidence problem. Several phenomenological interacting forms are proposed and are fitted with observations in the literature. In this paper we investigate the possible interaction in a way independent of specific interacting forms from observational data (SNe, BAO, CMB and Hubble parameter). We divide the whole range of redshift into four bins and set the interacting term $\\delta(z)$ to be piecewise constant in each redshift bin. We consider four parameterizations of the equation of state $w_{de}$ for DE and find that $\\delta(z)$ is likely to cross the non-interacting ($\\delta=0$) line at a recent time. It suggests that to study the interaction between DE and DM, more general phenomenological forms of the interacting term should be considered.

  20. Trapped Three Interacting Bosons with a Short-Ranged Interaction

    Institute of Scientific and Technical Information of China (English)

    XIE Wen-Fang

    2006-01-01

    A system of three bosons trapped by a parabolic confinement and interacting with a short-ranged interaction has been investigated by the exact diagonalization of the Hamiltonian matrix. We report a calculation for the energy spectrum of the low-lying states of a system of three interacting bosons. The important feature of the low-lying states of three interacting bosons trapped by a parabolic confinement is obtained via an analysis of the energy spectrum.

  1. Flavivirus-Mosquito Interactions

    Directory of Open Access Journals (Sweden)

    Yan-Jang S. Huang

    2014-11-01

    Full Text Available The Flavivirus genus is in the family Flaviviridae and is comprised of more than 70 viruses. These viruses have a broad geographic range, circulating on every continent except Antarctica. Mosquito-borne flaviviruses, such as yellow fever virus, dengue virus serotypes 1–4, Japanese encephalitis virus, and West Nile virus are responsible for significant human morbidity and mortality in affected regions. This review focuses on what is known about flavivirus-mosquito interactions and presents key data collected from the field and laboratory-based molecular and ultrastructural evaluations.

  2. Interacting Double Coset Magnons

    CERN Document Server

    Ali, Abdelhamid Mohamed Adam; Tahiridimbisoa, Nirina Hasina; Mahu, Augustine Larweh

    2015-01-01

    We consider the anomalous dimensions of restricted Schur polynomials constructed using n~O(N) complex adjoint scalars Z and m complex adjoint scalars Y. We fix m<interactions. The form of this new operator mixing is studied in detail for a system of two giant gravitons with four strings attached.

  3. Cultivating objects in interaction

    DEFF Research Database (Denmark)

    Hazel, Spencer

    2014-01-01

    is chapter explores patterns of repeated orientations to physical objects in interactants’ visuo-spatial and haptic surround. A number of examples are presented from advice-giving activities in various institutional settings, where participants-in-interaction initially draw on material objects...... on these associations for describing, disambiguating or clarifying aspects of the relatively complex procedural frameworks discussed in the settings. is suggests that the temporal stability of material objects available to participants makes them an ideal resource to be developed as visual motifs....

  4. [Tenofovir: pharmacology and interactions].

    Science.gov (United States)

    Azanza, José Ramón; García Quetglas, Emilio; Sádaba, Belén; Gómez-Giu, Almudena

    2008-06-01

    Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported.

  5. Interacting composite fermions

    DEFF Research Database (Denmark)

    nrc762, nrc762

    2016-01-01

    Numerical studies by Wójs, Yi, and Quinn have suggested that an unconventional fractional quantum Hall effect is plausible at filling factors ν=1/3 and 1/5, provided the interparticle interaction has an unusual form for which the energy of two fermions in the relative angular momentum three channel...... dominates. The interaction between composite fermions in the second Λ level (composite fermion analog of the electronic Landau level) satisfies this property, and recent studies have supported unconventional fractional quantum Hall effect of composite fermions at ν∗=4/3 and 5/3, which manifests...... as fractional quantum Hall effect of electrons at ν=4/11, 4/13, 5/13, and 5/17. I investigate in this article the nature of the fractional quantum Hall states at ν=4/5, 5/7, 6/17, and 6/7, which correspond to composite fermions at ν∗=4/3, 5/3, and 6/5, and find that all these fractional quantum Hall states...

  6. Herb-drug interactions.

    Science.gov (United States)

    Fugh-Berman, A

    2000-01-08

    Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

  7. Interacting Q-balls

    CERN Document Server

    Brihaye, Yves

    2007-01-01

    We construct explicit examples of new axially symmetric, non-spinning Q-ball solutions that have not been studied so far. These solutions can be interpreted as angular excitations of the fundamental Q-balls and are related to the spherical harmonics. Correspondingly, they have higher energy and their energy densities possess two local maxima on the positive z-axis. We also study two Q-balls interacting via a potential term in 3+1 dimensions and construct examples of stationary, solitonic-like objects in (3+1)-dimensional flat space-time that consist of two interacting global scalar fields. We concentrate on configurations composed of one spinning and one non-spinning Q-ball and study the parameter-dependence of the energy and charges of the configuration. In addition, we present numerical evidence that for fixed values of the coupling constants two different types of 2-Q-ball solutions exist: solutions with defined parity, but also solutions which are asymmetric with respect to reflexion through the x-y-axis.

  8. Electromagnetic Interactions of Muons

    CERN Multimedia

    2002-01-01

    This experiment was the first in a programme of physics experiments with high-energy muons using a large spectrometer facility. The aim of this experiment is to study the inelastic scattering of muons with various targets to try to understand better the physics of virtual photon interactions over a wide range of four-momentum transfer (q$^{2}$).\\\\ \\\\ The spectrometer includes a large aperture dipole magnet (2m x 1m) of bending power $\\simeq$5 T.m and a magnetized iron filter to distinguish the scattered muons from hadrons. Drift chambers and MWPC are used before and after the magnet to detect charged products of the interaction and to allow a momentum determination of the scattered muon to an accuracy of $\\simeq$at 100 GeV/c, and an angular definition of $\\pm$ 0.1 mrad. The triggering on scattered muons relies on three planes of scintillation counter hodoscopes before and after the magnetized iron, whose magnetic field serves to eliminate triggers from low momentum muons which are produced copiously by pion d...

  9. Charged Dust Aggregate Interactions

    Science.gov (United States)

    Matthews, Lorin; Hyde, Truell

    2015-11-01

    A proper understanding of the behavior of dust particle aggregates immersed in a complex plasma first requires a knowledge of the basic properties of the system. Among the most important of these are the net electrostatic charge and higher multipole moments on the dust aggregate as well as the manner in which the aggregate interacts with the local electrostatic fields. The formation of elongated, fractal-like aggregates levitating in the sheath electric field of a weakly ionized RF generated plasma discharge has recently been observed experimentally. The resulting data has shown that as aggregates approach one another, they can both accelerate and rotate. At equilibrium, aggregates are observed to levitate with regular spacing, rotating about their long axis aligned parallel to the sheath electric field. Since gas drag tends to slow any such rotation, energy must be constantly fed into the system in order to sustain it. A numerical model designed to analyze this motion provides both the electrostatic charge and higher multipole moments of the aggregate while including the forces due to thermophoresis, neutral gas drag, and the ion wakefield. This model will be used to investigate the ambient conditions leading to the observed interactions. This research is funded by NSF Grant 1414523.

  10. Cardiolipin Interactions with Proteins.

    Science.gov (United States)

    Planas-Iglesias, Joan; Dwarakanath, Himal; Mohammadyani, Dariush; Yanamala, Naveena; Kagan, Valerian E; Klein-Seetharaman, Judith

    2015-09-15

    Cardiolipins (CL) represent unique phospholipids of bacteria and eukaryotic mitochondria with four acyl chains and two phosphate groups that have been implicated in numerous functions from energy metabolism to apoptosis. Many proteins are known to interact with CL, and several cocrystal structures of protein-CL complexes exist. In this work, we describe the collection of the first systematic and, to the best of our knowledge, the comprehensive gold standard data set of all known CL-binding proteins. There are 62 proteins in this data set, 21 of which have nonredundant crystal structures with bound CL molecules available. Using binding patch analysis of amino acid frequencies, secondary structures and loop supersecondary structures considering phosphate and acyl chain binding regions together and separately, we gained a detailed understanding of the general structural and dynamic features involved in CL binding to proteins. Exhaustive docking of CL to all known structures of proteins experimentally shown to interact with CL demonstrated the validity of the docking approach, and provides a rich source of information for experimentalists who may wish to validate predictions.

  11. Hydrophobic interactions and chemical reactivity

    NARCIS (Netherlands)

    Otto, Sijbren; Engberts, Jan B.F.N.

    2003-01-01

    This perspective describes how kinetic studies of organic reactions can be used to increase our understanding of hydrophobic interactions. In turn, our understanding of hydrophobic interactions can be used as a tool to influence chemical reactions.

  12. Interaction in English Classroom Teaching

    Institute of Scientific and Technical Information of China (English)

    金晶

    2009-01-01

    This essay mainly elaborates on the interaction in English classroom teaching.It highlights the indispensable role interaction should play in teaching process.and give out a series of methods on how to promote the application of this strategy.

  13. Novicidin interactions with phospholipid membranes

    DEFF Research Database (Denmark)

    Balakrishnan, Vijay Shankar

    Antimicrobial peptides target bacterial cell membranes and are considered as potential antibiotics. Their interactions with cell membranes are studied using different approaches. This thesis comprises of the biophysical investigations on the antimicrobial peptide Novicidin, interacting with lipos...

  14. HUMAN INTERACTION WITH MOBILE APPLICATIONS

    OpenAIRE

    Alin Zamfiroiu; Emanuel Herteliu; Bogdan Vintila

    2012-01-01

    Computing - human interaction is a very important paradigm because informatics applications are created to be used by people via human interaction. Nowadays mobile applications are more used so is necessarily to talk about mobile - human interaction. In this paper types of mobile devices are presented. Citizen oriented character of mobile application and his utility are described. Different means of interactions with mobile devices are analyzed and in the end of the paper direction of mobile ...

  15. Design Principles for Interactive Software

    DEFF Research Database (Denmark)

    The book addresses the crucial intersection of human-computer interaction (HCI) and software engineering by asking both what users require from interactive systems and what developers need to produce well-engineered software. Needs are expressed as......The book addresses the crucial intersection of human-computer interaction (HCI) and software engineering by asking both what users require from interactive systems and what developers need to produce well-engineered software. Needs are expressed as...

  16. On the interaction meteor complex

    Science.gov (United States)

    Rajchl, J.

    An approach to the problem of a meteoric complex called the interaction meteor complex (IMC) is applied and discussed, generalizing the idea of the interaction layer (Rajchl 1969). The role of an extended interaction of meteoroids is emphasized, both with planet surfaces and/or their satellites and with planet atmospheres, elastic or inelastic in form. The dissipation and related formative aspect are joined in one complex and compared with a topological compact. Examples of these types of interaction are presented.

  17. Electrostatic interaction of soft particles.

    Science.gov (United States)

    Ohshima, Hiroyuki

    2015-12-01

    Theories of the electrostatic interaction between two soft particles (i.e., particles covered with an ion-penetrable surface layer of polyelectrolytes) in an electrolyte solution are reviewed. Interactions of soft particles after contact of their surface layers are particularly discussed. Interaction in a salt-free medium and the discrete-charge effect are also treated.

  18. Ridge Regression for Interactive Models.

    Science.gov (United States)

    Tate, Richard L.

    1988-01-01

    An exploratory study of the value of ridge regression for interactive models is reported. Assuming that the linear terms in a simple interactive model are centered to eliminate non-essential multicollinearity, a variety of common models, representing both ordinal and disordinal interactions, are shown to have "orientations" that are favorable to…

  19. Local Interaction on Random Graphs

    Directory of Open Access Journals (Sweden)

    Hans Haller

    2010-08-01

    Full Text Available We analyze dynamic local interaction in population games where the local interaction structure (modeled as a graph can change over time: A stochastic process generates a random sequence of graphs. This contrasts with models where the initial interaction structure (represented by a deterministic graph or the realization of a random graph cannot change over time.

  20. SNP interaction pattern identifier (SIPI)

    DEFF Research Database (Denmark)

    Lin, Hui-Yi; Chen, Dung-Tsa; Huang, Po-Yu

    2016-01-01

    MOTIVATION: Testing SNP-SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP-SNP interactions are underdeveloped. RESULTS: We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45...

  1. Interactive lectures in engineering education

    NARCIS (Netherlands)

    van Dijk, L.A.; van den Berg, G.C.; van Keulen, H.

    2001-01-01

    This article discusses an alternative approach to lecturing: the interactive lecture. In the literature, interactive teaching is forwarded as a means to increase the effectiveness of lectures. Members of lecturing staff still seem, however, reluctant to incorporate interactive teaching in their clas

  2. Bunyavirus-vector interactions.

    Science.gov (United States)

    Beaty, B J; Bishop, D H

    1988-06-01

    Recent advances in the genetics and molecular biology of bunyaviruses have been applied to understanding bunyavirus-vector interactions. Such approaches have revealed which virus gene and gene products are important in establishing infections in vectors and in transmission of viruses. However, much more information is required to understand the molecular mechanisms of persistent infections of vectors which are lifelong but apparently exert no untoward effect. In fact, it seems remarkable that LAC viral antigen can be detected in almost every cell in an ovarian follicle, yet no untoward effect on fecundity and no teratology is seen. Similarly the lifelong infection of the vector would seem to provide ample opportunity for bunyavirus evolution by genetic drift and, under the appropriate circumstances, by segment reassortment. The potential for bunyavirus evolution by segment reassortment in vectors certainly exists. For example the Group C viruses in a small forest in Brazil seem to constitute a gene pool, with the 6 viruses related alternately by HI/NT and CF reactions, which assay respectively M RNA and S RNA gene products (Casals and Whitman, 1960; Shope and Causey, 1962). Direct evidence for naturally occurring reassortant bunyaviruses has also been obtained. Oligonucleotide fingerprint analyses of field isolates of LAC virus and members of the Patois serogroup of bunyaviruses have demonstrated that reassortment does occur in nature (El Said et al., 1979; Klimas et al., 1981; Ushijima et al., 1981). Determination of the genotypic frequencies of viruses selected by the biological interactions of viruses and vectors after dual infection and segment reassortment is an important issue. Should a virus result that efficiently interacts with alternate vector species, the virus could be expressed in different circumstances with serious epidemiologic consequences. Dual infection of vectors with different viruses is not unlikely, because many bunyaviruses are sympatric in

  3. Human-Robot Interaction

    Science.gov (United States)

    Sandor, Aniko; Cross, E. Vincent, II; Chang, Mai Lee

    2015-01-01

    Human-robot interaction (HRI) is a discipline investigating the factors affecting the interactions between humans and robots. It is important to evaluate how the design of interfaces affect the human's ability to perform tasks effectively and efficiently when working with a robot. By understanding the effects of interface design on human performance, workload, and situation awareness, interfaces can be developed to appropriately support the human in performing tasks with minimal errors and with appropriate interaction time and effort. Thus, the results of research on human-robot interfaces have direct implications for the design of robotic systems. For efficient and effective remote navigation of a rover, a human operator needs to be aware of the robot's environment. However, during teleoperation, operators may get information about the environment only through a robot's front-mounted camera causing a keyhole effect. The keyhole effect reduces situation awareness which may manifest in navigation issues such as higher number of collisions, missing critical aspects of the environment, or reduced speed. One way to compensate for the keyhole effect and the ambiguities operators experience when they teleoperate a robot is adding multiple cameras and including the robot chassis in the camera view. Augmented reality, such as overlays, can also enhance the way a person sees objects in the environment or in camera views by making them more visible. Scenes can be augmented with integrated telemetry, procedures, or map information. Furthermore, the addition of an exocentric (i.e., third-person) field of view from a camera placed in the robot's environment may provide operators with the additional information needed to gain spatial awareness of the robot. Two research studies investigated possible mitigation approaches to address the keyhole effect: 1) combining the inclusion of the robot chassis in the camera view with augmented reality overlays, and 2) modifying the camera

  4. Wood–water interactions

    DEFF Research Database (Denmark)

    Engelund, Emil Tang

    2011-01-01

    must first know in which parts of the wood structure, water is located. If parts of the water in wood are held in capillaries in the wood structure, these water molecules interact with the material differently than those held within wood cell walls. In this study, the occurrence of capillary water......, for wood in equilibrium with surrounding climate in the RH range 0-99.5 %, water is only significantly present within cell walls. A structural model of a wood cell is developed in this study using Finite Element Method for predicting the mechanical performance of wood. The starting point for the model...... is the physical behaviour on the molecular level since water interferes with wood at this level. The elastic material properties of the wood cell wall are explained by the organisation of wood constituents and their properties. The effect of water as well as temperature is incorporated by considering the amount...

  5. Human Work Interaction Design

    DEFF Research Database (Denmark)

    2015-01-01

    In this paper, we review research in the emerging practice and research field of Human Work Interaction Design (HWID). We present a HWID frame-work, and a sample of 54 papers from workshops, conferences and journals from the period 2009-2014. We group the papers into six topical groups, and then at......-tempt to map these groups to the framework to find research gaps for future re-search. We find that the groups of papers cover all areas of the framework well for a variety of work and leisure domains. The area in strongest need for more research papers is the development of the holistic framework itself....... Furthermore, much focus has been on studying design sketching or implemented systems-in-use, while little attention has been paid to mature design (prototypes) or early implementation (content templates). In conclusion, we recommend an update to the framework so that it can be also useful for research...

  6. Human Work Interaction Design

    DEFF Research Database (Denmark)

    2015-01-01

    In this paper, we review research in the emerging practice and research field of Human Work Interaction Design (HWID). We present a HWID framework, and a sample of 54 HWID related papers from workshops, conferences and journals from the period 2009–2014. We group the papers into six topical groups......, and then attempt to map these groups to the framework to find research gaps for future research. We find that the groups of papers cover all areas of the framework well for a variety of work and leisure domains. The area in strongest need for more research papers is the development of the holistic framework itself....... Furthermore, much focus has been on studying design sketching or implemented systems-in-use, while little attention has been paid to mature design (prototypes) or early implementation (content templates). In conclusion, we recommend an update to the framework so that it can be also useful for research...

  7. Interactive molecular dynamics

    Science.gov (United States)

    Schroeder, Daniel V.

    2015-03-01

    Physics students now have access to interactive molecular dynamics simulations that can model and animate the motions of hundreds of particles, such as noble gas atoms, that attract each other weakly at short distances but repel strongly when pressed together. Using these simulations, students can develop an understanding of forces and motions at the molecular scale, nonideal fluids, phases of matter, thermal equilibrium, nonequilibrium states, the Boltzmann distribution, the arrow of time, and much more. This article summarizes the basic features and capabilities of such a simulation, presents a variety of student exercises using it at the introductory and intermediate levels, and describes some enhancements that can further extend its uses. A working simulation code, in html5 and javascript for running within any modern Web browser, is provided as an online supplement.

  8. Interactive molecular dynamics

    CERN Document Server

    Schroeder, Daniel V

    2015-01-01

    Physics students now have access to interactive molecular dynamics simulations that can model and animate the motions of hundreds of particles, such as noble gas atoms, that attract each other weakly at short distances but repel strongly when pressed together. Using these simulations, students can develop an understanding of forces and motions at the molecular scale, nonideal fluids, phases of matter, thermal equilibrium, nonequilibrium states, the Boltzmann distribution, the arrow of time, and much more. This article summarizes the basic features and capabilities of such a simulation, presents a variety of student exercises using it at the introductory and intermediate levels, and describes some enhancements that can further extend its uses. A working simulation code, in HTML5 and JavaScript for running within any modern Web browser, is provided as an online supplement.

  9. Parvovirus glycan interactions.

    Science.gov (United States)

    Huang, Lin-Ya; Halder, Sujata; Agbandje-McKenna, Mavis

    2014-08-01

    Members of the Parvoviridae utilize glycan receptors for cellular attachment and subsequent interactions determine transduction efficiency or pathogenic outcome. This review focuses on the identity of the glycan receptors utilized, their capsid binding footprints, and a discussion of the overlap of these sites with tropism, transduction, and pathogenicity determinants. Despite high sequence diversity between the different genera, most parvoviruses bind to negatively charged glycans, such as sialic acid and heparan sulfate, abundant on cell surface membranes. The capsid structure of these viruses exhibit high structural homology enabling common regions to be utilized for glycan binding. At the same time the sequence diversity at the common footprints allows for binding of different glycans or differential binding of the same glycan.

  10. Cultivating objects in interaction

    DEFF Research Database (Denmark)

    Hazel, Spencer

    2014-01-01

    is chapter explores patterns of repeated orientations to physical objects in interactants’ visuo-spatial and haptic surround. A number of examples are presented from advice-giving activities in various institutional settings, where participants-in-interaction initially draw on material objects...... at hand while pursuing a particular line of explanation, and then return to these objects at later intervals. e analysis suggests that the objects are afforded representational properties through their being anchored to some referent in the talk, and that participants subsequently draw...... on these associations for describing, disambiguating or clarifying aspects of the relatively complex procedural frameworks discussed in the settings. is suggests that the temporal stability of material objects available to participants makes them an ideal resource to be developed as visual motifs....

  11. Sustainable Buildings in Interaction

    DEFF Research Database (Denmark)

    Elle, Morten

    2007-01-01

    The first attempts to build sustainable buildings in Denmark were typically located on the countryside. The basic idea was to create buildings that were independent of the technical infrastructure. District heating has, however, been the dominating solution to heating in buildings in Denmark......, and the focus on sustainable building have gradually turned from special houses on the countryside to normally looking houses in the urban fabric, integrated in the technical infrastructure. Some new built urban areas in Denmark will, however, not have to be supplied with district heating – these developments...... are going to consist of passive houses. The first sustainable buildings were built by their users, and the user – building interaction still play a decisive role for the performance of the present sustainable buildings. The users have to understand how the building functions. Urban design is essential...

  12. Interactive Record Linkage

    Directory of Open Access Journals (Sweden)

    2000-12-01

    Full Text Available In order to carry out demographic analyses at individual and group levels, a manual method of linking individual event records from parish registers was developed in the late 1950s. In order to save time and to work with larger areas than small parishes, systems for automatic record linkage were developed a couple of decades later. A third method, an interactive record linkage, named Demolink, has been developed even more recently. The main new feature of the method is the possibility of linking from more than two historical sources simultaneously. This improves the process of sorting out which events belong to which individual life courses. This paper discusses how Demolink was used for record linkage in a large Norwegian parish for the period 1801-1878.

  13. Nekton Interaction Monitoring System

    Energy Technology Data Exchange (ETDEWEB)

    2017-03-15

    The software provides a real-time processing system for sonar to detect and track animals, and to extract water column biomass statistics in order to facilitate continuous monitoring of an underwater environment. The Nekton Interaction Monitoring System (NIMS) extracts and archives tracking and backscatter statistics data from a real-time stream of data from a sonar device. NIMS also sends real-time tracking messages over the network that can be used by other systems to generate other metrics or to trigger instruments such as an optical video camera. A web-based user interface provides remote monitoring and control. NIMS currently supports three popular sonar devices: M3 multi-beam sonar (Kongsberg), EK60 split-beam echo-sounder (Simrad) and BlueView acoustic camera (Teledyne).

  14. Antigen antibody interactions

    CERN Document Server

    DeLisi, Charles

    1976-01-01

    1. 1 Organization of the Immune System One of the most important survival mechanisms of vertebrates is their ability to recognize and respond to the onslaught of pathogenic microbes to which they are conti- ously exposed. The collection of host cells and molecules involved in this recognition­ 12 response function constitutes its immune system. In man, it comprises about 10 cells 20 (lymphocytes) and 10 molecules (immunoglobulins). Its ontogenic development is c- strained by the requirement that it be capable of responding to an almost limitless variety of molecular configurations on foreign substances, while simultaneously remaining inert to those on self components. It has thus evolved to discriminate, with exquisite precision, between molecular patterns. The foreign substances which induce a response, called antigens, are typically large molecules such as proteins and polysaccharides. The portions of these with which immunoglobulins interact are called epitopes or determinants. A typical protein epitope m...

  15. Pipeline‐Seabed Interaction

    DEFF Research Database (Denmark)

    Fredsøe, Jørgen

    2016-01-01

    A review of the existing research on the interaction between a pipeline and an erodible bed exposed to waves and/or currents is presented. The review covers three topics, i.e., scour, liquefaction and lateral stability of pipelines. The basic mechanism that leads to scour in two‐dimensional (2D...... on small‐scale laboratory experiments.. The state of the art of the mathematical/numerical modeling of the scour processes is presented. The associated self‐burial of the pipe is described and compared to field observations. In addition to scour, liquefaction may also constitute a risk 19 for pipeline...... stability. The cause of liquefaction and the resulting consequence for pipeline stability in a natural environment are then discussed. Finally, the lateral stability of pipelines placed on an erodible bed and exposed to waves is briefly described....

  16. Interactive Virtual Cinematography

    DEFF Research Database (Denmark)

    Burelli, Paolo

    control of the camera by the player increases the complexity of the interaction and reduces the designer's control on game storytelling. A completely designer-driven camera releases the player from the burden of controlling the point of view, but might generate undesired camera behaviours. Furthermore...... control architecture able to generate real-time, smooth and well composed camera animations. Moreover, we have designed and tested an approach to model the player's camera preferences using machine learning techniques and to tailor the automatic camera behaviour to the player and her game-play style...... to be able to accurately and smoothly control the camera. Finally, the results of a user survey, conducted to evaluate the suggested methodology for camera behaviour modelling and adaptation, shows that the resulting adaptive cinematographic experience is largely favoured by the players and it generates...

  17. Negotiated interactive observation:

    DEFF Research Database (Denmark)

    Wind, Gitte

    2008-01-01

    In this paper I discuss the possibilities and limitations of the ethnographer participating in the different on-going activities and events in highly specialised healthcare systems. The concept of participant observation is based on a number of assumptions, particularly that the ethnographer...... will become one of ‘them’ to be able to follow the steps belonging to the accepted ethnographic research practice of doing fieldwork. The character of fieldwork in highly specialised healthcare systems does not fit well with this assumption. I suggest that we need to rethink the concept of participant...... observation and I propose negotiated interactive observation as a more appropriate way to describe ethnographic fieldwork in a setting such as the hospital or the clinic....

  18. The interactive design collaboratorium

    DEFF Research Database (Denmark)

    Bødker, Susanne; Petersen, Marianne Graves; Krogh, Peter Gall

    2001-01-01

    This paper reports on experimental process in which a prototype was developed of an interactive design collaboatorium, in cooperation with a group of usability designers. In a longterm research cooperation, this usability group has changed its work practice in order to work in the design...... collaboratorium. The design collaboratorium was developed to move usability design away from a lab towards an open physical and organizational space where designer, users and engineers meet and collaborate, or work alongside each other. The cooperation between researchers and the usability gruop has resulted...... in practical experimentation in projects and in design of an experimental design collaboratorium emploing electronic whiteboards, 3D design documentation, etc. This experimental prototype has been evaluated in cooperative workshops. We report on the results of this evaluation....

  19. The Interaction Programming Problem

    Institute of Scientific and Technical Information of China (English)

    LI Rong-sheng; CHENG Ying

    2001-01-01

    Based upon the research to the economic equilibrium problems, we present a kind of new mathematical programming problem-interaction programming problem (abbreviated by IPP). The IPP is composed of two or multiple parametric programming problems which is interrelated with each other. The IPP reflects the equality and mutual benefit relationship between two (or among multiple) economic planners in an economic system. In essence, the IPP is similar to the generalized Nash equilibria (GNE) game which has been given several names in the literature: social equilibria games, pseudo-Nash equilibria games, and equilibrium programming problems. In this paper, we establish the mathematical model and some basic concepts to the IPP. We investigate the structure and the properties of the IPP. We also give a necessary and sufficient conditions for the existence of the equilibrium points to a kind of linear IPP.

  20. Glycosaminoglycan-lipoprotein interaction.

    Science.gov (United States)

    Olsson, U; Ostergren-Lundén, G; Moses, J

    2001-10-01

    Glycosaminoglycans (GAGs) bound to various proteoglycans (PGs) present in the cardiovascular system have been proposed to perform a wide range of functions. These include conferring viscoelastic properties; interacting with and modulating growth factors and enzymes; and as receptors and co-receptors in lipoprotein metabolism. Binding of apoB-100 lipoproteins, particularly low density lipoproteins (LDL), to GAGs of extracellular matrix PGs in arteries has been proposed to be an initiating event in development of atherosclerosis. This study was initiated with the aim of getting an overview of the binding patterns of different lipoprotein subclasses with individual GAG categories. We thus evaluated the interaction of lipoproteins with GAGs commonly found in the cardiovascular system using a gel mobility-shift assay developed for this purpose. The same procedure was used to measure lipoproteins binding to metabolically [(35)S]-labeled whole PGs prepared from three cell types, arterial smooth muscle cells, THP-1 macrophages and from HepG2 cells. The effect of GAG composition on PGs on lipoprotein binding was evaluated by enzymatic degradation of the carbohydrate chains. Heparan sulfate was found to bind beta very low density lipoproteins (beta-VLDL) and a chylomicron remnant model (beta-VLDL+apoE), but not LDL. Dermatan sulfate was found to bind LDL, but not beta-VLDL or the chylomicron remnant model. Chondroitin sulfate and heparin were found to bind all lipoproteins tested (LDL, beta-VLDL and beta-VLDL+apoE) although with different affinities. We can conclude that each lipoprotein subclass tested binds a specific assortment of the GAGs tested. The observations made contribute to the understanding of new and complex mechanisms by which carbohydrate and lipid metabolism may be linked.

  1. Warfarin and acetaminophen interaction.

    Science.gov (United States)

    Gebauer, Markus G; Nyfort-Hansen, Karin; Henschke, Philip J; Gallus, Alexander S

    2003-01-01

    A 74-year-old man who was receiving warfarin for atrial fibrillation experienced an abrupt increase in his international normalized ratio (INR) after taking acetaminophen. To investigate this effect, the patient's anticoagulation therapy was stabilized, and he was given acetaminophen 1 g 4 times/day for 3 days. His INR rose from 2.3 before receiving acetaminophen to 6.4 on the day after acetaminophen was discontinued. Warfarin was stopped for 2 days, and the patient's INR returned to 2.0. Warfarin was restarted at the same dosage, and his INR remained within 2.0-3.0 for 6 months. Factor VII activity decreased from 29.4% before acetaminophen therapy to 15.5% when his INR was 6.4, and factor X activity fell from 27.0% to 20.2%. His warfarin plasma concentration was 1.54 microg/ml before acetaminophen compared with 1.34 microg/ml when his INR was 6.4. No significant changes in drug intake, clinical status, diet, or lifestyle were noted. Changes in INR of this magnitude with the addition of another drug during stable anticoagulation therapy suggest a drug interaction. The lack of an increase in warfarin plasma concentration associated with the increased INR suggests a possible pharmacodynamic mechanism for this interaction. Acetaminophen or a metabolite may enhance the effect of oral coumarin anticoagulants by augmenting vitamin K antagonism. Thus, the anticoagulant effect of warfarin may be significantly elevated after only a few days of acetaminophen therapy. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 g/day.

  2. Multiobjective Interaction Programming Problem with Interaction Constraint for Two Players

    Directory of Open Access Journals (Sweden)

    Min Jiang

    2012-01-01

    Full Text Available This paper extends an existing cooperative multi-objective interaction programming problem with interaction constraint for two players (or two agents. First, we define an s-optimal joint solution with weight vector to multi-objective interaction programming problem with interaction constraint for two players and get some properties of it. It is proved that the s-optimal joint solution with weight vector to the multi-objective interaction programming problem can be obtained by solving a corresponding mathematical programming problem. Then, we define another s-optimal joint solution with weight value to multi-objective interaction programming problem with interaction constraint for two players and get some of its properties. It is proved that the s-optimal joint solution with weight vector to multi-objective interaction programming problem can be obtained by solving a corresponding mathematical programming problem. Finally, we build a pricing multi-objective interaction programming model for a bi-level supply chain. Numerical results show that the interaction programming pricing model is better than Stackelberg pricing model and the joint pricing model.

  3. Developing a general interaction potential for hydrophobic and hydrophilic interactions.

    Science.gov (United States)

    Donaldson, Stephen H; Røyne, Anja; Kristiansen, Kai; Rapp, Michael V; Das, Saurabh; Gebbie, Matthew A; Lee, Dong Woog; Stock, Philipp; Valtiner, Markus; Israelachvili, Jacob

    2015-02-24

    We review direct force measurements on a broad class of hydrophobic and hydrophilic surfaces. These measurements have enabled the development of a general interaction potential per unit area, W(D) = -2γ(i)Hy exp(-D/D(H)) in terms of a nondimensional Hydra parameter, Hy, that applies to both hydrophobic and hydrophilic interactions between extended surfaces. This potential allows one to quantitatively account for additional attractions and repulsions not included in the well-known combination of electrostatic double layer and van der Waals theories, the so-called Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The interaction energy is exponentially decaying with decay length D(H) ≈ 0.3-2 nm for both hydrophobic and hydrophilic interactions, with the exact value of D(H) depending on the precise system and conditions. The pre-exponential factor depends on the interfacial tension, γ(i), of the interacting surfaces and Hy. For Hy > 0, the interaction potential describes interactions between partially hydrophobic surfaces, with the maximum hydrophobic interaction (i.e., two fully hydrophobic surfaces) corresponding to Hy = 1. Hydrophobic interactions between hydrophobic monolayer surfaces measured with the surface forces apparatus (SFA) are shown to be well described by the proposed interaction potential. The potential becomes repulsive for Hy < 0, corresponding to partially hydrophilic (hydrated) interfaces. Hydrated surfaces such as mica, silica, and lipid bilayers are discussed and reviewed in the context of the values of Hy appropriate for each system.

  4. HYDRODYNAMIC INTERACTIONS BETWEEN TWO BODIES

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    On the basis of model tests, potential flow theory, and viscous Computational Fluid Dynamics (CFD) method, the hydrodynamic interactions between two underwater bodies were investigated to determine the influencing factors, changing rule, interaction mechanism, and appropriate methods describing them. Some special phenomena were discovered in two series of near-wall interaction experiments. The mathematical model and predicting methods were presented for interacting forces near wall, and the calculation results agreed well with the experimental ones. From the comparisons among numerical results with respect to nonviscosity, numerical results with respect to viscosity, and measured results, data on the influence of viscosity on hydrodynamic interactions were obtained. For hydrodynamic interaction related to multi-body unsteady motions with six degrees of freedom that is difficult to simulate in tests, numerical predictions of unsteady interacting forces were given.

  5. Interaction Themes in Music Therapy

    DEFF Research Database (Denmark)

    Holck, Ulla

    2006-01-01

    Based on a doctoral study, the author presents a type of music therapy interaction called ‘Interaction Themes.’ These are developed from session to session and often appear in music therapy interventions with children with severe functional limitations, especially children with autism. Although...... the Interaction Themes are characterised by a relatively simple and self-generated content, they have an essential function because they contain the child’s and music therapist’s joint interaction history. They make up the context within which it is possible to create meaningful interaction with a client group...... whose expressions are often difficult to understand. The presented article describes the characteristics and functions of Interaction Themes, compares the phenomenon with music therapy case literature and delimits it in regard to other types of music therapy interaction with this client group....

  6. Interaction Themes in Music Therapy

    DEFF Research Database (Denmark)

    Holck, Ulla

    2006-01-01

    Based on a doctoral study, the author presents a type of music therapy interaction called ‘Interaction Themes.’ These are developed from session to session and often appear in music therapy interventions with children with severe functional limitations, especially children with autism. Although...... the Interaction Themes are characterised by a relatively simple and self-generated content, they have an essential function because they contain the child’s and music therapist’s joint interaction history. They make up the context within which it is possible to create meaningful interaction with a client group...... whose expressions are often difficult to understand. This presentation describes the characteristics and functions of Interaction Themes, compares the phenomenon with music therapy case literature and delimits it in regard to other types of music therapy interaction with this client group....

  7. Interactive Data Eyeslasses

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The data eyeglasses can read from the engineer’s eyes which details he needs to see on the building plans.A CMOS chip with an eyetracker in the microdisplay makes this possible.The eyeglasses are connected to a PDA,display information and respond to commands.For car designers,secret agents in the movies and jet fighter pilots,data eyeglasses-also called head-mounted displays,orHMDs for short-are everyday objects.They transport the wearer into virtual worlds or provide the user with data from the real environment.At present these devices can only display information."We want to make the eyeglasses bidirectional and interactive so thatnew areas of application can be opened up,"says Dr.Michael Scholles,business unit manager at the Fraunhofer Institute for PhotonicMicrosystems IPMS in Dresden.A group of scientists at IPMS is working on a device which incorporates eye tracking-users can influence the content presented by moving their eyes or fixing on certain points in the image.Without having to use any other devices to

  8. Unity of Fundamental Interactions

    CERN Document Server

    Sastry, R R

    2000-01-01

    The vector representation of the linearized gravitational field (the graviton field) or the so called quantum gravitodynamics which describes the motion of masses in a weak gravitational field is employed to understand the unity of the four known interactions. We propose a gauge group SU(3)xSU(2)xU(1)xU(1) for such a unified field theory. In this paper we study the SU(2)xU(1)xU(1) sector of the theory and in analogy to the electroweak mixing angle we define a gravitoweak mixing angle. The unified gauge field theory predicts the existence of three massive vector bosons, the Y+/- and the X^0. and two massless vector bosons, the photon and the graviton (in its vector representation). We determine the mass spectrum of the Y+/- and the X^0 and predict a modification to the fine structure constant under unified field conditions. Furthermore, we briefly discuss the implications of the extended object formulation for the gauge hierarchy problem.

  9. Interactive Metro Map Editing.

    Science.gov (United States)

    Wang, Yu-Shuen; Peng, Wan-Yu

    2016-02-01

    Manual editing of a metro map is essential because many aesthetic and readability demands in map generation cannot be achieved by using a fully automatic method. In addition, a metro map should be updated when new metro lines are developed in a city. Considering that manually designing a metro map is time-consuming and requires expert skills, we present an interactive editing system that considers human knowledge and adjusts the layout to make it consistent with user expectations. In other words, only a few stations are controlled and the remaining stations are relocated by our system. Our system supports both curvilinear and octilinear layouts when creating metro maps. It solves an optimization problem, in which even spaces, route straightness, and maximum included angles at junctions are considered to obtain a curvilinear result. The system then rotates each edge to extend either vertically, horizontally, or diagonally while approximating the station positions provided by users to generate an octilinear layout. Experimental results, quantitative and qualitative evaluations, and user studies show that our editing system is easy to use and allows even non-professionals to design a metro map.

  10. Strongly interacting ultracold polar molecules

    CERN Document Server

    Gadway, Bryce

    2016-01-01

    This paper reviews recent advances in the study of strongly interacting systems of dipolar molecules. Heteronuclear molecules feature large and tunable electric dipole moments, which give rise to long-range and anisotropic dipole-dipole interactions. Ultracold samples of dipolar molecules with long-range interactions offer a unique platform for quantum simulations and the study of correlated many-body physics. We provide an introduction to the physics of dipolar quantum gases, both electric and magnetic, and summarize the multipronged efforts to bring dipolar molecules into the quantum regime. We discuss in detail the recent experimental progress in realizing and studying strongly interacting systems of polar molecules trapped in optical lattices, with particular emphasis on the study of interacting spin systems and non-equilibrium quantum magnetism. Finally, we conclude with a brief discussion of the future prospects for studies of strongly interacting dipolar molecules.

  11. Herbal drugs and drug interactions

    OpenAIRE

    Gül Dülger

    2014-01-01

    Herbal drugs are defined as any form of a plant or plant product that contains a single herb or combinations of herbs that are believed to have complementary effects. Although they are considered to be safe, because they are natural, they may have various adverse effects, and may interact with other herbal products or conventional drugs. These interactions are especially important for drugs with narrow therapeutic indices.In the present study, pharmacokinetic and pharmacodynamic interactions ...

  12. Facilitative root interactions in intercrops

    DEFF Research Database (Denmark)

    Hauggaard-Nielsen, H.; Jensen, E.S.

    2005-01-01

    Facilitation takes place when plants ameliorate the environment of their neighbours, and increase their growth and survival. Facilitation occurs in natural ecosystems as well as in agroecosystems. We discuss examples of facilitative root interactions in intercropped agroecosystems; including...... intensified cropping systems using chemical and mechanical inputs also show that facilitative interactions definitely can be of significance. It is concluded that a better understanding of the mechanisms behind facilitative interactions may allow us to benefit more from these phenomena in agriculture...

  13. Interactive Raytracing: The nirt Command

    Science.gov (United States)

    2009-04-01

    Interactive Raytracing : The nirt Command by Clifford Yapp ARL-CR-624 April 2009 prepared by Quantum Research...Laboratory Aberdeen Proving Ground, MD 21005-5068 ARL-CR-624 April 2009 Interactive Raytracing : The nirt Command Clifford Yapp Quantum...DATES COVERED (From - To) June 2008–October 2008 4. TITLE AND SUBTITLE Interactive Raytracing : The nirt Command 5a. CONTRACT NUMBER W911QX-06-F

  14. Efficient Interaction in English Classroom

    Institute of Scientific and Technical Information of China (English)

    董红叶

    2013-01-01

    Lack of communicative competence will result in failure to efficiently interact with others and also weaken linguistic competence. This paper shows the importance of interaction through analyzing Klashen’s input hypothesis,emotional factors,lat⁃er Wittgenstein’s linguistic philosophy,selectivity and dynamics of languages. Different interaction activities are used in different teaching methods. A teacher needs to face all the challenges so as to find the most efficient way to teach in a language classroom.

  15. Soliton interactions of integrable models

    Energy Technology Data Exchange (ETDEWEB)

    Ruan Hangyu E-mail: hyruan@mail.nbip.net; Chen Yixin

    2003-08-01

    The solution of integrable (n+1)-dimensional KdV system in bilinear form yields a dromion solution that is localized in all directions. The interactions between two dromions are studied both in analytical and in numerical for three (n+1)-dimensional KdV-type equations (n=1, 2, 3). The same interactive properties between two dromions (solitons) are revealed for these models. The interactions between two dromions (solitons) may be elastic or inelastic for different form of solutions.

  16. Soliton interactions of integrable models

    CERN Document Server

    Ruan Hang Yu

    2003-01-01

    The solution of integrable (n+1)-dimensional KdV system in bilinear form yields a dromion solution that is localized in all directions. The interactions between two dromions are studied both in analytical and in numerical for three (n+1)-dimensional KdV-type equations (n=1, 2, 3). The same interactive properties between two dromions (solitons) are revealed for these models. The interactions between two dromions (solitons) may be elastic or inelastic for different form of solutions.

  17. Searching for unwanted drug interactions

    OpenAIRE

    Ognjenović, Dejan

    2014-01-01

    Drug interactions are interweaving effects between two or more drugs that can have desirable or harmful effects on patients health. In this thesis we for searched harmful drug interactions. Our approach is based on two machine learning algorithms for association rule mining. We use two given hierarchies, one for drugs (ATC), the other for diseases (ICD), and one proprietary interaction database LexiComp. A generalized association rule algorithm tries to find rules that contain basic ...

  18. Nutrition and parasite interaction.

    Science.gov (United States)

    Coop, R L; Holmes, P H

    1996-01-01

    This overview focuses on the interaction between nutritional status and gastrointestinal nematode infection in ruminants and considers: (i) the influence of the parasite on host metabolism; and (ii) the effect of host nutrition on the establishment and survival of parasite populations, the development of the host-immune response and the pathophysiology of infection. Gastrointestinal nematodes reduce voluntary feed intake and efficiency of feed utilisation, a key feature being an increased endogenous loss of protein into the gastrointestinal tract. Overall there is movement of protein from productive processes into repair of the gastrointestinal tract, synthesis of plasma proteins and mucoprotein production. Although reduction in feed intake is a major factor contributing to the reduced performance of parasitised ruminants, the underlying mechanisms of the anorexia are poorly understood. Supplementation of the diet with additional protein does not appear to affect initial establishment of nematode infections but the pathophysiological consequences are generally more severe on lower planes of protein nutrition. The main effect of protein supplementation is to increase the rate of acquisition of immunity and increase resistance to reinfection and this has been associated with an enhanced cellular immune response in the gastrointestinal mucosa. The unresponsiveness of the young lamb can be improved by dietary protein supplementation. Recent trials have shown that growing sheep offered a free choice between a low and a high protein ration are able to modify their diet selection in order to alleviate the increase in protein requirements which result from gastrointestinal nematode infection. Studies on the influence of nutrition on the expression of genotype have shown that the benefits of a superior genotype are not lost on a low protein diet whereas a high protein diet can partially emeliorate the disadvantages of an inferior genotype. In addition to dietary protein

  19. Mobile Collocated Interactions With Wearables

    DEFF Research Database (Denmark)

    Lucero, Andrés; Wilde, Danielle; Robinson, Simon

    2015-01-01

    powerful, and closer to our bodies. Therefore, mobile collocated interactions research, which originally looked at smartphones and tablets, will inevitably move towards fully integrated wearable technologies. The focus of this workshop is to bring together a community of researchers, designers...... and practitioners to explore the potential of extending mobile collocated interactions from, through and around the body using wearable technologies.......Research on mobile collocated interactions has been looking at situations in which collocated users engage in collaborative activities using their mobile devices, thus going from personal/individual toward shared/multiuser experiences and interactions. However, computers are getting smaller, more...

  20. RKKY interaction in bilayer graphene

    Science.gov (United States)

    Mohammadi, Yawar; Moradian, Rostam

    2015-12-01

    We study the RKKY interaction between two magnetic impurities located on the same layer (intralayer case) or on different layers (interlayer case) in undoped bilayer graphene (BLG) in the four-bands model, by directly calculating the Green functions in the eigenvalues and eigenvectors representation. Our results show that both intra- and interlayer RKKY interactions between two magnetic impurities located on the same (opposite) sublattice are always ferromagnetic (antiferromagnetic). Furthermore we find unusual long-distance decay of the RKKY interaction in BLG. The intralyer RKKY interactions between two magnetic impurities located on the same sublattice, J AnAn(R) and J BnBn(R), decay closely as 1 /R6 and 1 /R2 at large impurity distances respectively, but when they are located on opposite sublattices the RKKY interactions exhibit 1 /R4 decays approximately. In the interlayer case, the RKKY interactions between two magnetic impurities located on the same sublattice show a decay close to 1 /R4 at large impurity distances, but if two magnetic impurities be on opposite sublattices the RKKY interactions, J A1B2(R) and J B1A2(R), decay closely as 1 /R6 and 1 /R2 respectively. Both intra- and interlayer RKKY interactions have anisotropic oscillatory factors which for intralayer case is equal to that for single layer graphene (SLG). Our results at weak and strong interlayer coupling limits reduce to the RKKY interaction of SLG and that of BLG in the two-bands approximation respectively.

  1. Dark patterns in proxemic interactions

    DEFF Research Database (Denmark)

    Greenberg, Saul; Boring, Sebastian; Vermeulen, Jo

    2014-01-01

    Proxemics theory explains peoples' use of interpersonal distances to mediate their social interactions with others. Within Ubicomp, proxemic interaction researchers argue that people have a similar social understanding of their spatial relations with nearby digital devices, which can be exploited...... to better facilitate seamless and natural interactions. To do so, both people and devices are tracked to determine their spatial relationships. While interest in proxemic interactions has increased over the last few years, it also has a dark side: knowledge of proxemics may (and likely will) be easily...

  2. Theoretical studies of molecular interactions

    Energy Technology Data Exchange (ETDEWEB)

    Lester, W.A. Jr. [Univ. of California, Berkeley (United States)

    1993-12-01

    This research program is directed at extending fundamental knowledge of atoms and molecules including their electronic structure, mutual interaction, collision dynamics, and interaction with radiation. The approach combines the use of ab initio methods--Hartree-Fock (HF) multiconfiguration HF, configuration interaction, and the recently developed quantum Monte Carlo (MC)--to describe electronic structure, intermolecular interactions, and other properties, with various methods of characterizing inelastic and reaction collision processes, and photodissociation dynamics. Present activity is focused on the development and application of the QMC method, surface catalyzed reactions, and reorientation cross sections.

  3. INCA- INTERACTIVE CONTROLS ANALYSIS

    Science.gov (United States)

    Bauer, F. H.

    1994-01-01

    The Interactive Controls Analysis (INCA) program was developed to provide a user friendly environment for the design and analysis of linear control systems, primarily feedback control systems. INCA is designed for use with both small and large order systems. Using the interactive graphics capability, the INCA user can quickly plot a root locus, frequency response, or time response of either a continuous time system or a sampled data system. The system configuration and parameters can be easily changed, allowing the INCA user to design compensation networks and perform sensitivity analysis in a very convenient manner. A journal file capability is included. This stores an entire sequence of commands, generated during an INCA session into a file which can be accessed later. Also included in INCA are a context-sensitive help library, a screen editor, and plot windows. INCA is robust to VAX-specific overflow problems. The transfer function is the basic unit of INCA. Transfer functions are automatically saved and are available to the INCA user at any time. A powerful, user friendly transfer function manipulation and editing capability is built into the INCA program. The user can do all transfer function manipulations and plotting without leaving INCA, although provisions are made to input transfer functions from data files. By using a small set of commands, the user may compute and edit transfer functions, and then examine these functions by using the ROOT_LOCUS, FREQUENCY_RESPONSE, and TIME_RESPONSE capabilities. Basic input data, including gains, are handled as single-input single-output transfer functions. These functions can be developed using the function editor or by using FORTRAN- like arithmetic expressions. In addition to the arithmetic functions, special functions are available to 1) compute step, ramp, and sinusoid functions, 2) compute closed loop transfer functions, 3) convert from S plane to Z plane with optional advanced Z transform, and 4) convert from Z

  4. Measuring L2 speakers’ interactional ability using interactive speech tasks

    NARCIS (Netherlands)

    van Batenburg, Eline S. L.; Oostdam, Ron J.; van Gelderen, Amos J. S.; de Jong, Nivja H.

    2016-01-01

    This article explores ways to assess interactional performance, and reports on the use of a test format that standardizes the interlocutor?s linguistic and interactional contributions to the exchange. It describes the construction and administration of six scripted speech tasks (instruction, advice,

  5. Discovering functional interaction patterns in protein-protein interaction networks

    Directory of Open Access Journals (Sweden)

    Can Tolga

    2008-06-01

    Full Text Available Abstract Background In recent years, a considerable amount of research effort has been directed to the analysis of biological networks with the availability of genome-scale networks of genes and/or proteins of an increasing number of organisms. A protein-protein interaction (PPI network is a particular biological network which represents physical interactions between pairs of proteins of an organism. Major research on PPI networks has focused on understanding the topological organization of PPI networks, evolution of PPI networks and identification of conserved subnetworks across different species, discovery of modules of interaction, use of PPI networks for functional annotation of uncharacterized proteins, and improvement of the accuracy of currently available networks. Results In this article, we map known functional annotations of proteins onto a PPI network in order to identify frequently occurring interaction patterns in the functional space. We propose a new frequent pattern identification technique, PPISpan, adapted specifically for PPI networks from a well-known frequent subgraph identification method, gSpan. Existing module discovery techniques either look for specific clique-like highly interacting protein clusters or linear paths of interaction. However, our goal is different; instead of single clusters or pathways, we look for recurring functional interaction patterns in arbitrary topologies. We have applied PPISpan on PPI networks of Saccharomyces cerevisiae and identified a number of frequently occurring functional interaction patterns. Conclusion With the help of PPISpan, recurring functional interaction patterns in an organism's PPI network can be identified. Such an analysis offers a new perspective on the modular organization of PPI networks. The complete list of identified functional interaction patterns is available at http://bioserver.ceng.metu.edu.tr/PPISpan/.

  6. Strategic interaction and conventions

    Directory of Open Access Journals (Sweden)

    Espinosa, María Paz

    2012-03-01

    Full Text Available The scope of the paper is to review the literature that employs coordination games to study social norms and conventions from the viewpoint of game theory and cognitive psychology. We claim that those two alternative approaches are in fact complementary, as they provide different insights to explain how people converge to a unique system of self-fulfilling expectations in presence of multiple, equally viable, conventions. While game theory explains the emergence of conventions relying on efficiency and risk considerations, the psychological view is more concerned with frame and labeling effects. The interaction between these alternative (and, sometimes, competing effects leads to the result that coordination failures may well occur and, even when coordination takes place, there is no guarantee that the convention eventually established will be the most efficient.

    El objetivo de este artículo es presentar la literatura que emplea los juegos de coordinación para el estudio de normas y convenciones sociales, que se han analizado tanto desde el punto de vista de la teoría de juegos como de la psicología cognitiva. Argumentamos en este trabajo que estos dos enfoques alternativos son en realidad complementarios, dado que ambos contribuyen al entendimiento de los procesos mediante los cuales las personas llegan a coordinarse en un único sistema de expectativas autorrealizadas, en presencia de múltiples convenciones todas ellas igualmente viables. Mientras que la teoría de juegos explica la aparición de convenciones basándose en argumentos de eficiencia y comportamientos frente al riesgo, el enfoque de la psicología cognitiva utiliza en mayor medida consideraciones referidas al entorno y naturaleza de las decisiones. La interacción entre estos efectos diferentes (y en ocasiones, rivales desemboca con frecuencia en fallos de coordinación y, aun cuando la coordinación se produce, no hay garantía de que la convención en vigor sea la m

  7. Environmental Interactions Working Group Report

    Science.gov (United States)

    Stevens, N. J.; Wiskerchen, M.

    1984-01-01

    Interactions between spacecraft systems and the space charged particle environment are reviewed and recommendations are presented for both near-term and far-term research considerations. Transient environment models, large space structures, solar and nuclear power systems/environment interactions, single event upsets, material degradation, and planetary missions are addressed.

  8. Distinguishing Ordinal and Disordinal Interactions

    Science.gov (United States)

    Widaman, Keith F.; Helm, Jonathan L.; Castro-Schilo, Laura; Pluess, Michael; Stallings, Michael C.; Belsky, Jay

    2012-01-01

    Re-parameterized regression models may enable tests of crucial theoretical predictions involving interactive effects of predictors that cannot be tested directly using standard approaches. First, we present a re-parameterized regression model for the Linear x Linear interaction of 2 quantitative predictors that yields point and interval estimates…

  9. Expertise revisited I: Interactional Expertise

    CERN Document Server

    Collins, Harry

    2016-01-01

    The notion of interactional expertise is explained starting with its origins and discussing its many applications. Interactional expertise is the ability to understand a technical area purely be deeply immersed in its 'practice-language' without actually practising. One of its many applications is to explain how large sciences are managed.

  10. Documentation of Appliances & Interaction Devices

    DEFF Research Database (Denmark)

    2004-01-01

    The interaction devices and appliances explored in the WorkSPACE project, address spatial computing in the context of work. We have developed and explored a range of appliances and interaction devices. The scope has been to develop tools for support of collaboration by mixing digital and physical...

  11. Interactive Information Visualization in Neuroimaging

    DEFF Research Database (Denmark)

    Nielsen, Finn Årup; Hansen, Lars Kai

    1998-01-01

    We describe a virtual environment for interactive visualization of 3D neuroimages. The environment is implemented in VRML and we will discuss the viability and limitation of this platform......We describe a virtual environment for interactive visualization of 3D neuroimages. The environment is implemented in VRML and we will discuss the viability and limitation of this platform...

  12. Urban Interaction and Affective Experience

    DEFF Research Database (Denmark)

    Fritsch, Jonas; Brynskov, Martin

    2008-01-01

    in favor of three points in that direction: First we argue that interaction – and the definition of interaction – is central to unfold the potential of digital urban media, from big, shared screens and media facades to small pri-vate, networked mobile and embedded platforms. Then we argue that an affective...

  13. 3-way Anova Interactions: Deconstructed

    OpenAIRE

    Phil Ender

    2008-01-01

    Three approaches to understanding 3-way anova interactions will be presented: 1) a conceptual approach, 2) an anova approach and 3) a regression approach using dummy coding. The three approaches are illustrated through the use of a synthetic dataset with a significant 3-way interaction.

  14. Interactive Flow in Exercise Pedagogy

    Science.gov (United States)

    Lloyd, Rebecca; Smith, Stephen

    2006-01-01

    A phenomenology of the bodily experience of interactive flow adds to Csikszentmihalyi's flow theory. Whereas Csikszentmihalyi attended to teachers' and students' experiences of flow separately, this inquiry explores flow through three water-inspired layers of physical interaction between fitness professionals and their clients. Teaching fitness is…

  15. Temporal form in interaction design

    DEFF Research Database (Denmark)

    Vallgårda, Anna; Winther, Morten Trøstrup; Mørch, Nina;

    2015-01-01

    a nuanced account of what temporal form is in interaction design, and we look at related work synthesizing what we already know of the temporal concerns in interaction design and HCI. In the second part we present a design experiment through which we explore the experiential qualities of a set of 11 simple...

  16. Narrative Cognition in Interactive Systems

    DEFF Research Database (Denmark)

    Bruni, Luis Emilio; Baceviciute, Sarune; Arief, Mohammed

    2014-01-01

    In this article we explore some of the methodological problems related to characterizing cognitive aspects of involvement with interactive narratives using well known EEG/ERP techniques. To exemplify this, we construct an experimental EEG-ERP set-up with an interactive narrative that considers...

  17. Eye Movements in Gaze Interaction

    DEFF Research Database (Denmark)

    Møllenbach, Emilie; Hansen, John Paulin; Lillholm, Martin

    2013-01-01

    Gaze as a sole input modality must support complex navigation and selection tasks. Gaze interaction combines specific eye movements and graphic display objects (GDOs). This paper suggests a unifying taxonomy of gaze interaction principles. The taxonomy deals with three types of eye movements: fix...

  18. The CHI 2013 interactive schedule

    DEFF Research Database (Denmark)

    Satyanarayan, Arvind; Strazzulla, Daniel; Klokmose, Clemens Nylandsted

    2013-01-01

    is available. The CHI'13 Interactive Schedule helps attendees navigate this wealth of video content in order to identify events they would like to attend. It consists of a number of large display screens throughout the conference venue which cycle through a video playlist of events. Attendees can interact...

  19. Nitrogen interactions at metal surfaces

    NARCIS (Netherlands)

    Gleeson, M. A.; Kleyn, A. W.

    2013-01-01

    Molecular beam experiments with specially prepared beams allow the study of the interaction of very reactive species with surfaces. In the present case the interaction of N-atoms with Ag(1 1 1) is studied. The energy of the atoms is around 5 eV, precisely between the classical energy regimes of seed

  20. Tangible Interaction in Industrial Plants

    DEFF Research Database (Denmark)

    Jensen, Mads Vedel

    With this dissertation, I answer the overall research question, which has been my focus through my research activities: How can interaction designers design user interfaces that invite, and allow interaction based on skilled practice in industrial contexts? My assumption is that the rapid invasio...

  1. Hadronic interactions and nuclear physics

    CERN Document Server

    Beane, S R

    2008-01-01

    I give an overview of efforts in the last year to calculate interactions among hadrons using lattice QCD. Results discussed include the extraction of low-energy phase shifts and three-body interactions, and the study of pion and kaon condensation. A critical appraisal is offered of recent attempts to calculate nucleon-nucleon and nucleon-hyperon potentials on the lattice.

  2. Results-Based Interaction Design

    Science.gov (United States)

    Weiss, Meredith

    2008-01-01

    Interaction design is a user-centered approach to development in which users and their goals are the driving force behind a project's design. Interaction design principles are fundamental to the design and implementation of effective websites, but they are not sufficient. This article argues that, to reach its full potential, a website should also…

  3. A Critique of Interactional Approach

    Institute of Scientific and Technical Information of China (English)

    Bao Fang

    2011-01-01

    Interactional approach is a very important theory in second language acquisition, including the input hypothesis and interaction hypothesis. This article first presents an exposition of these two hypotheses, and continues with a critical evaluation of them. Finally, the article concludes with the pedagogical implications of the approach.

  4. Moderating influences on interactivity effects

    NARCIS (Netherlands)

    Voorveld, H.; van Noort, G.

    2012-01-01

    Research on website interactivity is widespread and there are two important reasons for this popularity. The first is that interactivity is assumed to be the key characteristic that distinguishes communication in traditional media from communication in new media such as websites (Chung and Zhao, 200

  5. Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein

    Science.gov (United States)

    Homma, Miwako Kato; Li, Dongxia; Krebs, Edwin G.; Yuasa, Yasuhito; Homma, Yoshimi

    2002-01-01

    Mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis coli and also sporadic colorectal cancer development. By using antibodies raised against the N-terminal region of APC protein, we have detected the variable masses of endogenous APC proteins in individual cell lines established from human colorectal carcinomas caused by nonsense mutations of the gene. Phosphorylation of immunoprecipitates of full-length and truncated APC were observed in in vitro kinase reaction, indicating association of APC with protein kinase activity. The kinase activity complexed with APC was sensitive to heparin and used GTP as phosphoryl donor, suggesting an involvement of casein kinase 2 (CK2). Both CK2α- and β-subunits were found to associate with APC in immunoprecipitates as well as in pull-down assays, with preferential interaction of APC with tetrameric CK2 holoenzyme. In synchronized cell populations, the association of APC with CK2 was cell cycle dependent, with the highest association in G2/M. Unexpectedly, APC immunoprecipitates containing full-length APC protein inhibited CK2 in vitro, whereas immunoprecipitates of truncated APC had little effect. This was confirmed by using recombinant APC, and the inhibitory region was localized to the C terminus of APC between residues 2086 and 2394. Overexpression of this fragment in SW480 cells suppressed cell proliferation rates as well as tumorigenesis. These results demonstrate a previously uncharacterized functional interaction between the tumor suppressor protein APC and CK2 and suggest that growth-inhibitory effects of APC may be regulated by inhibition of CK2. PMID:11972058

  6. Emotional intelligence and social interaction.

    Science.gov (United States)

    Lopes, Paulo N; Brackett, Marc A; Nezlek, John B; Schütz, Astrid; Sellin, Ina; Salovey, Peter

    2004-08-01

    Two studies found positive relationships between the ability to manage emotions and the quality of social interactions, supporting the predictive and incremental validity of an ability measure of emotional intelligence, the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). In a sample of 118 American college students (Study 1), higher scores on the managing emotions subscale of the MSCEIT were positively related to the quality of interactions with friends, evaluated separately by participants and two friends. In a diary study of social interaction with 103 German college students (Study 2), managing emotions scores were positively related to the perceived quality of interactions with opposite sex individuals. Scores on this subscale were also positively related to perceived success in impression management in social interactions with individuals of the opposite sex. In both studies, the main findings remained statistically significant after controlling for Big Five personality traits.

  7. Synergistic Interactions in Multispecies Biofilms

    DEFF Research Database (Denmark)

    Ren, Dawei

    between plasmid host range and composition of the recipient community was investigated in Manuscript 5 by comparing plasmid permissiveness in single populations and in a microbial community composed of 15 soil strains. By use of flow cytometry (FCM) and 16S rRNA gene sequencing, the IncP1 plasmid, pKJK10...... bacterial species, the study to elucidate the impact of interaction networks on the multispecies biofilms in natural ecosystems, especially in soil, is still at an early stage. The diverse patterns of interactions within the mixed communities as well as the predatorprey relationship between protozoa...... interactions in this four-species biofilm model community. Manuscript 2 presents the further application of this developed approach on evaluating the synergistic/antagonistic interactions in multispecies biofilms composed of seven soil isolates. 63% of the four-species biofilms were found to interact...

  8. Noncovalent interaction of carbon nanostructures.

    Science.gov (United States)

    Umadevi, Deivasigamani; Panigrahi, Swati; Sastry, Garikapati Narahari

    2014-08-19

    The potential application of carbon nanomaterials in biology and medicine increases the necessity to understand the nature of their interactions with living organisms and the environment. The primary forces of interaction at the nano-bio interface are mostly noncovalent in nature. Quantifying such interactions and identifying various factors that influence such interactions is a question of outstanding fundamental interest in academia and industry. In this Account, we have summarized our recent studies in understanding the noncovalent interactions of carbon nanostructures (CNSs), which were obtained by employing first-principles calculations on various model systems representing carbon nanotubes (CNTs) and graphene. Bestowed with an extended sp(2) carbon network, which is a common feature in all of these nanostructures, they exhibit π-π interactions with aromatic molecules (benzene, naphthalene, nucleobases, amino acids), cation-π type of interactions with metal ions, anion-π interactions with anions, and other XH···π type of interactions with various small molecules (H2O, NH3, CH4, H2, etc.). CNTs are wrapped-up forms of two-dimensional graphene, and hence, it is interesting to compare the binding abilities of these two allotropes that differ in their curvature. The chirality and curvature of CNSs appear to play a major role in determining the structural, energetic, and functional properties. Flat graphene shows stronger noncovalent interactions than the curved nanotubes toward various substrates. Understanding the interactions of CNSs with organic molecules and biomolecules has gained a great deal of research interest because of their potential applications in various fields. Aromatic hydrocarbons show a strong propensity to interact with CNSs via the π-π mode of interaction rather than CH···π interaction. As DNA sequencing appears to be one of the most important potential applications of carbon nanomaterials, the study of CNS

  9. Controllability in protein interaction networks.

    Science.gov (United States)

    Wuchty, Stefan

    2014-05-13

    Recently, the focus of network research shifted to network controllability, prompting us to determine proteins that are important for the control of the underlying interaction webs. In particular, we determined minimum dominating sets of proteins (MDSets) in human and yeast protein interaction networks. Such groups of proteins were defined as optimized subsets where each non-MDSet protein can be reached by an interaction from an MDSet protein. Notably, we found that MDSet proteins were enriched with essential, cancer-related, and virus-targeted genes. Their central position allowed MDSet proteins to connect protein complexes and to have a higher impact on network resilience than hub proteins. As for their involvement in regulatory functions, MDSet proteins were enriched with transcription factors and protein kinases and were significantly involved in bottleneck interactions, regulatory links, phosphorylation events, and genetic interactions.

  10. Interaction themes in music therapy

    DEFF Research Database (Denmark)

    Holck, Ulla

    2004-01-01

    Based on a doctoral study, the author presents a type of music therapyinteraction called ?Interaction Themes.? These are developed fromsession to session and often appear in music therapy interventions withchildren with severe functional limitations, especially children withautism. Although...... the Interaction Themes are characterised by arelatively simple and self-generated content, they have an essentialfunction because they contain the child?s and music therapist?s jointinteraction history. They make up the context within which it ispossible to create meaningful interaction with a client group...... whoseexpressions are often difficult to understand. The article describes thecharacteristics and functions of Interaction Themes, compares thephenomenon with music therapy case literature and delimits it in regardto other types of music therapy interaction with this client group. Theresults are described through...

  11. Brownian motion of interacting particles

    Energy Technology Data Exchange (ETDEWEB)

    Ackerson, B.J.

    1976-01-01

    Guided by the descriptions which are used to describe noninteracting particles, it is argued that the generalized Smoluchowski equation, including the hydrodynamic interaction and corrections for ion cloud effects may be used to describe interacting particles for the temporal and spatial regimes probed by light beating spectroscopy. This equation is then used to find cumulants of decay of the intermediate scattering function. The generalized Smoluchowski equation is reduced to a simple diffusion equation. The resulting diffusion constant depends upon the interparticle forces and is reminiscent of some early descriptions for interacting systems. The generalized Smoluchowski equation is solved for the model system of a linear chain of colloidal particles interacting via nearest neighbor harmonic couplings. The results for the intermediate scattering function and the static structure factor are very reminiscent of corresponding measurements made for interacting colloidal systems. (GHT)

  12. Plant biotic interactions

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    occurring after infestation by olive fly larvae. The last research article by Niu et al.(2016) describes a growth-promoting rhizobacterium that primes induced systemic resistance by suppressing a host R gene-targeting micro RNA pairs and activating host immune responses. This finding further supports the important roles of plant endogenous small RNAs in plant-pathogen interactions. Hailing Jin, Professor Special Issue Editor UC President’s Chair Director of Genetics, Genomics and Bioinformatics Graduate Program, Center for Plant Cell Biology, Institute for Integrative Genome Biology, University of California, Riverside, USA doi:10.1111/jipb.12476 ©2016 Institute of Botany, Chinese Academy of Sciences REFERENCES Alagna F, Kal enbach M, Pompa A, De Marchis F, Rao R, Baldwin IT, Bonaventure G, Baldoni L (2016) Olive fruits infested with olive fly larvae respond with an ethylene burst and the emission of specific volatiles. J Integr Plant Biol 58:413–425 Castiblanco LF, Sundin GW (2016) New insights on molecular regulation of biofilm formation in plant-associated bacteria. J Integr Plant Biol 58:362–372 da GraSca JV, Douhan GW, Halbert SE, Keremane ML, Lee RF, Vidalakis G, Zhao H (2016) Huanglongbing: An overview of a complex pathosystem ravaging the world’s citrus. J Integr Plant Biol 58:373–387 Giovino A, Martinel i F, Saia S (2016) Rhynchophorus ferrugineus attack affects a group of compounds rather than rearranging Phoenix canariensis metabolic pathways. J Integr Plant Biol 58:388–396 Huang J, Yang M, Zhang X (2016) The function of smal RNAs in plant biotic stress response. J Integr Plant Biol 58:312–327 Kaloshian I, Wal ing LL (2016) Hemipteran and dipteran pests: Effectors and plant host immune regulators. J Integr Plant Biol 58:350–361 Mermigka G, Verret F, Kalantidis K (2016) RNA silencing movement in plants. J Integr Plant Biol 58:328–342 Niu D, Xia J, Jiang C, Qi B, Ling X, Lin S, Zhang W, Guo J, Jin H, Zhao H (2016) Bacil us cereus AR156

  13. Final State Interactions Effects in Neutrino-Nucleus Interactions

    Energy Technology Data Exchange (ETDEWEB)

    Golan, Tomasz [Univ. of Wroctaw (Poland); Juszczak, Cezary [Univ. of Wroctaw (Poland); Sobczyk, Jan T. [Fermi National Accelerator Laboratory (FNAL), Batavia, IL (United States)

    2012-07-01

    Final State Interactions effects are discussed in the context of Monte Carlo simulations of neutrino-nucleus interactions. A role of Formation Time is explained and several models describing this effect are compared. Various observables which are sensitive to FSI effects are reviewed including pion-nucleus interaction and hadron yields in backward hemisphere. NuWro Monte Carlo neutrino event generator is described and its ability to understand neutral current $\\pi^0$ production data in $\\sim 1$ GeV neutrino flux experiments is demonstrated.

  14. Interaction between learners in an interactive learning environment

    DEFF Research Database (Denmark)

    Davidsen, Jacob; Georgsen, Marianne

    and how we are going to teach children of tomorrow. It is widely believed, also by policy makers, that technology can transform learning environments for both teachers and students. Over the past 10 years, the Danish government - like those in other countries - has been investing in interactive....... 2010). However, such a learning design still requires a teacher to facilitate, manage and lead the participation and interaction patterns of the learners. In this paper, we present an empirical long term study of class room interaction in a setting where technology is introduced to enhance...... collaboration between peer learners. For one year, the authors have followed the development of a learning practice and a learning design based on use of interactive touch screens. Methodologically, this research is based on action research, dialogue design and ethnographic methods. More than 150 hours of video...

  15. Hemoglobin interacting proteins and implications of spectrin hemoglobin interaction.

    Science.gov (United States)

    Basu, Avik; Chakrabarti, Abhijit

    2015-10-14

    In this report we have analyzed interacting partners of hemoglobin inside erythrocyte and sought possible implications of hemoglobin-spectrin interaction. Our list of identified cytosolic hemoglobin interacting proteins includes redox regulators like peroxiredoxin-2, Cu-Zn superoxide dismutase, catalase, aldehyde dehydrogenase-1, flavin reductase and chaperones like HSP70, α-hemoglobin stabilizing protein. Others include metabolic enzymes like carbonic anhydrase-1, selenium binding protein-1, purine nucleoside phosphorylase and nucleoside diphosphate kinase. Additionally, various membrane proteins like α and β spectrin, ankyrin, band3, protein4.1, actin and glyceraldehyde 3 phosphate dehydrogenase have been shown to interact with hemoglobin. Our result indicates that major membrane skeleton protein spectrin, that also has a chaperone like activity, helps to fold the unstable alpha-globin chains in vitro. Taken together our results could provide insight into a protein network evolved around hemoglobin molecule inside erythrocyte that may add a new perspective in understanding the hemoglobin function and homeostasis.

  16. Interactions, Starbursts, and Star Formation

    Directory of Open Access Journals (Sweden)

    Johan H. Knapen

    2015-12-01

    Full Text Available We study how interactions between galaxies affect star formation within them by considering a sample of almost 1500 of the nearest galaxies, all within a distance of ∼45 Mpc. We use the far-IR emission to define the massive star formation rate (SFR, and then normalise the SFR by the stellar mass of the galaxy to obtain the specific star formation rate (SSFR. We explore the distribution of (SSFR with morphological type and with stellar mass. We calculate the relative enhancement of SFR and SSFR for each galaxy by normalising them by the median SFR and SSFR values of individual control samples of similar non-interacting galaxies. We find that both the median SFR and SSFR are enhanced in interacting galaxies, and more so as the degree of interaction is higher. The increase is moderate, reaching a maximum of a factor of 1.9 for the highest degree of interaction (mergers. While the SFR and SSFR are enhanced statistically by interactions, in many individual interacting galaxies they are not enhanced at all. Our study is based on a representative sample of nearby galaxies and should be used to place constraints on studies based on samples of galaxies at larger distances.

  17. Detecting mutually exclusive interactions in protein-protein interaction maps.

    KAUST Repository

    Sánchez Claros, Carmen

    2012-06-08

    Comprehensive protein interaction maps can complement genetic and biochemical experiments and allow the formulation of new hypotheses to be tested in the system of interest. The computational analysis of the maps may help to focus on interesting cases and thereby to appropriately prioritize the validation experiments. We show here that, by automatically comparing and analyzing structurally similar regions of proteins of known structure interacting with a common partner, it is possible to identify mutually exclusive interactions present in the maps with a sensitivity of 70% and a specificity higher than 85% and that, in about three fourth of the correctly identified complexes, we also correctly recognize at least one residue (five on average) belonging to the interaction interface. Given the present and continuously increasing number of proteins of known structure, the requirement of the knowledge of the structure of the interacting proteins does not substantially impact on the coverage of our strategy that can be estimated to be around 25%. We also introduce here the Estrella server that embodies this strategy, is designed for users interested in validating specific hypotheses about the functional role of a protein-protein interaction and it also allows access to pre-computed data for seven organisms.

  18. Detecting mutually exclusive interactions in protein-protein interaction maps.

    Directory of Open Access Journals (Sweden)

    Carmen Sánchez Claros

    Full Text Available Comprehensive protein interaction maps can complement genetic and biochemical experiments and allow the formulation of new hypotheses to be tested in the system of interest. The computational analysis of the maps may help to focus on interesting cases and thereby to appropriately prioritize the validation experiments. We show here that, by automatically comparing and analyzing structurally similar regions of proteins of known structure interacting with a common partner, it is possible to identify mutually exclusive interactions present in the maps with a sensitivity of 70% and a specificity higher than 85% and that, in about three fourth of the correctly identified complexes, we also correctly recognize at least one residue (five on average belonging to the interaction interface. Given the present and continuously increasing number of proteins of known structure, the requirement of the knowledge of the structure of the interacting proteins does not substantially impact on the coverage of our strategy that can be estimated to be around 25%. We also introduce here the Estrella server that embodies this strategy, is designed for users interested in validating specific hypotheses about the functional role of a protein-protein interaction and it also allows access to pre-computed data for seven organisms.

  19. Diatomic interaction potential theory applications

    CERN Document Server

    Goodisman, Jerry

    2013-01-01

    Diatomic Interaction Potential Theory, Volume 2: Applications discusses the variety of applicable theoretical material and approaches in the calculations for diatomic systems in their ground states. The volume covers the descriptions and illustrations of modern calculations. Chapter I discusses the calculation of the interaction potential for large and small values of the internuclear distance R (separated and united atom limits). Chapter II covers the methods used for intermediate values of R, which in principle means any values of R. The Hartree-Fock and configuration interaction schemes des

  20. Aligned interactions in cosmic rays

    Energy Technology Data Exchange (ETDEWEB)

    Kempa, J., E-mail: kempa@pw.plock.pl [Warsaw University of Technology Branch Plock (Poland)

    2015-12-15

    The first clean Centauro was found in cosmic rays years many ago at Mt Chacaltaya experiment. Since that time, many people have tried to find this type of interaction, both in cosmic rays and at accelerators. But no one has found a clean cases of this type of interaction.It happened finally in the last exposure of emulsion at Mt Chacaltaya where the second clean Centauro has been found. The experimental data for both the Centauros and STRANA will be presented and discussed in this paper. We also present our comments to the intriguing question of the existence of a type of nuclear interactions at high energy with alignment.